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+{"_id": "4983", "title": "", "text": "Microstructural development of human newborncerebral white matter assessed in vivo bydiffusion tensor magnetic resonanceimaging.Alterations of the architecture ofcerebral white matter in the developing humanbrain can affect cortical development and resultin functional disabilities. A line scandiffusion-weighted magnetic resonance imaging(MRI) sequence with diffusion tensor analysiswas applied to measure the apparent diffusioncoefficient, to calculate relative anisotropy, andto delineate three-dimensional fiber architecturein cerebral white matter in preterm (n = 17) andfull-term infants (n = 7). To assess effects ofprematurity on cerebral white matterdevelopment, early gestation preterm infants (n= 10) were studied a second time at term. In thecentral white matter the mean apparent diffusioncoefficient at 28 wk was high, 1.8 microm2/ms,and decreased toward term to 1.2 microm2/ms.In the posterior limb of the internal capsule, themean apparent diffusion coefficients at both", "metadata": {}}
+{"_id": "5836", "title": "", "text": "Induction of myelodysplasia by myeloid-derivedsuppressor cells.Myelodysplastic syndromes(MDS) are age-dependent stem cell malignanciesthat share biological features of activatedadaptive immune response and ineffectivehematopoiesis. Here we report thatmyeloid-derived suppressor cells (MDSC), whichare classically linked to immunosuppression,inflammation, and cancer, were markedlyexpanded in the bone marrow of MDS patientsand played a pathogenetic role in thedevelopment of ineffective hematopoiesis. Theseclonally distinct MDSC overproducehematopoietic suppressive cytokines andfunction as potent apoptotic effectors targetingautologous hematopoietic progenitors. Usingmultiple transfected cell models, we found thatMDSC expansion is driven by the interaction ofthe proinflammatory molecule S100A9 withCD33. These 2 proteins formed a functionalligand/receptor pair that recruited components toCD33’s immunoreceptor tyrosine-based", "metadata": {}}
+{"_id": "7912", "title": "", "text": "BC1 RNA, the transcript from a master gene forID element amplification, is able to prime its ownreverse transcription.ID elements are shortinterspersed elements (SINEs) found in highcopy number in many rodent genomes. BC1RNA, an ID-related transcript, is derived fromthe single copy BC1 RNA gene. The BC1 RNAgene has been shown to be a master gene for IDelement amplification in rodent genomes. IDelements are dispersed through a processtermed retroposition. The retroposition processinvolves a number of potential regulatory steps.These regulatory steps may include transcriptionin the appropriate tissue, transcript stability,priming of the RNA transcript for reversetranscription and integration. This study focuseson priming of the RNA transcript for reversetranscription. BC1 RNA gene transcripts areshown to be able to prime their own reversetranscription in an efficient intramolecular andsite-specific fashion. This self-priming ability is aconsequence of the secondary structure of the", "metadata": {}}
+{"_id": "18670", "title": "", "text": "The DNA Methylome of Human Peripheral BloodMononuclear CellsDNA methylation plays animportant role in biological processes in humanhealth and disease. Recent technologicaladvances allow unbiased whole-genome DNAmethylation (methylome) analysis to be carriedout on human cells. Using whole-genomebisulfite sequencing at 24.7-fold coverage(12.3-fold per strand), we report acomprehensive (92.62%) methylome andanalysis of the unique sequences in humanperipheral blood mononuclear cells (PBMC) fromthe same Asian individual whose genome wasdeciphered in the YH project. PBMC constitute animportant source for clinical blood testsworld-wide. We found that 68.4% of CpG sitesand <0.2% of non-CpG sites were methylated,demonstrating that non-CpG cytosinemethylation is minor in human PBMC. Analysis ofthe PBMC methylome revealed a rich epigenomiclandscape for 20 distinct genomic features,including regulatory, protein-coding, non-coding,", "metadata": {}}
+{"_id": "19238", "title": "", "text": "The human myelin basic protein gene is includedwithin a 179-kilobase transcription unit:expression in the immune and central nervoussystems.Two human Golli (for gene expressed inthe oligodendrocyte lineage)-MBP (for myelinbasic protein) cDNAs have been isolated from ahuman oligodendroglioma cell line. Analysis ofthese cDNAs has enabled us to determine theentire structure of the human Golli-MBP gene.The Golli-MBP gene, which encompasses the MBPtranscription unit, is approximately 179 kb inlength and consists of 10 exons, seven of whichconstitute the MBP gene. The human Golli-MBPgene contains two transcription start sites, eachof which gives rise to a family of alternativelyspliced transcripts. At least two Golli-MBPtranscripts, containing the first three exons ofthe gene and one or more MBP exons, areproduced from the first transcription start site.The second family of transcripts contains onlyMBP exons and produces the well-known MBPs.In humans, RNA blot analysis revealed that", "metadata": {}}
+{"_id": "33370", "title": "", "text": "Targeting A20 Decreases Glioma Stem CellSurvival and Tumor GrowthGlioblastomas aredeadly cancers that display a functional cellularhierarchy maintained by self-renewingglioblastoma stem cells (GSCs). GSCs areregulated by molecular pathways distinct fromthe bulk tumor that may be useful therapeutictargets. We determined that A20 (TNFAIP3), aregulator of cell survival and the NF-kappaBpathway, is overexpressed in GSCs relative tonon-stem glioblastoma cells at both the mRNAand protein levels. To determine the functionalsignificance of A20 in GSCs, we targeted A20expression with lentiviral-mediated delivery ofshort hairpin RNA (shRNA). Inhibiting A20expression decreased GSC growth and survivalthrough mechanisms associated with decreasedcell-cycle progression and decreasedphosphorylation of p65/RelA. Elevated levels ofA20 in GSCs contributed to apoptotic resistance:GSCs were less susceptible to TNFalpha-inducedcell death than matched non-stem glioma cells,", "metadata": {}}
+{"_id": "36474", "title": "", "text": "Efficient targeting of expressed and silent genesin human ESCs and iPSCs using zinc-fingernucleasesRealizing the full potential of humanembryonic stem cells (hESCs) and inducedpluripotent stem cells (hiPSCs) requires efficientmethods for genetic modification. However,techniques to generate cell type–specific lineagereporters, as well as reliable tools to disrupt,repair or overexpress genes by gene targeting,are inefficient at best and thus are not routinelyused. Here we report the highly efficienttargeting of three genes in human pluripotentcells using zinc-finger nuclease (ZFN)–mediatedgenome editing. First, using ZFNs specific for theOCT4 (POU5F1) locus, we generated OCT4-eGFPreporter cells to monitor the pluripotent state ofhESCs. Second, we inserted a transgene into theAAVS1 locus to generate a robust drug-inducibleoverexpression system in hESCs. Finally, wetargeted the PITX3 gene, demonstrating thatZFNs can be used to generate reporter cells bytargeting non-expressed genes in hESCs and", "metadata": {}}
+{"_id": "54440", "title": "", "text": "Empirical Bayesian models for analysingmolecular serotyping microarraysBACKGROUNDMicroarrays offer great potential as a platformfor molecular diagnostics, testing clinical samplesfor the presence of numerous biomarkers inhighly multiplexed assays. In this study appliedto infectious diseases, data from a microarraydesigned for molecular serotyping ofStreptococcus pneumoniae was used, identifyingthe presence of any one of 91 knownpneumococcal serotypes from DNA extracts. Thismicroarray incorporated oligonucleotide probesfor all known capsular polysaccharide synthesisgenes and required a statistical analysis of themicroarray intensity data to determine whichserotype, or combination of serotypes, werepresent within a sample based on thecombination of genes detected. RESULTS Wepropose an empirical Bayesian model forcalculating the probabilities of combinations ofserotypes from the microarray data. The modeltakes into consideration the dependencies", "metadata": {}}
+{"_id": "70115", "title": "", "text": "Bayesian measures of model complexity andfitSummary. We consider the problem ofcomparing complex hierarchical models in whichthe number of parameters is not clearly defined.Using an information theoretic argument wederive a measure pD for the effective number ofparameters in a model as the difference betweenthe posterior mean of the deviance and thedeviance at the posterior means of theparameters of interest. In general pDapproximately corresponds to the trace of theproduct of Fisher's information and the posteriorcovariance, which in normal models is the traceof the ‘hat’ matrix projecting observations ontofitted values. Its properties in exponentialfamilies are explored. The posterior meandeviance is suggested as a Bayesian measure offit or adequacy, and the contributions ofindividual observations to the fit and complexitycan give rise to a diagnostic plot of devianceresiduals against leverages. Adding pD to theposterior mean deviance gives a deviance", "metadata": {}}
+{"_id": "70490", "title": "", "text": "Simplifying likelihood ratiosLikelihood ratios areone of the best measures of diagnostic accuracy,although they are seldom used, becauseinterpreting them requires a calculator to convertback and forth between “probability” and “odds”of disease. This article describes a simplermethod of interpreting likelihood ratios, one thatavoids calculators, nomograms, and conversionsto “odds” of disease. Several examples illustratehow the clinician can use this method to refinediagnostic decisions at the bedside.", "metadata": {}}
+{"_id": "72159", "title": "", "text": "induction of early IFN-inducible genes in theabsence of typeOn recognition of influenza virus(Flu) by TLR7, plasmacytoid dendritic cells(pDCs) produce type I IFN in significantamounts. Synthetic TLR7 ligands induce thematuration of pDCs, as evidenced by theexpression of costimulatory molecules and theproduction of proinflammatory cytokines;however, they induce only low-level productionof IFN-alpha. To dissect the TLR7 signaling inpDCs and how these different profiles areinduced, we studied the effects of 2 TLR7 ligands(Flu and CL097) on the activation ofblood-isolated pDCs and the human GEN2.2 pDCcell line. Type I IFN production by pDCscorrelates with differential interferon regulatoryfactor 7 (IRF7) translocation into the nucleusinduced by the 2 TLR7 ligands. Surprisingly, withboth activators we nevertheless observed therapid expression of the IFN-inducible genes mxa,cxcl10, and trail within 4 hours of stimulation.This expression, controlled by STAT1", "metadata": {}}
+{"_id": "79447", "title": "", "text": "Arteriolar function in visceral adipose tissue isimpaired in human obesity.OBJECTIVE Thepurpose of this study was to characterize therelationship between adipose tissue phenotypeand depot-specific microvascular function in fat.METHODS AND RESULTS In 30 obese subjects(age 42±11 years, body mass index 46±11kg/m(2)) undergoing bariatric surgery, weintraoperatively collected visceral andsubcutaneous adipose tissue and characterizeddepot-specific adipose phenotypes. We assessedvasomotor function of the adiposemicrovasculature using videomicroscopy of smallarterioles (75-250 μm) isolated from different fatcompartments. Endothelium-dependent,acetylcholine-mediated vasodilation was severelyimpaired in visceral arterioles, compared to thesubcutaneous depot (P<0.001 by ANOVA).Nonendothelium dependent responses topapaverine and nitroprusside were similar.Endothelial nitric oxide synthase inhibition withN(ω)-nitro-l-arginine methyl ester reduced", "metadata": {}}
+{"_id": "87758", "title": "", "text": "Common Carotid Intima Media Thickness andAnkle-Brachial Pressure Index Correlate withLocal but Not Global Atheroma Burden: A CrossSectional Study Using Whole Body MagneticResonance AngiographyBACKGROUND Commoncarotid intima media thickness (CIMT) and anklebrachial pressure index (ABPI) are used assurrogate marker of atherosclerosis, and havebeen shown to correlate with arterial stiffness,however their correlation with globalatherosclerotic burden has not been previouslyassessed. We compare CIMT and ABPI withatheroma burden as measured by whole bodymagnetic resonance angiography (WB-MRA).METHODS 50 patients with symptomaticperipheral arterial disease were recruited. CIMTwas measured using ultrasound while rest andexercise ABPI were performed. WB-MRA wasperformed in a 1.5T MRI scanner using 4 volumeacquisitions with a divided dose of intravenousgadolinium gadoterate meglumine (Dotarem,Guerbet, FR). The WB-MRA data was divided into", "metadata": {}}
+{"_id": "92308", "title": "", "text": "Loss of immune escape mutations duringpersistent HCV infection in pregnancy enhancesreplication of vertically transmittedvirusesGlobally, about 1% of pregnant womenare persistently infected with the hepatitis Cvirus (HCV). Mother-to-child transmission of HCVoccurs in 3-5% of pregnancies and accounts formost new childhood infections. HCV-specificCD8(+) cytotoxic T lymphocytes (CTLs) are vitalin the clearance of acute HCV infections, but inthe 60-80% of infections that persist, these cellsbecome functionally exhausted or select formutant viruses that escape T cell recognition.Increased HCV replication during pregnancysuggests that maternofetal immune tolerancemechanisms may further impair HCV-specificCTLs, limiting their selective pressure onpersistent viruses. To assess this possibility, wecharacterized circulating viral quasispeciesduring and after consecutive pregnancies in twowomen. This revealed a loss of some escapemutations in HLA class I epitopes during", "metadata": {}}
+{"_id": "92499", "title": "", "text": "The journey of developing hematopoietic stemcells.Hematopoietic stem cells (HSCs) developduring embryogenesis in a complex process thatinvolves multiple anatomical sites. Once HSCprecursors have been specified from mesoderm,they have to mature into functional HSCs andundergo self-renewing divisions to generate apool of HSCs. During this process, developingHSCs migrate through various embryonic niches,which provide signals for their establishment andthe conservation of their self-renewal ability.These processes have to be recapitulated togenerate HSCs from embryonic stem cells.Elucidating the interactions between developingHSCs and their niches should facilitate thegeneration and expansion of HSCs in vitro toexploit their clinical potential.", "metadata": {}}
+{"_id": "97884", "title": "", "text": "The sacroiliac joint in thespondyloarthropathies.The termspondyloarthropathy (SpA) describes and definesa group of related inflammatory joint diseasethat share characteristic clinical features and aunique association with the majorhistocompatibility complex class I moleculeHLA-B27. Five subgroups can be differentiated:ankylosing spondylitis, reactive arthritis,psoriatic arthritis, arthritis associated withinflammatory bowel disease, andundifferentiated SpA. The sacroiliac joints arecentrally involved in the SpA, most clearly andpathognomonic in ankylosing spondylitis, inwhich most patients are affected early in thedisease. Overcoming some of the diagnosticdifficulties of early sacroiliitis, dynamic magneticresonance imaging was shown to visualize bothacute and chronic changes in the sacroiliacjoints. The inflammation in the sacroiliac joints inpatients with SpA was recently examined in moredetail; using immunohistology and in situ", "metadata": {}}
+{"_id": "102662", "title": "", "text": "A rapid method for extraction of cotton(Gossypium spp.) genomic DNA suitable for RFLPor PCR analysisExtraction of high-qualitygenomic DNA fromGossypium (cotton) species isdifficult due to high levels of polysaccharide,oxidizable quinones, and other interferingsubstances. We describe a procedure thatconsistently permits isolation of cotton genomicDNA of satisfactory size and quality for RFLP andPCR analysis, as well as for most routine cloningapplications. Several antioxidants,phenol-binding reagents, and phenol oxidaseinhibitors are used throughout the procedure,and most polysaccharides are eliminated early inthe procedure by isolation of nuclei.", "metadata": {}}
+{"_id": "103007", "title": "", "text": "Cross sectional stature and weight referencecurves for the UK, 1990.The current referencecurves of stature and weight for the UK were firstpublished in 1966 and have been used ever sincedespite increasing concern that they may notadequately describe the growth of present dayBritish children. Using current data from sevensources new reference curves have beenestimated from birth to 20 years for children in1990. The great majority of the data arenationally representative. The analysis usedCole's LMS method and has produced efficientestimates of the conventional centiles and givesa good fit to the data. These curves differ fromthe currently used curves at key ages for bothstature and weight. In view of the concernsexpressed about the current curves and thedifferences between them and the new curves, itis proposed that the curves presented hereshould be adopted as the new UK referencecurves.", "metadata": {}}
+{"_id": "104130", "title": "", "text": "The suture provides a niche for mesenchymalstem cells of craniofacial bonesBone tissueundergoes constant turnover supported by stemcells. Recent studies showed that perivascularmesenchymal stem cells (MSCs) contribute tothe turnover of long bones. Craniofacial bonesare flat bones derived from a different embryonicorigin than the long bones. The identity andregulating niche for craniofacial-bone MSCsremain unknown. Here, we identify Gli1+ cellswithin the suture mesenchyme as the main MSCpopulation for craniofacial bones. They are notassociated with vasculature, give rise to allcraniofacial bones in the adult and are activatedduring injury repair. Gli1+ cells are typical MSCsin vitro. Ablation of Gli1+ cells leads tocraniosynostosis and arrest of skull growth,indicating that these cells are an indispensablestem cell population. Twist1(+/-) mice withcraniosynostosis show reduced Gli1+ MSCs insutures, suggesting that craniosynostosis mayresult from diminished suture stem cells. Our", "metadata": {}}
+{"_id": "106301", "title": "", "text": "Cardiac neural crest cells contribute to thedormant multipotent stem cell in the mammalianheartArodent cardiac side population cell fractionformed clonal spheroids in serum-free medium,which expressed nestin, Musashi-1, andmulti-drug resistance transporter gene 1,markers of undifferentiated neural precursorcells. These markers were lost followingdifferentiation, and were replaced by theexpression of neuron-, glial-, smooth musclecell–, or cardiomyocyte-specific proteins.Cardiosphere-derived cells transplanted intochick embryos migrated to the truncus arteriosusand cardiac outflow tract and contributed todorsal root ganglia, spinal nerves, and aorticsmooth muscle cells. Lineage studies usingdouble transgenic mice encoding protein0–Cre/Floxed-EGFP revealed undifferentiatedand differentiated neural crest-derived cells inthe fetal myocardium. Undifferentiated cellsexpressed GATA-binding protein 4 and nestin,but not actinin, whereas the differentiated cells", "metadata": {}}
+{"_id": "116792", "title": "", "text": "The mammalian target of rapamycin signalingpathway mediates epileptogenesis in a model oftemporal lobe epilepsy.Understanding molecularmechanisms mediating epileptogenesis is criticalfor developing more effective therapies forepilepsy. We recently found that the mammaliantarget of rapamycin (mTOR) signaling pathway isinvolved in epileptogenesis, and mTOR inhibitorsprevent epilepsy in a mouse model of tuberoussclerosis complex. Here, we investigated thepotential role of mTOR in a rat model of temporallobe epilepsy initiated by status epilepticus.Acute kainate-induced seizures resulted inbiphasic activation of the mTOR pathway, asevident by an increase in phospho-S6 (P-S6)expression. An initial rise in P-S6 expressionstarted approximately 1 h after seizure onset,peaked at 3-6 h, and returned to baseline by 24h in both hippocampus and neocortex, reflectingwidespread stimulation of mTOR signaling byacute seizure activity. After resolution of statusepilepticus, a second increase in P-S6 was", "metadata": {}}
+{"_id": "118568", "title": "", "text": "Acute administration of recombinantAngiopoietin-1 ameliorates multiple-organdysfunction syndrome and improves survival inmurine sepsis.INTRODUCTION Endothelialactivation leading to vascular barrier breakdownplays an essential role in the pathophysiology ofmultiple-organ dysfunction syndrome (MODS) insepsis. Increasing evidence suggests that thefunction of the vessel-protective factorAngiopoietin-1 (Ang-1), a ligand of theendothelial-specific Tie2 receptor, is inhibited byits antagonist Angiopoietin-2 (Ang-2) duringsepsis. In order to reverse the effects of thesepsis-induced suppression of Ang-1 andelevation of Ang-2 we aimed to investigatewhether an intravenous injection of recombinanthuman (rh) Ang-1 protects against MODS inmurine sepsis. METHODS Polymicrobiologicalabdominal sepsis was induced by cecal ligationand puncture (CLP). Mice were treated witheither 1 μg of intravenous rhAng-1 or controlbuffer immediately after CLP induction and every", "metadata": {}}
+{"_id": "120626", "title": "", "text": "Mechanisms linking obesity to insulin resistanceand type 2 diabetesObesity is associated with anincreased risk of developing insulin resistanceand type 2 diabetes. In obese individuals,adipose tissue releases increased amounts ofnon-esterified fatty acids, glycerol, hormones,pro-inflammatory cytokines and other factorsthat are involved in the development of insulinresistance. When insulin resistance isaccompanied by dysfunction of pancreatic isletβ-cells — the cells that release insulin — failureto control blood glucose levels results.Abnormalities in β-cell function are thereforecritical in defining the risk and development oftype 2 diabetes. This knowledge is fosteringexploration of the molecular and genetic basis ofthe disease and new approaches to its treatmentand prevention.", "metadata": {}}
+{"_id": "123859", "title": "", "text": "Tracking the fate of glomerular epithelial cells invivo using serial multiphoton imaging in novelmouse models with fluorescent lineagetagsPodocytes are critical in the maintenance ofa healthy glomerular filter; however, they havebeen difficult to study in the intact kidneybecause of technical limitations. Here we reportthe development of serial multiphotonmicroscopy (MPM) of the same glomeruli overseveral days to visualize the motility ofpodocytes and parietal epithelial cells (PECs) invivo. In podocin-GFP mice, podocytes formedsporadic multicellular clusters after unilateralureteral ligation and migrated into the parietalBowman's capsule. The tracking of single cells inpodocin-confetti mice featuring cell-specificexpression of CFP, GFP, YFP or RFP revealed thesimultaneous migration of multiple podocytes. Inphosphoenolpyruvate carboxykinase(PEPCK)-GFP mice, serial MPM foundPEC-to-podocyte migration and nanotubuleconnections. Our data support a highly dynamic", "metadata": {}}
+{"_id": "140874", "title": "", "text": "CTCF binding at the H19 imprinting controlregion mediates maternally inheritedhigher-order chromatin conformation to restrictenhancer access to Igf2.It is thought that theH19 imprinting control region (ICR) directs thesilencing of the maternally inherited Igf2 allelethrough a CTCF-dependent chromatin insulator.The ICR has been shown to interact physicallywith a silencer region in Igf2, differentiallymethylated region (DMR)1, but the role of CTCFin this chromatin loop and whether it restrictsthe physical access of distal enhancers to Igf2 isnot known. We performed systematicchromosome conformation capture analyses inthe Igf2/H19 region over >160 kb, identifyingsequences that interact physically with the distalenhancers and the ICR. We found that, on thepaternal chromosome, enhancers interact withthe Igf2 promoters but that, on the maternalallele, this is prevented by CTCF binding withinthe H19 ICR. CTCF binding in the maternal ICRregulates its interaction with matrix attachment", "metadata": {}}
+{"_id": "143251", "title": "", "text": "De novo assembly of a PML nuclearsubcompartment occurs through multiplepathways and induces telomereelongation.Telomerase-negative tumor cells usean alternative lengthening of telomeres (ALT)pathway that involves DNA recombination andrepair to maintain their proliferative potential.The cytological hallmark of this process is theaccumulation of promyelocytic leukemia (PML)nuclear protein at telomeric DNA to formALT-associated PML bodies (APBs). Here, the denovo formation of a telomeric PML nuclearsubcompartment was investigated by recruitingAPB protein components. We show thatfunctionally distinct proteins were able to initiatethe formation of bona fide APBs with highefficiency in a self-organizing andself-propagating manner. These included: (1)PML and Sp100 as the constituting componentsof PML nuclear bodies, (2) telomere repeatbinding factors 1 and 2 (TRF1 and TRF2,respectively), (3) the DNA repair protein NBS1", "metadata": {}}
+{"_id": "152245", "title": "", "text": "Effects of an opal termination codon precedingthe nsP4 gene sequence in the O'Nyong-Nyongvirus genome on Anopheles gambiaeinfectivity.The genomic RNA of an alphavirusencodes four different nonstructural proteins,nsP1, nsP2, nsP3, and nsP4. The polyproteinP123 is produced when translation terminates atan opal termination codon between nsP3 andnsP4. The polyprotein P1234 is produced whentranslational readthrough occurs or when theopal termination codon has been replaced by asense codon in the alphavirus genome.Evolutionary pressures appear to havemaintained genomic sequences encoding both astop codon (opal) and an open reading frame(arginine) as a general feature of theO'nyong-nyong virus (ONNV) genome, indicatingthat both are required at some point. Alternatereplication of ONNVs in both vertebrate andinvertebrate hosts may determine predominanceof a particular codon at this locus in the viralquasispecies. However, no systematic study has", "metadata": {}}
+{"_id": "153744", "title": "", "text": "Down-regulation of a host microRNA by aHerpesvirus saimiri noncoding RNA.T cellstransformed by Herpesvirus saimiri expressseven viral U-rich noncoding RNAs of unknownfunction called HSURs. We noted that conservedsequences in HSURs 1 and 2 constitute potentialbinding sites for three host-cell microRNAs(miRNAs). Coimmunoprecipitation experimentsconfirmed that HSURs 1 and 2 interact with thepredicted miRNAs in virally transformed T cells.The abundance of one of these miRNAs, miR-27,is dramatically lowered in transformed cells, withconsequent effects on the expression of miR-27target genes. Transient knockdown and ectopicexpression of HSUR 1 demonstrate that it directsdegradation of mature miR-27 in asequence-specific and binding-dependentmanner. This viral strategy illustrates use of ancRNA to manipulate host-cell gene expressionvia the miRNA pathway.", "metadata": {}}
+{"_id": "159469", "title": "", "text": "HTRF: A Technology Tailored for Drug Discovery–A Review of Theoretical Aspects and RecentApplicationsHTRF (Homogeneous Time ResolvedFluorescence) is the most frequently usedgeneric assay technology to measure analytes ina homogenous format, which is the idealplatform used for drug target studies inhigh-throughput screening (HTS). Thistechnology combines fluorescence resonanceenergy transfer technology (FRET) withtime-resolved measurement (TR). In TR-FRETassays, a signal is generated through fluorescentresonance energy transfer between a donor andan acceptor molecule when in close proximity toeach other. Buffer and media interference isdramatically reduced by dual-wavelengthdetection, and the final signal is proportional tothe extent of product formation. The HTRF assayis usually sensitive and robust that can beminiaturized into the 384 and 1536-well plateformats. This assay technology has been appliedto many antibody-based assays including GPCR", "metadata": {}}
+{"_id": "164189", "title": "", "text": "Chk1 inhibits replication factory activation butallows dormant origin firing in existingfactoriesReplication origins are licensed byloading MCM2-7 hexamers before entry into Sphase. However, only \u000010% of licensed originsare normally used in S phase, with the othersremaining dormant. When fork progression isinhibited, dormant origins initiate nearby toensure that all of the DNA is eventuallyreplicated. In apparent contrast, replicativestress activates ataxia telangiectasia andrad-3-related (ATR) and Chk1 checkpoint kinasesthat inhibit origin firing. In this study, we showthat at low levels of replication stress, ATR/Chk1predominantly suppresses origin initiation byinhibiting the activation of new replicationfactories, thereby reducing the number of activefactories. At the same time, inhibition ofreplication fork progression allows dormantorigins to initiate within existing replicationfactories. The inhibition of new factory activationby ATR/Chk1 therefore redirects replication", "metadata": {}}
+{"_id": "164985", "title": "", "text": "Fra-1 protooncogene regulates IL-6 expression inmacrophages and promotes the generation ofM2d macrophagesThe tumor microenvironment(TME) plays a prominent role in the growth oftumor cells. As the major inflammatorycomponent of the TME, M2d macrophages areeducated by the TME such that they adopt animmunosuppressive role that promotes tumormetastasis and progression. Fra-1 formsactivator protein-1 heterodimers with Junpartners and drives gene transcription. Fra-1 isthought to drastically induce tumorigenesis andprogression. However, the functional role ofFra-1 in the generation of M2d macrophages ispoorly understood to date. Here, we demonstratethat 4T1 mammary carcinoma cells, whenco-cultured with RAW264.7 macrophage cells,skew the RAW264.7 macrophage celldifferentiation into M2d macrophages. The 4T1cells stimulate de novo overexpression of Fra-1in RAW264.7 cells, and then Fra-1 binds to theinterleukin 6 (IL-6) promoter to increase the", "metadata": {}}
+{"_id": "169264", "title": "", "text": "Analysis of SiO2 nanoparticles binding proteins inrat blood and brain homogenateA multitude ofnanoparticles, such as titanium oxide (TiO2),zinc oxide, aluminum oxide, gold oxide, silveroxide, iron oxide, and silica oxide, are found inmany chemical, cosmetic, pharmaceutical, andelectronic products. Recently, SiO2 nanoparticleswere shown to have an inert toxicity profile andno association with an irreversible toxicologicalchange in animal models. Hence, exposure toSiO2 nanoparticles is on the increase. SiO2nanoparticles are routinely used in numerousmaterials, from strengthening filler for concreteand other construction composites, to nontoxicplatforms for biomedical application, such asdrug delivery and theragnostics. On the otherhand, recent in vitro experiments indicated thatSiO2 nanoparticles were cytotoxic. Therefore, weinvestigated these nanoparticles to identifypotentially toxic pathways by analyzing theadsorbed protein corona on the surface of SiO2nanoparticles in the blood and brain of the rat.", "metadata": {}}
+{"_id": "175735", "title": "", "text": "Inferring nucleosome positions with their histonemark annotation from ChIP dataMOTIVATIONThe nucleosome is the basic repeating unit ofchromatin. It contains two copies each of thefour core histones H2A, H2B, H3 and H4 andabout 147 bp of DNA. The residues of the histoneproteins are subject to numerouspost-translational modifications, such asmethylation or acetylation. Chromatinimmunoprecipitiation followed by sequencing(ChIP-seq) is a technique that providesgenome-wide occupancy data of these modifiedhistone proteins, and it requires appropriatecomputational methods. RESULTS We presentNucHunter, an algorithm that uses the data fromChIP-seq experiments directed against manyhistone modifications to infer positionednucleosomes. NucHunter annotates each of thesenucleosomes with the intensities of the histonemodifications. We demonstrate that theseannotations can be used to infer nucleosomalstates with distinct correlations to underlying", "metadata": {}}
+{"_id": "188911", "title": "", "text": "Generation of large numbers of dendritic cellsfrom mouse bone marrow cultures supplementedwith granulocyte/macrophage colony-stimulatingfactorAntigen-presenting, majorhistocompatibility complex (MHC) class II-richdendritic cells are known to arise from bonemarrow. However, marrow lacks maturedendritic cells, and substantial numbers ofproliferating less-mature cells have yet to beidentified. The methodology for inducingdendritic cell growth that was recently describedfor mouse blood now has been modified to MHCclass II-negative precursors in marrow. A keystep is to remove the majority of nonadherent,newly formed granulocytes by gentle washesduring the first 2-4 d of culture. This leavesbehind proliferating clusters that are looselyattached to a more firmly adherent \"stroma. \" Atdays 4-6 the clusters can be dislodged, isolatedby 1-g sedimentation, and upon reculture, largenumbers of dendritic cells are released. Thelatter are readily identified on the basis of their", "metadata": {}}
+{"_id": "195352", "title": "", "text": "Insulin action and resistance in obesity and type2 diabetesNutritional excess is a majorforerunner of type 2 diabetes. It enhances thesecretion of insulin, but attenuates insulin'smetabolic actions in the liver, skeletal muscleand adipose tissue. However, conflictingevidence indicates a lack of knowledge of thetiming of these events during the development ofobesity and diabetes, pointing to a key gap inour understanding of metabolic disease. ThisPerspective reviews alternate viewpoints andrecent results on the temporal and mechanisticconnections between hyperinsulinemia, obesityand insulin resistance. Although much attentionhas addressed early steps in the insulin signalingcascade, insulin resistance in obesity seems tobe largely elicited downstream of these steps.New findings also connect insulin resistance toextensive metabolic cross-talk between the liver,adipose tissue, pancreas and skeletal muscle.These and other advances over the past 5 yearsoffer exciting opportunities and daunting", "metadata": {}}
+{"_id": "202259", "title": "", "text": "Effect of lowering blood pressure oncardiovascular events and mortality in patientson dialysis: a systematic review andmeta-analysis of randomised controlledtrialsBACKGROUND Patients undergoing dialysishave a substantially increased risk ofcardiovascular mortality and morbidity. Althoughseveral trials have shown the cardiovascularbenefits of lowering blood pressure in thegeneral population, there is uncertainty aboutthe efficacy and tolerability of reducing bloodpressure in patients on dialysis. We did asystematic review and meta-analysis to assessthe effect of blood pressure lowering in patientson dialysis. METHODS We systematicallysearched Medline, Embase, and the CochraneLibrary database for trials reported between1950 and November, 2008, without languagerestriction. We extracted a standardised datasetfrom randomised controlled trials of bloodpressure lowering in patients on dialysis thatreported cardiovascular outcomes. Meta-analysis", "metadata": {}}
+{"_id": "207972", "title": "", "text": "Interaction of an adenovirus E3 14.7-kilodaltonprotein with a novel tumor necrosis factoralpha-inducible cellular protein containing leucinezipper domains.Early region 3 (E3) of group Chuman adenoviruses (Ad) encodes severalinhibitors of tumor necrosis factor alpha(TNF-alpha) cytolysis, including an E3 14.7-kDaprotein (E3-14.7K) and a heterodimer containingtwo polypeptides of 10.4 and 14.5 kDa. Tounderstand the mechanism by which the viralproteins inhibit TNF-alpha functions, theE3-14.7K protein was used to screen a HeLa cellcDNA library to search for interacting proteins inthe yeast two-hybrid system. A novel proteincontaining multiple leucine zipper domainswithout any significant homology with any knownprotein was identified and has been named FIP-2(for 14.7K-interacting protein). FIP-2 interactedwith E3-14.7K both in vitro and in vivo. Itcolocalized with Ad E3-14.7K in the cytoplasm,especially near the nuclear membrane, andcaused redistribution of the viral protein. FIP-2", "metadata": {}}
+{"_id": "213017", "title": "", "text": "PML induces compaction, TRF2 depletion andDNA damage signaling at telomeres andpromotes their alternative lengthening.Thealternative lengthening of telomeres (ALT)mechanism allows cancer cells to escapesenescence and apoptosis in the absence ofactive telomerase. A characteristic feature of thispathway is the assembly of ALT-associatedpromyelocytic leukemia (PML) nuclear bodies(APBs) at telomeres. Here, we dissected the roleof APBs in a human ALT cell line by performingan RNA interference screen using an automated3D fluorescence microscopy platform andadvanced 3D image analysis. We identified 29proteins that affected APB formation, whichincluded proteins involved in telomere andchromatin organization, protein sumoylation andDNA repair. By integrating and extending thesefindings, we found that APB formation inducedclustering of telomere repeats, telomerecompaction and concomitant depletion of theshelterin protein TRF2 (also known as TERF2).", "metadata": {}}
+{"_id": "219475", "title": "", "text": "Gr-1+CD11b+ myeloid cells tip the balance ofimmune protection to tumor promotion in thepremetastatic lung.The mechanisms by which aprimary tumor affects a selected distant organbefore tumor cell arrival remain to be elucidated.This report shows that Gr-1+CD11b+ cells aresignificantly increased in lungs of mice bearingmammary adenocarcinomas before tumor cellarrival. In the premetastatic lungs, theseimmature myeloid cells significantly decreaseIFN-gamma production and increaseproinflammatory cytokines. In addition, theyproduce large quantities of matrixmetalloproteinase 9 (MMP9) and promotevascular remodeling. Deletion of MMP9normalizes aberrant vasculature in thepremetastatic lung and diminishes lungmetastasis. The production and activity of MMP9is selectively restricted to lungs and organs witha large number of Gr-1+CD11b+ cells. Our workreveals a novel protumor mechanism forGr-1+CD11b+ cells that changes the", "metadata": {}}
+{"_id": "226488", "title": "", "text": "Activin/Nodal signalling in stemcells.Activin/Nodal growth factors control a broadrange of biological processes, including early cellfate decisions, organogenesis and adult tissuehomeostasis. Here, we provide an overview ofthe mechanisms by which the Activin/Nodalsignalling pathway governs stem cell function inthese different stages of development. Wedescribe recent findings that associateActivin/Nodal signalling to pathologicalconditions, focusing on cancer stem cells intumorigenesis and its potential as a target fortherapies. Moreover, we will discuss futuredirections and questions that currently remainunanswered on the role of Activin/Nodalsignalling in stem cell self-renewal,differentiation and proliferation.", "metadata": {}}
+{"_id": "236204", "title": "", "text": "Distinct RNA-dependent RNA polymerases arerequired for RNAi triggered by double-strandedRNA versus truncated transgenes in ParameciumtetraureliaIn many eukaryotes, RNA-dependentRNA polymerases (RdRPs) play key roles in theRNAi pathway. They have been implicated in therecognition and processing of aberranttranscripts triggering the process, and inamplification of the silencing response. We havetested the functions of RdRP genes from theciliate Paramecium tetraurelia in experimentallyinduced and endogenous mechanisms of genesilencing. In this organism, RNAi can betriggered either by high-copy, truncatedtransgenes or by directly feeding cells withdouble-stranded RNA (dsRNA). Surprisingly,dsRNA-induced silencing depends on theputatively functional RDR1 and RDR2 genes,which are required for the accumulation of bothprimary siRNAs and a distinct class of small RNAssuggestive of secondary siRNAs. In contrast, athird gene with a highly divergent catalytic", "metadata": {}}
+{"_id": "238409", "title": "", "text": "Mechanisms of Renal Cell Apoptosis Induced byCyclosporine A: A Systematic Review of in vitroStudiesBackground:Chronic cyclosporine A (CsA)nephrotoxicity (CCN) is a major cause of chronicrenal dysfunction and has no effective clinicalinterventions yet. Objective: To reveal themechanisms of renal cell apoptosis in CCN, weanalyzed all in vitro studies of such mechanisms.Methods: We collected all in vitro studies aboutthe mechanisms of renal cell apoptosis inducedby CsA in Medline (1966 to July 2010), Embase(1980 to July 2010) and ISI (1986 to July 2010),evaluated their quality according to in vitrostandards and extracted data following thePICOS principles and synthesized the data.Results: First,CsA could upregulate Fas and Fas-Lexpression, increase FADD and apoptosisenzymes (caspase-2, -3, -4, -7, -8, -9 and -10)and downregulate the Bcl-2 and Bcl-xL. Second,CsA could induce oxidative stress and damagethe antioxidant defense system. Third, CsA couldincrease the expression of HERP, GRP78 and", "metadata": {}}
+{"_id": "243694", "title": "", "text": "Blood stem cells emerge from aortic endotheliumby a novel type of cell transitionThe ontogeny ofhaematopoietic stem cells (HSCs) duringembryonic development is still highly debated,especially their possible lineage relationship tovascular endothelial cells. The first anatomicalsite from which cells with long-term HSCpotential have been isolated is theaorta-gonad-mesonephros (AGM), morespecifically the vicinity of the dorsal aortic floor.But although some authors have presentedevidence that HSCs may arise directly from theaortic floor into the dorsal aortic lumen, otherssupport the notion that HSCs first emerge withinthe underlying mesenchyme. Here we show bynon-invasive, high-resolution imaging of livezebrafish embryos, that HSCs emerge directlyfrom the aortic floor, through a stereotypedprocess that does not involve cell division but astrong bending then egress of single endothelialcells from the aortic ventral wall into thesub-aortic space, and their concomitant", "metadata": {}}
+{"_id": "253672", "title": "", "text": "Probable person to person transmission of novelavian influenza A (H7N9) virus in Eastern China,2013: epidemiological investigationOBJECTIVETo determine whether the novel avian influenzaH7N9 virus can transmit from person to personand its efficiency. DESIGN Epidemiologicalinvestigations conducted after a family cluster oftwo patients with avian H7N9 in March 2013.SETTING Wuxi, Eastern China. PARTICIPANTSTwo patients, their close contacts, and relevantenvironments. Samples from the patients andenvironments were collected and tested by realtime reverse transcriptase-polymerase chainreaction (rRT-PCR), viral culture, andhaemagglutination inhibition assay. Any contactswho became ill had samples tested for avianH7N9 by rRT-PCR. Paired serum samples wereobtained from contacts for serological testing byhaemagglutination inhibition assays. MAINOUTCOMES MEASURES Clinical data, history ofexposure before the onset of illnesses, andresults of laboratory testing of pathogens and", "metadata": {}}
+{"_id": "263364", "title": "", "text": "Genetic Variation in the Interleukin-28B Gene IsAssociated with Spontaneous Clearance andProgression of Hepatitis C Virus in MoroccanPatientsBACKGROUND Genetic variation in theIL28B gene has been strongly associated withtreatment outcomes, spontaneous clearance andprogression of the hepatitis C virus infection(HCV). The aim of the present study was toinvestigate the role of polymorphisms at thislocus with progression and outcome of HCVinfection in a Moroccan population. METHODS Weanalyzed a cohort of 438 individuals among them232 patients with persistent HCV infection, ofwhom 115 patients had mild chronic hepatitisand 117 had advanced liver disease (cirrhosisand hepatocellular carcinoma), 68 individualswho had naturally cleared HCV and 138 healthysubjects. The IL28B SNPs rs12979860 andrs8099917 were genotyped using a TaqMan 5'allelic discrimination assay. RESULTS Theprotective rs12979860-C and rs8099917-Talleles were more common in subjects with", "metadata": {}}
+{"_id": "266641", "title": "", "text": "CD127 expression inversely correlates withFoxP3 and suppressive function of human CD4+T reg cellsRegulatory T (T reg) cells are criticalregulators of immune tolerance. Most T reg cellsare defined based on expression of CD4, CD25,and the transcription factor, FoxP3. However,these markers have proven problematic foruniquely defining this specialized T cell subset inhumans. We found that the IL-7 receptor(CD127) is down-regulated on a subset of CD4+T cells in peripheral blood. We demonstrate thatthe majority of these cells are FoxP3+, includingthose that express low levels or no CD25. Acombination of CD4, CD25, and CD127 resultedin a highly purified population of T reg cellsaccounting for significantly more cells thatpreviously identified based on other cell surfacemarkers. These cells were highly suppressive infunctional suppressor assays. In fact, cellsseparated based solely on CD4 and CD127expression were anergic and, althoughrepresenting at least three times the number of", "metadata": {}}
+{"_id": "275294", "title": "", "text": "Environmental factors that influence thecutaneous production of vitamin DAllvertebrates, including humans, obtain most oftheir daily vitamin D requirement from casualexposure to sunlight. During exposure tosunlight, the solar ultraviolet B photons(290-315 nm) penetrate into the skin where theycause the photolysis of 7-dehydrocholesterol toprecholecalciferol. Once formed,precholecalciferol undergoes a thermally inducedrearrangement of its double bonds to formcholecalciferol. An increase in skin pigmentation,aging, and the topical application of a sunscreendiminishes the cutaneous production ofcholecalciferol. Latitude, season, and time of dayas well as ozone pollution in the atmosphereinfluence the number of solar ultraviolet Bphotons that reach the earth's surface, andthereby, alter the cutaneous production ofcholecalciferol. In Boston, exposure to sunlightduring the months of November throughFebruary will not produce any significant", "metadata": {}}
+{"_id": "279052", "title": "", "text": "Genomic imprinting in development, growth,behavior and stem cells.Genes that are subjectto genomic imprinting in mammals arepreferentially expressed from a single parentalallele. This imprinted expression of a smallnumber of genes is crucial for normaldevelopment, as these genes often directlyregulate fetal growth. Recent work has alsodemonstrated intricate roles for imprinted genesin the brain, with important consequences onbehavior and neuronal function. Finally, newstudies have revealed the importance of properexpression of specific imprinted genes in inducedpluripotent stem cells and in adult stem cells. Aswe review here, these findings highlight thecomplex nature and developmental importanceof imprinted genes.", "metadata": {}}
+{"_id": "285794", "title": "", "text": "Quantitative Detection of Hepatitis C Virus RNAby Light Cycler PCR and Comparison with TwoDifferent PCR AssaysThe new Light Cyclertechnology was adapted to the detection ofhepatitis C virus (HCV) RNA in clinical samples.Sera from 81 patients were tested by LightCycler PCR, AMPLICOR HCV Monitor assay, andin-house PCR. Our data demonstrate that LightCycler is a fast and reliable method for thedetection and quantitation of HCV RNA.", "metadata": {}}
+{"_id": "293661", "title": "", "text": "Targeting arginine metabolism pathway to treatarginine-dependent cancers.The significantdisparities in metabolism between tumor andnormal cells have inspired the development ofmetabolism-based anti-tumor therapeutics.Arginine is a semi-essential amino acid becausenormal cells can not only synthesize arginine denovo but also take up extracellular arginine.Several types of tumors have abnormalities inarginine metabolism enzymes and completelyrely on extracellular arginine to supportnecessary biological processes. This property isreferred to as arginine auxotrophy. Takingadvantage of characteristic arginine auxotrophyin tumors, arginine deprivation, which isgenerally induced by the use of argininedeiminase (ADI) and arginase I, has beeninvestigated as a novel strategy for cancertherapy. Arginine deprivation demonstratedpromising efficacy against arginine-auxotrophictumors. By integrating perspectives from bothclinical oncologists and laboratory scientists, this", "metadata": {}}
+{"_id": "301838", "title": "", "text": "Rank Signaling Links the Development ofInvariant γδ T Cell Progenitors and Aire+Medullary EpitheliumThe thymic medullaprovides a specialized microenvironment for thenegative selection of T cells, with the presence ofautoimmune regulator (Aire)-expressingmedullary thymic epithelial cells (mTECs) duringthe embryonic-neonatal period being bothnecessary and sufficient to establish long-lastingtolerance. Here we showed that emergence ofthe first cohorts of Aire(+) mTECs at this keydevelopmental stage, prior to αβ T cell repertoireselection, was jointly directed by Rankl(+)lymphoid tissue inducer cells and invariantVγ5(+) dendritic epidermal T cell (DETC)progenitors that are the first thymocytes toexpress the products of gene rearrangement. Inturn, generation of Aire(+) mTECs then fosteredSkint-1-dependent, but Aire-independent, DETCprogenitor maturation and the emergence of aninvariant DETC repertoire. Hence, our dataattributed a functional importance to the", "metadata": {}}
+{"_id": "301866", "title": "", "text": "Long-term immune deficiency after allogeneicstem cell transplantation: B-cell deficiency isassociated with late infections.Immunereconstitution was analyzed in 140 consecutivepatients who were 2-year disease-free and whounderwent myeloablative allogeneictransplantation. A CD4 and CD8 defect wasobserved involving naive, terminallydifferentiated, memory and competent cells andabove limits values for activated subsets. Naturalkiller cells normalize at six months while weobserved expansion of CD19(+)/CD5(+) B cellsafter three months and a persisting defect ofmemory B cells. Chronic graft-versus-hostdisease did not influence significantly thoseparameters for CD8 subsets while the naïve andcompetent CD4 subsets were strongly affected.But the most profound impact of chronicgraft-versus-host disease was on B-cell subsets,especially on the memory B population. Thecumulative incidence of late severe infectionswas low (14% at four years). Using Cox's", "metadata": {}}
+{"_id": "306006", "title": "", "text": "The stimulatory potency of T cell antigens isinfluenced by the formation of the immunologicalsynapse.T cell activation is predicated on theinteraction between the T cell receptor andpeptide-major histocompatibility (pMHC) ligands.The factors that determine the stimulatorypotency of a pMHC molecule remain unclear. Wedescribe results showing that a peptideexhibiting many hallmarks of a weak agoniststimulates T cells to proliferate more than thewild-type agonist ligand. An in silico approachsuggested that the inability to form the centralsupramolecular activation cluster (cSMAC) couldunderlie the increased proliferation. Thisconclusion was supported by experiments thatshowed that enhancing cSMAC formationreduced stimulatory capacity of the weakpeptide. Our studies highlight the fact that acomplex interplay of factors determines thequality of a T cell antigen.", "metadata": {}}
+{"_id": "306311", "title": "", "text": "Control of glutamate clearance and synapticefficacy by glial coverage of neurons.Analysis ofexcitatory synaptic transmission in the rathypothalamic supraoptic nucleus revealed thatglutamate clearance and, as a consequence,glutamate concentration and diffusion in theextracellular space, is associated with the degreeof astrocytic coverage of its neurons. Reductionin glutamate clearance, whether inducedpharmacologically or associated with a relativedecrease of glial coverage in the vicinity ofsynapses, affected transmitter release throughmodulation of presynaptic metabotropicglutamate receptors. Astrocytic wrapping ofneurons, therefore, contributes to the regulationof synaptic efficacy in the central nervoussystem.", "metadata": {}}
+{"_id": "308862", "title": "", "text": "Duration of androgen suppression in thetreatment of prostate cancer.BACKGROUND Thecombination of radiotherapy plus long-termmedical suppression of androgens (> or = 2years) improves overall survival in patients withlocally advanced prostate cancer. We comparedthe use of radiotherapy plus short-termandrogen suppression with the use ofradiotherapy plus long-term androgensuppression in the treatment of locally advancedprostate cancer. METHODS We randomlyassigned patients with locally advanced prostatecancer who had received external-beamradiotherapy plus 6 months of androgensuppression to two groups, one to receive nofurther treatment (short-term suppression) andthe other to receive 2.5 years of furthertreatment with a luteinizing hormone-releasinghormone agonist (long-term suppression). Anoutcome of noninferiority of short-term androgensuppression as compared with long-termsuppression required a hazard ratio of more than", "metadata": {}}
+{"_id": "313394", "title": "", "text": "A Functional Neuroimaging Study of SoundLocalization: Visual Cortex Activity PredictsPerformance in Early-Blind IndividualsBlindindividuals often demonstrate enhancednonvisual perceptual abilities. However, theneural substrate that underlies this improvedperformance remains to be fully understood. Anearlier behavioral study demonstrated that someearly-blind people localize sounds moreaccurately than sighted controls using monauralcues. In order to investigate the neural basis ofthese behavioral differences in humans, wecarried out functional imaging studies usingpositron emission tomography and a speakerarray that permitted pseudo-free-fieldpresentations within the scanner. During binauralsound localization, a sighted control groupshowed decreased cerebral blood flow in theoccipital lobe, which was not seen in early-blindindividuals. During monaural sound localization(one ear plugged), the subgroup of early-blindsubjects who were behaviorally superior at sound", "metadata": {}}
+{"_id": "313403", "title": "", "text": "High-Infiltration of Tumor-AssociatedMacrophages Predicts Unfavorable ClinicalOutcome for Node-Negative Breast CancerThetumor microenvironment is composed of tumorcells, fibroblasts, endothelial cells and infiltratingimmune cells, which may inhibit or promotetumor growth and progression. The objectives ofthis retrospective study were to characterize thedensity of tumor-associated macrophages(TAMs) in breast cancer, and to correlate thedensity of TAMs with clinicopathologicalparameters. Paraffin-embedded specimens andclinicopathological data, including up to 5 yearsfollow-up information, were obtained from 172breast cancer patients. Immunohistochemicalstaining for CD68 (marker for macrophages) wasperformed and evaluated in a blinded fashion.We found that TAMs were significantly frequentin high histopathological grade breast cancerpatients. Breast cancer patients with a highdensity of TAMs had significantly lower rates ofdisease-free survival and 5-year overall survival", "metadata": {}}
+{"_id": "317204", "title": "", "text": "Murine Dishevelled 3 Functions in RedundantPathways with Dishevelled 1 and 2 in NormalCardiac Outflow Tract, Cochlea, and Neural TubeDevelopmentDishevelled (Dvl) proteins areimportant signaling components of both thecanonical beta-catenin/Wnt pathway, whichcontrols cell proliferation and patterning, and theplanar cell polarity (PCP) pathway, whichcoordinates cell polarity within a sheet of cellsand also directs convergent extension cell (CE)movements that produce narrowing andelongation of the tissue. Three mammalian Dvlgenes have been identified and thedevelopmental roles of Dvl1 and Dvl2 werepreviously determined. Here, we identify thefunctions of Dvl3 in development and provideevidence of functional redundancy among thethree murine Dvls. Dvl3(-/-) mice diedperinatally with cardiac outflow tractabnormalities, including double outlet rightventricle and persistent truncus arteriosis. Thesemutants also displayed a misorientated", "metadata": {}}
+{"_id": "323030", "title": "", "text": "Dynamics of adherens junctions in epithelialestablishment, maintenance, and remodelingTheepithelial cadherin (E-cadherin)-catenin complexbinds to cytoskeletal components and regulatoryand signaling molecules to form a matureadherens junction (AJ). This dynamic structurephysically connects neighboring epithelial cells,couples intercellular adhesive contacts to thecytoskeleton, and helps define each cell'sapical-basal axis. Together these activitiescoordinate the form, polarity, and function of allcells in an epithelium. Several molecules regulateAJ formation and integrity, including Rho familyGTPases and Par polarity proteins. However, onlyrecently, with the development of live-cellimaging, has the extent to which E-cadherin isactively turned over at junctions begun to beappreciated. This turnover contributes tojunction formation and to the maintenance ofepithelial integrity during tissue homeostasis andremodeling.", "metadata": {}}
+{"_id": "323335", "title": "", "text": "Long-term outcome of patients with asystoleinduced by head-up tilt test.AIMS To analyse thelong-term outcome of the largest reported cohortof patients presenting asystole during head-uptilt test. METHODS AND RESULTS Since 1990,1322 patients with syncope of unknown originhave undergone tilt-table testing. Of those, 330patients (24 X 9%) presented an abnormalresponse (syncope or pre-syncope).Furthermore, 58 of those patients (17 X 5%)suffered a period of asystole (> or = 3000 ms)during the test. Asystole (median (interquartilerange)) lasted 10 (4, 19 X 2) s (range 3-90).Two different protocols (angles) of tilting(Westminster (60 degrees) n=1124;isoproterenol (80 degrees) n=198)) influencedthe time to the syncopal episode (13 (6 X 5, 20 X5) vs 2 (1, 6 X 5) min, P=0,0005) but not theduration of the asystole. During this period,therapy for asystole featured three differentstages: first patients were treated withpacemakers; later drug therapy (metoprolol", "metadata": {}}
+{"_id": "327319", "title": "", "text": "ZINC 15 – Ligand Discovery for EveryoneManyquestions about the biological activity andavailability of small molecules remaininaccessible to investigators who could mostbenefit from their answers. To narrow the gapbetween chemoinformatics and biology, we havedeveloped a suite of ligand annotation,purchasability, target, and biology associationtools, incorporated into ZINC and meant forinvestigators who are not computer specialists.The new version contains over 120 millionpurchasable \"drug-like\" compounds--effectivelyall organic molecules that are for sale--a quarterof which are available for immediate delivery.ZINC connects purchasable compounds tohigh-value ones such as metabolites, drugs,natural products, and annotated compoundsfrom the literature. Compounds may be accessedby the genes for which they are annotated aswell as the major and minor target classes towhich those genes belong. It offers new analysistools that are easy for nonspecialists yet with few", "metadata": {}}
+{"_id": "335029", "title": "", "text": "Condensin-mediated remodeling of the mitoticchromatin landscape in fission yeastTheeukaryotic genome consists of DNA molecules farlonger than the cells that contain them. Theyreach their greatest compaction duringchromosome condensation in mitosis. Thisprocess is aided by condensin, a structuralmaintenance of chromosomes (SMC) familymember. The spatial organization of mitoticchromosomes and how condensin shapeschromatin architecture are not yet fullyunderstood. Here we use chromosomeconformation capture (Hi-C) to study mitoticchromosome condensation in the fission yeastSchizosaccharomyces pombe. This showed thatthe interphase landscape characterized by smallchromatin domains is replaced by fewer butlarger domains in mitosis. Condensin achievesthis by setting up longer-range,intrachromosomal DNA interactions, whichcompact and individualize chromosomes. At thesame time, local chromatin contacts are", "metadata": {}}
+{"_id": "341324", "title": "", "text": "Efficacy of the 6-month thrice-weekly regimen inthe treatment of new sputum smear-positivepulmonary tuberculosis under clinical trialconditions.BACKGROUND Under the RevisedNational Tuberculosis Control Programme ofIndia, patients with new smear-positivepulmonary tuberculosis are treated with athrice-weekly regimen of antitubercular drugs(2H(3)R(3)Z(3)E(3)/4H(3)R(3) [H isoniazid, Rrifampicin, Z pyrazinamide and E ethambutol])for 6 months. We conducted a retrospectiveanalysis of the efficacy andtolerability of thisregimen under clinical trial conditions inHIV-negative patients with newly diagnosedsmear-positive pulmonary tuberculosis.METHODS We retrospectively analysed the dataon patients assigned to the control regimen (2H(3)R(3)Z(3)E(3)/4H(3)R(3)) in two clinical trialsduring 2001-06 at the National Institute forResearch in Tuberculosis, Chennai, India.RESULTS Of the 268 patients treated with thisregimen, data for efficacy analysis were available", "metadata": {}}
+{"_id": "343052", "title": "", "text": "Curcumin attenuates inflammatory response inIL-1beta-induced human synovial fibroblasts andcollagen-induced arthritis in mousemodel.Curcumin, a major component ofturmeric, has been shown to exhibit anti-oxidantand anti-inflammatory activities. The presentstudy was performed to determine whethercurcumin is efficacious against bothcollagen-induced arthritis (CIA) in mice andIL-1beta-induced activation in fibroblast-likesynoviocytes (FLSs). DBA/1 mice wereimmunized with bovine type II collagen (CII) andtreated with curcumin every other day for2weeks after the initial immunization. Forarthritis, we evaluated the incidence of diseaseand used an arthritis index based on pawthickness. In vitro proliferation of CII- orconcanavalin A-induced splenic T cells wasexamined using IFN-gamma production.Pro-inflammatory cytokines TNF-alpha andIL-1beta were examined in the mouse ankle jointand serum IgG1 and IgG2a isotypes were", "metadata": {}}
+{"_id": "344240", "title": "", "text": "Loss of IGF-IEa or IGF-IEb impairs myogenicdifferentiation.Actions of protein productsresulting from alternative splicing of the Igf1gene have received increasing attention in recentyears. However, the significance and functionalrelevance of these observations remain poorlydefined. To address functions of IGF-I splicevariants, we examined the impact of loss ofIGF-IEa and IGF-IEb on the proliferation anddifferentiation of cultured mouse myoblasts. RNAinterference-mediated reductions in total IGF-I,IGF-IEa alone, or IGF-IEb alone had no effect oncell viability in growth medium. However, cellsdeficient in total IGF-I or IGF-IEa aloneproliferated significantly slower than control cellsor cells deficient in IGF-IEb in serum-free media.Simultaneous loss of both or specific loss ofeither splice variant significantly inhibited myosinheavy chain (MyHC) immunoreactivity by70-80% (P < 0.01) under differentiationconditions (48 h in 2% horse serum) asdetermined by Western immunoblotting. This", "metadata": {}}
+{"_id": "350542", "title": "", "text": "Antimicrobial peptide pleurocidin synergizes withantibiotics through hydroxyl radical formationand membrane damage, and exerts antibiofilmactivity.BACKGROUND Pleurocidin, a 25-merantimicrobial peptide (AMP), is known to exertbactericidal activity. However, the synergisticactivity and mechanism(s) of pleurocidin incombination with conventional antibiotics, andthe antibiofilm effect of the peptide are poorlyunderstood. METHODS The interaction betweenpleurocidin and antibiotics was evaluated usingcheckerboard assay. To study the mechanism(s)involved in their synergism, we detectedhydroxyl radical formation using3'-(p-hydroxyphenyl) fluorescein, measured theNAD(+)/NADH ratio by NAD(+) cycling assay,observed change in bacterial viability with thehydroxyl radical scavenger thiourea, andinvestigated cytoplasmic membrane damageusing propidium iodide. Also, the antibiofilmeffect of pleurocidin was examined with thetissue culture plate method. RESULTS All", "metadata": {}}
+{"_id": "356218", "title": "", "text": "Outcome of pregnancy in women with moderateor severe renal insufficiency.BACKGROUNDPregnant women with mild preexisting renaldisease have relatively few complications ofpregnancy, but the risks of maternal andobstetrical complications in women withmoderate or severe renal insufficiency remainuncertain. METHODS We determined thefrequency and types of maternal and obstetricalcomplications and the outcomes of pregnancy in67 women with primary renal disease (82pregnancies). All the women had initial serumcreatinine concentrations of at least 1.4 mg perdeciliter (124 mumol per liter) and gestationsthat continued beyond the first trimester.RESULTS The mean (+/- SD) serum creatinineconcentration increased from 1.9 +/- 0.8 mg perdeciliter (168 +/- 71 mumol per liter) in earlypregnancy to 2.5 +/- 1.3 mg per deciliter (221+/- 115 mumol per liter) in the third trimester.The frequency of hypertension rose from 28percent at base line to 48 percent in the third", "metadata": {}}
+{"_id": "364522", "title": "", "text": "High-mobility group box-1 protein inducesosteogenic phenotype changes in aortic valveinterstitial cells.OBJECTIVES Calcific aortic valve(AV) disease is known to be aninflammation-related process. High-mobilitygroup box-1 (HMGB1) protein and Toll-likereceptor 4 (TLR4) have been reported toparticipate in several inflammatory diseases. Thepurpose of the present study was to determinewhether the HMGB1-TLR4 axis is involved incalcific AV disease, and to evaluate the effect ofHMGB1, and its potential mechanisms, on thepro-osteogenic phenotype change of valvularinterstitial cells (VICs). METHODS Expression ofHMGB1 and TLR4 in human calcific AVs wasevaluated using immunohistochemical stainingand immunoblotting. Cultured VICs were used asan in vitro model. The VICs were stimulated withHMGB1 for analysis, with versus without TLR4small interfering ribonucleic acid (siRNA), c-JunN-terminal kinase mitogen-activated proteinkinase (JNK MAPK), and nuclear factor kappa-B", "metadata": {}}
+{"_id": "365896", "title": "", "text": "RiboSys, a high-resolution, quantitative approachto measure the in vivo kinetics of pre-mRNAsplicing and 3'-end processing in Saccharomycescerevisiae.We describe methods for obtaining aquantitative description of RNA processing athigh resolution in budding yeast. As a modelgene expression system, we constructed tetON(for induction studies) and tetOFF (forrepression, derepression, and RNA degradationstudies) yeast strains with a series of reportergenes integrated in the genome under thecontrol of a tetO7 promoter. Reversetranscription and quantitative real-time-PCR(RT-qPCR) methods were adapted to allow thedetermination of mRNA abundance as theaverage number of copies per cell in apopulation. Fluorescence in situ hybridization(FISH) measurements of transcript numbers inindividual cells validated the RT-qPCR approachfor the average copy-number determinationdespite the broad distribution of transcript levelswithin a population of cells. In addition, RT-qPCR", "metadata": {}}
+{"_id": "368506", "title": "", "text": "Generation of mice with a conditional allele forthe p75(NTR) neurotrophin receptor gene.Thep75(NTR) neurotrophin receptor has beenimplicated in multiple biological and pathologicalprocesses. While significant advances haverecently been made in understanding thephysiologic role of p75(NTR) , many details andaspects remain to be determined. This is in partbecause the two existing knockout mousemodels (Exons 3 or 4 deleted, respectively), bothdisplay features that defy definitive conclusions.Here we describe the generation of mice thatcarry a conditional p75(NTR) (p75(NTR-FX) )allele made by flanking Exons 4-6, which encodethe transmembrane and all cytoplasmic domains,by loxP sites. To validate this novel conditionalallele, both neural crest-specific p75(NTR)/Wnt1-Cre mutants and conventional p75(NTR)null mutants were generated. Both mutantsdisplayed abnormal hind limb reflexes, implyingthat loss of p75(NTR) in neural crest-derivedcells causes a peripheral neuropathy similar to", "metadata": {}}
+{"_id": "371289", "title": "", "text": "A Triple-Stain Flow Cytometric Method to AssessPlasma- and Acrosome-Membrane Integrity ofCryopreserved Bovine Sperm Immediately afterThawing in Presence of Egg-YolkParticles1Abstract Simultaneously evaluatingpostthaw viability and acrosome integrity ofspermatozoa by flow cytometry would provide avaluable testing tool in both research and routinework. In the present study, a new triple-staincombination was developed for the simultaneousevaluation of viability and acrosome integrity ofbovine sperm processed in egg yolk-basedextender by flow cytometer. SYBR-14 andpropidium iodide (PI) enabled the discriminationof sperm cells from egg yolk and debris particles,which was instrumental for the flow cytometricanalyses of frozen-thawed bovine sperm,because it implied that washing steps to removeegg yolk were no longer required. In addition,phycoerythrin-conjugated peanut agglutinin(PE-PNA) was used to discriminateacrosome-damaged/reacted sperm cells from", "metadata": {}}
+{"_id": "374902", "title": "", "text": "Universal voluntary HIV testing with immediateantiretroviral therapy as a strategy forelimination of HIV transmission: a mathematicalmodel.BACKGROUND Roughly 3 million peopleworldwide were receiving antiretroviral therapy(ART) at the end of 2007, but an estimated 6.7million were still in need of treatment and afurther 2.7 million became infected with HIV in2007. Prevention efforts might reduce HIVincidence but are unlikely to eliminate thisdisease. We investigated a theoretical strategy ofuniversal voluntary HIV testing and immediatetreatment with ART, and examined theconditions under which the HIV epidemic couldbe driven towards elimination. METHODS Weused mathematical models to explore the effecton the case reproduction number (stochasticmodel) and long-term dynamics of the HIVepidemic (deterministic transmission model) oftesting all people in our test-case community(aged 15 years and older) for HIV every year andstarting people on ART immediately after they", "metadata": {}}
+{"_id": "380526", "title": "", "text": "Common variants in DGKK are stronglyassociated with risk of hypospadiasHypospadiasis a common congenital malformation of themale external genitalia. We performed agenome-wide association study using pooledDNA from 436 individuals with hypospadias(cases) and 494 controls of European descentand selected the highest ranked SNPs forindividual genotyping in the discovery sample, anadditional Dutch sample of 133 cases and theirparents, and a Swedish series of 266 cases and402 controls. Individual genotyping of two SNPs(rs1934179 and rs7063116) in DGKK, encodingdiacylglycerol kinase κ, produced compellingevidence for association with hypospadias in thediscovery sample (allele-specific odds ratio (OR)= 2.5, P = 2.5 × 10−11 and OR = 2.3, P = 2.9 ×10−9, respectively) and in the Dutch (OR = 3.9,P = 2.4 × 10−5 and OR = 3.8, P = 3.4 × 10−5)and Swedish (OR = 2.5, P = 2.6 × 10−8 and OR= 2.2, P = 2.7 × 10−6) replication samples.Expression studies showed expression of DGKK", "metadata": {}}
+{"_id": "381602", "title": "", "text": "Neutrophils Suppress Intraluminal NKCell-Mediated Tumor Cell Clearance and EnhanceExtravasation of Disseminated CarcinomaCells.UNLABELLED Immune cells promote theinitial metastatic dissemination of carcinoma cellsfrom primary tumors. In contrast to theirwell-studied functions in the initial stages ofmetastasis, the specific roles of immunocytes infacilitating progression through the critical latersteps of the invasion-metastasis cascade remainpoorly understood. Here, we define novelfunctions of neutrophils in promoting intraluminalsurvival and extravasation at sites of metastaticdissemination. We show that CD11b(+)/Ly6G(+)neutrophils enhance metastasis formation viatwo distinct mechanisms. First, neutrophilsinhibit natural killer cell function, which leads toa significant increase in the intraluminal survivaltime of tumor cells. Thereafter, neutrophilsoperate to facilitate extravasation of tumor cellsthrough the secretion of IL1β and matrixmetalloproteinases. These results identify", "metadata": {}}
+{"_id": "393001", "title": "", "text": "High Km soluble 5'-nucleotidase from humanplacenta. Properties and allosteric regulation byIMP and ATP.A human placental soluble \"highKm\" 5'-nucleotidase has been separated from\"low Km\" 5'-nucleotidase and nonspecificphosphatase by AMP-Sepharose affinitychromatography. The enzyme was purified8000-fold to a specific activity of 25.6mumol/min/mg. The subunit molecular mass is53 kDa, and the native molecular mass is 210kDa, suggesting a tetrameric structure. Solublehigh Km 5'-nucleotidase is most active with IMPand GMP and their deoxy derivatives. IMP ishydrolyzed 15 times faster than AMP. Theenzyme has a virtually absolute requirement formagnesium ions and is regulated by them.Purine nucleoside 5'-triphosphates stronglyactivate the enzyme with the potency order dATPgreater than ATP greater than GTP.2,3-Diphosphoglycerate activates the enzyme aspotently as ATP. Three millimolar ATP decreasedthe Km for IMP from 0.33 to 0.09 mM and", "metadata": {}}
+{"_id": "406733", "title": "", "text": "Histones are incorporated in trans duringreassembly of the yeast PHO5 promoter.Inyeast, remodeling of PHO5 promoter chromatinupon activation is accompanied by transienthyperacetylation and subsequent eviction ofhistones from the promoter in trans. In thecourse of rerepression, nucleosomes have to bereassembled on the promoter. We have analyzedwhere the histones for reassembly of the inactivepromoter chromatin come from. The use of astrain with two differently tagged and differentlyregulated versions of histone H3 allowed us todiscriminate between histones originating fromthe chromatin fraction and histones arising fromthe soluble histone pool. In this way, we showthat the incorporated histones originate from asource in trans. Promoter closure occurs veryrapidly, and the histone chaperones Asf1 andHir1 as well as the SWI/SNF nucleosomeremodeling complex appear to be important forrapid reassembly of nucleosomes at the PHO5promoter.", "metadata": {}}
+{"_id": "409280", "title": "", "text": "National study of physician awareness andadherence to cardiovascular disease preventionguidelines.BACKGROUND Few data haveevaluated physician adherence to cardiovasculardisease (CVD) prevention guidelines according tophysician specialty or patient characteristics,particularly gender. METHODS AND RESULTS Anonline study of 500 randomly selected physicians(300 primary care physicians, 100obstetricians/gynecologists, and 100cardiologists) used a standardized questionnaireto assess awareness of, adoption of, and barriersto national CVD prevention guidelines byspecialty. An experimental case study designtested physician accuracy and determinants ofCVD risk level assignment and application ofguidelines among high-, intermediate-, orlow-risk patients. Intermediate-risk women, asassessed by the Framingham risk score, weresignificantly more likely to be assigned to alower-risk category by primary care physiciansthan men with identical risk profiles (P<0.0001),", "metadata": {}}
+{"_id": "410286", "title": "", "text": "TECHNICAL ADVANCE Floral dip: a simplifiedmethod for Agrobacterium-mediatedTheAgrobacterium vacuum infiltration method hasmade it possible to transform Arabidopsisthaliana without plant tissue culture orregeneration. In the present study, this methodwas evaluated and a substantially modifiedtransformation method was developed. Thelabor-intensive vacuum infiltration process waseliminated in favor of simple dipping ofdeveloping floral tissues into a solutioncontaining Agrobacterium tumefaciens, 5%sucrose and 500 microliters per litre of surfactantSilwet L-77. Sucrose and surfactant were criticalto the success of the floral dip method. Plantsinoculated when numerous immature floral budsand few siliques were present producedtransformed progeny at the highest rate. Planttissue culture media, the hormone benzylaminopurine and pH adjustment were unnecessary,and Agrobacterium could be applied to plants ata range of cell densities. Repeated application of", "metadata": {}}
+{"_id": "418246", "title": "", "text": "Pathway connectivity and signaling coordinationin the yeast stress-activated signalingnetworkStressed cells coordinate a multi-facetedresponse spanning many levels of physiology.Yet knowledge of the complete stress-activatedregulatory network as well as design principlesfor signal integration remains incomplete. Wedeveloped an experimental and computationalapproach to integrate available proteininteraction data with gene fitness contributions,mutant transcriptome profiles, andphospho-proteome changes in cells respondingto salt stress, to infer the salt-responsivesignaling network in yeast. The inferredsubnetwork presented many novel predictions byimplicating new regulators, uncoveringunrecognized crosstalk between knownpathways, and pointing to previously unknown'hubs' of signal integration. We exploited thesepredictions to show that Cdc14 phosphatase is acentral hub in the network and that modificationof RNA polymerase II coordinates induction of", "metadata": {}}
+{"_id": "427082", "title": "", "text": "Premigratory and migratory neural crest cells aremultipotent in vivo.The neural crest (NC) is anembryonic stem/progenitor cell population thatgenerates a diverse array of cell lineages,including peripheral neurons, myelinatingSchwann cells, and melanocytes, among others.However, there is a long-standing controversy asto whether this broad developmental perspectivereflects in vivo multipotency of individual NCcells or whether the NC is comprised of aheterogeneous mixture of lineage-restrictedprogenitors. Here, we resolve this controversy byperforming in vivo fate mapping of single trunkNC cells both at premigratory and migratorystages using the R26R-Confetti mouse model. Bycombining quantitative clonal analyses withdefinitive markers of differentiation, wedemonstrate that the vast majority of individualNC cells are multipotent, with only few clonescontributing to single derivatives. Intriguingly,multipotency is maintained in migratory NC cells.Thus, our findings provide definitive evidence for", "metadata": {}}
+{"_id": "427865", "title": "", "text": "Implementing the ESHRE 'poor responder'criteria in research studies: methodologicalimplications.The Bologna criteria for definingpoor ovarian response (POR) during IVF providea useful template for new research in this field ofassisted conception. However, designing studiesaround the European Society for HumanReproduction and Embryology POR criteria canbe methodologically challenging, as the newdefinition includes various POR subpopulationswith diverse baseline characteristics andunknown clinical prognosis. When designingRCTs, potential result bias may be introduced ifwomen from each subpopulation are not evenlyallocated between intervention groups. In thecase of small or moderate-size RCTs, asingle-sequence randomization method may notensure balanced allocation between groups.Stratified randomization methods provide analternative methodological approach. Dependingon the chosen methodology, patientcharacteristics and outcomes within each", "metadata": {}}
+{"_id": "432261", "title": "", "text": "Generation of gene-edited rats by delivery ofCRISPR/Cas9 protein and donor DNA into intactzygotes using electroporationThe generation ofgene-edited animals using the CRISPRs/Cas9system is based on microinjection into zygoteswhich is inefficient, time consuming anddemands high technical skills. We report theoptimization of an electroporation method forintact rat zygotes using sgRNAs and Cas9 proteinin combination or not with ssODNs (~100 nt).This resulted in high frequency of knockouts,between 15 and 50% of analyzed animals.Importantly, using ssODNs as donor templateresulted in precise knock-in mutations in25-100% of analyzed animals, comparable tomicroinjection. Electroporation of long ssDNA ordsDNA donors successfully used in microinjectionin the past did not allow generation ofgenome-edited animals despite dsDNAvisualization within zygotes. Thus, simultaneouselectroporation of a large number of intact ratzygotes is a rapid, simple, and efficient method", "metadata": {}}
+{"_id": "435529", "title": "", "text": "Uridylation of miRNAs by HEN1 SUPPRESSOR1 inArabidopsisHEN1-mediated 2'-O-methylation hasbeen shown to be a key mechanism to protectplant microRNAs (miRNAs) and small interferingRNAs (siRNAs) as well as animal piwi-interactingRNAs (piRNAs) from degradation and 3' terminaluridylation [1-8]. However, enzymes uridylatingunmethylated miRNAs, siRNAs, or piRNAs inhen1 are unknown. In this study, a geneticscreen identified a second-site mutation hen1suppressor1-2 (heso1-2) that partiallysuppresses the morphological phenotypes of thehypomorphic hen1-2 allele and the null hen1-1allele in Arabidopsis. HESO1 encodes a terminalnucleotidyl transferase that prefers to adduntemplated uridine to the 3' end of RNA, whichis completely abolished by 2'-O-methylation.heso1-2 affects the profile of u-tailed miRNAsand siRNAs and increases the abundance oftruncated and/or normal sized ones in hen1,which often results in increased total amount ofmiRNAs and siRNAs in hen1. In contrast,", "metadata": {}}
+{"_id": "437924", "title": "", "text": "Pre-Exposure Prophylaxis to Prevent HIVInfection: Current Status, Future Opportunitiesand ChallengesAs the global incidence of HIVexceeds 2 million new infections annually,effective interventions to decrease HIVtransmission are needed. Randomized,placebo-controlled studies have demonstratedthat daily oral antiretroviral pre-exposureprophylaxis (PrEP) with a fixed-dose combinationtablet containing tenofovir disoproxil fumarateand emtricitabine can significantly reduce HIVincidence among diverse at-risk populations. Inthese studies, the efficacy of PrEP was correlatedwith levels of adherence. Official guidelinesrecommend provision of PrEP to people atgreatest risk of HIV acquisition, anddemonstration projects suggest that high levelsof uptake and adherence are possible outside ofcontrolled studies. However, several potentialbarriers to implementing PrEP remain. Thesechallenges include low awareness and utilizationof PrEP by at-risk individuals, uncertainty about", "metadata": {}}
+{"_id": "439670", "title": "", "text": "Prepregnancy BMI and the risk of gestationaldiabetes: a systematic review of the literaturewith meta-analysis.The objective of this study isto assess and quantify the risk for gestationaldiabetes mellitus (GDM) according toprepregnancy maternal body mass index (BMI).The design is a systematic review ofobservational studies published in the last 30years. Four electronic databases were searchedfor publications (1977-2007). BMI was elected asthe only measure of obesity, and all diagnosticcriteria for GDM were accepted. Studies withselective screening for GDM were excluded.There were no language restrictions. Themethodological quality of primary studies wasassessed. Some 1745 citations were screened,and 70 studies (two unpublished) involving 671945 women were included (59 cohorts and 11case-controls). Most studies were of high ormedium quality. Compared with women with anormal BMI, the unadjusted pooled odds ratio(OR) of an underweight woman developing GDM", "metadata": {}}
+{"_id": "456304", "title": "", "text": "Multiple risk behaviour: increasingsocio-economic gap over time?BACKGROUNDUnhealthy behaviours often occur incombination. In this study the relationshipbetween education and lifestyle, defined as acluster of risk behaviours, has been analysedwith the purpose to assess socio-economicchanges in multiple risk behaviour over time.METHODS Cross-sectional data from the BelgianHealth Interview Surveys 1997, 2001 and 2004were analysed. This study is restricted to personsaged ≥ 15 years with information on thosehealth behaviours and education (n = 7431, n =8142 and n = 7459, respectively). A lifestyleindex was created based on the sum of the fourunhealthy behaviours: smokers vs.non-smokers, risky versus non-risky alcohol use,sedentaryness vs. physically active and poor vs.healthy diet. The lifestyle index wasdichotomized as low (0-2) vs. high (3-4). For theassessment of socio-economic inequalities inmultiple risk behaviour, summary measures as", "metadata": {}}
+{"_id": "457630", "title": "", "text": "Variations and Trends in Health Burden of VisualImpairment Due to Cataract: A GlobalAnalysis.Purpose To evaluate the global trends inhealth burden of people visually impaired fromcataract in terms of disability-adjusted life years(DALY) and its correlations with national levels ofsocioeconomic development. Methods Global,regional, and national DALY numbers, crude rate,and age-standardized rate of cataract vision lossby age and sex were obtained from the databaseof the Global Burden of Disease Study 2015. Thehuman development index, per capita grossdomestic product, and other country-level datawere derived from international open databases.Regression analysis was used to assess thecorrelations between age-standardized DALY rateand socioeconomic variables. Results The globalDALY numbers of cataract vision loss increasedby 89.42%, from 2048.18 (95%CI [confidenceinterval]: 1457.60-2761.80) thousands in 1990to 3879.74 (95% CI: 2766.07-5232.43)thousands in 2015 (P < 0.001). Females had", "metadata": {}}
+{"_id": "461550", "title": "", "text": "Multiplex genome engineering using CRISPR/Cassystems.Functional elucidation of causal geneticvariants and elements requires precise genomeediting technologies. The type II prokaryoticCRISPR (clustered regularly interspaced shortpalindromic repeats)/Cas adaptive immunesystem has been shown to facilitate RNA-guidedsite-specific DNA cleavage. We engineered twodifferent type II CRISPR/Cas systems anddemonstrate that Cas9 nucleases can be directedby short RNAs to induce precise cleavage atendogenous genomic loci in human and mousecells. Cas9 can also be converted into a nickingenzyme to facilitate homology-directed repairwith minimal mutagenic activity. Lastly, multipleguide sequences can be encoded into a singleCRISPR array to enable simultaneous editing ofseveral sites within the mammalian genome,demonstrating easy programmability and wideapplicability of the RNA-guided nucleasetechnology.", "metadata": {}}
+{"_id": "463309", "title": "", "text": "Transformation of intact yeast cells treated withalkali cations.Intact yeast cells treated with alkalications took up plasmid DNA. Li+, Cs+, Rb+,K+, and Na+ were effective in inducingcompetence. Conditions for the transformation ofSaccharomyces cerevisiae D13-1A with plasmidYRp7 were studied in detail with CsCl. Theoptimum incubation time was 1 h, and theoptimum cell concentration was 5 x 10(7) cellsper ml. The optimum concentration of Cs+ was1.0 M. Transformation efficiency increased withincreasing concentrations of plasmid DNA.Polyethylene glycol was absolutely required.Heat pulse and various polyamines or basicproteins stimulated the uptake of plasmid DNA.Besides circular DNA, linear plasmid DNA wasalso taken up by Cs+-treated yeast cells,although the uptake efficiency was considerablyreduced. The transformation efficiency with Cs+or Li+ was comparable with that of conventionalprotoplast methods for a plasmid containingars1, although not for plasmids containing a 2", "metadata": {}}
+{"_id": "463533", "title": "", "text": "Health-Related Quality of Life as Measured withEQ-5D among Populations with and withoutSpecific Chronic Conditions: A Population-BasedSurvey in Shaanxi Province,ChinaINTRODUCTION The aim of this study wasto examine health-related quality of life (HRQoL)as measured by EQ-5D and to investigate theinfluence of chronic conditions and other riskfactors on HRQoL based on a distributed samplelocated in Shaanxi Province, China. METHODS Amulti-stage stratified cluster sampling methodwas performed to select subjects. EQ-5D wasemployed to measure the HRQoL. The likelihoodthat individuals with selected chronic diseaseswould report any problem in the EQ-5Ddimensions was calculated and tested relative tothat of each of the two reference groups.Multivariable linear regression models were usedto investigate factors associated with EQ VAS.RESULTS The most frequently reported problemsinvolved pain/discomfort (8.8%) andanxiety/depression (7.6%). Nearly half of the", "metadata": {}}
+{"_id": "464511", "title": "", "text": "Memory and Modularity in Cell-Fate DecisionMakingGenetically identical cells sharing anenvironment can display markedly differentphenotypes. It is often unclear how much of thisvariation derives from chance, external signals,or attempts by individual cells to exertautonomous phenotypic programs. By observingthousands of cells for hundreds of consecutivegenerations under constant conditions, wedissect the stochastic decision between asolitary, motile state and a chained, sessile statein Bacillus subtilis. We show that the motile stateis 'memoryless', exhibiting no autonomouscontrol over the time spent in the state. Incontrast, the time spent as connected chains ofcells is tightly controlled, enforcing coordinationamong related cells in the multicellular state. Weshow that the three-protein regulatory circuitgoverning the decision is modular, as initiationand maintenance of chaining are geneticallyseparable functions. As stimulation of the sameinitiating pathway triggers biofilm formation, we", "metadata": {}}
+{"_id": "469066", "title": "", "text": "Lpd depletion reveals that SRF specifies radialversus tangential migration of pyramidalneuronsDuring corticogenesis, pyramidalneurons (\u000080% of cortical neurons) arise fromthe ventricular zone, pass through a multipolarstage to become bipolar and attach to radial glia,and then migrate to their proper position withinthe cortex. As pyramidal neurons migrateradially, they remain attached to their glialsubstrate as they pass through thesubventricular and intermediate zones, regionsrich in tangentially migrating interneurons andaxon fibre tracts. We examined the role oflamellipodin (Lpd), a homologue of a keyregulator of neuronal migration and polarizationin Caenorhabditis elegans, in corticogenesis. Lpddepletion caused bipolar pyramidal neurons toadopt a tangential, rather than radial-glial,migration mode without affecting cell fate.Mechanistically, Lpd depletion reduced theactivity of SRF, a transcription factor regulatedby changes in the ratio of polymerized to", "metadata": {}}
+{"_id": "470625", "title": "", "text": "Identification of p18 INK4c as a tumorsuppressor gene in glioblastomamultiforme.Genomic alterations leading toaberrant activation of cyclin/cyclin-dependentkinase (cdk) complexes drive the pathogenesis ofmany common human tumor types. In the caseof glioblastoma multiforme (GBM), thesealterations are most commonly due tohomozygous deletion of p16(INK4a) and lesscommonly due to genomic amplifications ofindividual genes encoding cyclins or cdks. Here,we describe deletion of the p18(INK4c) cdkinhibitor as a novel genetic alteration driving thepathogenesis of GBM. Deletions of p18(INK4c)often occurred in tumors also harboringhomozygous deletions of p16(INK4a). Expressionof p18(INK4c) was completely absent in 43% ofGBM primary tumors studied byimmunohistochemistry. Lentiviral reconstitutionof p18(INK4c) expression at physiologic levels inp18(INK4c)-deficient but notp18(INK4c)-proficient GBM cells led to", "metadata": {}}
+{"_id": "471735", "title": "", "text": "Two-stage control of an oxidative stress regulon:the Escherichia coli SoxR protein triggersredox-inducible expression of the soxSregulatory gene.Escherichia coli responds to theredox stress imposed by superoxide-generatingagents such as paraquat by activating thesynthesis of as many as 80 polypeptides.Expression of a key group of these inducibleproteins is controlled at the transcriptional levelby the soxRS locus (the soxRS regulon). Atwo-stage control system was hypothesized forsoxRS, in which an intracellular redox signalwould trigger the SoxR protein as atranscriptional activator of the soxS gene and theresulting increased levels of SoxS protein wouldactivate transcription of the various soxRSregulon genes (B. Demple and C.F. AmábileCuevas, Cell 67:837-839, 1990). We haveconstructed operon fusions of the E. coli lacgenes to the soxS promoter to monitor soxStranscription. Expression from the soxS promoteris strongly inducible by paraquat in a manner", "metadata": {}}
+{"_id": "471921", "title": "", "text": "Air pollution and cardiovascular disease: astatement for healthcare professionals from theExpert Panel on Population and PreventionScience of the American Heart Association.Airpollution is a heterogeneous, complex mixture ofgases, liquids, and particulate matter.Epidemiological studies have demonstrated aconsistent increased risk for cardiovascularevents in relation to both short- and long-termexposure to present-day concentrations ofambient particulate matter. Several plausiblemechanistic pathways have been described,including enhanced coagulation/thrombosis, apropensity for arrhythmias, acute arterialvasoconstriction, systemic inflammatoryresponses, and the chronic promotion ofatherosclerosis. The purpose of this statement isto provide healthcare professionals andregulatory agencies with a comprehensive reviewof the literature on air pollution andcardiovascular disease. In addition, theimplications of these findings in relation to public", "metadata": {}}
+{"_id": "474325", "title": "", "text": "Non-invasive ventilation in chronic obstructivepulmonary disease patients: helmet versus facialmaskThe helmet is a new interface with thepotential of increasing the success rate ofnon-invasive ventilation by improving tolerance.To perform a physiological comparison betweenthe helmet and the conventional facial mask indelivering non-invasive ventilation in hypercapnicpatients with chronic obstructive pulmonarydisease. Prospective, controlled, randomizedstudy with cross-over design. In 10 patients weevaluated gas exchange, inspiratory effort,patient–ventilator synchrony and patienttolerance after 30 min of non-invasive ventilationdelivered either by helmet or facial mask; bothtrials were preceded by periods of spontaneousunassisted breathing. Arterial blood gases,inspiratory effort, duration of diaphragmcontraction and ventilator assistance,effort-to-support delays (at the beginning and atthe end of inspiration), number of ineffectiveefforts, and patient comfort. Non-invasive", "metadata": {}}
+{"_id": "485020", "title": "", "text": "Case Management and Client Access to Healthand Social Services in Outpatient SubstanceAbuse TreatmentA primary goal of casemanagement is to coordinate services acrosstreatment settings and to integrate substanceabuse services with other types of servicesoffered in the community, including housing,mental health, medical, and social services.However, case management is a global constructthat consists of several key dimensions, whichinclude extent of case management coverage,the degree of management of the referralprocess, and the location of case managementactivity (on-site, off-site, or both). This studyexamines the relationship between specificdimensions of case management and theutilization of health and ancillary social servicesin outpatient substance abuse treatment. Ingeneral, results suggest that more active casemanagement during the referral process andproviding case management both on-site andoff-site are most consistent with our predictions", "metadata": {}}
+{"_id": "493346", "title": "", "text": "Evidence that the Ipl1-Sli15 (AuroraKinase-INCENP) Complex Promotes ChromosomeBi-orientation by Altering Kinetochore-SpindlePole ConnectionsHow sister kinetochores attachto microtubules from opposite spindle polesduring mitosis (bi-orientation) remains poorlyunderstood. In yeast, the ortholog of the AuroraB-INCENP protein kinase complex (Ipl1-Sli15)may have a role in this crucial process, becauseit is necessary to prevent attachment of sisterkinetochores to microtubules from the samespindle pole. We investigated IPL1 function incells that cannot replicate their chromosomes butnevertheless duplicate their spindle pole bodies(SPBs). Kinetochores detach from old SPBs andreattach to old and new SPBs with equalfrequency in IPL1+ cells, but remain attached toold SPBs in ipl1 mutants. This raises thepossibility that Ipl1-Sli15 facilitates bi-orientationby promoting turnover of kinetochore-SPBconnections until traction of sister kinetochorestoward opposite spindle poles creates tension in", "metadata": {}}
+{"_id": "496873", "title": "", "text": "CRITICAL REVIEW Cutaneous Vasculitis Update:Diagnostic Criteria,Vasculitis, inflammation of thevessel wall, can result in mural destruction withhemorrhage, aneurysm formation, andinfarction, or intimal-medial hyperplasia andsubsequent stenosis leading to tissue ischemia.The skin, in part due to its large vascular bed,exposure to cold temperatures, and frequentpresence of stasis, is involved in many distinct aswell as un-named vasculitic syndromes that varyfrom localized and self-limited to generalized andlife-threatening with multi-organ disease. Toexclude mimics of vasculitis, diagnosis ofcutaneous vasculitis requires biopsy confirmationwhere its acute signs (fibrinoid necrosis), chronicsigns (endarteritis obliterans), or past signs(acellular scar of healed arteritis) must berecognized and presence of extravascularfindings such as patterned fibrosis orcollagenolytic granulomas noted. Althoughvasculitis can be classified by etiology, manycases have no identifiable cause, and a single", "metadata": {}}
+{"_id": "502591", "title": "", "text": "E2F-dependent histone acetylation andrecruitment of the Tip60 acetyltransferasecomplex to chromatin in late G1.E2F proteins caneither activate or repress transcription. Followingmitogenic stimulation, repressiveE2F4-p130-histone deacetylase complexesdissociate from, while activating species (E2F1,-2, and -3) associate with, target promoters.Histones H3 and H4 simultaneously becomehyperacetylated, but it remains unclear whetherthis is a prerequisite or a consequence of E2Fbinding. Here, we show that activating E2Fspecies are required for hyperacetylation oftarget chromatin in human cells. Overexpressionof a dominant-negative (DN) E2F1 mutant inserum-stimulated T98G cells blocked all E2Fbinding, H4 acetylation, and, albeit partially, H3acetylation. Target gene activation and S-phaseentry were also blocked by DN E2F1. Conversely,ectopic activation of E2F1 rapidly induced H3 andH4 acetylation, demonstrating a direct role forE2F in these events. E2F1 was previously shown", "metadata": {}}
+{"_id": "502797", "title": "", "text": "Chemical approaches to stem cell biology andtherapeutics.Small molecules that modulatestem cell fate and function offer significantopportunities that will allow the full realization ofthe therapeutic potential of stem cells. Rationaldesign and screening for small molecules haveidentified useful compounds to probefundamental mechanisms of stem cellself-renewal, differentiation, and reprogrammingand have facilitated the development ofcell-based therapies and therapeutic drugstargeting endogenous stem and progenitor cellsfor repair and regeneration. Here, we will discussrecent scientific and therapeutic progress, as wellas new perspectives and future challenges forusing chemical approaches in stem cell biologyand regenerative medicine.", "metadata": {}}
+{"_id": "503050", "title": "", "text": "Genome-wide maps of chromatin state inpluripotent and lineage-committed cellsWereport the application of single-molecule-basedsequencing technology for high-throughputprofiling of histone modifications in mammaliancells. By obtaining over four billion bases ofsequence from chromatin immunoprecipitatedDNA, we generated genome-widechromatin-state maps of mouse embryonic stemcells, neural progenitor cells and embryonicfibroblasts. We find that lysine 4 and lysine 27trimethylation effectively discriminates genesthat are expressed, poised for expression, orstably repressed, and therefore reflect cell stateand lineage potential. Lysine 36 trimethylationmarks primary coding and non-codingtranscripts, facilitating gene annotation.Trimethylation of lysine 9 and lysine 20 isdetected at satellite, telomeric and activelong-terminal repeats, and can spread intoproximal unique sequences. Lysine 4 and lysine9 trimethylation marks imprinting control", "metadata": {}}
+{"_id": "515489", "title": "", "text": "Oncofetal long noncoding RNA PVT1 promotesproliferation and stem cell-like property ofhepatocellular carcinoma cells by stabilizingNOP2.UNLABELLED Many protein-codingoncofetal genes are highly expressed in murineand human fetal liver and silenced in adult liver.The protein products of these hepatic oncofetalgenes have been used as clinical markers for therecurrence of hepatocellular carcinoma (HCC)and as therapeutic targets for HCC. Herein weexamined the expression profiles of longnoncoding RNAs (lncRNAs) found in fetal andadult liver in mice. Many fetal hepatic lncRNAswere identified; one of these, lncRNA-mPvt1, isan oncofetal RNA that was found to promote cellproliferation, cell cycling, and the expression ofstem cell-like properties of murine cells.Interestingly, we found that humanlncRNA-hPVT1 was up-regulated in HCC tissuesand that patients with higher lncRNA-hPVT1expression had a poor clinical prognosis. Theprotumorigenic effects of lncRNA-hPVT1 on cell", "metadata": {}}
+{"_id": "516867", "title": "", "text": "Candida albicans, a distinctive fungal model forcellular aging studyThe unicellular eukaryoticorganisms represent the popular model systemsto understand aging in eukaryotes. Candidaalbicans, a polymorphic fungus, appears to beanother distinctive unicellular aging model inaddition to the budding yeast Saccharomycescerevisiae and fission yeastSchizosaccharomyces pombe. The two types ofCandida cells, yeast (blastospore) form andhyphal (filamentous) form, have similarreplicative lifespan. Taking the advantage ofmorphologic changes, we are able to obtain cellsof different ages. Old Candida cells tend toaccumulate glycogen and oxidatively damagedproteins. Deletion of the SIR2 gene causes adecrease of lifespan, while insertion of an extracopy of SIR2 extends lifespan, indicating that likein S. cerevisiae, Sir2 regulates cellular aging inC. albicans. Interestingly, Sir2 deletion does notresult in the accumulation of extra-chromosomalrDNA molecules, but influences the retention of", "metadata": {}}
+{"_id": "519974", "title": "", "text": "ANKTM1, a TRP-like Channel Expressed inNociceptive Neurons, Is Activated by ColdTemperaturesMammals detect temperature withspecialized neurons in the peripheral nervoussystem. Four TRPV-class channels have beenimplicated in sensing heat, and one TRPM-classchannel in sensing cold. The combined range oftemperatures that activate these channels coversa majority of the relevant physiological spectrumsensed by most mammals, with a significant gapin the noxious cold range. Here, we describe thecharacterization of ANKTM1, a cold-activatedchannel with a lower activation temperaturecompared to the cold and menthol receptor,TRPM8. ANKTM1 is a distant family member ofTRP channels with very little amino acidsimilarity to TRPM8. It is found in a subset ofnociceptive sensory neurons where it iscoexpressed with TRPV1/VR1 (the capsaicin/heatreceptor) but not TRPM8. Consistent with theexpression of ANKTM1, we identify noxiouscold-sensitive sensory neurons that also respond", "metadata": {}}
+{"_id": "520579", "title": "", "text": "Plasma vitamin D metabolites and risk ofcolorectal cancer in women.OBJECTIVEExperimental evidence suggests that1,25-dihydroxyvitamin D and its precursor,25-hydroxyvitamin D [25(OH)D], may aid in theprevention of colorectal cancer. We thereforeexamined risk in relation to plasmaconcentrations of these vitamin D metabolites.METHODS In a nested case-control study amongwomen in the Nurses' Health Study, we identified193 colorectal cancer cases, ages 46 to 78 years,diagnosed up to 11 years after blood collection.Two controls were matched per case on year ofbirth and month of blood draw. Odds ratios (OR)for risk of colorectal cancer were calculated usingconditional logistic regression adjusted for bodymass index, physical activity, smoking, familyhistory, use of hormone replacement therapy,aspirin use, and dietary intakes. RESULTS Wefound a significant inverse linear associationbetween plasma 25(OH)D and risk of colorectalcancer (P = 0.02). Among women in the highest", "metadata": {}}
+{"_id": "544971", "title": "", "text": "DNA Deamination Mediates Innate Immunity toRetroviral InfectionCEM15/APOBEC3G is acellular protein required for resistance toinfection by virion infectivity factor (Vif)-deficienthuman immunodeficiency virus (HIV). Here,using a murine leukemia virus (MLV)-basedsystem, we provide evidence thatCEM15/APOBEC3G is a DNA deaminase that isincorporated into virions during viral productionand subsequently triggers massive deaminationof deoxycytidine to deoxyuridine within theretroviral minus (first)-strand cDNA, thusproviding a probable trigger for viral destruction.Furthermore, HIV Vif can protect MLV from thisCEM15/APOBEC3G-dependent restriction. Thesefindings imply that targeted DNA deamination isa major strategy of innate immunity toretroviruses and likely also contributes to thesequence variation observed in many viruses(including HIV).", "metadata": {}}
+{"_id": "581832", "title": "", "text": "Global, regional, and national disability-adjustedlife-years (DALYs) for 315 diseases and injuriesand healthy life expectancy (HALE), 1990–2015:a systematic analysis for the Global Burden ofDisease Study 2015BACKGROUND Healthy lifeexpectancy (HALE) and disability-adjustedlife-years (DALYs) provide summary measures ofhealth across geographies and time that caninform assessments of epidemiological patternsand health system performance, help to prioritiseinvestments in research and development, andmonitor progress toward the SustainableDevelopment Goals (SDGs). We aimed to provideupdated HALE and DALYs for geographiesworldwide and evaluate how disease burdenchanges with development. METHODS We usedresults from the Global Burden of Diseases,Injuries, and Risk Factors Study 2015 (GBD2015) for all-cause mortality, cause-specificmortality, and non-fatal disease burden to deriveHALE and DALYs by sex for 195 countries andterritories from 1990 to 2015. We calculated", "metadata": {}}
+{"_id": "583260", "title": "", "text": "Adverse drug events: database construction andin silico prediction.Adverse drug events (ADEs)are the harms associated with uses of givenmedications at normal dosages, which are crucialfor a drug to be approved in clinical use orcontinue to stay on the market. Many ADEs arenot identified in trials until the drug is approvedfor clinical use, which results in adversemorbidity and mortality. To date, millions ofADEs have been reported around the world.Methods to avoid or reduce ADEs are animportant issue for drug discovery anddevelopment. Here, we reported acomprehensive database of adverse drug events(namely MetaADEDB), which included more than520,000 drug-ADE associations among 3059unique compounds (including 1330 drugs) and13,200 ADE items by data integration and textmining. All compounds and ADEs were annotatedwith the most commonly used concepts definedin Medical Subject Headings (MeSH). Meanwhile,a computational method, namely the phenotypic", "metadata": {}}
+{"_id": "596817", "title": "", "text": "Genetic Tests for Ecological and AllopatricSpeciation in Anoles on an IslandArchipelagoFrom Darwin's study of theGalapagos and Wallace's study of Indonesia,islands have played an important role inevolutionary investigations, and radiations withinarchipelagos are readily interpreted assupporting the conventional view of allopatricspeciation. Even during the ongoing paradigmshift towards other modes of speciation, islandradiations, such as the Lesser Antillean anoles,are thought to exemplify this process. Geologicaland molecular phylogenetic evidence show that,in this archipelago, Martinique anoles provideseveral examples of secondary contact of islandspecies. Four precursor island species, with up to8 mybp divergence, met when their islandscoalesced to form the current island ofMartinique. Moreover, adjacent anole populationsalso show marked adaptation to distinct habitatzonation, allowing both allopatric and ecologicalspeciation to be tested in this system. We take", "metadata": {}}
+{"_id": "597790", "title": "", "text": "Deficiency and pharmacological stabilization ofmast cells reduce diet-induced obesity anddiabetes in miceAlthough mast cell functionshave classically been related to allergicresponses, recent studies indicate that thesecells contribute to other common diseases suchas multiple sclerosis, rheumatoid arthritis,atherosclerosis, aortic aneurysm and cancer.This study presents evidence that mast cells alsocontribute to diet-induced obesity and diabetes.For example, white adipose tissue (WAT) fromobese humans and mice contain more mast cellsthan WAT from their lean counterparts.Furthermore, in the context of mice on aWestern diet, genetically induced deficiency ofmast cells, or their pharmacological stabilization,reduces body weight gain and levels ofinflammatory cytokines, chemokines andproteases in serum and WAT, in concert withimproved glucose homeostasis and energyexpenditure. Mechanistic studies reveal thatmast cells contribute to WAT and muscle", "metadata": {}}
+{"_id": "599582", "title": "", "text": "Familial aphasic episodes: another variant ofpartial epilepsy with simple inheritance?Wereport on a family having partial epilepsy withsimple inheritance. The affected memberscommonly have aphasic episodes with secondarygeneralization; onset occurred either inadolescence or adulthood. Patients' response tomedication has varied greatly. No neurologicaldefects or decline in intelligence were found. Thecase represents another variety of rare familialpartial epilepsy with neocortical epilepsyfeatures.", "metadata": {}}
+{"_id": "600437", "title": "", "text": "Endosome-ER Contacts Control Actin Nucleationand Retromer Function through VAP-DependentRegulation of PI4PVAP (VAPA and VAPB) is anevolutionarily conserved endoplasmic reticulum(ER)-anchored protein that helps generatetethers between the ER and other membranesthrough which lipids are exchanged acrossadjacent bilayers. Here, we report that byregulating PI4P levels on endosomes, VAP affectsWASH-dependent actin nucleation on theseorganelles and the function of the retromer, aprotein coat responsible for endosome-to-Golgitraffic. VAP is recruited to retromer budding siteson endosomes via an interaction with theretromer SNX2 subunit. Cells lacking VAPaccumulate high levels of PI4P, actin comets,and trans-Golgi proteins on endosomes. Suchdefects are mimicked by downregulation ofOSBP, a VAP interactor and PI4P transporter thatparticipates in VAP-dependent ER-endosomestethers. These results reveal a role of PI4P inretromer-/WASH-dependent budding from", "metadata": {}}
+{"_id": "600808", "title": "", "text": "Anaphase-PromotingComplex/Cyclosome–Dependent Proteolysis ofHuman Cyclin a Starts at the Beginning of Mitosisand Is Not Subject to the Spindle AssemblyCheckpointCyclin A is a stable protein in S andG2 phases, but is destabilized when cells entermitosis and is almost completely degradedbefore the metaphase to anaphase transition.Microinjection of antibodies against subunits ofthe anaphase-promoting complex/cyclosome(APC/C) or against human Cdc20 (fizzy) arrestedcells at metaphase and stabilized both cyclins Aand B1. Cyclin A was efficiently polyubiquitylatedby Cdc20 or Cdh1-activated APC/C in vitro, butin contrast to cyclin B1, the proteolysis of cyclinA was not delayed by the spindle assemblycheckpoint. The degradation of cyclin B1 wasaccelerated by inhibition of the spindle assemblycheckpoint. These data suggest that the APC/C isactivated as cells enter mitosis and immediatelytargets cyclin A for degradation, whereas thespindle assembly checkpoint delays the", "metadata": {}}
+{"_id": "601033", "title": "", "text": "Human T Cell Leukemia Virus Reactivation withProgression of Adult T-CellLeukemia-LymphomaBACKGROUND HumanT-cell leukemia virus-associated adult T-cellleukemia-lymphoma (ATLL) has a very poorprognosis, despite trials of a variety of differenttreatment regimens. Virus expression has beenreported to be limited or absent when ATLL isdiagnosed, and this has suggested thatsecondary genetic or epigenetic changes areimportant in disease pathogenesis. METHODSAND FINDINGS We prospectively investigatedcombination chemotherapy followed byantiretroviral therapy for this disorder. Nineteenpatients were prospectively enrolled between2002 and 2006 at five medical centers in a phaseII clinical trial of infusional chemotherapy withetoposide, doxorubicin, and vincristine, dailyprednisone, and bolus cyclophosphamide(EPOCH) given for two to six cycles until maximalclinical response, and followed by antiviraltherapy with daily zidovudine, lamivudine, and", "metadata": {}}
+{"_id": "602760", "title": "", "text": "Montelukast and fluticasone compared withsalmeterol and fluticasone in protecting againstasthma exacerbation in adults: one year, doubleblind, randomised, comparative trial.OBJECTIVESTo assess the effect of montelukast versussalmeterol added to inhaled fluticasonepropionate on asthma exacerbation in patientswhose symptoms are inadequately controlledwith fluticasone alone. Design and setting A 52week, two period, double blind, multicentre trialduring which patients whose symptomsremained uncontrolled by inhaled corticosteroidswere randomised to add montelukast orsalmeterol. PARTICIPANTS Patients (15-72years; n = 1490) had a clinical history of chronicasthma for > or = 1 year, a baseline forcedexpiratory volume in one second (FEV1) value50-90% predicted, and a beta agonistimprovement of > or = 12% in FEV1. MAINOUTCOME MEASURES The primary end point wasthe percentage of patients with at least oneasthma exacerbation. RESULTS 20.1% of the", "metadata": {}}
+{"_id": "612002", "title": "", "text": "Control of assembly and function of glutamatereceptors by the amino-terminal domain.Theextracellular amino-terminal domains (ATDs) ofthe ionotropic glutamate receptor subunits forma semiautonomous component of all glutamatereceptors that resides distal to the membraneand controls a surprisingly diverse set of receptorfunctions. These functions include subunitassembly, receptor trafficking, channel gating,agonist potency, and allosteric modulation. Themany divergent features of the differentionotropic glutamate receptor classes anddifferent subunits within a class may stem fromdifferential regulation by the amino-terminaldomains. The emerging knowledge of thestructure and function of the amino-terminaldomains reviewed here may enable targeting ofthis region for the therapeutic modulation ofglutamatergic signaling. Toward this end, NMDAreceptor antagonists that interact with theGluN2B ATD show promise in animal models ofischemia, neuropathic pain, and Parkinson's", "metadata": {}}
+{"_id": "615047", "title": "", "text": "Fission yeast and other yeasts as emergentmodels to unravel cellular aging in eukaryotes.Inthe past years, simple organisms such as yeastsand worms have contributed a great deal toaging research. Studies pioneered inSaccharomyces cerevisiae were useful toelucidate a significant number of molecularmechanisms underlying cellular aging and todiscover novel longevity genes. Importantly,these genes proved many times to be conservedin multicellular eukaryotes. Consequently, suchdiscovery approaches are being extended toother yeast models, such asSchizosaccharomyces pombe, Candida albicans,Kluyveromyces lactis, and Cryptococcusneoformans. In fission yeast, researchers havefound links between asymmetrical cell divisionand nutrient signaling pathways with aging. Inthis review, we discuss the state of knowledge onthe mechanisms controlling both replicative andchronological aging in S pombe and the otheremergent yeast models.", "metadata": {}}
+{"_id": "623486", "title": "", "text": "Centrifugal elutriation as a method for isolationof large numbers of functionally intact humanperipheral blood monocytes.Centrifugalelutriation was used further to isolate humanperipheral blood monocytes (HPBM) frommononuclear-enriched cells harvested as asecondary component following plateletconcentration collection samples. HPBM wererecovered in either one or two populationsconsisting of either total HPBM or small (SM) andlarge monocytes (LM). The elutriation wascarried out at 3,500 +/- 5 rpm for the separationof lymphocytes and HPBM in Ca++- andMg++-free PBS without EDTA. An average of5.05 +/- 1.50 X 10(8) HPBM were recovered inthe total HPBM with a purity of 95% +/- 3%. TheSM and LM were obtained by splitting the totalHPBM into two equal populations with an HPBMpurity of 92% +/- 3% and 93% +/- 3,respectively, by nonspecific esterase staining.The elutriation media were shown to have noeffect on viability by trypan blue exclusion. All", "metadata": {}}
+{"_id": "641459", "title": "", "text": "Asthma in United States Olympic athletes whoparticipated in the 1996 SummerGames.BACKGROUND Asthma prevalenceappears to be increasing in the generalpopulation. We sought to determine whetherasthma prevalence has also increased in highlycompetitive athletes. OBJECTIVE Our aim was todetermine how many United States Olympicathletes who were chosen to participate in the1996 Summer Olympic Games had a past historyof asthma or symptoms that suggested asthmaor took asthma medications. METHODS Weanalyzed responses to questions that askedabout allergic and respiratory diseases on theUnited States Olympic Committee (USOC)Medical History Questionnaire that wascompleted by all athletes who were chosen torepresent the US at the 1996 Summer OlympicGames in Atlanta. RESULTS Of the 699 athleteswho completed the questionnaire, 107 (15.3%)had a previous diagnosis of asthma, and 97(13.9%) recorded use of an asthma medication", "metadata": {}}
+{"_id": "641786", "title": "", "text": "Relapse specific mutations in NT5C2 in childhoodacute lymphoblastic leukemiaRelapsed childhoodacute lymphoblastic leukemia (ALL) carries apoor prognosis, despite intensive retreatment,owing to intrinsic drug resistance. The biologicalpathways that mediate resistance are unknown.Here, we report the transcriptome profiles ofmatched diagnosis and relapse bone marrowspecimens from ten individuals with pediatricB-lymphoblastic leukemia using RNA sequencing.Transcriptome sequencing identified 20 newlyacquired, novel nonsynonymous mutations notpresent at initial diagnosis, with 2 individualsharboring relapse-specific mutations in the samegene, NT5C2, encoding a 5'-nucleotidase.Full-exon sequencing of NT5C2 was completed in61 further relapse specimens, identifyingadditional mutations in 5 cases. Enzymaticanalysis of mutant proteins showed that basesubstitutions conferred increased enzymaticactivity and resistance to treatment withnucleoside analog therapies. Clinically, all", "metadata": {}}
+{"_id": "643765", "title": "", "text": "Relationship between Sloan-Kettering virusexpression and mouse folliculardevelopmentSloan-Kettering virus gene product(Ski) is an unique nuclear pro-oncoprotein andbelongs to the ski/sno proto-oncogene family.Ski plays multiple roles in a variety of cell types,it can induce both oncogenic transformation andterminal muscle differentiation when expressedat high levels. Ski/SnoN are importanttranscription regulators of the transforminggrowth factor-β (TGF-β) superfamily and functionmainly through heterodimers. Since TGF-βsuperfamily are key regulators of follicledevelopment and it has been previously shownthat SnoN is also vital to follicle development,this research was conducted to clarify therelationship between Ski expression and mousefollicular development, in ovaries of neonatal andgonadotropin-induced immature mice byimmunohistochemical and real-time PCRtechniques. In postnatal mice, positive stainingfor Ski was highly detected in oocyte nuclei at", "metadata": {}}
+{"_id": "649951", "title": "", "text": "Involvement of CB1 cannabinoid receptors inemotional behaviourRationale: Endogenous andexogenous cannabinoids acting through the CB1cannabinoid receptors are implicated in thecontrol of a variety of behavioural andneuroendocrine functions, including emotionalresponses, and learning and memory processes.Recently, knockout mice deficient in the CB1cannabinoid receptor have been generated, andthese animals result in an excellent tool toevaluate the neurophysiology of the endogenouscannabinoid system. Objectives: To establish therole of the CB1 cannabinoid receptor in severalemotional-related behavioural responses,including aggressiveness, anxiety, depressionand learning models, using CB1 knockout mice.Methods: We evaluated the spontaneousresponses of CB1 knockout mice and wild-typecontrols under different behavioural paradigms,including the light/dark box, the chronicunpredictable mild stress, the resident–intrudertest and the active avoidance paradigm. Results:", "metadata": {}}
+{"_id": "654735", "title": "", "text": "Exosomal levels of miRNA-21 from cerebrospinalfluids associated with poor prognosis and tumorrecurrence of glioma patientsGlioma is a mostcommon type of primary brain tumors.Extracellular vesicles, in the form of exosomes,are known to mediate cell-cell communication bytransporting cell-derived proteins and nucleicacids, including various microRNAs (miRNAs).Here we examined the cerebrospinal fluid (CSF)from patients with recurrent glioma for the levelsof cancer-related miRNAs, and evaluated thevalues for prognosis by comparing the measuresof CSF-, serum-, and exosome-contained miR-21levels. Samples from seventy glioma patientsfollowing surgery were compared with thosefrom brain trauma patients as a non-tumorcontrol group. Exosomal miR-21 levels in theCSF of glioma patients were found significantlyhigher than in the controls; whereas nodifference was detected in serum-derivedexosomal miR-21 expression. The CSF-derivedexosomal miR-21 levels correlated with tumor", "metadata": {}}
+{"_id": "663464", "title": "", "text": "Age\u0000associated microRNA expression in humanperipheral blood is associated with all\u0000causemortality and age\u0000related traitsRecent studiesprovide evidence of correlations of DNAmethylation and expression of protein-codinggenes with human aging. The relations ofmicroRNA expression with age and age-relatedclinical outcomes have not been characterizedthoroughly. We explored associations of age withwhole-blood microRNA expression in 5221 adultsand identified 127 microRNAs that weredifferentially expressed by age at P < 3.3 × 10-4(Bonferroni-corrected). Most microRNAs wereunderexpressed in older individuals. Integrativeanalysis of microRNA and mRNA expressionrevealed changes in age-associated mRNAexpression possibly driven by age-associatedmicroRNAs in pathways that involve RNAprocessing, translation, and immune function.We fitted a linear model to predict 'microRNAage' that incorporated expression levels of 80microRNAs. MicroRNA age correlated modestly", "metadata": {}}
+{"_id": "665817", "title": "", "text": "Histone deacetylases (HDACs) in frontotemporallobar degeneration.AIMS Frontotemporal lobardegeneration (FTLD) is clinically andpathologically heterogeneous. Althoughassociated with variations in MAPT, GRN andC9ORF72, the pathogenesis of these, and ofother nongenetic, forms of FTLD, remainsunknown. Epigenetic factors such as histoneregulation by histone deacetylases (HDAC) mayplay a role in the dysregulation of transcriptionalactivity, thought to underpin theneurodegenerative process. METHODS Thedistribution and intensity of HDACs 4, 5 and 6was assessed semi-quantitatively inimmunostained sections of temporal cortex withhippocampus, and cerebellum, from 33pathologically confirmed cases of FTLD and 27controls. RESULTS We found a significantlygreater intensity of cytoplasmic immunostainingfor HDAC4 and HDAC6 in granule cells of thedentate gyrus in cases of FTLD overall comparedwith controls, and specifically in cases of FTLD", "metadata": {}}
+{"_id": "667451", "title": "", "text": "Evolution and Impact of Subclonal Mutations inChronic Lymphocytic LeukemiaClonal evolution isa key feature of cancer progression and relapse.We studied intratumoral heterogeneity in 149chronic lymphocytic leukemia (CLL) cases byintegrating whole-exome sequence and copynumber to measure the fraction of cancer cellsharboring each somatic mutation. We identifieddriver mutations as predominantly clonal (e.g.,MYD88, trisomy 12, and del(13q)) or subclonal(e.g., SF3B1 and TP53), corresponding to earlierand later events in CLL evolution. We sampledleukemia cells from 18 patients at two timepoints. Ten of twelve CLL cases treated withchemotherapy (but only one of six withouttreatment) underwent clonal evolution,predominantly involving subclones with drivermutations (e.g., SF3B1 and TP53) that expandedover time. Furthermore, presence of a subclonaldriver mutation was an independent risk factorfor rapid disease progression. Our study thusuncovers patterns of clonal evolution in CLL,", "metadata": {}}
+{"_id": "680949", "title": "", "text": "The transcriptional program of sporulation inbudding yeastDiploid cells of budding yeastproduce haploid cells through the developmentalprogram of sporulation, which consists of meiosisand spore morphogenesis. DNA microarrayscontaining nearly every yeast gene were used toassay changes in gene expression duringsporulation. At least seven distinct temporalpatterns of induction were observed. Thetranscription factor Ndt80 appeared to beimportant for induction of a large group of genesat the end of meiotic prophase. Consensussequences known or proposed to be responsiblefor temporal regulation could be identified solelyfrom analysis of sequences of coordinatelyexpressed genes. The temporal expressionpattern provided clues to potential functions ofhundreds of previously uncharacterized genes,some of which have vertebrate homologs thatmay function during gametogenesis.", "metadata": {}}
+{"_id": "695938", "title": "", "text": "Grass plants bind, retain, uptake, and transportinfectious prions.Prions are the protein-basedinfectious agents responsible for prion diseases.Environmental prion contamination has beenimplicated in disease transmission. Here, weanalyzed the binding and retention of infectiousprion protein (PrP(Sc)) to plants. Smallquantities of PrP(Sc) contained in diluted brainhomogenate or in excretory materials (urine andfeces) can bind to wheat grass roots and leaves.Wild-type hamsters were efficiently infected byingestion of prion-contaminated plants. Theprion-plant interaction occurs with prions fromdiverse origins, including chronic wastingdisease. Furthermore, leaves contaminated byspraying with a prion-containing preparationretained PrP(Sc) for several weeks in the livingplant. Finally, plants can uptake prions fromcontaminated soil and transport them to aerialparts of the plant (stem and leaves). Thesefindings demonstrate that plants can efficientlybind infectious prions and act as carriers of", "metadata": {}}
+{"_id": "696006", "title": "", "text": "Innate lymphoid cells mediate influenza-inducedairway hyper-reactivity independently ofadaptive immunityPatients with asthma, a majorpublic health problem, are at high risk for seriousdisease from influenza virus infection, but thepathogenic mechanisms by which influenza Acauses airway disease and asthma are not fullyknown. We show here in a mouse model thatinfluenza infection acutely induced airwayhyper-reactivity (AHR), a cardinal feature ofasthma, independently of T helper type 2 (TH2)cells and adaptive immunity. Instead, influenzainfection induced AHR through a previouslyunknown pathway that required the interleukin13 (IL-13)–IL-33 axis and cells of the non-T cell,non-B cell innate lymphoid type called 'naturalhelper cells'. Infection with influenza A virus,which activates the NLRP3 inflammasome,resulted in much more production of IL-33 byalveolar macrophages, which in turn activatednatural helper cells producing substantial IL-13.", "metadata": {}}
+{"_id": "704526", "title": "", "text": "The behaviour change wheel: A new method forcharacterising and designing behaviour changeinterventionsBACKGROUND Improving thedesign and implementation of evidence-basedpractice depends on successful behaviour changeinterventions. This requires an appropriatemethod for characterising interventions andlinking them to an analysis of the targetedbehaviour. There exists a plethora of frameworksof behaviour change interventions, but it is notclear how well they serve this purpose. Thispaper evaluates these frameworks, and developsand evaluates a new framework aimed atovercoming their limitations. METHODS Asystematic search of electronic databases andconsultation with behaviour change experts wereused to identify frameworks of behaviour changeinterventions. These were evaluated according tothree criteria: comprehensiveness, coherence,and a clear link to an overarching model ofbehaviour. A new framework was developed tomeet these criteria. The reliability with which it", "metadata": {}}
+{"_id": "708425", "title": "", "text": "Intermittent prophylaxis with oral truvadaprotects macaques from rectal SHIVinfection.HIV continues to spread globally,mainly through sexual contact. Despite advancesin treatment and care, preventing transmissionwith vaccines or microbicides has provendifficult. A promising strategy to avoidtransmission is prophylactic treatment withantiretroviral drugs before exposure to HIV.Clinical trials evaluating the efficacy of dailytreatment with the reverse transcriptaseinhibitors tenofovir disoproxil fumarate (TDF) orTruvada (TDF plus emtricitabine) are under way.We hypothesized that intermittent prophylactictreatment with long-acting antiviral drugs wouldbe as effective as daily dosing in blocking theearliest stages of viral replication and preventingmucosal transmission. We tested this hypothesisby intermittently giving prophylactic Truvada tomacaque monkeys and then exposing themrectally to simian-human immunodeficiency virus(SHIV) once a week for 14 weeks. A simple", "metadata": {}}
+{"_id": "711256", "title": "", "text": "RNA is favourable for analysing EGFR mutationsin malignant pleural effusion of lungcancer.Malignant pleural effusion (MPE) is auseful specimen allowing for the evaluation ofEGFR status in nonsmall cell lung cancer(NSCLC). However, direct sequencing of genomicDNA from MPE samples was found not to besensitive for EGFR mutation detection. To testwhether EGFR analysis from RNA is less prone tointerference from nontumour cells that have noor lower EGFR expression, we compared threemethods (sequencing from cell-derived RNAversus sequencing and mass-spectrometricanalysis from genomic DNA), in parallel, forEGFR mutation detection from MPE samples in150 lung adenocarcinoma patients receivingfirst-line tyrosine kinase inhibitors (TKIs). Amongthese MPE samples, EGFR mutations were muchmore frequently identified by sequencing usingRNA than by sequencing and mass-spectrometricanalysis from genomic DNA (for all mutations,67.3 versus 44.7 and 46.7%; for L858R or exon", "metadata": {}}
+{"_id": "712078", "title": "", "text": "Pharmacological correction of a defect in PPARγsignaling ameliorates disease severity inCftr-deficient miceCystic fibrosis is caused bymutations in the cystic fibrosis transmembraneconductance regulator (encoded by Cftr) thatimpair its role as an apical chloride channel thatsupports bicarbonate transport. Individuals withcystic fibrosis show retained, thickened mucusthat plugs airways and obstructs luminal organsas well as numerous other abnormalities thatinclude inflammation of affected organs,alterations in lipid metabolism and insulinresistance. Here we show that colonic epithelialcells and whole lung tissue from Cftr-deficientmice show a defect in peroxisomeproliferator-activated receptor-gamma(PPAR-gamma, encoded by Pparg) function thatcontributes to a pathological program of geneexpression. Lipidomic analysis of colonicepithelial cells suggests that this defect results inpart from reduced amounts of the endogenousPPAR-gamma ligand 15-keto-prostaglandin E(2)", "metadata": {}}
+{"_id": "712320", "title": "", "text": "Visualization of volatile substances in differentorganelles with an atmospheric-pressure massmicroscope.We have developed a massmicroscope (mass spectrometry imager withspatial resolution higher than the naked eye)equipped with an atmospheric pressureion-source chamber for laserdesorption/ionization (AP-LDI) and a quadrupoleion trap time-of-flight (QIT-TOF) analyzer. Theoptical microscope combined with the massspectrometer permitted us to preciselydetermine the relevant tissue region prior toperforming imaging mass spectrometry (IMS).An ultraviolet laser tightly focused with a tripletlens was used to achieve high spatial resolution.An atmospheric pressure ion-source chamberenables us to analyze fresh samples withminimal loss of intrinsic water or volatilecompounds. Mass-microscopic AP-LDI imaging offreshly cut ginger rhizome sections revealed that6-gingerol ([M + K](+)at m/z 333.15, positivemode; [M - H](-) at m/z 293.17, negative mode)", "metadata": {}}
+{"_id": "718601", "title": "", "text": "Coding of Sweet, Bitter, and Umami TastesDifferent Receptor Cells Sharing Similar SignalingPathwaysMammals can taste a wide repertoire ofchemosensory stimuli. Two unrelated families ofreceptors (T1Rs and T2Rs) mediate responses tosweet, amino acids, and bitter compounds. Here,we demonstrate that knockouts of TRPM5, ataste TRP ion channel, or PLCbeta2, aphospholipase C selectively expressed in tastetissue, abolish sweet, amino acid, and bittertaste reception, but do not impact sour or saltytastes. Therefore, despite relying on differentreceptors, sweet, amino acid, and bittertransduction converge on common signalingmolecules. Using PLCbeta2 taste-blind animals,we then examined a fundamental question intaste perception: how taste modalities areencoded at the cellular level. Mice engineered torescue PLCbeta2 function exclusively inbitter-receptor expressing cells respond normallyto bitter tastants but do not taste sweet or aminoacid stimuli. Thus, bitter is encoded", "metadata": {}}
+{"_id": "719812", "title": "", "text": "Green synthesis of silver nanoparticles andcharacterization of their inhibitory effects onAGEs formation using biophysicaltechniquesAdvanced glycation end-products(AGEs) resulting from non-enzymatic glycationare one of the major factors implicated insecondary complications of diabetes. Scientistsare focusing on discovering new compounds thatmay be used as potential AGEs inhibitors withoutaffecting the normal structure and function ofbiomolecules. A number of natural and syntheticcompounds have been proposed as AGEinhibitors. In this study, we investigated theinhibitory effects of AgNPs (silver nanoparticles)in AGEs formation. AgNPs (~30.5 nm)synthesized from Aloe Vera leaf extract werecharacterized using UV-Vis spectroscopy,energy-dispersive X-ray spectroscopy (EDX),high resolution-transmission electronmicroscopy, X-ray diffraction and dynamic lightscattering (DLS) techniques. The inhibitoryeffects of AgNPs on AGEs formation were", "metadata": {}}
+{"_id": "735130", "title": "", "text": "Myosin Light Chain–activating PhosphorylationSites Are Required for Oogenesis inDrosophilaThe Drosophila spaghetti squash ( sqh) gene encodes the regulatory myosin light chain(RMLC) of nonmuscle myosin II. Biochemicalanalysis of vertebrate nonmuscle and smoothmuscle myosin II has established thatphosphorylation of certain amino acids of theRMLC greatly increases the actin-dependentmyosin ATPase and motor activity of myosin invitro. We have assessed the in vivo importanceof these sites, which in Drosophila correspond toserine-21 and threonine-20, by creating a seriesof transgenes in which these specific amino acidswere altered. The phenotypes of the transgeneswere examined in an otherwise null mutantbackground during oocyte development inDrosophila females. Germ line cystoblastsentirely lacking a functional sqh gene showsevere defects in proliferation and cytokinesis.The ring canals, cytoplasmic bridges linking theoocyte to the nurse cells in the egg chamber, are", "metadata": {}}
+{"_id": "739734", "title": "", "text": "Stages of the pathologic process in Alzheimerdisease: age categories from 1 to 100 years.Twothousand three hundred and thirty twononselected brains from 1- to 100-year-oldindividuals were examined usingimmunocytochemistry (AT8) and Gallyas silverstaining for abnormal tau; immunocytochemistry(4G8) and Campbell-Switzer staining were usedfor the detection ofβ-amyloid. A total of 342cases was negative in the Gallyas stain but whenrestaged for AT8 only 10 were immunonegative.Fifty-eight cases had subcortical taupredominantly in the locus coeruleus, but therewas no abnormal cortical tau (subcortical Stagesa-c). Cortical involvement (abnormal tau inneurites) was identified first in thetransentorhinal region (Stage 1a, 38 cases).Transentorhinal pyramidal cells displayedpretangle material (Stage 1b, 236 cases).Pretangles gradually became argyrophilicneurofibrillary tangles (NFTs) that progressed inparallel with NFT Stages I to VI. Pretangles", "metadata": {}}
+{"_id": "750781", "title": "", "text": "Coronary bypass graft patency in patients withdiabetes in the Bypass AngioplastyRevascularization Investigation(BARI).BACKGROUND Few studies havecompared long-term status of bypass graftsbetween patients with and without diabetes, anduncertainty exists as to whether diabetesindependently predicts poor clinical outcomeafter CABG. METHODS AND RESULTS Among1526 patients in BARI who underwent CABG asinitial revascularization, 99 of 292 (34%) withtreated diabetes mellitus (TDM) (those on insulinor oral hypoglycemic agents) and 469 of 1234(38%) without TDM had follow-up angiography.Angiograms with the longest interval from initialsurgery and before any percutaneous graftintervention (mean 3.9 years) were reviewed. Anaverage of 3.0 grafts were placed at initial CABGfor patients with TDM (n=297; internalmammary artery [IMA], 33%) and 2.9 grafts forpatients without TDM (n=1347; IMA, 34%).Patients with TDM were more likely than those", "metadata": {}}
+{"_id": "751192", "title": "", "text": "A novel ATAC-seq approach revealslineage-specific reinforcement of the openchromatin landscape via cooperation betweenBAF and p63BACKGROUND Open chromatinregions are correlated with active regulatoryelements in development and are dysregulated indiseases. The BAF (SWI/SNF) complex isessential for development, and has beendemonstrated to remodel reconstitutedchromatin in vitro and to control the accessibilityof a few individual regions in vivo. However, itremains unclear where and how BAF controls theopen chromatin landscape to regulatedevelopmental processes, such as humanepidermal differentiation. RESULTS Using a novel\"on-plate\" ATAC-sequencing approach forprofiling open chromatin landscapes with a lownumber of adherent cells, we demonstrate thatthe BAF complex is essential for maintaining 11.6% of open chromatin regions in epidermaldifferentiation. These BAF-dependent openchromatin regions are highly cell-type-specific", "metadata": {}}
+{"_id": "752423", "title": "", "text": "Aging, habitual exercise, and dynamic arterialcompliance.BACKGROUND A reduction incompliance of the large-sized cardiothoracic(central) arteries is an independent risk factor forthe development of cardiovascular disease withadvancing age. METHODS AND RESULTS Wedetermined the role of habitual exercise on theage-related decrease in central arterialcompliance by using both cross-sectional andinterventional approaches. First, we studied 151healthy men aged 18 to 77 years: 54 weresedentary, 45 were recreationally active, and 53were endurance exercise-trained. Central arterialcompliance (simultaneous B-mode ultrasoundand arterial applanation tonometry on thecommon carotid artery) was lower (P:<0.05) inmiddle-aged and older men than in young men inall 3 groups. There were no significantdifferences between sedentary and recreationallyactive men at any age. However, arterialcompliance in the endurance-trainedmiddle-aged and older men was 20% to 35%", "metadata": {}}
+{"_id": "756887", "title": "", "text": "A comparison of cancer screening practices incancer survivors and in the general population:the Korean national health and nutritionexamination survey (KNHANES) 2001–2007Thisstudy aimed to describe cancer screening ratesfor second primary cancer among cancersurvivors in Korea, and to compare these rateswith those of two control groups: individualswithout a history of cancer but with other chronicdiseases, and individuals without a history ofcancer and without other chronic diseases. Thestudy is a cross-sectional analysis of 15,556adults ≥30 years old who participated in the2001, 2005, and 2007 Korean National Healthand Nutrition Examination Surveys (KNHANES).The prevalence of breast, cervical, gastric, andcolorectal cancer screening examinationsaccording to national guidelines was assessedand compared to two control groups. Screeningrates among cancer survivors were 48.5, 54.7,34.7, and 28.6% for breast, cervical, gastric, andcolorectal cancer screening, respectively. Cancer", "metadata": {}}
+{"_id": "778436", "title": "", "text": "Negative effect of the transcriptional activatorGAL4The yeast transcriptional activator GAL4binds specific sites on DNA to activatetranscription of adjacent genes1–5. The distinctactivating regions of GAL4 are rich in acidicresidues and it has been suggested that theseregions interact with another protein componentof the transcriptional machinery (such as theTATA-binding protein or RNA polymerase II)while the DNA-binding region serves to positionthe activating region near the gene6,7,8. Herewe show that various GAL4 derivatives, whenexpressed at high levels in yeast, inhibittranscription of certain genes lacking GAL4binding sites, that more efficient activatorsinhibit more strongly and that inhibition does notdepend on the DNA-binding domain. We suggestthat this inhibition, which we call squelching,reflects titration of a transcription factor by theactivating region of GAL4.", "metadata": {}}
+{"_id": "790598", "title": "", "text": "The Bayh–Dole Act and university research anddevelopmentThis paper examines therelationship between university research anddevelopment (R&D) activities and the Bayh-DoleAct. This act made it much easier for universitiesto obtain patents from research funded by thefederal government and may have provideduniversities with an incentive to alter their R&Dactivities. The Act may provide an incentive toreduce basic research (which does not generatelicensing fees) and increase applied research(which does generate patents and licensingfees). In addition, industry might be more willingto fund university R&D projects since the resultswould now be easier to patent. This paper differsfrom the existing literature which uses patentdata (a measure of research output) by usingresearch and development data (a measure ofinventive input) to examine the effect of the Act.", "metadata": {}}
+{"_id": "791050", "title": "", "text": "The relation between past exposure to fineparticulate air pollution and prevalent anxiety:observational cohort studyOBJECTIVE Todetermine whether higher past exposure toparticulate air pollution is associated withprevalent high symptoms of anxiety. DESIGNObservational cohort study. SETTING Nurses'Health Study. PARTICIPANTS 71,271 womenenrolled in the Nurses' Health Study residingthroughout the contiguous United States whohad valid estimates on exposure to particulatematter for at least one exposure period ofinterest and data on anxiety symptoms. MAINOUTCOME MEASURES Meaningfully highsymptoms of anxiety, defined as a score of 6points or greater on the phobic anxiety subscaleof the Crown-Crisp index, administered in 2004.RESULTS The 71,271 eligible women were agedbetween 57 and 85 years (mean 70 years) at thetime of assessment of anxiety symptoms, with aprevalence of high anxiety symptoms of 15%.Exposure to particulate matter was characterized", "metadata": {}}
+{"_id": "797114", "title": "", "text": "A mitochondrially targeted compound delaysaging in yeast through a mechanism linkingmitochondrial membrane lipid metabolism tomitochondrial redox biology\u0000A recent studyrevealed a mechanism of delaying aging in yeastby a natural compound which specifically impactsmitochondrial redox processes. In thismechanism, exogenously added lithocholic bileacid enters yeast cells, accumulates mainly inthe inner mitochondrial membrane, and elicits anage-related remodeling of phospholipid synthesisand movement within both mitochondrialmembranes. Such remodeling of mitochondrialphospholipid dynamics progresses with thechronological age of a yeast cell and ultimatelycauses significant changes in mitochondrialmembrane lipidome. These changes in thecomposition of membrane phospholipids altermitochondrial abundance and morphology,thereby triggering changes in the age-relatedchronology of such longevity-defining redoxprocesses as mitochondrial respiration, the", "metadata": {}}
+{"_id": "798152", "title": "", "text": "Isolation from African Sykes' monkeys(Cercopithecus mitis) of a lentivirus related tohuman and simian immunodeficiencyviruses.Analysis of serum samples from 100wild-caught or colony-born Sykes' monkeys(Cercopithecus mitis) in Kenya revealed that 59animals had antibodies cross-reactive to humanimmunodeficiency virus type 2 (HIV-2) and tosimian immunodeficiency viruses (SIVs). Alentivirus, designated SIVsyk, was isolated fromfive of six seropositive asymptomatic Sykes'monkeys, but in four cases isolation was possibleonly after depletion of CD8+ lymphocytes andcocultivation of the CD4(+)-enriched cellpopulation with peripheral blood mononuclearcells from seronegative Sykes' monkeys. SIVsykresembled other SIVs and HIVs morphologically,had an Mg2(+)-dependent reverse transcriptaseenzyme, and replicated in and was cytopathic forCEMx174 and Sup-T1 cells. SIVsyk differredsubstantially from other SIVs, however, in that itfailed to replicate in normal human, mangabey,", "metadata": {}}
+{"_id": "799586", "title": "", "text": "Role of the Single-Stranded DNA–Binding ProteinSsbB in Pneumococcal Transformation:Maintenance of a Reservoir for GeneticPlasticityBacteria encode a single-stranded DNA(ssDNA) binding protein (SSB) crucial forgenome maintenance. In Bacillus subtilis andStreptococcus pneumoniae, an alternative SSB,SsbB, is expressed uniquely during competencefor genetic transformation, but its precise rolehas been disappointingly obscure. Here, wereport our investigations involving comparison ofa null mutant (ssbB(-)) and a C-ter truncation(ssbBΔ7) of SsbB of S. pneumoniae, the latterconstructed because SSBs' acidic tail hasemerged as a key site for interactions withpartner proteins. We provide evidence that SsbBdirectly protects internalized ssDNA. We showthat SsbB is highly abundant, potentially allowingthe binding of ~1.15 Mb ssDNA (half a genomeequivalent); that it participates in the processingof ssDNA into recombinants; and that, at highDNA concentration, it is of crucial importance for", "metadata": {}}
+{"_id": "803312", "title": "", "text": "Cerebral organoids model human braindevelopment and microcephalyThe complexity ofthe human brain has made it difficult to studymany brain disorders in model organisms,highlighting the need for an in vitro model ofhuman brain development. Here we havedeveloped a human pluripotent stem cell-derivedthree-dimensional organoid culture system,termed cerebral organoids, that develop variousdiscrete, although interdependent, brain regions.These include a cerebral cortex containingprogenitor populations that organize and producemature cortical neuron subtypes. Furthermore,cerebral organoids are shown to recapitulatefeatures of human cortical development, namelycharacteristic progenitor zone organization withabundant outer radial glial stem cells. Finally, weuse RNA interference and patient-specificinduced pluripotent stem cells to modelmicrocephaly, a disorder that has been difficultto recapitulate in mice. We demonstratepremature neuronal differentiation in patient", "metadata": {}}
+{"_id": "810480", "title": "", "text": "Localization of a gene for partial epilepsy tochromosome 10qThere is strong evidence for agenetic contribution to epilepsy, but it iscommonly assumed that this genetic contributionis limited to ‘generalized’ epilepsies, and thatmost forms of ‘partial’ epilepsy are nongenetic.In a linkage analysis of a single family containing11 affected individuals, we obtained strongevidence for localization of a gene for partialepilepsy. This susceptibility gene maps tochromosome 10q, with a maximum two–pointlod score for D10S192 of 3.99 at θ=0.0. Allaffected individuals share a single haplotype forseven tightly linked contiguous markers; themaximum lod score for this haplotype is 4.83 atθ=0.0. Key recombinants place the susceptibilitylocus within a 10 centimorgan interval.", "metadata": {}}
+{"_id": "825728", "title": "", "text": "Metastatic colonization requires the repression ofthe epithelial-mesenchymal transition inducerPrrx1.The epithelial-mesenchymal transition(EMT) is required in the embryo for the formationof tissues for which cells originate far from theirfinal destination. Carcinoma cells hijack thisprogram for tumor dissemination. The relevanceof the EMT in cancer is still debated because it isunclear how these migratory cells colonizedistant tissues to form macrometastases. Weshow that the homeobox factor Prrx1 is an EMTinducer conferring migratory and invasiveproperties. The loss of Prrx1 is required forcancer cells to metastasize in vivo, which revertto the epithelial phenotype concomitant with theacquisition of stem cell properties. Thus, unlikethe classical EMT transcription factors, Prrx1uncouples EMT and stemness, and is a biomarkerassociated with patient survival and lack ofmetastasis.", "metadata": {}}
+{"_id": "829646", "title": "", "text": "A cohort study of the risk of cervicalintraepithelial neoplasia grade 2 or 3 in relationto papillomavirus infection.BACKGROUND Humanpapillomavirus (HPV) has been associated withcervical intraepithelial neoplasia, but thetemporal relation between the infection and theneoplasia remains unclear, as does the relativeimportance of the specific type of HPV, othersexually transmitted diseases, and other riskfactors. METHODS We studied prospectively acohort of 241 women who presented forevaluation of sexually transmitted disease andhad negative cervical cytologic tests. The womenwere followed every four months with cytologicand colposcopic examinations of the uterinecervix and tests for HPV DNA and other sexuallytransmitted diseases. RESULTS Cervicalintraepithelial neoplasia grade 2 or 3 wasconfirmed by biopsy in 28 women. On the basisof survival analysis, the cumulative incidence ofcervical intraepithelial neoplasia at two yearswas 28 percent among women with a positive", "metadata": {}}
+{"_id": "831167", "title": "", "text": "Investigating survival prognosis of glioblastomausing evolutional properties of gene networksInrecent years, there has been widespread interestand a large number of publications on theapplication of graph theory techniques intoconstructing and analyzing biologically-informedgene networks from cancer cell line data sets.Current research efforts have predominantlylooked at an overall static, topological,representation of the network, and have notinvestigated the application of graph theoreticaltechniques to evolutionary investigations ofcancer. A number of these studies have usedgraph theory metrics, such as degree,betweenness, and closeness centrality, toidentify important hub genes in these networks.However, these have not fully investigated theimportance of genes across the different stagesof the disease. Previous human glioblastomapublications have identified four subtypes ofglioblastoma in adults, based on signaturegenes. In one such publication, Verhaak et al.", "metadata": {}}
+{"_id": "834336", "title": "", "text": "Compound heterozygous ZMPSTE24 mutationsreduce prelamin A processing and result in asevere progeroid phenotype.Hutchinson–Gilfordprogeria syndrome (HGPS; OMIM 176670) is anextremely rare but devastating disorder thatmimics premature aging.1–3 Affected childrenappear normal at birth but typically developfailure to thrive in the first two years. Otherfeatures include alopecia, micrognathia, loss ofsubcutaneous fat with prominent veins,abnormal dentition, sclerodermatous skinchanges, and osteolysis of the clavicles anddistal phalanges. The mean age of death is atage 13 years, most commonly due toatherosclerosis. HGPS is mainly sporadic inoccurrence, but a genetic cause has now beenimplicated following the identification of de novoheterozygous mutations in the LMNA gene in themajority of HGPS patients.4,5 A single familyshowing autosomal recessive inheritance ofhomozygous LMNA mutations has also beenreported.6  LMNA encodes lamins A and C,", "metadata": {}}
+{"_id": "841371", "title": "", "text": "Reliability of patient responses in pay forperformance schemes: analysis of nationalGeneral Practitioner Patient Survey data inEnglandOBJECTIVE To assess the robustness ofpatient responses to a new national survey ofpatient experience as a basis for providingfinancial incentives to doctors. DESIGN Analysisof the representativeness of the respondents tothe GP Patient Survey compared with those whowere sampled (5.5 million patients registeredwith 8273 general practices in England inJanuary 2009) and with the general population.Analysis of non-response bias looked at therelation between practice response rates andscores on the survey. Analysis of the reliability ofthe survey estimated the proportion of thevariance of practice scores attributable to truedifferences between practices. RESULTS Theoverall response rate was 38.2% (2.2 millionresponses), which is comparable to that insurveys using similar methodology in the UK.Men, young adults, and people living in deprived", "metadata": {}}
+{"_id": "849771", "title": "", "text": "Impact of low alcohol verbal descriptors onperceived strength: An experimentalstudyOBJECTIVES Low alcohol labels are a set oflabels that carry descriptors such as 'low' or'lighter' to denote alcohol content in beverages.There is growing interest from policymakers andproducers in lower strength alcohol products.However, there is a lack of evidence on how thegeneral population perceives verbal descriptorsof strength. The present research examinesconsumers' perceptions of strength (% ABV) andappeal of alcohol products using low or highalcohol verbal descriptors. DESIGN Awithin-subjects experimental study in whichparticipants rated the strength and appeal of 18terms denoting low (nine terms), high (eightterms) and regular (one term) strengths foreither (1) wine or (2) beer according to drinkingpreference. METHODS Thousand six hundredadults (796 wine and 804 beer drinkers) sampledfrom a nationally representative UK panel.RESULTS Low, Lower, Light, Lighter, and", "metadata": {}}
+{"_id": "854417", "title": "", "text": "Transgenic Interleukin 10 Prevents Induction ofExperimental Autoimmune EncephalomyelitisTheeffectiveness of interleukin 10 (IL-10) in thetreatment of autoimmune-mediated centralnervous system inflammation is controversial.Studies of the model system, experimentalautoimmune encephalomyelitis (EAE), usingvarious routes, regimens, and delivery methodsof IL-10 suggest that these variables may affectits immunoregulatory function. To study theinfluence of these factors on IL-10 regulation ofEAE pathogenesis, we have analyzed transgenicmice expressing human IL-10 (hIL-10) transgeneunder the control of a class II majorhistocompatibility complex (MHC) promoter. ThehIL-10 transgenic mice are highly resistant toEAE induced by active immunization, and thisresistance appears to be mediated bysuppression of autoreactive T cell function.Myelin-reactive T helper 1 cells are induced butnonpathogenic in the IL-10 transgenic mice.Antibody depletion confirmed that EAE resistance", "metadata": {}}
+{"_id": "857189", "title": "", "text": "Autosomal dominant immune dysregulationsyndrome in humans with CTLA4 mutationsTheprotein cytotoxic T lymphocyte antigen-4(CTLA-4) is an essential negative regulator ofimmune responses, and its loss causes fatalautoimmunity in mice. We studied a large familyin which five individuals presented with acomplex, autosomal dominant immunedysregulation syndrome characterized byhypogammaglobulinemia, recurrent infectionsand multiple autoimmune clinical features. Weidentified a heterozygous nonsense mutation inexon 1 of CTLA4. Screening of 71 unrelatedpatients with comparable clinical phenotypesidentified five additional families (nineindividuals) with previously undescribed splicesite and missense mutations in CTLA4. Clinicalpenetrance was incomplete (eight adults of atotal of 19 genetically proven CTLA4 mutationcarriers were considered unaffected). However,CTLA-4 protein expression was decreased inregulatory T cells (Treg cells) in both patients", "metadata": {}}
+{"_id": "864491", "title": "", "text": "Specific inhibition of cyclin-dependent kinase 4/6by PD 0332991 and associated antitumor activityin human tumor xenografts.PD 0332991 is ahighly specific inhibitor of cyclin-dependentkinase 4 (Cdk4) (IC50, 0.011 micromol/L) andCdk6 (IC50, 0.016 micromol/L), having noactivity against a panel of 36 additional proteinkinases. It is a potent antiproliferative agentagainst retinoblastoma (Rb)-positive tumor cellsin vitro, inducing an exclusive G1 arrest, with aconcomitant reduction ofphospho-Ser780/Ser795 on the Rb protein. Oraladministration of PD 0332991 to mice bearingthe Colo-205 human colon carcinoma producesmarked tumor regression. Therapeutic doses ofPD 0332991 cause elimination of phospho-Rband the proliferative marker Ki-67 in tumortissue and down-regulation of genes under thetranscriptional control of E2F. The resultsindicate that inhibition of Cdk4/6 alone issufficient to cause tumor regression and a netreduction in tumor burden in some tumors.", "metadata": {}}
+{"_id": "878526", "title": "", "text": "Neutrophils support lung colonization ofmetastasis-initiating breast cancer cellsDespiteprogress in the development of drugs thatefficiently target cancer cells, treatments formetastatic tumours are often ineffective. Thenow well-established dependency of cancer cellson their microenvironment suggests thattargeting the non-cancer-cell component of thetumour might form a basis for the developmentof novel therapeutic approaches. However, theas-yet poorly characterized contribution of hostresponses during tumour growth and metastaticprogression represents a limitation to exploitingthis approach. Here we identify neutrophils asthe main component and driver of metastaticestablishment within the (pre-)metastatic lungmicroenvironment in mouse breast cancermodels. Neutrophils have a fundamental role ininflammatory responses and their contribution totumorigenesis is still controversial. Using variousstrategies to block neutrophil recruitment to thepre-metastatic site, we demonstrate that", "metadata": {}}
+{"_id": "881332", "title": "", "text": "Effect of Previous Miscarriage on DepressiveSymptoms During Subsequent Pregnancy andPostpartum in the First Baby StudyOur objectivewas to test the hypothesis that nulliparouswomen with a history of miscarriage have anincreased risk of depression during latepregnancy, and at 1, 6, and 12 monthspostpartum compared to women without ahistory of miscarriage. We conducted secondaryanalysis of a longitudinal cohort study, the FirstBaby Study, and compared 448 pregnant womenwith a history of miscarriage to 2,343 pregnantwomen without a history of miscarriage on riskof probable depression (score >12 on theEdinburgh Postnatal Depression Scale). Logisticregression models were used to estimate oddsratios at each time point and generalizedestimating equations were used to obtainestimates in longitudinal analysis. Women with ahistory of miscarriage were not more likely thanwoman without a history of miscarriage to scorein the probable depression range during the third", "metadata": {}}
+{"_id": "883747", "title": "", "text": "IL-1β, IL-4 and IL-12 control the fate of group 2innate lymphoid cells in human airwayinflammation in the lungsGroup 2 innatelymphoid cells (ILC2s) secrete type 2 cytokines,which protect against parasites but can alsocontribute to a variety of inflammatory airwaydiseases. We report here that interleukin 1β(IL-1β) directly activated human ILC2s and thatIL-12 induced the conversion of these activatedILC2s into interferon-γ (IFN-γ)-producing ILC1s,which was reversed by IL-4. The plasticity ofILCs was manifested in diseased tissues ofpatients with severe chronic obstructivepulmonary disease (COPD) or chronicrhinosinusitis with nasal polyps (CRSwNP), whichdisplayed IL-12 or IL-4 signatures and theaccumulation of ILC1s or ILC2s, respectively.Eosinophils were a major cellular source of IL-4,which revealed cross-talk betweenIL-5-producing ILC2s and IL-4-producingeosinophils. We propose that IL-12 and IL-4govern ILC2 functional identity and that their", "metadata": {}}
+{"_id": "885056", "title": "", "text": "SummarySteroid receptor RNA activator (SRA),the only known RNA coactivator, augmentstransactivation by nuclear receptors (NRs). Weidentified SLIRP (SRA stem-loop interacting RNAbinding protein) binding to a functionalsubstructure of SRA, STR7. SLIRP is expressed innormal and tumor tissues, contains an RNArecognition motif (RRM), represses NRtransactivation in a SRA- and RRM-dependentmanner, augments the effect of Tamoxifen, andmodulates association of SRC-1 with SRA.SHARP, a RRM-containing corepressor, also bindsSTR7, augmenting repression with SLIRP. SLIRPcolocalizes with SKIP (Chr14q24.3), another NRcoregulator, and reduces SKIP-potentiated NRsignaling. SLIRP is recruited to endogenouspromoters (pS2 and metallothionein), the latterin a SRA-dependent manner, while NCoRpromoter recruitment is dependent on SLIRP.The majority of the endogenous SLIRP resides inthe mitochondria. Our data demonstrate thatSLIRP modulates NR transactivation, suggest it", "metadata": {}}
+{"_id": "888896", "title": "", "text": "Naringenin inhibits allergen-induced airwayinflammation and airway responsiveness andinhibits NF-kappaB activity in a murine model ofasthma.Naringenin, a flavonoid, hasantiinflammatory and immunomodulatoryproperties. We investigated whether naringenincould attenuate allergen-induced airwayinflammation and its possible mechanism in amurine model of asthma. Mice were sensitizedand challenged with ovalbumin. Some mice wereadministered with naringenin before ovalbuminchallenge. We evaluated the development ofairway inflammation and airway reactivity.Interleukin (IL)4, IL13, chemokine (C-C motif)ligand (CCL)5, and CCL11 in bronchoalveolarlavage fluid and serum total IgE were detectedby ELISA. IkappaBalpha degradation andinducible nitric oxide synthase (iNOS) in lungswere measured by Western blot. We also testedNF-kappaB binding activity by electrophoreticmobility shift assay. The mRNA levels of iNOS,CCL5, and CCL11 were detected by real-time", "metadata": {}}
+{"_id": "919007", "title": "", "text": "The evolution of Fox genes and their role indevelopment and diseaseThe forkhead box (Fox)family of transcription factors, which originatedin unicellular eukaryotes, has expanded overtime through multiple duplication events, andsometimes through gene loss, to over 40members in mammals. Fox genes have evolvedto acquire a specialized function in many keybiological processes. Mutations in Fox geneshave a profound effect on human disease,causing phenotypes as varied as cancer,glaucoma and language disorders. Wesummarize the salient features of the evolutionof the Fox gene family and highlight the diversecontribution of various Fox subfamilies todevelopmental processes, from organogenesis tospeech acquisition.", "metadata": {}}
+{"_id": "927561", "title": "", "text": "Emergent structures and dynamics of cellcolonies by contact inhibition of locomotionCellsin tissues can organize into a broad spectrum ofstructures according to their function. Drasticchanges of organization, such asepithelial-mesenchymal transitions or theformation of spheroidal aggregates, are oftenassociated either to tissue morphogenesis or tocancer progression. Here, we study theorganization of cell colonies by means ofsimulations of self-propelled particles withgeneric cell-like interactions. The interplaybetween cell softness, cell-cell adhesion, andcontact inhibition of locomotion (CIL) yieldsstructures and collective dynamics observed inseveral existing tissue phenotypes. These includeregular distributions of cells, dynamic cellclusters, gel-like networks, collectively migratingmonolayers, and 3D aggregates. We giveanalytical predictions for transitions betweennoncohesive, cohesive, and 3D cellarrangements. We explicitly show how CIL yields", "metadata": {}}
+{"_id": "928281", "title": "", "text": "Failure of cell cleavage induces senescence intetraploid primary cellsTetraploidy can arise fromvarious mitotic or cleavage defects inmammalian cells, and inheritance of multiplecentrosomes induces aneuploidy when tetraploidcells continue to cycle. Arrest of the tetraploidcell cycle is therefore potentially a critical cellularcontrol. We report here that primary rat embryofibroblasts (REF52) and human foreskinfibroblasts become senescent in tetraploid G1after drug- or small interfering RNA(siRNA)-induced failure of cell cleavage. Incontrast, T-antigen-transformed REF52 andp53+/+ HCT116 tumor cells rapidly becomeaneuploid by continuing to cycle after cleavagefailure. Tetraploid primary cells quickly becomequiescent, as determined by loss of the Ki-67proliferation marker and of the fluorescentubiquitination-based cell cycle indicator/late cellcycle marker geminin. Arrest is not due to DNAdamage, as the γ-H2AX DNA damage markerremains at control levels after tetraploidy", "metadata": {}}
+{"_id": "935034", "title": "", "text": "Cell death: the significance ofapoptosis.Publisher Summary The classificationof cell death can be based on morphological orbiochemical criteria or on the circumstances ofits occurrence. Currently, irreversible structuralalteration provides the only unequivocal evidenceof death; biochemical indicators of cell death thatare universally applicable have to be preciselydefined and studies of cell function or ofreproductive capacity do not necessarilydifferentiate between death and dormant statesfrom which recovery may be possible. It has alsoproved feasible to categorize most if not all dyingcells into one or the other of two discrete anddistinctive patterns of morphological change,which have, generally, been found to occurunder disparate but individually characteristiccircumstances. One of these patterns is theswelling proceeding to rupture of plasma andorganelle membranes and dissolution oforganized structure—termed “coagulativenecrosis. ” It results from injury by agents, such", "metadata": {}}
+{"_id": "935538", "title": "", "text": "The mitochondrial RNA-binding protein GRSF1localizes to RNA granules and is required forposttranscriptional mitochondrial geneexpression.RNA-binding proteins are at the heartof posttranscriptional gene regulation,coordinating the processing, storage, andhandling of cellular RNAs. We show here thatGRSF1, previously implicated in the binding andselective translation of influenza mRNAs, istargeted to mitochondria where it forms granulesthat colocalize with foci of newly synthesizedmtRNA next to mitochondrial nucleoids. GRSF1preferentially binds RNAs transcribed from threecontiguous genes on the light strand of mtDNA,the ND6 mRNA, and the long noncoding RNAs forcytb and ND5, each of which contains multipleconsensus binding sequences. RNAi-mediatedknockdown of GRSF1 leads to alterations inmitochondrial RNA stability, abnormal loading ofmRNAs and lncRNAs on the mitochondrialribosome, and impaired ribosome assembly. Thisresults in a specific protein synthesis defect and", "metadata": {}}
+{"_id": "946756", "title": "", "text": "Identification and purification of a 62,000-daltonprotein that binds specifically to thepolypyrimidine tract of introns.A protein ofmolecular size 62,000 daltons (p62) wasdetected in HeLa cell nuclear extracts by UVcross-linking to mRNA precursors. p62 bindsspecifically to the polypyrimidine tract of the 3'splice site region of introns. p62 purified tohomogeneity binds the polypyrimidine tract ofpre-mRNAs. This binding does not require the AGdinucleotide at the 3' splice site. Alterations inthe polypyrimidine tract that reduce the bindingof p62 yield a corresponding reduction in theefficiency of formation of a U2 snRNP/pre-mRNAcomplex and splicing. The p62 protein is retainedin the spliceosome, where it remains bound tothe pre-mRNA. This polypyrimidine tract bindingprotein (pPTB) is proposed to be a criticalcomponent in recognition of the 3' splice siteduring splicing.", "metadata": {}}
+{"_id": "947631", "title": "", "text": "Capsule endoscopy in acute uppergastrointestinal hemorrhage: a prospectivecohort study.BACKGROUND AND STUDY AIMSCapsule endoscopy may play a role in theevaluation of patients presenting with acuteupper gastrointestinal hemorrhage in theemergency department. PATIENTS ANDMETHODS We evaluated adults with acute uppergastrointestinal hemorrhage presenting to theemergency departments of two academiccenters. Patients ingested a wireless videocapsule, which was followed immediately by anasogastric tube aspiration and later byesophagogastroduodenoscopy (EGD). Wecompared capsule endoscopy with nasogastrictube aspiration for determination of the presenceof blood, and with EGD for discrimination of thesource of bleeding, identification ofpeptic/inflammatory lesions, safety, and patientsatisfaction. RESULTS The study enrolled 49patients (32 men, 17 women; mean age 58.3 ±19 years), but three patients did not complete", "metadata": {}}
+{"_id": "949309", "title": "", "text": "Electroporation of Cas9 protein/sgRNA into earlypronuclear zygotes generates non-mosaicmutants in the mouse.The CRISPR/Cas9 systemis a powerful tool for elucidating the roles ofgenes in a wide variety of organisms includingmice. To obtain genetically modified embryos ormice by this method, Cas9 mRNA and sgRNA areusually introduced into zygotes by microinjectionor electroporation. However, most mutantsgenerated with this method are geneticallymosaic, composed of several types of cellscarrying different mutations, which complicatesphenotype analysis in founder embryos or mice.To simplify the analysis and to elucidate the rolesof genes involved in developmental processes, amethod for producing non-mosaic mutants isneeded. Here, we established a method forgenerating non-mosaic mouse mutant embryos.We introduced Cas9 protein and sgRNA into invitro fertilized (IVF) zygotes by electroporation,which enabled the genome editing to occurbefore the first replication of the mouse genome.", "metadata": {}}
+{"_id": "950306", "title": "", "text": "Molecular Basis for Target RNA Recognition andCleavage by Human RISCThe RNA-InducedSilencing Complex (RISC) is a ribonucleoproteinparticle composed of a single-stranded shortinterfering RNA (siRNA) and anendonucleolytically active Argonaute protein,capable of cleaving mRNAs complementary tothe siRNA. The mechanism by which RISCcleaves a target RNA is well understood, howeverit remains enigmatic how RISC finds its targetRNA. Here, we show, both in vitro and in vivo,that the accessibility of the target site correlatesdirectly with the efficiency of cleavage,demonstrating that RISC is unable to unfoldstructured RNA. In the course of targetrecognition, RISC transiently contactssingle-stranded RNA nonspecifically andpromotes siRNA-target RNA annealing.Furthermore, the 5' part of the siRNA withinRISC creates a thermodynamic threshold thatdetermines the stable association of RISC andthe target RNA. We therefore provide", "metadata": {}}
+{"_id": "952111", "title": "", "text": "Cancer associated fibroblasts (CAFs) in tumormicroenvironment.Cancer associated fibroblasts(CAFs) is one of the most crucial components ofthe tumor microenvironment which promotes thegrowth and invasion of cancer cells by variousmechanisms. CAFs demonstrate a high degree ofheterogeneity due to their various origins;however, many distinct morphological featuresand physiological functions of CAFs have beenidentified. It is becoming clear that the crosstalkbetween the cancer cells and the CAFs plays akey role in the progression of cancer, andunderstanding this mutual relationship wouldeventually enable us to treat cancer patients bytargeting CAFs. In this review, we will discussthe latest findings on the role of CAFs intumorigenesis and metastasis as well aspotential therapeutic implication of CAFs.", "metadata": {}}
+{"_id": "970012", "title": "", "text": "Cold Exposure Promotes Atherosclerotic PlaqueGrowth and Instability via UCP1-DependentLipolysisMolecular mechanisms underlying thecold-associated high cardiovascular risk remainunknown. Here, we show that the cold-triggeredfood-intake-independent lipolysis significantlyincreased plasma levels of small low-densitylipoprotein (LDL) remnants, leading toaccelerated development of atheroscleroticlesions in mice. In two genetic mouse knockoutmodels (apolipoprotein E(-/-) [ApoE(-/-)] andLDL receptor(-/-) [Ldlr(-/-)] mice), persistentcold exposure stimulated atherosclerotic plaquegrowth by increasing lipid deposition.Furthermore, marked increase of inflammatorycells and plaque-associated microvessels weredetected in the cold-acclimated ApoE(-/-) andLdlr(-/-) mice, leading to plaque instability.Deletion of uncoupling protein 1 (UCP1), a keymitochondrial protein involved in thermogenesisin brown adipose tissue (BAT), in the ApoE(-/-)strain completely protected mice from the", "metadata": {}}
+{"_id": "980008", "title": "", "text": "Mild overexpression of MeCP2 causes aprogressive neurological disorder inmice.Mutations in the X-linkedmethyl-CpG-binding protein 2 (MECP2), encodinga transcriptional repressor, cause Rett syndromeand a variety of related neurodevelopmentaldisorders. The vast majority of mutationsassociated with human disease areloss-of-function mutations, but precisely whataspect of MeCP2 function is responsible for thesephenotypes remains unknown. Weoverexpressed wild-type human protein intransgenic mice using a large genomic clonecontaining the entire human MECP2 locus.Detailed neurobehavioral andelectrophysiological studies in transgenic lineMeCP2(Tg1), which expresses MeCP2 atapproximately 2-fold wild-type levels,demonstrated onset of phenotypes around 10weeks of age. Surprisingly, these mice displayedenhanced motor and contextual learning andenhanced synaptic plasticity in the hippocampus.", "metadata": {}}
+{"_id": "980196", "title": "", "text": "Alcohol Sales and Risk of SeriousAssaultBACKGROUND Alcohol is a contributingcause of unintentional injuries, such as motorvehicle crashes. Prior research on the associationbetween alcohol use and violent injury waslimited to survey-based data, and the inclusionof cases from a single trauma centre, withoutadequate controls. Beyond these limitations wasthe inability of prior researchers tocomprehensively capture most alcohol sales. InOntario, most alcohol is sold through retailoutlets run by the provincial government, andhospitals are financed under a provincial healthcare system. We assessed the risk of beinghospitalized due to assault in association withretail alcohol sales across Ontario. METHODSAND FINDINGS We performed apopulation-based case-crossover analysis of allpersons aged 13 years and older hospitalized forassault in Ontario from 1 April 2002 to 1December 2004. On the day prior to each assaultcase's hospitalization, the volume of alcohol sold", "metadata": {}}
+{"_id": "982650", "title": "", "text": "miR-375 inhibits autophagy and reduces viabilityof hepatocellular carcinoma cells under hypoxicconditions.BACKGROUND & AIMS Tumor cellssurvive hypoxic conditions by inducingautophagy. We investigated the roles ofmicroRNAs (miRNAs) in regulating autophagy ofhepatocellular carcinoma (HCC) cells underhypoxic conditions. METHODS We used gain- andloss-of-function methods to evaluate the effect ofmiRNAs on autophagy in human HCC cell lines(Huh7 and Hep3B) under hypoxic conditions.Autophagy was quantified by immunoblot,immunofluoresence, and transmission electronmicroscopy analyses, and after incubation ofcells with bafilomycin A1. We used a luciferasereporter assay to confirm associations betweenmiRNAs and their targets. We analyzed growth ofHCC xenograft tumors in nude mice. RESULTSmiR-375 was down-regulated in HCC cells andtissues; it inhibited autophagy under hypoxicconditions by suppressing the conversion of LC3Ito LC3II and thereby autophagic flux. The ability", "metadata": {}}
+{"_id": "984825", "title": "", "text": "Pseudouridine profiling reveals regulated mRNApseudouridylation in yeast and humancellsPost-transcriptional modification of RNAnucleosides occurs in all living organisms.Pseudouridine, the most abundant modifiednucleoside in non-coding RNAs, enhances thefunction of transfer RNA and ribosomal RNA bystabilizing the RNA structure. Messenger RNAswere not known to contain pseudouridine, butartificial pseudouridylation dramatically affectsmRNA function--it changes the genetic code byfacilitating non-canonical base pairing in theribosome decoding centre. However, withoutevidence of naturally occurring mRNApseudouridylation, its physiological relevancewas unclear. Here we present a comprehensiveanalysis of pseudouridylation in Saccharomycescerevisiae and human RNAs using Pseudo-seq, agenome-wide, single-nucleotide-resolutionmethod for pseudouridine identification.Pseudo-seq accurately identifies knownmodification sites as well as many novel sites in", "metadata": {}}
+{"_id": "991137", "title": "", "text": "The descent of memory T-cell subsetsTheimmune system has evolved by continuouslyincreasing its complexity to provide the host withan advantage over infectious agents. Thedevelopment of immunological memoryengenders long-lasting protection and lengthensthe lifespan of the host. The generation ofsubsets of memory T cells with distinct homingand functional properties increases our defensivecapabilities. However, the developmentalrelationship of memory T-cell subsets is a matterof debate. In this Opinion article, in light ofrecent developments, we suggest that it isprobable that two distinct lineages comprise thememory CD8+ T-cell population generated inresponse to infection.", "metadata": {}}
+{"_id": "991139", "title": "", "text": "Differential distribution of IL28B.rs12979860single-nucleotide polymorphism among Egyptianhealthcare workers with and without a hepatitisC virus-specific cellular immune responseThe CCgenotype of the interleukin (IL)-28B.rs12979860gene has been associated with spontaneoushepatitis C virus (HCV) clearance and treatmentresponse. The distribution and correlation of anIL28B.rs12979860 single-nucleotidepolymorphism (SNP) with HCV-specificcell-mediated immune (CMI) responses amongEgyptian healthcare workers (HCWs) is notknown. We determined this relationship in 402HCWs who serve a patient cohort with ~85 %HCV prevalence. We enrolled 402 HCWs in fourgroups: group 1 (n = 258), seronegativeaviremic subjects; group 2 (n = 25),seronegative viremic subjects; group 3 (n = 41),subjects with spontaneously resolved HCVinfection; and group 4 (n = 78), chronic HCVpatients. All subjects were tested for anHCV-specific CMI response using an ex-vivo", "metadata": {}}
+{"_id": "994800", "title": "", "text": "TCR ligand density and affinity determineperipheral induction of Foxp3 in vivoT cellreceptor (TCR) ligation is required for theextrathymic differentiation of forkhead boxp3(+) (Foxp3(+)) regulatory T cells. Severallines of evidence indicate that weak TCRstimulation favors induction of Foxp3 in theperiphery; however, it remains to be determinedhow TCR ligand potency influences this process.We characterized the density and affinity of TCRligand favorable for Foxp3 induction and foundthat a low dose of a strong agonist resulted inmaximal induction of Foxp3 in vivo. Initial Foxp3induction by weak agonist peptide could beenhanced by disruption of TCR-peptide majorhistocompatibility complex (pMHC) interactionsor alteration of peptide dose. However, timecourse experiments revealed that Foxp3-positivecells induced by weak agonist stimulation aredeleted, along with their Foxp3-negativecounterparts, whereas Foxp3-positive cellsinduced by low doses of the strong agonist", "metadata": {}}
+{"_id": "997143", "title": "", "text": "Electromagnetic interference from radiofrequency identification inducing potentiallyhazardous incidents in critical care medicalequipment.CONTEXT Health care applications ofautoidentification technologies, such as radiofrequency identification (RFID), have beenproposed to improve patient safety and also thetracking and tracing of medical equipment.However, electromagnetic interference (EMI) byRFID on medical devices has never beenreported. OBJECTIVE To assess and classifyincidents of EMI by RFID on critical careequipment. DESIGN AND SETTING Without apatient being connected, EMI by 2 RFID systems(active 125 kHz and passive 868 MHz) wasassessed under controlled conditions during May2006, in the proximity of 41 medical devices (in17 categories, 22 different manufacturers) at theAcademic Medical Centre, University ofAmsterdam, Amsterdam, The Netherlands.Assessment took place according to aninternational test protocol. Incidents of EMI were", "metadata": {}}
+{"_id": "1006165", "title": "", "text": "Potent RNAi by short RNA triggers.RNAinterference (RNAi) is a gene-silencingmechanism by which a ribonucleoproteincomplex, the RNA-induced silencing complex(RISC) and a double-stranded (ds)short-interfering RNA (siRNA), targets acomplementary mRNA for site-specific cleavageand subsequent degradation. While longer dsRNAare endogenously processed into 21- to24-nucleotide (nt) siRNAs or miRNAs to inducegene silencing, RNAi studies in human cellstypically use synthetic 19- to 20-nt siRNAduplexes with 2-nt overhangs at the 3'-end ofboth strands. Here, we report that systematicsynthesis and analysis of siRNAs with deletionsat the passenger and/or guide strand revealed ashort RNAi trigger, 16-nt siRNA, which inducespotent RNAi in human cells. Our results indicatethat the minimal requirement for dsRNA totrigger RNAi is an approximately 42 A A-formhelix with approximately 1.5 helical turns. The16-nt siRNA more effectively knocked down", "metadata": {}}
+{"_id": "1022115", "title": "", "text": "IL-23–responsive innate lymphoid cells areincreased in inflammatory bowel diseaseResultsof experimental and genetic studies havehighlighted the role of the IL-23/IL-17 axis in thepathogenesis of inflammatory bowel disease(IBD). IL-23-driven inflammation has beenprimarily linked to Th17 cells; however, we haverecently identified a novel population of innatelymphoid cells (ILCs) in mice that producesIL-17, IL-22, and IFN-γ in response to IL-23 andmediates innate colitis. The relevance of ILCpopulations in human health and disease iscurrently poorly understood. In this study, wehave analyzed the role of IL-23-responsive ILCsin the human intestine in control and IBDpatients. Our results show increased expressionof the Th17-associated cytokine genes IL17A andIL17F among intestinal CD3\u0000 cells in IBD. IL17Aand IL17F expression is restricted to CD56\u0000ILCs, whereas IL-23 induces IL22 and IL26 in theCD56\u0000 ILC compartment. Furthermore, weobserved a significant and selective increase in", "metadata": {}}
+{"_id": "1031534", "title": "", "text": "Scaling of Dorsal-Ventral Patterning by EmbryoSize-Dependent Degradation of Spemann’sOrganizer SignalsSpemann's organizer plays akey role in dorsal-ventral (DV) patterning in theamphibian embryo by secreting diffusibleproteins such as Chordin, an antagonist toventralizing bone morphogenetic proteins(BMPs). The DV patterning is so robust that anamphibian embryo with its ventral half surgicallyremoved can develop into a smaller butproportionally patterned larva. Here, we showthat this robust patterning depends on facilitatedChordin degradation and requires the expressionof the Chordin-proteinase inhibitor Sizzled on theopposite side. Sizzled, which is stable anddiffuses widely along the DV axis, stabilizesChordin and expands its distribution in theventral direction. This expanded Chordindistribution, in turn, limits BMP-dependentSizzled production, forming an axis-widefeedback loop for shaping Chordin's activity.Using bisection assays, we demonstrate that", "metadata": {}}
+{"_id": "1032372", "title": "", "text": "Augmenting Antitumor Immune Responses withEpigenetic Modifying AgentsEpigenetic silencingof immune-related genes is a striking feature ofthe cancer genome that occurs in the process oftumorigenesis. This phenomena impacts antigenprocessing and antigen presentation by tumorcells and facilitates evasion ofimmunosurveillance. Further modulation of thetumor microenvironment by altered expressionof immunosuppressive cytokines impairsantigen-presenting cells and cytolytic T-cellfunction. The potential reversal ofimmunosuppression by epigenetic modulation istherefore a promising and versatile therapeuticapproach to reinstate endogenous immunerecognition and tumor lysis. Pre-clinical studieshave identified multiple elements of the immunesystem that can be modulated by epigeneticmechanisms and result in improved antigenpresentation, effector T-cell function, andbreakdown of suppressor mechanisms. Recentclinical studies are utilizing epigenetic therapies", "metadata": {}}
+{"_id": "1044552", "title": "", "text": "Activation of proteinase-activated receptor 2 inhuman osteoarthritic cartilage upregulatescatabolic and proinflammatory pathways capableof inducing cartilage degradation: a basic sciencestudyProteinase-activated receptors (PARs)belong to a family of G protein-coupledreceptors. PARs are activated by aserine-dependent cleavage generating a tetheredactivating ligand. PAR-2 was shown to beinvolved in inflammatory pathways. Weinvestigated the in situ levels and modulation ofPAR-2 in human normal and osteoarthritis (OA)cartilage/chondrocytes. Furthermore, weevaluated the role of PAR-2 on the synthesis ofthe major catabolic factors in OA cartilage,including metalloproteinase (MMP)-1 andMMP-13 and the inflammatory mediatorcyclooxygenase 2 (COX-2), as well as thePAR-2-activated signalling pathways in OAchondrocytes. PAR-2 expression was determinedusing real-time reverse transcription-polymerasechain reaction and protein levels by", "metadata": {}}
+{"_id": "1049501", "title": "", "text": "Neutrophil extracellular traps enriched inoxidized mitochondrial DNA are interferogenicand contribute to lupus-like diseaseNeutrophilextracellular traps (NETs) are implicated inautoimmunity, but how they are generated andtheir roles in sterile inflammation remain unclear.Ribonucleoprotein immune complexes (RNP ICs),inducers of NETosis, require mitochondrialreactive oxygen species (ROS) for maximal NETstimulation. After RNP IC stimulation ofneutrophils, mitochondria become hypopolarizedand translocate to the cell surface. Extracellularrelease of oxidized mitochondrial DNA isproinflammatory in vitro, and when this DNA isinjected into mice, it stimulates type I interferon(IFN) signaling through a pathway dependent onthe DNA sensor STING. Mitochondrial ROS arealso necessary for spontaneous NETosis oflow-density granulocytes from individuals withsystemic lupus erythematosus. This was alsoobserved in individuals with chronicgranulomatous disease, who lack NADPH oxidase", "metadata": {}}
+{"_id": "1065627", "title": "", "text": "Microenvironment rigidity modulates responsesto the HER2 receptor tyrosine kinase inhibitorlapatinib via YAP and TAZ transcriptionfactors.Stiffness is a biophysical property of theextracellular matrix that modulates cellularfunctions, including proliferation, invasion, anddifferentiation, and it also may affect therapeuticresponses. Therapeutic durability in cancertreatments remains a problem for bothchemotherapies and pathway-targeted drugs,but the reasons for this are not well understood.Tumor progression is accompanied by changes inthe biophysical properties of the tissue, and weasked whether matrix rigidity modulated thesensitive versus resistant states inHER2-amplified breast cancer cell responses tothe HER2-targeted kinase inhibitor lapatinib. Theantiproliferative effect of lapatinib was inverselyproportional to the elastic modulus of theadhesive substrata. Down-regulation of themechanosensitive transcription coactivators YAPand TAZ, either by siRNA or with the", "metadata": {}}
+{"_id": "1067605", "title": "", "text": "Effective population size and patterns ofmolecular evolution and variationThe effectivesize of a population, Ne, determines the rate ofchange in the composition of a population causedby genetic drift, which is the random sampling ofgenetic variants in a finite population. Ne iscrucial in determining the level of variability in apopulation, and the effectiveness of selectionrelative to drift. This article reviews theproperties of Ne in a variety of differentsituations of biological interest, and the factorsthat influence it. In particular, the action ofselection means that Ne varies across thegenome, and advances in genomic techniquesare giving new insights into how selection shapesNe.", "metadata": {}}
+{"_id": "1068106", "title": "", "text": "Is emotional dysregulation part of thepsychopathology of ADHD inadults?Attention-deficit hyperactivity disorder isa common condition in adulthood. The disorder ischaracterized by symptoms of inattention,hyperactivity, and impulsivity. Alongside thesesymptoms, it is discussed whether symptoms ofemotional dysregulation could add additional andbetter description of the psychopathology ofADHD. Neither the current ICD-10 and DSM-IVnor the upcoming DSM-5 includes symptoms ofemotional dysregulation as a core aspect ofADHD. Several authors (e.g., Wender 1995)describe adult ADHD in a more differentiated wayand propose concepts of the disorder thatconsider the subjective experiences of the adultpatient by introducing the symptomatology ofemotional symptoms. Empirical studies attestthis dimension sufficient reliability and validity.Symptoms of emotional dysregulation aredefinable and seem to be distinct factors of thepsychopathology of adult ADHD. Pharmacological", "metadata": {}}
+{"_id": "1070920", "title": "", "text": "A neural basis for melanocortin-4 receptorregulated appetitePro-opiomelanocortin (POMC)-and agouti-related peptide (AgRP)-expressingneurons of the arcuate nucleus of thehypothalamus (ARC) are oppositely regulated bycaloric depletion and coordinately stimulate andinhibit homeostatic satiety, respectively. Thisbimodality is principally underscored by theantagonistic actions of these ligands atdownstream melanocortin-4 receptors (MC4R) inthe paraventricular nucleus of the hypothalamus(PVH). Although this population is critical toenergy balance, the underlying neural circuitryremains unknown. Using mice expressing Crerecombinase in MC4R neurons, we demonstratebidirectional control of feeding followingreal-time activation and inhibition of PVH(MC4R)neurons and further identify these cells as afunctional exponent of ARC(AgRP) neuron-drivenhunger. Moreover, we reveal this function to bemediated by a PVH(MC4R)\u0000lateral parabrachialnucleus (LPBN) pathway. Activation of this circuit", "metadata": {}}
+{"_id": "1071991", "title": "", "text": "Lymph node T cell responses predict the efficacyof live attenuated SIV vaccinesLive attenuatedsimian immunodeficiency virus (SIV) vaccines(LAVs) remain the most efficacious of allvaccines in nonhuman primate models of HIVand AIDS, yet the basis of their robust protectionremains poorly understood. Here we show thatthe degree of LAV-mediated protection againstintravenous wild-type SIVmac239 challengestrongly correlates with the magnitude andfunction of SIV-specific, effector-differentiated Tcells in the lymph node but not with theresponses of such T cells in the blood or withother cellular, humoral and innate immuneparameters. We found that maintenance ofprotective T cell responses is associated withpersistent LAV replication in the lymph node,which occurs almost exclusively in follicularhelper T cells. Thus, effective LAVs maintainlymphoid tissue-based, effector-differentiated,SIV-specific T cells that intercept and suppressearly wild-type SIV amplification and, if present", "metadata": {}}
+{"_id": "1084062", "title": "", "text": "Activation of Serotonin 2C Receptors inDopamine Neurons Inhibits Binge-like Eating inMiceBACKGROUND Neural networks that regulatebinge eating remain to be identified, andeffective treatments for binge eating are limited.METHODS We combined neuroanatomic,pharmacologic, electrophysiological, Cre-lox, andchemogenetic approaches to investigate thefunctions of 5-hydroxytryptamine (5-HT) 2Creceptor (5-HT2CR) expressed by dopamine (DA)neurons in the regulation of binge-like eatingbehavior in mice. RESULTS We showed that 5-HTstimulates DA neural activity through a5-HT2CR-mediated mechanism, and activation ofthis midbrain 5-HT\u0000DA neural circuit effectivelyinhibits binge-like eating behavior in mice.Notably, 5-HT medications, including fluoxetine,d-fenfluramine, and lorcaserin (a selective5-HT2CR agonist), act on 5-HT2CRs expressedby DA neurons to inhibit binge-like eating inmice. CONCLUSIONS We identified the 5-HT2CRpopulation in DA neurons as one potential target", "metadata": {}}
+{"_id": "1084345", "title": "", "text": "Restoration of chaperone-mediated autophagy inaging liver improves cellular maintenance andhepatic functionChaperone-mediated autophagy(CMA), a selective mechanism for degradation ofcytosolic proteins in lysosomes, contributes tothe removal of altered proteins as part of thecellular quality-control systems. We havepreviously found that CMA activity declines inaged organisms and have proposed that thisfailure in cellular clearance could contribute tothe accumulation of altered proteins, theabnormal cellular homeostasis and, eventually,the functional loss characteristic of agedorganisms. To determine whether these negativefeatures of aging can be prevented bymaintaining efficient autophagic activity until latein life, in this work we have corrected the CMAdefect in aged rodents. We have generated adouble transgenic mouse model in which theamount of the lysosomal receptor for CMA,previously shown to decrease in abundance withage, can be modulated. We have analyzed in this", "metadata": {}}
+{"_id": "1102268", "title": "", "text": "The Incidence and Repetition of Hospital-TreatedDeliberate Self Harm: Findings from the World'sFirst National RegistryBACKGROUND Suicide is asignificant public health issue with almost onemillion people dying by suicide each yearworldwide. Deliberate self harm (DSH) is thesingle most important risk factor for suicide yetfew countries have reliable data on DSH. Wedeveloped a national DSH registry in theRepublic of Ireland to establish the incidence ofhospital-treated DSH at national level and thespectrum and pattern of presentations with DSHand repetition. METHODS AND FINDINGSBetween 2003 and 2009, the Irish NationalRegistry of Deliberate Self Harm collected dataon DSH presentations to all 40 hospitalemergency departments in the country. Datawere collected by trained data registrationofficers using standard methods of caseascertainment and definition. The Registryrecorded 75,119 DSH presentations involving48,206 individuals. The total incidence rate fell", "metadata": {}}
+{"_id": "1103795", "title": "", "text": "A Common Mechanism of Cellular Death Inducedby Bactericidal AntibioticsAntibioticmode-of-action classification is based upondrug-target interaction and whether the resultantinhibition of cellular function is lethal to bacteria.Here we show that the three major classes ofbactericidal antibiotics, regardless of drug-targetinteraction, stimulate the production of highlydeleterious hydroxyl radicals in Gram-negativeand Gram-positive bacteria, which ultimatelycontribute to cell death. We also show, incontrast, that bacteriostatic drugs do notproduce hydroxyl radicals. We demonstrate thatthe mechanism of hydroxyl radical formationinduced by bactericidal antibiotics is the endproduct of an oxidative damage cellular deathpathway involving the tricarboxylic acid cycle, atransient depletion of NADH, destabilization ofiron-sulfur clusters, and stimulation of theFenton reaction. Our results suggest that allthree major classes of bactericidal drugs can bepotentiated by targeting bacterial systems that", "metadata": {}}
+{"_id": "1122198", "title": "", "text": "Increased atherosclerosis in mice reconstitutedwith apolipoprotein E nullmacrophages.Macrophage-derived foam cellsexpress apolipoprotein E (apoE) abundantly inatherosclerotic lesions. To examine thephysiologic role of apoE secretion by themacrophage in atherogenesis, bone marrowtransplantation was used to reconstitute C57BL/6mice with macrophages that were either null orwild type for the apoE gene. After 13 weeks onan atherogenic diet, C57BL/6 mice reconstitutedwith apoE null marrow developed 10-fold moreatherosclerosis than controls in the absence ofsignificant differences in serum cholesterol levelsor lipoprotein profiles. ApoE expression wasabsent in the macrophage-derived foam cells ofC57BL/6 mice reconstituted with apoE nullmarrow. Thus, lack of apoE expression by themacrophage promotes foam cell formation.These data support a protective role for apoEexpression by the macrophage in earlyatherogenesis.", "metadata": {}}
+{"_id": "1122279", "title": "", "text": "Endothelium-mediated relaxation of porcinecollateral-dependent arterioles is improved byexercise training.BACKGROUNDEndothelium-dependent modulation of coronarytone is impaired in the collateral-dependentcoronary microcirculation. We used a porcinemodel of chronic coronary occlusion andcollateral development to evaluate thehypothesis that exercise training enhancesendothelium-mediated relaxation and increasesendothelial nitric oxide synthase (ecNOS) mRNAlevels of collateral-dependent microvasculature.METHODS AND RESULTS Adult female miniatureswine were subjected to chronic, progressiveameroid occlusion of the proximal left circumflexcoronary artery (LCx); after 2 months, animalswere randomly exposed to 16-weekexercise-training (EX group; treadmill running)or sedentary (SED group; cage confinement)protocols. After completion of EX or SEDprograms, coronary arterioles ( approximately100 microm in diameter) were isolated from", "metadata": {}}
+{"_id": "1127562", "title": "", "text": "Loss of the RhoGAP SRGP-1 promotes theclearance of dead and injured cells inCaenorhabditis elegansMulticellular animalsrapidly clear dying cells from their bodies. Manyof the pathways that mediate this cell removalare conserved through evolution. Here, weidentify srgp-1 as a negative regulator of cellclearance in both Caenorhabditis elegans andmammalian cells. Loss of srgp-1 function resultsin improved engulfment of apoptotic cells,whereas srgp-1 overexpression inhibits apoptoticcell corpse removal. We show that SRGP-1functions in engulfing cells and functions as aGTPase activating protein (GAP) for CED-10(Rac1). Interestingly, loss of srgp-1 functionpromotes not only the clearance of already deadcells, but also the removal of cells that havebeen brought to the verge of death throughsublethal apoptotic, necrotic or cytotoxic insults.In contrast, impaired engulfment allowsdamaged cells to escape clearance, which resultsin increased long-term survival. We propose that", "metadata": {}}
+{"_id": "1145473", "title": "", "text": "Abnormalities in the myeloid progenitorcompartment in Down syndrome fetal liverprecede acquisition of GATA1 mutations.Downsyndrome (DS) children have a high frequency ofacute megakaryoblastic leukemia (AMKL) in earlychildhood. At least 2 in utero genetic events arerequired, although not sufficient, for DS-AMKL:trisomy 21 (T21) and N-terminal-truncatingGATA1 mutations. To investigate the role of T21in DS-AMKL, we compared second trimesterhemopoiesis in DS without GATA1 mutations togestation-matched normal controls. In all DSfetal livers (FLs), but not marrows,megakaryocyte-erythroid progenitor frequencywas increased (55.9% +/- 4% vs 17.1% +/-3%, CD34(+)CD38(+) cells; P < .001) withcommon myeloid progenitors (19.6% +/- 2% vs44.0% +/- 7%) and granulocyte-monocyte (GM)progenitors (15.8% +/- 4% vs 34.5% +/- 9%)commensurately reduced. Clonogenicity of DS-FLversus normal FL CD34(+) cells was markedlyincreased (78% +/- 7% vs 15% +/- 3%)", "metadata": {}}
+{"_id": "1148122", "title": "", "text": "Regulatory and metabolic rewiring duringlaboratory evolution of ethanol tolerance in E.coliUnderstanding the genetic basis of adaptationis a central problem in biology. However,revealing the underlying molecular mechanismshas been challenging as changes in fitness mayresult from perturbations to many pathways, anyof which may contribute relatively little. We havedeveloped a combinedexperimental/computational framework toaddress this problem and used it to understandthe genetic basis of ethanol tolerance inEscherichia coli. We used fitness profiling tomeasure the consequences of single-locusperturbations in the context of ethanol exposure.A module-level computational analysis was thenused to reveal the organization of thecontributing loci into cellular processes andregulatory pathways (e.g. osmoregulation andcell-wall biogenesis) whose modificationssignificantly affect ethanol tolerance. Strikingly,we discovered that a dominant component of", "metadata": {}}
+{"_id": "1153655", "title": "", "text": "Familial risk of lymphoproliferative tumors infamilies of patients with chronic lymphocyticleukemia: results from the SwedishFamily-Cancer Database.The importance ofgenetic factors in etiology of chronic lymphocyticleukemia (CLL) is suggested by family andpopulation studies. However, the spectrum ofmalignancies sharing common genetic factorswith CLL and the effects of sex and age onfamilial risk are unknown. We used the SwedishFamily-Cancer Database to test for increasedfamilial risks of CLL and otherlymphoproliferative tumors. Cancer diagnosesfrom 1958 to 1998 were assessed in 14 336first-degree relatives of 5918 CLL cases and in28 876 first-degree relatives of 11 778 controls.Cancer risks in relatives of cases were comparedwith those in relatives of controls using marginalsurvival models. Relatives of cases were atsignificantly increased risk for CLL (relative risk[RR] = 7.52; 95% confidence interval [CI],3.63-15.56), for non-Hodgkin lymphoma (RR =", "metadata": {}}
+{"_id": "1156322", "title": "", "text": "Collagen/Polypropylene composite meshbiocompatibility in abdominal wallreconstruction.BACKGROUND Intraperitonealplacement of polypropylene mesh leads toextensive visceral adhesions and iscontraindicated. Different coatings are used toimprove polypropylene mesh properties.Collagen is a protein with unique biocompatibilityand cell ingrowth enhancement potential. A novelacetic acid extracted collagen coating wasdeveloped to allow placement of polypropylenemesh in direct contact with viscera. The authors'aim was to evaluate the long-term influence ofacetic acid extracted collagen coating on surgicalaspects and biomechanical properties ofpolypropylene mesh implanted in direct contactwith viscera, including complications, adhesionswith viscera, strength of incorporation, andmicroscopic inflammatory reaction. METHODSForty adult Wistar rats were divided into twogroups: experimental (polypropylenemesh/acetic acid extracted collagen coating) and", "metadata": {}}
+{"_id": "1171121", "title": "", "text": "Microvessel Density and Status of p53 Protein asPotential Prognostic Factors for AdjuvantAnthracycline Chemotherapy in RetrospectiveAnalysis of Early Breast Cancer Patients GroupAconsiderable subgroup of patients with earlybreast cancer does not address benefits ofanthracycline based chemotherapy. The aim ofthis retrospective study was to investigate theeffect of microvessel density (MVD) and status ofp53 protein on 5-year disease free survival (DFS)in the group of breast cancer patients treatedwith anthracyclines in adjuvant setting.Correlations between MVD, p53 status and otherclinicopathological parameters were alsoassessed. MVD and p53 status were analyzedimmunohistochemically in the group of 172women with breast cancer in clinical stage T1-2,N1-N2, M0. There were 123 tumors (71.5 %)with lower MVD (≤ 214.8 microvesells/mm(2))and 49 (28.5 %) with higher MVD (>214.8microvesells/mm(2)). The proportion of higherMVD tumors significantly increased in N2 (P =", "metadata": {}}
+{"_id": "1173667", "title": "", "text": "Ranking of elimination feasibility betweenmalaria-endemic countriesExperience gainedfrom the Global Malaria Eradication Program(1955-72) identified a set of shared technicaland operational factors that enabled somecountries to successfully eliminate malaria.Spatial data for these factors were assembled forall malaria-endemic countries and combined toprovide an objective, relative ranking ofcountries by technical, operational, andcombined elimination feasibility. The analysiswas done separately for Plasmodium falciparumand Plasmodium vivax, and the limitations of theapproach were discussed. The relative rankingssuggested that malaria elimination would bemost feasible in countries in the Americas andAsia, and least feasible in countries in centraland west Africa. The results differed whenfeasibility was measured by technical oroperational factors, highlighting the differenttypes of challenge faced by each country. Theresults are not intended to be prescriptive,", "metadata": {}}
+{"_id": "1180972", "title": "", "text": "Genetics of obesity in adult adoptees and theirbiological siblings.An adoption study of geneticeffects on obesity in adulthood was carried out inwhich adoptees separated from their naturalparents very early in life were compared withtheir biological full and half siblings reared bytheir natural parents. The adoptees representedfour groups who by sampling from a largerpopulation were categorised as either thin,medium weight, overweight, or obese. Weightand height were obtained for 115 full siblings of57 adoptees and for 850 half siblings of 341adoptees. In full siblings body mass index(kg/m2) significantly increased with weight ofthe adoptees. Body mass index of the halfsiblings showed a steady but weaker increaseacross the four weight groups of adoptees. Therewere no significant interactions with sex of theadoptees, sex of the siblings, or (for the halfsiblings) sex of the common parent. In contrastwith the findings in half siblings and (previously)the natural parents there was a striking,", "metadata": {}}
+{"_id": "1191830", "title": "", "text": "2010 rheumatoid arthritis classification criteria:an American College of Rheumatology/EuropeanLeague Against Rheumatism collaborativeinitiative.OBJECTIVE The 1987 American Collegeof Rheumatology (ACR; formerly the AmericanRheumatism Association) classification criteriafor rheumatoid arthritis (RA) have been criticisedfor their lack of sensitivity in early disease. Thiswork was undertaken to develop newclassification criteria for RA. METHODS A jointworking group from the ACR and the EuropeanLeague Against Rheumatism developed, in threephases, a new approach to classifying RA. Thework focused on identifying, among patientsnewly presenting with undifferentiatedinflammatory synovitis, factors that bestdiscriminated between those who were and thosewho were not at high risk for persistent and/orerosive disease--this being the appropriatecurrent paradigm underlying the diseaseconstruct 'RA'. RESULTS In the new criteria set,classification as 'definite RA' is based on the", "metadata": {}}
+{"_id": "1192458", "title": "", "text": "A role for fibroblasts in mediating the effects oftobacco-induced epithelial cell growth andinvasion.Cigarette smoke and smokeless tobaccoextracts contain multiple carcinogeniccompounds, but little is known about themechanisms by which tumors develop andprogress upon chronic exposure to carcinogenssuch as those present in tobacco products. Here,we examine the effects of smokeless tobaccoextracts on human oral fibroblasts. We show thatsmokeless tobacco extracts elevated the levels ofintracellular reactive oxygen, oxidative DNAdamage, and DNA double-strand breaks in adose-dependent manner. Extended exposure toextracts induced fibroblasts to undergo asenescence-like growth arrest, with strikingaccompanying changes in the secretoryphenotype. Using cocultures of smokelesstobacco extracts-exposed fibroblasts andimmortalized but nontumorigenic keratinocytes,we further show that factors secreted byextracts-modified fibroblasts increase the", "metadata": {}}
+{"_id": "1196631", "title": "", "text": "ImmTAC-redirected tumour cell killing inducesand potentiates antigen cross-presentation bydendritic cellsAntigen cross-presentation bydendritic cells (DCs) is thought to play a criticalrole in driving a polyclonal and durable T cellresponse against cancer. It follows, therefore,that the capacity of emergingimmunotherapeutic agents to orchestrate tumoureradication may depend on their ability to induceantigen cross-presentation. ImmTACs[immune-mobilising monoclonal TCRs (T cellreceptors) against cancer] are a new class ofsoluble bi-specific anti-cancer agents thatcombine pico-molar affinity TCR-based antigenrecognition with T cell activation via aCD3-specific antibody fragment. ImmTACsspecifically recognise human leucocyte antigen(HLA)-restricted tumour-associated antigens,presented by cancer cells, leading to T cellredirection and a potent anti-tumour response.Using an ImmTAC specific for aHLA-A*02-restricted peptide derived from the", "metadata": {}}
+{"_id": "1203035", "title": "", "text": "Basal keratinocyte tetrasomy in low-gradesquamous intra-epithelial lesions of the cervix isrestricted to high and intermediate risk HPVinfection but is not type-specificHumanpapillomavirus (HPV) infection appears to be anearly event in cervical carcinogenesis withadditional abnormalities being required forbiological transformation. We have analysed 179low-grade cervical squamous intra-epitheliallesions (SILs) and 15 normal cervices for thepresence of HPV using both in situ hybridizationand polymerase chain reaction (PCR). PCR wasperformed with GP5+/GP6+ primers followed byhybridization using probes for low (HPV 6, 11,40, 42, 43, 44), intermediate (HPV 31, 33, 35,39, 51, 52, 58, 59, 66 and 68) and high-riskHPVs (HPV 16, 18, 45 and 56). Interphasecytogenetic analysis using pericentromericprobes for chromosomes 1, 3, 4, 6, 10, 11, 17,18 and X was also performed to identifynumerical chromosomal abnormalities.Tetrasomy of all nine chromosomes was", "metadata": {}}
+{"_id": "1215116", "title": "", "text": "“Rapid-Impact Interventions”: How a Policy ofIntegrated Control for Africa's Neglected TropicalDiseases Could Benefit the PoorOver the pasttwo decades there have been significantachievements in the control of a handful ofimportant human tropical infections [1]. Theseachievements include the substantive reductionsin the prevalence and incidence of the so-calledneglected diseases such as lymphatic filariasis,onchocerciasis, guinea worm, leprosy, andtrachoma (Box 1) [2]. Each of these neglecteddiseases is a poverty-promoting and oftenstigmatizing condition occurring primarily in ruralareas of low-income countries (Box 2) [3]. Theyare ancient afflictions, described in the Bible andother ancient texts, which have burdenedhumanity for millennia [3]. But now, as a resultof aggressive regional vertical interventions,there is a possibility that some neglected tropicalinfections could be eventually controlled to thepoint of elimination in some areas of endemicity[2–8]. In the case of guinea worm infection,", "metadata": {}}
+{"_id": "1220287", "title": "", "text": "FTY720 (fingolimod) is a neuroprotective anddisease-modifying agent in cellular and mousemodels of Huntington disease.Huntington disease(HD) is a genetic neurodegenerative disorder forwhich there is currently no cure and no way tostop or even slow the brain changes it causes. Inthe present study, we aimed to investigatewhether FTY720, the first approved oral therapyfor multiple sclerosis, may be effective in HDmodels and eventually constitute an alternativetherapeutic approach for the treatment of thedisease. Here, we utilized preclinical targetvalidation paradigms and examined the in vivoefficacy of chronic administration of FTY720 inR6/2 HD mouse model. Our findings indicate thatFTY720 improved motor function, prolongedsurvival and reduced brain atrophy in R6/2 mice.The beneficial effect of FTY720 administrationwas associated with a significant strengtheningof neuronal activity and connectivity and, withreduction of mutant huntingtin aggregates, andit was also paralleled by increased", "metadata": {}}
+{"_id": "1225513", "title": "", "text": "Specificity Residues Determine Binding Affinityfor Two-Component Signal TransductionSystemsUNLABELLED Two-component systems(TCS) comprise histidine kinases and theircognate response regulators and allow bacteriato sense and respond to a wide variety ofsignals. Histidine kinases (HKs) phosphorylateand dephosphorylate their cognate responseregulators (RRs) in response to stimuli. Ingeneral, these reactions appear to be highlyspecific and require an appropriate associationbetween the HK and RR proteins. TheMyxococcus xanthus genome encodes one of thelargest repertoires of signaling proteins inbacteria (685 open reading frames [ORFs]),including at least 127 HKs and at least 143 RRs.Of these, 27 are bona fide NtrC-family responseregulators, 21 of which are encoded adjacent totheir predicted cognate kinases. Usingsystem-wide profiling methods, we determinedthat the HK-NtrC RR pairs display a kineticpreference during both phosphotransfer and", "metadata": {}}
+{"_id": "1226452", "title": "", "text": "hnRNP A1 associates with telomere ends andstimulates telomerase activity.Telomerase is aribonucleoprotein enzyme complex thatreverse-transcribes an integral RNA template toadd short DNA repeats to the 3'-ends oftelomeres. G-quadruplex structure in a DNAsubstrate can block its extension by telomerase.We have found that hnRNP A1--which waspreviously implicated in telomere lengthregulation--binds to both single-stranded andstructured human telomeric repeats, and in thelatter case, it disrupts their higher-orderstructure. Using an in vitro telomerase assay, weobserved that depletion of hnRNP A/B proteinsfrom 293 human embryonic kidney cell extractsdramatically reduced telomerase activity, whichwas fully recovered upon addition of purifiedrecombinant hnRNP A1. This finding suggeststhat hnRNP A1 functions as an auxiliary, if notessential, factor of telomerase holoenzyme. Wefurther show, using chromatinimmunoprecipitation, that hnRNP A1 associates", "metadata": {}}
+{"_id": "1227277", "title": "", "text": "Rapamycin passes the torch: a new generation ofmTOR inhibitorsMammalian target of rapamycin(mTOR) is an atypical protein kinase thatcontrols growth and metabolism in response tonutrients, growth factors and cellular energylevels, and it is frequently dysregulated in cancerand metabolic disorders. Rapamycin is anallosteric inhibitor of mTOR, and was approvedas an immuno-suppressant in 1999. In recentyears, interest has focused on its potential as ananticancer drug. However, the performance ofrapamycin and its analogues (rapalogues) hasbeen undistinguished despite isolated successesin subsets of cancer, suggesting that the fulltherapeutic potential of targeting mTOR has yetto be exploited. A new generation ofATP-competitive inhibitors that directly targetthe mTOR catalytic site display potent andcomprehensive mTOR inhibition and are in earlyclinical trials.", "metadata": {}}
+{"_id": "1234098", "title": "", "text": "Dynamic capsule restructuring by the mainpneumococcal autolysin LytA in response to theepitheliumBacterial pathogens produce complexcarbohydrate capsules to protect againstbactericidal immune molecules. Paradoxically,the pneumococcal capsule sensitizes thebacterium to antimicrobial peptides found onepithelial surfaces. Here we show that uponinteraction with antimicrobial peptides,encapsulated pneumococci survive by removingcapsule from the cell surface within minutes in aprocess dependent on the suicidal amidaseautolysin LytA. In contrast to classical bacterialautolysis, during capsule shedding, LytApromotes bacterial survival and is dispersedcircumferentially around the cell. However, bothautolysis and capsule shedding depend on thecell wall hydrolytic activity of LytA. Capsuleshedding drastically increases invasion ofepithelial cells and is the main pathway by whichpneumococci reduce surface bound capsuleduring early acute lung infection of mice. The", "metadata": {}}
+{"_id": "1241113", "title": "", "text": "The mammalian Scribble polarity proteinregulates epithelial cell adhesion and migrationthrough E-cadherinScribble (Scrib) is aconserved polarity protein required in Drosophilamelanogaster for synaptic function, neuroblastdifferentiation, and epithelial polarization. It isalso a tumor suppressor. In rodents, Scrib hasbeen implicated in receptor recycling and planarpolarity but not in apical/basal polarity. We nowshow that knockdown of Scrib disrupts adhesionbetween Madin–Darby canine kidney epithelialcells. As a consequence, the cells acquire amesenchymal appearance, migrate more rapidly,and lose directionality. Although tight junctionassembly is delayed, confluent monolayersremain polarized. These effects are independentof Rac activation or Scrib binding to βPIX.Rather, Scrib depletion disruptsE-cadherin–mediated cell–cell adhesion. Thechanges in morphology and migration arephenocopied by E-cadherin knockdown. Adhesionis partially rescued by expression of an", "metadata": {}}
+{"_id": "1243475", "title": "", "text": "Histone acetylation and DNA demethylation of Tcells result in an anaplastic large celllymphoma-like phenotype.A characteristicfeature of anaplastic large cell lymphoma is thesignificant repression of the T-cell expressionprogram despite its T-cell origin. The reasons forthis down-regulation of T-cell phenotype are stillunknown. To elucidate whether epigeneticmechanisms are responsible for the loss of theT-cell phenotype, we treated anaplastic large celllymphoma and T-cell lymphoma/leukemia celllines (n=4, each) with epigenetic modifiers toevoke DNA demethylation and histoneacetylation. Global gene expression data fromtreated and untreated cell lines were generatedand selected, and differentially expressed geneswere evaluated by real-time reversetranscriptase polymerase chain reaction andwestern blot analysis. Additionally, histone H3lysine 27 trimethylation was analyzed bychromatin immunoprecipitation. Combined DNAdemethylation and histone acetylation of", "metadata": {}}
+{"_id": "1256116", "title": "", "text": "YEASTRACT: providing a programmatic access tocurated transcriptional regulatory associations inSaccharomyces cerevisiae through a webservices interfaceThe YEAst Search forTranscriptional Regulators And ConsensusTracking (YEASTRACT) information system(http://www.yeastract.com) was developed tosupport the analysis of transcription regulatoryassociations in Saccharomyces cerevisiae. Lastupdated in June 2010, this database containsover 48,200 regulatory associations betweentranscription factors (TFs) and target genes,including 298 specific DNA-binding sites for 110characterized TFs. All regulatory associationsstored in the database were revisited anddetailed information on the experimentalevidences that sustain those associations wasadded and classified as direct or indirectevidences. The inclusion of this new data,gathered in response to the requests ofYEASTRACT users, allows the user to restrict itsqueries to subsets of the data based on the", "metadata": {}}
+{"_id": "1259280", "title": "", "text": "Mechanisms that Specify Promoter NucleosomeLocation and IdentityThe chromatin architectureof eukaryotic gene promoters is generallycharacterized by a nucleosome-free region (NFR)flanked by at least one H2A.Z variantnucleosome. Computational predictions ofnucleosome positions based on thermodynamicproperties of DNA-histone interactions have metwith limited success. Here we show that theaction of the essential RSC remodeling complexin S. cerevisiae helps explain the discrepancybetween theory and experiment. InRSC-depleted cells, NFRs shrink such that theaverage positions of flanking nucleosomes movetoward predicted sites. Nucleosome positioningat distinct subsets of promoters additionallyrequires the essential Myb family proteins Abf1and Reb1, whose binding sites are enriched inNFRs. In contrast, H2A.Z deposition isdispensable for nucleosome positioning. Byregulating H2A.Z deposition using asteroid-inducible protein splicing strategy, we", "metadata": {}}
+{"_id": "1259359", "title": "", "text": "HIV seropositivity and tuberculosis in a largegeneral hospital in Malawi.The incidence of theacquired immunodeficiency syndrome (AIDS) inMalawi is one of the highest in Central Africa.Since tuberculosis is an important initialmanifestations of the disease, consecutivepatients admitted to the tuberculosis (TB) wardsof Zomba General Hospital, Malawi, were askedfor permission to undergo a humanimmunodeficiency virus (HIV)-antibodies test. Inaddition, two other studies were done: fromSeptember 1986 all medical in-patients, clinicallysuspected for immune deficiency and from April1988 all blood donors were tested for HIVseropositivity. Seventy-five percent of the TBpatients volunteered; 32 out of 125 (26%) wereseropositive. In the high-risk age groups (20-40years) this percentage rose to 32. Among themedical in-patients suspected of immunedeficiency the seropositivity rose sharply fromApril 1987 to October 1988. Among the blooddonors tested, 20% were seropositive.", "metadata": {}}
+{"_id": "1263446", "title": "", "text": "Determinants of neonatal mortality inIndonesiaBACKGROUND Neonatal mortalityaccounts for almost 40 per cent of under-fivechild mortality, globally. An understanding of thefactors related to neonatal mortality is importantto guide the development of focused andevidence-based health interventions to preventneonatal deaths. This study aimed to identify thedeterminants of neonatal mortality in Indonesia,for a nationally representative sample of birthsfrom 1997 to 2002. METHODS The data sourcefor the analysis was the 2002-2003 IndonesiaDemographic and Health Survey from whichsurvival information of 15,952 singletonlive-born infants born between 1997 and 2002was examined. Multilevel logistic regressionusing a hierarchical approach was performed toanalyze the factors associated with neonataldeaths, using community, socio-economic statusand proximate determinants. RESULTS At thecommunity level, the odds of neonatal death wassignificantly higher for infants from East Java", "metadata": {}}
+{"_id": "1265945", "title": "", "text": "High density mapping of the MHC identifies ashared role for HLA-DRB1*01:03 in inflammatorybowel diseases and heterozygous advantage inulcerative colitisGenome-wide association studiesof the related chronic inflammatory boweldiseases (IBD) known as Crohn's disease andulcerative colitis have shown strong evidence ofassociation to the major histocompatibilitycomplex (MHC). This region encodes a largenumber of immunological candidates, includingthe antigen-presenting classical human leukocyteantigen (HLA) molecules. Studies in IBD haveindicated that multiple independent associationsexist at HLA and non-HLA genes, but they havelacked the statistical power to define thearchitecture of association and causal alleles. Toaddress this, we performed high-density SNPtyping of the MHC in >32,000 individuals withIBD, implicating multiple HLA alleles, with aprimary role for HLA-DRB1*01:03 in bothCrohn's disease and ulcerative colitis.Noteworthy differences were observed between", "metadata": {}}
+{"_id": "1275505", "title": "", "text": "High-Threshold Mechanosensitive Ion ChannelsBlocked by a Novel Conopeptide MediatePressure-Evoked PainLittle is known about themolecular basis of somatosensorymechanotransduction in mammals. We screeneda library of peptide toxins for effects onmechanically activated currents in cultureddorsal root ganglion neurons. One conopeptideanalogue, termed NMB-1 for noxiousmechanosensation blocker 1, selectively inhibits(IC50 1 µM) sustained mechanically activatedcurrents in a subset of sensory neurons.Biotinylated NMB-1 retains activity and bindsselectively to peripherin-positive nociceptivesensory neurons. The selectivity of NMB-1 wasconfirmed by the fact that it has no inhibitoryeffects on voltage-gated sodium and calciumchannels, or ligand-gated channels such asacid-sensing ion channels or TRPA1 channels.Conversely, the tarantula toxin, GsMTx-4, whichinhibits stretch-activated ion channels, had noeffects on mechanically activated currents in", "metadata": {}}
+{"_id": "1281769", "title": "", "text": "Hyperactive Neuroendocrine Secretion CausesSize, Feeding, and Metabolic Defects of C.elegans Bardet-Biedl SyndromeMutantsBardet-Biedl syndrome, BBS, is a rareautosomal recessive disorder with clinicalpresentations including polydactyly, retinopathy,hyperphagia, obesity, short stature, cognitiveimpairment, and developmental delays.Disruptions of BBS proteins in a variety oforganisms impair cilia formation and functionand the multi-organ defects of BBS have beenattributed to deficiencies in variouscilia-associated signaling pathways. In C.elegans, bbs genes are expressed exclusively inthe sixty ciliated sensory neurons of theseanimals and bbs mutants exhibit sensory defectsas well as body size, feeding, and metabolicabnormalities. Here we show that in contrast tomany other cilia-defective mutants, C. elegansbbs mutants exhibit increased release ofdense-core vesicles and organism-widephenotypes associated with enhanced activities", "metadata": {}}
+{"_id": "1283401", "title": "", "text": "Fiji: an open-source platform for biological-imageanalysisFiji is a distribution of the popularopen-source software ImageJ focused onbiological-image analysis. Fiji uses modernsoftware engineering practices to combinepowerful software libraries with a broad range ofscripting languages to enable rapid prototypingof image-processing algorithms. Fiji facilitatesthe transformation of new algorithms intoImageJ plugins that can be shared with endusers through an integrated update system. Wepropose Fiji as a platform for productivecollaboration between computer science andbiology research communities.", "metadata": {}}
+{"_id": "1285713", "title": "", "text": "Pharmacologic characterization of a potentinhibitor of class I phosphatidylinositide3-kinases.Extensive evidence implicatesactivation of the lipid phosphatidylinositide3-kinase (PI3K) pathway in the genesis andprogression of various human cancers. PI3Kinhibitors thus have considerable potential asmolecular cancer therapeutics. Here, we detailthe pharmacologic properties of a prototype of anew series of inhibitors of class I PI3K. PI103 is apotent inhibitor with low IC50 values againstrecombinant PI3K isoforms p110alpha (2nmol/L), p110beta (3 nmol/L), p110delta (3nmol/L), and p110gamma (15 nmol/L). PI103also inhibited TORC1 by 83.9% at 0.5micromol/L and exhibited an IC50 of 14 nmol/Lagainst DNA-PK. A high degree of selectivity forthe PI3K family was shown by the lack of activityof PI103 in a panel of 70 protein kinases. PI103potently inhibited proliferation and invasion of awide variety of human cancer cells in vitro andshowed biomarker modulation consistent with", "metadata": {}}
+{"_id": "1286352", "title": "", "text": "Optimized CRISPR/Cas tools for efficientgermline and somatic genome engineering inDrosophila.The type II clustered regularlyinterspaced short palindromic repeats(CRISPR)/CRISPR-associated (Cas) system hasemerged recently as a powerful method tomanipulate the genomes of various organisms.Here, we report a toolbox for high-efficiencygenome engineering of Drosophila melanogasterconsisting of transgenic Cas9 lines and versatileguide RNA (gRNA) expression plasmids.Systematic evaluation reveals Cas9 lines withubiquitous or germ-line-restricted patterns ofactivity. We also demonstrate differential activityof the same gRNA expressed from different U6snRNA promoters, with the previously untestedU6:3 promoter giving the most potent effect. Anappropriate combination of Cas9 and gRNAallows targeting of essential and nonessentialgenes with transmission rates ranging from25-100%. We also demonstrate that ouroptimized CRISPR/Cas tools can be used for", "metadata": {}}
+{"_id": "1287809", "title": "", "text": "Cost-effectiveness of 10-Year Risk Thresholds forInitiation of Statin Therapy for PrimaryPrevention of CardiovascularDisease.IMPORTANCE The American College ofCardiology and the American Heart Association(ACC/AHA) cholesterol treatment guidelines havewide-scale implications for treating adultswithout history of atherosclerotic cardiovasculardisease (ASCVD) with statins. OBJECTIVE Toestimate the cost-effectiveness of various10-year ASCVD risk thresholds that could beused in the ACC/AHA cholesterol treatmentguidelines. DESIGN, SETTING, ANDPARTICIPANTS Microsimulation model, includinglifetime time horizon, US societal perspective,3% discount rate for costs, and health outcomes.In the model, hypothetical individuals from arepresentative US population aged 40 to 75years received statin treatment, experiencedASCVD events, and died from ASCVD-related ornon-ASCVD-related causes based on ASCVDnatural history and statin treatment parameters.", "metadata": {}}
+{"_id": "1292369", "title": "", "text": "Biochemical Properties of Highly NeuroinvasivePrion StrainsInfectious prions propagate fromperipheral entry sites into the central nervoussystem (CNS), where they cause progressiveneurodegeneration that ultimately leads todeath. Yet the pathogenesis of prion disease canvary dramatically depending on the strain, orconformational variant of the aberrantly foldedand aggregated protein, PrP(Sc). Although mostprion strains invade the CNS, some prion strainscannot gain entry and do not cause clinical signsof disease. The conformational basis for thisremarkable variation in the pathogenesis amongstrains is unclear. Using mouse-adapted prionstrains, here we show that highly neuroinvasiveprion strains primarily form diffuse aggregates inbrain and are noncongophilic, conformationallyunstable in denaturing conditions, and lead torapidly lethal disease. These neuroinvasivestrains efficiently generate PrP(Sc) over shortincubation periods. In contrast, the weaklyneuroinvasive prion strains form large fibrillary", "metadata": {}}
+{"_id": "1320137", "title": "", "text": "The twin-arginine translocation (Tat) proteinexport pathwayThe twin-arginine translocation(Tat) protein export system is present in thecytoplasmic membranes of most bacteria andarchaea and has the highly unusual property oftransporting fully folded proteins. The systemmust therefore provide a transmembranepathway that is large enough to allow thepassage of structured macromolecular substratesof different sizes but that maintains theimpermeability of the membrane to ions. In theGram-negative bacterium Escherichia coli, thiscomplex task can be achieved by using onlythree small membrane proteins: TatA, TatB andTatC. In this Review, we summarize recentadvances in our understanding of how thisremarkable machine operates.", "metadata": {}}
+{"_id": "1322614", "title": "", "text": "New developments in the ATSAS programpackage for small-angle scattering dataanalysisNew developments in the programpackage ATSAS (version 2.4) for the processingand analysis of isotropic small-angle X-ray andneutron scattering data are described. Theyinclude (i) multiplatform data manipulation anddisplay tools, (ii) programs for automated dataprocessing and calculation of overall parameters,(iii) improved usage of high- and low-resolutionmodels from other structural methods, (iv) newalgorithms to build three-dimensional modelsfrom weakly interacting oligomeric systems andcomplexes, and (v) enhanced tools to analysedata from mixtures and flexible systems. Thenew ATSAS release includes installers for currentmajor platforms (Windows, Linux and Mac OSX)and provides improved indexed userdocumentation. The web-related developments,including a user discussion forum and a widenedonline access to run ATSAS programs, are alsopresented.", "metadata": {}}
+{"_id": "1332250", "title": "", "text": "The First Myriapod Genome Sequence RevealsConservative Arthropod Gene Content andGenome Organisation in the Centipede StrigamiamaritimaMyriapods (e.g., centipedes andmillipedes) display a simple homonomous bodyplan relative to other arthropods. All members ofthe class are terrestrial, but they attainedterrestriality independently of insects. Myriapodais the only arthropod class not represented by asequenced genome. We present an analysis ofthe genome of the centipede Strigamia maritima.It retains a compact genome that has undergoneless gene loss and shuffling than previouslysequenced arthropods, and many orthologues ofgenes conserved from the bilaterian ancestorthat have been lost in insects. Our analysislocates many genes in conserved macro-syntenycontexts, and many small-scale examples ofgene clustering. We describe several exampleswhere S. maritima shows different solutions frominsects to similar problems. The insect olfactoryreceptor gene family is absent from S. maritima,", "metadata": {}}
+{"_id": "1333643", "title": "", "text": "Genetic and Functional Diversification of SmallRNA Pathways in PlantsMulticellular eukaryotesproduce small RNA molecules (approximately21–24 nucleotides) of two general types,microRNA (miRNA) and short interfering RNA(siRNA). They collectively function assequence-specific guides to silence or regulategenes, transposons, and viruses and to modifychromatin and genome structure. Formation oractivity of small RNAs requires factors belongingto gene families that encode DICER (orDICER-LIKE [DCL]) and ARGONAUTE proteinsand, in the case of some siRNAs, RNA-dependentRNA polymerase (RDR) proteins. Unlike manyanimals, plants encode multiple DCL and RDRproteins. Using a series of insertion mutants ofArabidopsis thaliana, unique functions for threeDCL proteins in miRNA (DCL1), endogenoussiRNA (DCL3), and viral siRNA (DCL2) biogenesiswere identified. One RDR protein (RDR2) wasrequired for all endogenous siRNAs analyzed.The loss of endogenous siRNA in dcl3 and rdr2", "metadata": {}}
+{"_id": "1336292", "title": "", "text": "Immunosuppressant FTY720 inhibits thymocyteemigration.One major role of the thymus is toprovide the peripheral immune system withmature T cells, but the mechanisms involving thecellular export are not fully understood. In thisstudy, we examined the ability of a novelimmunosuppressive reagent, FTY720, to inhibit Tcell export from the thymus. Daily administrationof FTY720 at a dose of 1 mg / kg resulted in amarked decrease in the number of peripheralblood T lymphocytes. In the thymus, long-termdaily administration of FTY720 caused a three- tofourfold increase in the proportion of maturemedullary thymocytes (CD4(+)CD8(-) andCD4(-)CD8(+)) as well as a slight decrease inthe double-positive cell (CD4(+)CD8(+)) ratio.Phenotypic analysis (TCRalpha beta, H-2K(d),CD44, CD69 and CD24) revealed that theseincreased subsets represent possible peripheralrecent thymic emigrants. High level expressionof L-selectin by these subsets further suggeststhat they were prevented from leaving the", "metadata": {}}
+{"_id": "1338283", "title": "", "text": "Validating a conceptual model for aninter-professional approach to shared decisionmaking: a mixed methods studyRATIONALE,AIMS AND OBJECTIVES Following increasedinterest in having inter-professional (IP) healthcare teams engage patients in decision making,we developed a conceptual model for an IPapproach to shared decision making (SDM) inprimary care. We assessed the validity of themodel with stakeholders in Canada. METHODS In15 individual interviews and 7 group interviewswith 79 stakeholders, we asked them to: (1)propose changes to the IP-SDM model; (2)identify barriers and facilitators to the model'simplementation in clinical practice; and (3)assess the model using a theory appraisalquestionnaire. We performed a thematic analysisof the transcripts and a descriptive analysis ofthe questionnaires. RESULTS Stakeholderssuggested placing the patient at its centre;extending the concept of family to includesignificant others; clarifying outcomes;", "metadata": {}}
+{"_id": "1344498", "title": "", "text": "Glutaminolysis activates Rag-mTORC1signaling.Amino acids control cell growth viaactivation of the highly conserved kinase TORC1.Glutamine is a particularly important amino acidin cell growth control and metabolism. However,the role of glutamine in TORC1 activationremains poorly defined. Glutamine ismetabolized through glutaminolysis to produceα-ketoglutarate. We demonstrate that glutaminein combination with leucine activates mammalianTORC1 (mTORC1) by enhancing glutaminolysisand α-ketoglutarate production. Inhibition ofglutaminolysis prevented GTP loading of RagBand lysosomal translocation and subsequentactivation of mTORC1. Constitutively active Ragheterodimer activated mTORC1 in the absence ofglutaminolysis. Conversely, enhancedglutaminolysis or a cell-permeableα-ketoglutarate analog stimulated lysosomaltranslocation and activation of mTORC1. Finally,cell growth and autophagy, two processescontrolled by mTORC1, were regulated by", "metadata": {}}
+{"_id": "1346695", "title": "", "text": "microRNA-31/factor-inhibiting hypoxia-induciblefactor 1 nexus regulates keratinocytedifferentiation.Notch plays a critical role in thetransition from proliferation to differentiation inthe epidermis and corneal epithelium.Furthermore, aberrant Notch signaling is afeature of diseases like psoriasis, eczema,nonmelanoma skin cancer, and melanoma wheredifferentiation and proliferation are impaired.Whereas much is known about the downstreamevents following Notch signaling, factorsresponsible for negatively regulating Notchreceptor signaling after ligand activation areincompletely understood. Notch can undergohydroxylation by factor-inhibitinghypoxia-inducible factor 1 (FIH-1); however, thebiological significance of this phenomenon isunclear. Here we show that FIH-1 expression isup-regulated in diseased epidermis and cornealepithelium. Elevating FIH-1 levels in primaryhuman epidermal keratinocytes (HEKs) andhuman corneal epithelial keratinocytes (HCEKs)", "metadata": {}}
+{"_id": "1349033", "title": "", "text": "Advantages of larval control for African malariavectors: Low mobility and behaviouralresponsiveness of immature mosquito stagesallow high effective coverageBased on sensitivityanalysis of the MacDonald-Ross model, it haslong been argued that the best way to reducemalaria transmission is to target adult femalemosquitoes with insecticides that can reduce thelongevity and human-feeding frequency ofvectors. However, these analyses have ignored afundamental biological difference betweenmosquito adults and the immature stages thatprecede them: adults are highly mobile flyinginsects that can readily detect and avoid manyintervention measures whereas mosquito eggs,larvae and pupae are confined within relativelysmall aquatic habitats and cannot readily escapecontrol measures. We hypothesize that thecontrol of adult but not immature mosquitoes iscompromised by their ability to avoidinterventions such as excito-repellantinsecticides. We apply a simple model of", "metadata": {}}
+{"_id": "1354567", "title": "", "text": "The Arabidopsis Chromatin-Modifying NuclearsiRNA Pathway Involves a Nucleolar RNAProcessing CenterIn Arabidopsis thaliana, smallinterfering RNAs (siRNAs) direct cytosinemethylation at endogenous DNA repeats in apathway involving two forms of nuclear RNApolymerase IV (Pol IVa and Pol IVb),RNA-DEPENDENT RNA POLYMERASE 2 (RDR2),DICER-LIKE 3 (DCL3), ARGONAUTE4 (AGO4),the chromatin remodeler DRD1, and the de novocytosine methyltransferase DRM2. We show thatRDR2, DCL3, AGO4, and NRPD1b (the largestsubunit of Pol IVb) colocalize with siRNAs withinthe nucleolus. By contrast, Pol IVa and DRD1 areexternal to the nucleolus and colocalize withendogenous repeat loci. Mutation-induced loss ofpathway proteins causes downstream proteins tomislocalize, revealing their order of action. PolIVa acts first, and its localization is RNAdependent, suggesting an RNA template. Wehypothesize that maintenance of theheterochromatic state involves locus-specific Pol", "metadata": {}}
+{"_id": "1358909", "title": "", "text": "Peripheral arterial disease in the elderly: TheRotterdam Study.To assess the age- andsex-specific prevalence of peripheral arterialdisease (PAD) and intermittent claudication (IC)in an elderly population, we performed apopulation-based study in 7715 subjects (40%men, 60% women) aged 55 years and over. Thepresence of PAD and IC was determined bymeasuring the ankle-arm systolic blood pressureindex (AAI) and by means of the World HealthOrganization/Rose questionnaire, respectively.PAD was considered present when the AAI was<0.90 in either leg. The prevalence of PAD was19.1% (95% confidence interval, 18.1% to20.0%): 16.9% in men and 20.5% in women.Symptoms of IC were reported by 1.6% (95%confidence interval, 1.3% to 1.9%) of the studypopulation (2.2% in men, 1.2% in women). Ofthose with PAD, 6.3% reported symptoms of IC(8.7% in men, 4.9% in women), whereas in68.9% of those with IC an AAI below 0.90 wasfound. Subjects with an AAI <0.90 were more", "metadata": {}}
+{"_id": "1360607", "title": "", "text": "Antioxidants attenuate the plasma cytokineresponse to exercise in humans.Exerciseincreases plasma TNF-alpha, IL-1beta, and IL-6,yet the stimuli and sources of TNF-alpha andIL-1beta remain largely unknown. We tested therole of oxidative stress and the potentialcontribution of monocytes in this cytokine(especially IL-1beta) response in previouslyuntrained individuals. Six healthy nonathletesperformed two 45-min bicycle exercise sessionsat 70% of Vo(2 max) before and after acombination of antioxidants (vitamins E, A, andC for 60 days; allopurinol for 15 days; andN-acetylcysteine for 3 days). Blood was drawn atbaseline, end-exercise, and 30 and 120 minpostexercise. Plasma cytokines were determinedby ELISA and monocyte intracellular cytokinelevel by flow cytometry. Before antioxidants,TNF-alpha increased by 60%, IL-1beta bythreefold, and IL-6 by sixfold secondary toexercise (P < 0.05). After antioxidants, plasmaIL-1beta became undetectable, the TNF-alpha", "metadata": {}}
+{"_id": "1365188", "title": "", "text": "Relation between colonic proglucagon expressionand metabolic response to oligofructose in highfat diet-fed mice.Several data suggest thatfermentable dietary fiber could play a role in thecontrol of obesity and associated metabolicdisorders. The aim of this study was toinvestigate the putative role of short chainfructo-oligosaccharide (OFS) - a non-digestibleoligosaccharide - in mice fed a standard diet andin mice fed two distinct high fat diets inducingmetabolic disorders associated to obesity. Weconfirmed, in mice, several effects previouslyshown in rats fed a standard diet enriched withOFS, namely an increase in total and emptycaecum weight, a significant decrease inepididymal fat mass, and an increase in colonicand portal plasma glucagon-like peptide-1(GLP-1), a phenomenon positively correlatedwith a higher colonic proglucagon mRNA level.Curiously, 4-week treatment with OFS added atthe same dose induced different effects whenadded in the two different high fat diets. OFS", "metadata": {}}
+{"_id": "1371440", "title": "", "text": "Aurora B phosphorylates spatially distinct targetsto differentially regulate thekinetochore-microtubule interface.Accuratechromosome segregation requires carefullyregulated interactions between kinetochores andmicrotubules, but how plasticity is achieved tocorrect diverse attachment defects remainsunclear. Here we demonstrate that Aurora Bkinase phosphorylates three spatially distincttargets within the conserved outer kinetochoreKNL1/Mis12 complex/Ndc80 complex (KMN)network, the key player inkinetochore-microtubule attachments. Thecombinatorial phosphorylation of the KMNnetwork generates graded levels ofmicrotubule-binding activity, with fullphosphorylation severely compromisingmicrotubule binding. Altering thephosphorylation state of each protein causescorresponding chromosome segregation defects.Importantly, the spatial distribution of thesetargets along the kinetochore axis leads to their", "metadata": {}}
+{"_id": "1373287", "title": "", "text": "Prognostic importance of 6-mercaptopurine doseintensity in acute lymphoblasticleukemia.6-Mercaptopurine (6MP) andmethotrexate are the backbone of continuationtherapy for childhood acute lymphoblasticleukemia (ALL). In studies of oral 6MP andmethotrexate, indices of chronic systemicexposure to active metabolites of these agents,namely, red blood cell (RBC) concentrations ofmethotrexate polyglutamates (MTXPGs) andthioguanine nucleotides (TGNs) have positivelycorrelated with event-free survival (EFS). Ourobjective was to evaluate whether MTXPGs,TGNs, and the dose intensity of administeredmethotrexate and 6MP were prognostic in thesetting of a treatment protocol in which alltreatment was coordinated through a singlecenter, and the weekly doses of methotrexatewere given parenterally. On protocol Total XII,182 children achieved remission and receivedweekly methotrexate 40 mg/m2 parenterally anddaily oral 6MP, interrupted every 6 weeks during", "metadata": {}}
+{"_id": "1379127", "title": "", "text": "Orai1 and STIM1 are critical for breast tumor cellmigration and metastasis.Tumor metastasis isthe primary cause of death of cancer patients.Understanding the molecular mechanismsunderlying tumor metastasis will providepotential drug targets. We report here that Orai1and STIM1, both of which are involved instore-operated calcium entry, are essential forbreast tumor cell migration in vitro and tumormetastasis in mice. Reduction of Orai1 or STIM1by RNA interference in highly metastatic humanbreast cancer cells or treatment with apharmacological inhibitor of store-operatedcalcium channels decreased tumor metastasis inanimal models. Our data demonstrate a role forOrai1 and STIM1 in tumor metastasis andsuggest store-operated calcium entry channelsas potential cancer therapeutic targets.", "metadata": {}}
+{"_id": "1381673", "title": "", "text": "Mouse Spermatogenic Stem Cells ContinuallyInterconvert between Equipotent Singly Isolatedand Syncytial StatesThe identity and behavior ofmouse spermatogenic stem cells have been along-standing focus of interest. In the prevailing\"As model,\" stem cell function is restricted tosingly isolated (As) spermatogonia. Byexamining single-cell dynamics of GFRα1+ stemcells in vivo, we evaluate an alternativehypothesis that, through fragmentation,syncytial spermatogonia also contribute to stemcell function in homeostasis. We use live imagingand pulse labeling to quantitatively determinethe fates of individual GFRα1+ cells and findthat, during steady-state spermatogenesis, theentire GFRα1+ population comprises a singlestem cell pool, in which cells continuallyinterconvert between As and syncytial states. Aminimal biophysical model, relying only on therates of incomplete cell division and syncytialfragmentation, precisely predicts the stochasticfates of GFRα1+ cells during steady state and", "metadata": {}}
+{"_id": "1383826", "title": "", "text": "Pseudoknots: RNA Structures with DiverseFunctionsRNA molecules fulfill a diverse set ofbiological functions within cells, from the transferof genetic information from DNA to protein, toenzymatic catalysis. Reflecting this range ofroles, simple linear strings of RNA—made up ofuracil, guanine, cytosine, and adenine—form avariety of complex three-dimensional structures.Just as proteins form distinct structural motifssuch as zinc fingers and beta barrels, certainstructures are also commonly adopted by RNAmolecules. Among the most prevalent RNAstructures is a motif known as the pseudoknot.First recognized in the turnip yellow mosaic virus[1], a pseudoknot is an RNA structure that isminimally composed of two helical segmentsconnected by single-stranded regions or loops(Figure 1). Although several distinct foldingtopologies of pseudoknots exist, the bestcharacterized is the H type. In the H-type fold,the bases in the loop of a hairpin formintramolecular pairs with bases outside of the", "metadata": {}}
+{"_id": "1386103", "title": "", "text": "An essential role for interferon gamma inresistance to Mycobacterium tuberculosisinfectionTuberculosis, a major health problem indeveloping countries, has reemerged in recentyears in many industrialized countries. Theincreased susceptibility of immunocompromisedindividuals to tuberculosis, and manyexperimental studies indicate that Tcell-mediated immunity plays an important rolein resistance. The lymphokine interferon gamma(IFN-gamma) is thought to be a principalmediator of macrophage activation andresistance to intracellular pathogens. Mice havebeen developed which fail to produceIFN-gamma (gko), because of a targeteddisruption of the gene for IFN-gamma. Uponinfection with Mycobacterium tuberculosis,although they develop granulomas, gko mice failto produce reactive nitrogen intermediates andare unable to restrict the growth of the bacilli. Incontrast to control mice, gko mice exhibitheightened tissue necrosis and succumb to a", "metadata": {}}
+{"_id": "1387104", "title": "", "text": "Malignancies, prothrombotic mutations, and therisk of venous thrombosis.CONTEXT Venousthrombosis is a common complication in patientswith cancer, leading to additional morbidity andcompromising quality of life. OBJECTIVE Toidentify individuals with cancer with an increasedthrombotic risk, evaluating different tumor sites,the presence of distant metastases, and carrierstatus of prothrombotic mutations. DESIGN,SETTING, AND PATIENTS A largepopulation-based, case-control (MultipleEnvironmental and Genetic Assessment [MEGA]of risk factors for venous thrombosis) study of3220 consecutive patients aged 18 to 70 years,with a first deep venous thrombosis of the leg orpulmonary embolism, between March 1, 1999,and May 31, 2002, at 6 anticoagulation clinics inthe Netherlands, and separate 2131 controlparticipants (partners of the patients) reportedvia a questionnaire on acquired risk factors forvenous thrombosis. Three months afterdiscontinuation of the anticoagulant therapy, all", "metadata": {}}
+{"_id": "1387654", "title": "", "text": "The Hippo signaling pathway restricts theoncogenic potential of an intestinal regenerationprogram.Although a developmental role forHippo signaling in organ size control is wellappreciated, how this pathway functions in tissueregeneration is largely unknown. Here weaddress this issue using a dextran sodium sulfate(DSS)-induced colonic regeneration model. Wefind that regenerating crypts express elevatedYes-associated protein (YAP) levels. Inactivationof YAP causes no obvious intestinal defects undernormal homeostasis, but severely impairsDSS-induced intestinal regeneration. Conversely,hyperactivation of YAP results in widespreadearly-onset polyp formation following DSStreatment. Thus, the YAP oncoprotein must beexquisitely controlled in tissue regeneration toallow compensatory proliferation and prevent theintrinsic oncogenic potential of a tissueregeneration program.", "metadata": {}}
+{"_id": "1388704", "title": "", "text": "The essence of SNPs.Single nucleotidepolymorphisms (SNPs) are an abundant form ofgenome variation, distinguished from rarevariations by a requirement for the leastabundant allele to have a frequency of 1% ormore. A wide range of genetics disciplines standto benefit greatly from the study and use ofSNPs. The recent surge of interest in SNPs stemsfrom, and continues to depend upon, themerging and coincident maturation of severalresearch areas, i.e. (i) large-scale genomeanalysis and related technologies, (ii)bio-informatics and computing, (iii) geneticanalysis of simple and complex disease states,and (iv) global human population genetics. Thesefields will now be propelled forward, often intouncharted territories, by ongoing discoveryefforts that promise to yield hundreds ofthousands of human SNPs in the next few years.Major questions are now being asked,experimentally, theoretically and ethically, aboutthe most effective ways to unlock the full", "metadata": {}}
+{"_id": "1389264", "title": "", "text": "Combination inhibition of PI3K and mTORC1yields durable remissions in orthotopicpatient-derived xenografts of HER2-positivebreast cancer brain metastasesBrain metastasesrepresent the greatest clinical challenge intreating HER2-positive breast cancer. We reportthe development of orthotopic patient-derivedxenografts (PDXs) of HER2-expressing breastcancer brain metastases (BCBM), and their usefor the identification of targeted combinationtherapies. Combined inhibition of PI3K andmTOR resulted in durable tumor regressions inthree of five PDXs, and therapeutic response wascorrelated with a reduction in thephosphorylation of 4EBP1, an mTORC1 effector.The two nonresponding PDXs showedhypermutated genomes with enrichment ofmutations in DNA-repair genes, which suggestsan association of genomic instability withtherapeutic resistance. These findings suggestthat a biomarker-driven clinical trial of PI3Kinhibitor in combination with an mTOR inhibitor", "metadata": {}}
+{"_id": "1391126", "title": "", "text": "Activation of Frontal Neocortical Areas by VocalProduction in MarmosetsPrimates often rely onvocal communication to mediate socialinteractions. Although much is known about theacoustic structure of primate vocalizations andthe social context in which they are usuallyuttered, our knowledge about the neocorticalcontrol of audio-vocal interactions in primates isstill incipient, being mostly derived from lesionstudies in squirrel monkeys and macaques. Tomap the neocortical areas related to vocalcontrol in a New World primate species, thecommon marmoset, we employed a methodpreviously used with success in other vertebratespecies: Analysis of the expression of theimmediate early gene Egr-1 in freely behavinganimals. The neocortical distribution of Egr-1immunoreactive cells in three marmosets thatwere exposed to the playback of conspecificvocalizations and vocalized spontaneously (H/Vgroup) was compared to data from three othermarmosets that also heard the playback but did", "metadata": {}}
+{"_id": "1398021", "title": "", "text": "Familial hiatal hernia in a large five generationfamily confirming true autosomal dominantinheritance.BACKGROUND Familial hiatal herniahas only rarely been documented. AIMS Todescribe the pattern of inheritance of familialhiatal hernia within an affected family. SUBJECTSThirty eight members of a family pedigree acrossfive generations. METHODS All family memberswere interviewed and investigated by bariummeal for evidence of a hiatal hernia. RESULTSTwenty three of 38 family members hadradiological evidence of a hiatal hernia. Noindividual with a hiatal hernia was born tounaffected parents. In one case direct male tomale transmission was shown. CONCLUSIONSFamilial inheritance of hiatal hernia does occur.Evidence of direct male to male transmissionpoints to an autosomal dominant mode ofinheritance.", "metadata": {}}
+{"_id": "1410197", "title": "", "text": "An Excitatory Loop with Astrocytes Contributesto Drive Neurons to Seizure ThresholdSeizures infocal epilepsies are sustained by a highlysynchronous neuronal discharge that arises atrestricted brain sites and subsequently spreadsto large portions of the brain. Despite intenseexperimental research in this field, the earliercellular events that initiate and sustain a focalseizure are still not well defined. Theiridentification is central to understand thepathophysiology of focal epilepsies and todevelop new pharmacological therapies fordrug-resistant forms of epilepsy. The prominentinvolvement of astrocytes in ictogenesis wasrecently proposed. We test here whether acooperation between astrocytes and neurons is aprerequisite to support ictal (seizure-like) andinterictal epileptiform events. Simultaneouspatch-clamp recording and Ca2+ imagingtechniques were performed in a new in vitromodel of focal seizures induced by localapplications of N-methyl-D-aspartic acid (NMDA)", "metadata": {}}
+{"_id": "1412089", "title": "", "text": "Diminished performance on neuropsychologicaltesting in late life depression is correlated withmicrostructural white matterabnormalities.BACKGROUND Traditional T2weighted MR imaging results are non-specific forthe extent of underlying white matter structuralabnormalities present in late life depression(LLD). Diffusion tensor imaging provides aunique opportunity to investigate the extent andnature of structural injury, but has been limitedby examining only a subset of regions of interest(ROI) and by confounds common to the study ofan elderly population, including comorbidvascular pathology. Furthermore, comprehensivecorrelation of diffusion tensor imaging (DTI)measurements, including axial and radialdiffusivity measurements, has not beendemonstrated in the late life depressionpopulation. METHODS 51 depressed and 16non-depressed, age- and cerebrovascular riskfactor-matched elderly subjects underwenttraditional anatomic T1 and T2 weight imaging,", "metadata": {}}
+{"_id": "1428830", "title": "", "text": "The atypical antipsychotic olanzapine causesweight gain by targeting serotonin receptor2C.Atypical antipsychotics such as olanzapineoften induce excessive weight gain and type 2diabetes. However, the mechanisms underlyingthese drug-induced metabolic perturbationsremain poorly understood. Here, we used anexperimental model that reproducesolanzapine-induced hyperphagia and obesity infemale C57BL/6 mice. We found that olanzapinetreatment acutely increased food intake,impaired glucose tolerance, and altered physicalactivity and energy expenditure in mice.Furthermore, olanzapine-induced hyperphagiaand weight gain were blunted in mice lacking theserotonin 2C receptor (HTR2C). Finally, weshowed that treatment with the HTR2C-specificagonist lorcaserin suppressedolanzapine-induced hyperphagia and weightgain. Lorcaserin treatment also improved glucosetolerance in olanzapine-fed mice. Collectively,our studies suggest that olanzapine exerts some", "metadata": {}}
+{"_id": "1428840", "title": "", "text": "Case-control study of endogenous steroidhormones and endometrial cancer.BACKGROUNDIt has been suggested that identified risk factorsfor endometrial cancer operate through a singleetiologic pathway, i.e., exposure to relativelyhigh levels of unopposed estrogen (estrogen inthe absence of progestins). Only a few studies,however, have addressed this issue directly.PURPOSE We assessed the risk of developingendometrial cancer among both premenopausaland postmenopausal women in relation to thecirculating levels of steroid hormones and sexhormone-binding globulin (SHBG). Theindependent effect of hormones was assessedafter adjustment for other known risk factors.METHODS The data used in the analysis are froma case-control study conducted in fivegeographic regions in the United States. Incidentcases were newly diagnosed during the periodfrom June 1, 1987, through May 15, 1990. Thecase patients, aged 20-74 years, were matchedto control subjects by age, race, and geographic", "metadata": {}}
+{"_id": "1447990", "title": "", "text": "FOXO4 is necessary for neural differentiation ofhuman embryonic stem cells.Proteostasis iscritical for maintaining cell function andproteome stability may play an important role inhuman embryonic stem cell (hESC) immortality.Notably, hESC populations exhibit a highassembly of active proteasomes, a key node ofthe proteostasis network. FOXO4, aninsulin/IGF-1 responsive transcription factor,regulates proteasome activity in hESCs. We findthat loss of FOXO4 reduces the potential ofhESCs to differentiate into neural lineages.Therefore, FOXO4 crosses evolutionaryboundaries and links hESC function toinvertebrate longevity modulation.", "metadata": {}}
+{"_id": "1449692", "title": "", "text": "Gestational protein restriction affects trophoblastdifferentiation.Whether and how gestationalprotein restriction (PR) affects placentaldevelopment and function remain unknown. Totest the hypothesis that PR can affect trophoblastdifferentiation in mid-and late pregnancy, ratswere fed a 20% or an isocaloric 6% protein dietfrom Day 1 to 14 or 18 of pregnancy and effectsof PR on trophoblast differentiation weredetermined by changes in expressions of markergene(s) for trophoblast lineages. At Day 18 ofpregnancy, PR increased expressions of Esrrb,Id1 andId2 (trophoblast stem cell markers),decreased expressions of Ascl2(spongiotrophblast cell marker) and Prl2c1(trophoblast giant cell marker), but did not alterexpressions of Gjb3 and Pcdh12(glycogen cellmarkers) in the junctional zone (JZ). In thelabyrinth zone (LZ), PR did not changeexpressions of Prl2b1 (trophoblast giant cellmarker), Gcm1 and Syna (syncytiotrophoblastcell markers), but decrease expression of Ctsq", "metadata": {}}
+{"_id": "1454773", "title": "", "text": "In vitro characterization of the anti-PD-1antibody nivolumab, BMS-936558, and in vivotoxicology in non-human primates.Theprogrammed death-1 (PD-1) receptor serves asan immunologic checkpoint, limiting bystandertissue damage and preventing the developmentof autoimmunity during inflammatory responses.PD-1 is expressed by activated T cells anddownmodulates T-cell effector functions uponbinding to its ligands, PD-L1 and PD-L2, onantigen-presenting cells. In patients with cancer,the expression of PD-1 on tumor-infiltratinglymphocytes and its interaction with the ligandson tumor and immune cells in the tumormicroenvironment undermine antitumorimmunity and support its rationale for PD-1blockade in cancer immunotherapy. This reportdetails the development and characterization ofnivolumab, a fully human IgG4 (S228P)anti-PD-1 receptor-blocking monoclonalantibody. Nivolumab binds to PD-1 with highaffinity and specificity, and effectively inhibits the", "metadata": {}}
+{"_id": "1456068", "title": "", "text": "Combined Impact of Lifestyle-Related Factors onTotal and Cause-Specific Mortality amongChinese Women: Prospective CohortStudyBACKGROUND Although cigarette smoking,excessive alcohol drinking, obesity, and severalother well-studied unhealthy lifestyle-relatedfactors each have been linked to the risk ofmultiple chronic diseases and premature death,little is known about the combined impact onmortality outcomes, in particular among Chineseand other non-Western populations. Theobjective of this study was to quantify the overallimpact of lifestyle-related factors beyond that ofactive cigarette smoking and alcoholconsumption on all-cause and cause-specificmortality in Chinese women. METHODS ANDFINDINGS We used data from the ShanghaiWomen's Health Study, an ongoingpopulation-based prospective cohort study inChina. Participants included 71,243 women aged40 to 70 years enrolled during 1996-2000 whonever smoked or drank alcohol regularly. A", "metadata": {}}
+{"_id": "1469751", "title": "", "text": "Aptamer-functionalized lipid nanoparticlestargeting osteoblasts as a novel RNAinterference–based bone anabolicstrategyCurrently, major concerns about thesafety and efficacy of RNA interference(RNAi)-based bone anabolic strategies still existbecause of the lack of direct osteoblast-specificdelivery systems for osteogenic siRNAs. Here wescreened the aptamer CH6 by cell-SELEX,specifically targeting both rat and humanosteoblasts, and then we developed CH6aptamer–functionalized lipid nanoparticles(LNPs) encapsulating osteogenic pleckstrinhomology domain-containing family O member 1(Plekho1) siRNA (CH6-LNPs-siRNA). Our resultsshowed that CH6 facilitated in vitroosteoblast-selective uptake of Plekho1 siRNA,mainly via macropinocytosis, and boosted in vivoosteoblast-specific Plekho1 gene silencing, whichpromoted bone formation, improved bonemicroarchitecture, increased bone mass andenhanced mechanical properties in both", "metadata": {}}
+{"_id": "1471041", "title": "", "text": "High abundance of plasma cells secretingtransglutaminase 2–specific IgA autoantibodieswith limited somatic hypermutation in celiacdisease intestinal lesionsCeliac disease is animmune-mediated disorder in which mucosalautoantibodies to the enzyme transglutaminase2 (TG2) are generated in response to theexogenous antigen gluten in individuals whoexpress human leukocyte antigen HLA-DQ2 orHLA-DQ8 (ref. 3). We assessed in acomprehensive and nonbiased manner the IgAanti-TG2 response by expression cloning of theantibody repertoire of ex vivo–isolated intestinalantibody-secreting cells (ASCs). We found thatTG2-specific plasma cells are markedly expandedwithin the duodenal mucosa in individuals withactive celiac disease. TG2-specific antibodieswere of high affinity yet showed little adaptationby somatic mutations. Unlike infection-inducedperipheral blood plasmablasts, the TG2-specificASCs had not recently proliferated and were notshort-lived ex vivo. Altogether, these", "metadata": {}}
+{"_id": "1472815", "title": "", "text": "Alterations of white matter integrity in adultswith major depressive disorder: a magneticresonance imaging study.OBJECTIVE Thepurpose of our study was to investigatealterations of white matter integrity in adultswith major depressive disorder (MDD) usingmagnetic resonance imaging (MRI). METHODSWe performed diffusion tensor imaging with a 3TMRI scanner on 45 patients with majordepression and 45 healthy controls matched forage, sex and education. Using a voxel-basedanalysis, we measured the fractional anisotropy(FA), and we investigated the differencesbetween the patient and control groups. Weexamined the correlations between themicrostructure abnormalities of white matter andsymptom severity, age of illness onset andcumulative illness duration, respectively.RESULTS We found a significant decrease in FAin the left hemisphere, including the anteriorlimb of the internal capsule and the inferiorparietal portion of the superior longitudinal", "metadata": {}}
+{"_id": "1495563", "title": "", "text": "[Clinical study on the therapeutic effect ofacupuncture in the treatment of post-strokedepression].OBJECTIVE To observe thetherapeutic effect of \"Xingnao Kaiqiao Zhenfa\"(Acupuncture Technique for RestoringConsciousness) in the treatment of post-strokedepression. METHODS A total of 256 strokepatients were divided into acupuncture group (n= 180, male 138, female 42) and medicationgroup (n = 76, male 57 and female 19)according to their visiting sequence to ourhospital. Acupoints used were Neiguan (PC 6),Renzhong (GV 26), Baihui (GV 20), Yintang(EX-HN 3) and Sanyinjiao (SP 6,the affectedside) and the needles were retained for 20 minevery time. Patients of medication group wereasked to take Amitriptyline (50 mg/d at first, 200mg/d). Acupuncture treatment was conductedtwice daily, and after one month's treatment thetherapeutic effect was evaluated. Self-RatingDepression Scale (SDS) and Hamilton RatingScale for Depression (HRSD) were used to assess", "metadata": {}}
+{"_id": "1499964", "title": "", "text": "30 Years of NF-κB: A Blossoming of Relevance toHuman PathobiologyNF-κB was discovered 30years ago as a rapidly inducible transcriptionfactor. Since that time, it has been found to havea broad role in gene induction in diverse cellularresponses, particularly throughout the immunesystem. Here, we summarize elaborateregulatory pathways involving this transcriptionfactor and use recent discoveries in humangenetic diseases to place specific proteins withintheir relevant medical and biological contexts.", "metadata": {}}
+{"_id": "1507222", "title": "", "text": "Increased gene expression of brown fatuncoupling protein (UCP)1 and skeletal muscleUCP2 and UCP3 in MAC16-induced cancercachexia.Weight loss in cancer cachexia isattributable to decreased food intake and/orenhanced energy expenditure. We investigatedthe roles of the uncoupling proteins (UCPs) UCPI,-2, and -3 in a murine model of cachexia, theMAC16 adenocarcinoma. Weight fell to 24%below that of non-tumor-bearing controls (P <0.01) 18 days after MAC16 inoculation, withsignificant reductions in fat-pad mass (-67%; P< 0.01) and muscle mass (-20%; P < 0.01).Food intake was 26-60% lower (P < 0.01) thanin controls on days 17-18. Non-tumor-bearingmice, pair-fed to match MAC16-inducedhypophagia, showed less weight loss (10% belowcontrols, P < 0.01; 16% above MAC-16, P <0.01) and smaller decreases in fat-pad mass(21% below controls, P < 0.01). Coretemperature in MAC16 mice was significantlylower (-2.4 degrees C, P < 0.01) than in", "metadata": {}}
+{"_id": "1522336", "title": "", "text": "In vitro Anti-Tumor Effects of Statins on Headand Neck Squamous Cell Carcinoma: ASystematic ReviewBACKGROUND Statins arecommonly used against arteriosclerotic disease,but recent retrospective analyses havesuggested that statins also prevent cancer. Theaim of this systematic review is to verify the vitroanti-tumor effects of statins on head and necksquamous cell carcinoma. METHODS Studieswere gathered by searching Cochrane, MEDLINE,EMBASE, LILACS, and PubMed, up until May 9,2015, with no time or language restrictions. Onlyin vitro studies that discuss the effect of statinson head and neck carcinoma were selected.RESULTS Of 153 identified papers, 14 studiesmet the inclusion criteria. These studiesdemonstrated that statins had a significant effecton head and neck squamous cell carcinoma celllines and influenced cell viability, cell cycle, celldeath, and protein expression levels involved inpathways of carcinogenesis, which corroborateswith the potential in vitro anti-tumor effects. It", "metadata": {}}
+{"_id": "1522647", "title": "", "text": "Circulating Mitochondrial DNA in Patients in theICU as a Marker of Mortality: Derivation andValidationBACKGROUND Mitochondrial DNA(mtDNA) is a critical activator of inflammationand the innate immune system. However,mtDNA level has not been tested for its role as abiomarker in the intensive care unit (ICU). Wehypothesized that circulating cell-free mtDNAlevels would be associated with mortality andimprove risk prediction in ICU patients.METHODS AND FINDINGS Analyses of mtDNAlevels were performed on blood samplesobtained from two prospective observationalcohort studies of ICU patients (the Brigham andWomen's Hospital Registry of Critical Illness[BWH RoCI, n = 200] and MolecularEpidemiology of Acute Respiratory DistressSyndrome [ME ARDS, n = 243]). mtDNA levelsin plasma were assessed by measuring the copynumber of the NADH dehydrogenase 1 geneusing quantitative real-time PCR. Medical ICUpatients with an elevated mtDNA level (≥3,200", "metadata": {}}
+{"_id": "1538080", "title": "", "text": "Fructosamine Is a Useful Indicator ofHyperglycaemia and Glucose Control in Clinicaland Epidemiological Studies – Cross-Sectionaland Longitudinal Experience from the AMORISCohortCONTEXT Fructosamine is a glycemicbiomarker which may be useful for indication andcontrol of diabetes respectively. OBJECTIVE Theobjective of the study was to evaluatefructosamine as an indicator of hyperglycaemiaand glucose control in subjects with diabetes.DESIGN, SETTING & PATIENTS From theAMORIS cohort, subjects with serum glucose,fructosamine and HbA1c from the sameexamination were studied cross-sectionally andlongitudinally (n = 10,987; 5,590overnight-fasting). The guidelines of theAmerican Diabetes Association were followed forclassification of prediabetes and diabetes.Separate analyses were performed in patientswith a newly detected or a known diagnosis oftype 1 or type 2 diabetes respectively. RESULTSAll three biomarkers were strongly correlated.", "metadata": {}}
+{"_id": "1539159", "title": "", "text": "Lifeact: a versatile marker to visualizeF-actinLive imaging of the actin cytoskeleton iscrucial for the study of many fundamentalbiological processes, but current approaches tovisualize actin have several limitations. Here wedescribe Lifeact, a 17-amino-acid peptide, whichstained filamentous actin (F-actin) structures ineukaryotic cells and tissues. Lifeact did notinterfere with actin dynamics in vitro and in vivoand in its chemically modified peptide formallowed visualization of actin dynamics innontransfectable cells.", "metadata": {}}
+{"_id": "1542437", "title": "", "text": "Robustness of Random Forest-based geneselection methodsGene selection is an importantpart of microarray data analysis because itprovides information that can lead to a bettermechanistic understanding of an investigatedphenomenon. At the same time, gene selection isvery difficult because of the noisy nature ofmicroarray data. As a consequence, geneselection is often performed with machinelearning methods. The Random Forest method isparticularly well suited for this purpose. In thiswork, four state-of-the-art Random Forest-basedfeature selection methods were compared in agene selection context. The analysis focused onthe stability of selection because, although it isnecessary for determining the significance ofresults, it is often ignored in similar studies. Thecomparison of post-selection accuracy in thevalidation of Random Forest classifiers revealedthat all investigated methods were equivalent inthis context. However, the methods substantiallydiffered with respect to the number of selected", "metadata": {}}
+{"_id": "1544804", "title": "", "text": "Improved variant discovery through localre-alignment of short-read next-generationsequencing data using SRMAA primarycomponent of next-generation sequencinganalysis is to align short reads to a referencegenome, with each read aligned independently.However, reads that observe the samenon-reference DNA sequence are highlycorrelated and can be used to better model thetrue variation in the target genome. A novelshort-read micro realigner, SRMA, that leveragesthis correlation to better resolve a consensus ofthe underlying DNA sequence of the targetedgenome is described here.", "metadata": {}}
+{"_id": "1546650", "title": "", "text": "Functional elements within the dyneinmicrotubule-binding domainDynein interacts withmicrotubules through an ATP-sensitive linkagemapped to a structurally complex region of theheavy chain following the fourth P-loop motif.Virtually nothing is known regarding how bindingaffinity is achieved and modulated during ATPhydrolysis. We have performed a detaileddissection of the microtubule contact site, usingfragment expression, alanine substitution, andpeptide competition. Our work identifies threeclusters of amino acids important for the physicalcontact with microtubules; two of these fallwithin a region sharing sequence homology withMAP1B, the third in a region just downstream.Amino acid substitutions within any one of theseregions can eliminate or weaken microtubulebinding (KK3379, 80, E3385, K3387, K3397,KK3410,11, W3414, RKK3418-20, F3426,R3464, S3466, and K3467), suggesting thattheir activities are highly coordinated. A peptidethat actively displaces MAP1B from microtubules", "metadata": {}}
+{"_id": "1550937", "title": "", "text": "The Transcription Factors Egr2 and Egr3 AreEssential for the Control of Inflammation andAntigen-Induced Proliferation of B and TCellsLymphocytes provide optimal responsesagainst pathogens with minimal inflammatorypathology. However, the intrinsic mechanismsregulating these responses are unknown. Here,we report that deletion of both transcriptionfactors Egr2 and Egr3 in lymphocytes resulted ina lethal autoimmune syndrome with excessiveserum proinflammatory cytokines but alsoimpaired antigen receptor-induced proliferationof B and T cells. Egr2- and Egr3-defective B andT cells had hyperactive signal transducer andactivator of transcription-1 (STAT1) and STAT3while antigen receptor-induced activation oftranscription factor AP-1 was severely impaired.We discovered that Egr2 and/or Egr3 directlyinduced expression of suppressor of cytokinesignaling-1 (SOCS1) and SOCS3, inhibitors ofSTAT1 and STAT3, and also blocked the functionof Batf, an AP-1 inhibitor, in B and T cells. Thus,", "metadata": {}}
+{"_id": "1554348", "title": "", "text": "Effect of hyperosmolality on alkalinephosphatase and stress-response protein 27 ofMCF-7 breast cancer cellsMCF-7, a continuouscell line derived from a human breast carcinoma,exhibits very low alkaline phosphatase (ALP)activity. The enzyme is heat-stable and isinhibited by L-phenylalanine andL-phenylalanylgly-cylglycine, but not byL-homoarginine, 1-bromotetramisole, orlevamisole. These data indicate that MCF-7produces term-placental ALP, theoncodevelopmental enzyme form inappropriatelyexpressed by a variety of human tumors. Incontrast to human cancer cells that produce thisenzyme monophenotypically, ALP activity ofMCF-7 cells is not significantly increased byglucocorticoids or sodium butyrate. Bycomparison, exposure to hyperosmolality causesa striking increase in enzyme activity.Cycloheximide blocks this effect. The resultsobtained with cell-free assays were confirmed bycytochemical and immunocytochemical assays", "metadata": {}}
+{"_id": "1568684", "title": "", "text": "The Bile Acid Chenodeoxycholic Acid IncreasesHuman Brown Adipose Tissue Activity.Theinterest in brown adipose tissue (BAT) as atarget to combat metabolic disease has recentlybeen renewed with the discovery of functionalBAT in humans. In rodents, BAT can be activatedby bile acids, which activate type 2 iodothyroninedeiodinase (D2) in BAT via the G-coupled proteinreceptor TGR5, resulting in increased oxygenconsumption and energy expenditure. Here weexamined the effects of oral supplementation ofthe bile acid chenodeoxycholic acid (CDCA) onhuman BAT activity. Treatment of 12 healthyfemale subjects with CDCA for 2 days resulted inincreased BAT activity. Whole-body energyexpenditure was also increased upon CDCAtreatment. In vitro treatment of primary humanbrown adipocytes derived with CDCA or specificTGR5 agonists increased mitochondrialuncoupling and D2 expression, an effect that wasabsent in human primary white adipocytes.These findings identify bile acids as a target to", "metadata": {}}
+{"_id": "1569031", "title": "", "text": "RNase H and Postreplication Repair Protect Cellsfrom Ribonucleotides Incorporated in DNAThechemical identity and integrity of the genome ischallenged by the incorporation of ribonucleosidetriphosphates (rNTPs) in place ofdeoxyribonucleoside triphosphates (dNTPs)during replication. Misincorporation is limited bythe selectivity of DNA replicases. We show thataccumulation of ribonucleoside monophosphates(rNMPs) in the genome causes replication stressand has toxic consequences, particularly in theabsence of RNase H1 and RNase H2, whichremove rNMPs. We demonstrate thatpostreplication repair (PRR)pathways-MMS2-dependent template switch andPol ζ-dependent bypass-are crucial for toleratingthe presence of rNMPs in the chromosomes;indeed, we show that Pol ζ efficiently replicatesover 1-4 rNMPs. Moreover, cells lacking RNase Haccumulate mono- and polyubiquitylated PCNAand have a constitutively activated PRR. Ourfindings describe a crucial function for RNase H1,", "metadata": {}}
+{"_id": "1574014", "title": "", "text": "Selective elimination of high constitutive activityor chemokine binding in the human herpesvirus8 encoded seven transmembrane oncogeneORF74.Open reading frame 74 (ORF74) encodedby human herpesvirus 8 is a highly constitutivelyactive seven transmembrane (7TM) receptorstimulated by angiogenic chemokines, e.g.growth-related oncogene-alpha, and inhibited byangiostatic chemokines e.g.interferon-gamma-inducible protein. Transgenicmice expressing ORF74 under control of the CD2promoter develop highly vascularized Kaposi'ssarcoma-like tumors. Through targetedmutagenesis we here create three distinctphenotypes of ORF74: a receptor with normal,high constitutive signaling through thephospholipase C pathway but deprived of bindingand action of chemokines obtained throughdeletion of 22 amino acids from the N-terminalextension; an ORF74 with high constitutiveactivity but with selective elimination ofstimulatory regulation by angiogenic chemokines", "metadata": {}}
+{"_id": "1576955", "title": "", "text": "An insulin-like signaling pathway affects bothlongevity and reproduction in Caenorhabditiselegans.Mutations in daf-2 and age-1 cause adramatic increase in longevity as well asdevelopmental arrest at the dauer diapausestage in Caenorhabditis elegans. daf-2 and age-1encode components of an insulin-like signalingpathway. Both daf-2 and age-1 act at a similarpoint in the genetic epistasis pathway for dauerarrest and longevity and regulate the activity ofthe daf-16 gene. Mutations in daf-16 cause adauer-defective phenotype and are epistatic tothe diapause arrest and life span extensionphenotypes of daf-2 and age-1 mutants. Here weshow that mutations in this pathway also affectfertility and embryonic development. Weak daf-2alleles, and maternally rescued age-1 alleles thatcause life span extension but do not arrest at thedauer stage, also reduce fertility and viability.We find that age-1(hx546) has reduced bothmaternal and zygotic age-1 activity. daf-16mutations suppress all of the daf-2 and age-1", "metadata": {}}
+{"_id": "1583041", "title": "", "text": "Estimating prion concentration in fluids andtissues by quantitative PMCAPrions, theproteinaceous infectious agent responsible forprion diseases, can be detected with highsensitivity by protein misfolding cyclicamplification (PMCA) technology. Here wedescribe a quantitative PMCA procedure tocalculate the concentration of very low levels ofprions in biological samples. Using thisprocedure, we determined the quantities ofmisfolded prion protein (PrPSc) in brain, spleen,blood and urine of scrapie-affected hamsters.", "metadata": {}}
+{"_id": "1583134", "title": "", "text": "Positional cloning of the APECEDgeneAutoimmune polyglandular syndrome type I(APS 1, also called APECED) is anautosomal-recessive disorder that maps tohuman chromosome 21q22.3 between markersD21S49 and D21S171 by linkage studies. Wehave isolated a novel gene from this region, AIRE(autoimmune regulator), which encodes aprotein containing motifs suggestive of atranscription factor including two zinc-finger(PHD-finger) motifs, a proline-rich region andthree LXXLL motifs. Two mutations, a C\u0000Tsubstitution that changes the Arg 257 (CGA) to astop codon (TGA) and an A\u0000G substitution thatchanges the Lys 83 (AAG) to a Glu codon (GAG),were found in this novel gene in Swiss andFinnish APECED patients. The Arg257stop(R257X) is the predominant mutation in FinnishAPECED patients, accounting for 10/12 allelesstudied. These results indicate that this gene isresponsible for the pathogenesis of APECED. Theidentification of the gene defective in APECED", "metadata": {}}
+{"_id": "1590744", "title": "", "text": "AMP-Activated Protein Kinase: An UbiquitousSignaling Pathway With Key Roles in theCardiovascular SystemThe AMP-activated proteinkinase (AMPK) is a key regulator of cellular andwhole-body energy homeostasis, which acts torestore energy homoeostasis whenever cellularenergy charge is depleted. Over the last 2decades, it has become apparent that AMPKregulates several other cellular functions and hasspecific roles in cardiovascular tissues, acting toregulate cardiac metabolism and contractilefunction, as well as promoting anticontractile,anti-inflammatory, and antiatherogenic actions inblood vessels. In this review, we discuss the roleof AMPK in the cardiovascular system, includingthe molecular basis of mutations in AMPK thatalter cardiac physiology and the proposedmechanisms by which AMPK regulates vascularfunction under physiological andpathophysiological conditions.", "metadata": {}}
+{"_id": "1595617", "title": "", "text": "Differentiation of trophoblast stem cells intogiant cells is triggered by p57/Kip2 inhibition ofCDK1 activity.Genome endoreduplication duringmammalian development is a rare event forwhich the mechanism is unknown. It firstappears when fibroblast growth factor 4 (FGF4)deprivation induces differentiation of trophoblaststem (TS) cells into the nonproliferatingtrophoblast giant (TG) cells required for embryoimplantation. Here we show that RO3306inhibition of cyclin-dependent protein kinase 1(CDK1), the enzyme required to enter mitosis,induced differentiation of TS cells into TG cells.In contrast, RO3306 induced abortiveendoreduplication and apoptosis in embryonicstem cells, revealing that inactivation of CDK1triggers endoreduplication only in cellsprogrammed to differentiate into polyploid cells.Similarly, FGF4 deprivation resulted in CDK1inhibition by overexpressing two CDK-specificinhibitors, p57/KIP2 and p21/CIP1. TS cellmutants revealed that p57 was required to", "metadata": {}}
+{"_id": "1605196", "title": "", "text": "Atg5-independent autophagy regulatesmitochondrial clearance and is essential for iPSCreprogrammingSuccessful generation of inducedpluripotent stem cells entails a major metabolicswitch from mitochondrial oxidativephosphorylation to glycolysis during thereprogramming process. The mechanism of thismetabolic reprogramming, however, remainselusive. Here, our results suggest that anAtg5-independent autophagic process mediatesmitochondrial clearance, a characteristic eventinvolved in the metabolic switch. We found thatblocking such autophagy, but not canonicalautophagy, inhibits mitochondrial clearance, inturn, preventing iPSC induction. Furthermore,AMPK seems to be upstream of this autophagicpathway and can be targeted by small moleculesto modulate mitochondrial clearance duringmetabolic reprogramming. Our work not onlyreveals that the Atg5-independent autophagy iscrucial for establishing pluripotency, but it alsosuggests that iPSC generation and tumorigenesis", "metadata": {}}
+{"_id": "1605392", "title": "", "text": "A mutation in Orai1 causes immune deficiency byabrogating CRAC channel functionAntigenstimulation of immune cells triggers Ca2+ entrythrough Ca2+ release-activated Ca2+ (CRAC)channels, promoting the immune response topathogens by activating the transcription factorNFAT. We have previously shown that cells frompatients with one form of hereditary severecombined immune deficiency (SCID) syndromeare defective in store-operated Ca2+ entry andCRAC channel function. Here we identify thegenetic defect in these patients, using acombination of two unbiased genome-wideapproaches: a modified linkage analysis withsingle-nucleotide polymorphism arrays, and aDrosophila RNA interference screen designed toidentify regulators of store-operated Ca2+ entryand NFAT nuclear import. Both approachesconverged on a novel protein that we call Orai1,which contains four putative transmembranesegments. The SCID patients are homozygousfor a single missense mutation in ORAI1, and", "metadata": {}}
+{"_id": "1606628", "title": "", "text": "Estimates of global prevalence of childhoodunderweight in 1990 and 2015.CONTEXT Onekey target of the United Nations MillenniumDevelopment goals is to reduce the prevalence ofunderweight among children younger than 5years by half between 1990 and 2015.OBJECTIVE To estimate trends in childhoodunderweight by geographic regions of the world.DESIGN, SETTING, AND PARTICIPANTS Timeseries study of prevalence of underweight,defined as weight 2 SDs below the mean weightfor age of the National Center for HealthStatistics and World Health Organization (WHO)reference population. National prevalence ratesderived from the WHO Global Database on ChildGrowth and Malnutrition, which includes data onapproximately 31 million children younger than 5years who participated in 419 national nutritionalsurveys in 139 countries from 1965 through2002. MAIN OUTCOME MEASURES Linearmixed-effects modeling was used to estimateprevalence rates and numbers of underweight", "metadata": {}}
+{"_id": "1616661", "title": "", "text": "Canonical Wnt signaling regulates organ-specificassembly and differentiation of CNSvasculature.Every organ depends on bloodvessels for oxygen and nutrients, but thevasculature associated with individual organs canbe structurally and molecularly diverse. Thecentral nervous system (CNS) vasculatureconsists of a tightly sealed endothelium thatforms the blood-brain barrier, whereas bloodvessels of other organs are more porous. Wnt7aand Wnt7b encode two Wnt ligands produced bythe neuroepithelium of the developing CNScoincident with vascular invasion. Using geneticmouse models, we found that these ligandsdirectly target the vascular endothelium and thatthe CNS uses the canonical Wnt signalingpathway to promote formation and CNS-specificdifferentiation of the organ's vasculature.", "metadata": {}}
+{"_id": "1617327", "title": "", "text": "Bone progenitor dysfunction inducesmyelodysplasia and secondaryleukemiaMesenchymal cells contribute to the'stroma' of most normal and malignant tissues,with specific mesenchymal cells participating inthe regulatory niches of stem cells. By examininghow mesenchymal osteolineage cells modulatehaematopoiesis, here we show that deletion ofDicer1 specifically in mouse osteoprogenitors,but not in mature osteoblasts, disrupts theintegrity of haematopoiesis. Myelodysplasiaresulted and acute myelogenous leukaemiaemerged that had acquired several geneticabnormalities while having intact Dicer1.Examining gene expression altered inosteoprogenitors as a result of Dicer1 deletionshowed reduced expression of Sbds, the genemutated in Schwachman-Bodian-Diamondsyndrome-a human bone marrow failure andleukaemia pre-disposition condition. Deletion ofSbds in mouse osteoprogenitors induced bonemarrow dysfunction with myelodysplasia.", "metadata": {}}
+{"_id": "1624106", "title": "", "text": "Generating diploid embryos from Xenopustropicalis.A spectacular advantage of Xenopustropicalis is the ease with which diploid embryoscan be generated year round. By the simpleadministration of human chorionic gonadotropin,an investigator can generate many hundreds ofsynchronized embryos by in vitro fertilization orthousands of embryos from a mating pair. Theability to induce ovulations when desiredfacilitates many different experiments such asexperimental embryology, molecularmanipulation of gene products, and genetics.", "metadata": {}}
+{"_id": "1630949", "title": "", "text": "Oct4-Induced Pluripotency in Adult Neural StemCellsThe four transcription factors Oct4, Sox2,Klf4, and c-Myc can induce pluripotency inmouse and human fibroblasts. We previouslydescribed direct reprogramming of adult mouseneural stem cells (NSCs) by Oct4 and either Klf4or c-Myc. NSCs endogenously express Sox2,c-Myc, and Klf4 as well as several intermediatereprogramming markers. Here we report thatexogenous expression of the germline-specifictranscription factor Oct4 is sufficient to generatepluripotent stem cells from adult mouse NSCs.These one-factor induced pluripotent stem cells(1F iPS) are similar to embryonic stem cells invitro and in vivo. Not only can these cells can beefficiently differentiated into NSCs,cardiomyocytes, and germ cells in vitro, but theyare also capable of teratoma formation andgermline transmission in vivo. Our resultsdemonstrate that Oct4 is required and sufficientto directly reprogram NSCs to pluripotency.", "metadata": {}}
+{"_id": "1631583", "title": "", "text": "Getting started with yeast.Publisher SummaryThe yeast Saccharomyces cerevisiae is nowrecognized as a model system representing asimple eukaryote whose genome can be easilymanipulated. Yeast has only a slightly greatergenetic complexity than bacteria and sharesmany of the technical advantages that permittedrapid progress in the molecular genetics ofprokaryotes and their viruses. Some of theproperties that make yeast particularly suitablefor biological studies include rapid growth,dispersed cells, the ease of replica plating andmutant isolation, a well-defined genetic system,and most important, a highly versatile DNAtransformation system. Being nonpathogenic,yeast can be handled with little precautions.Large quantities of normal baker's yeast arecommercially available and can provide a cheapsource for biochemical studies. The developmentof DNA transformation has made yeastparticularly accessible to gene cloning andgenetic engineering techniques. Structural genes", "metadata": {}}
+{"_id": "1635872", "title": "", "text": "PCNA functions as a molecular platform to triggerCdt1 destruction and preventre-replicationUbiquitin-mediated proteolysis ofthe replication licensing factor Cdt1(Cdc10-dependent transcript 1) in S phase is akey mechanism that limits DNA replication to asingle round per cell cycle in metazoans. InXenopus egg extracts, Cdt1 is destroyed onchromatin during DNA replication. Here, wereport that replication-dependent proteolysis ofCdt1 requires its interaction with proliferating cellnuclear antigen (PCNA), a homotrimericprocessivity factor for DNA polymerases. Cdt1binds to PCNA through a consensusPCNA-interaction motif that is conserved in Cdt1of all metazoans, and removal of PCNA from eggextracts inhibits replication-dependent Cdt1destruction. Mutation of the PCNA-interactionmotif yields a stabilized Cdt1 protein that inducesre-replication. DDB1, a component of the Cul4E3 ubiquitin ligase that mediates human Cdt1proteolysis in response to DNA damage, is also", "metadata": {}}
+{"_id": "1641873", "title": "", "text": "Meiosis in Drosophila: seeing isbelieving.Recently many exciting advances havebeen achieved in our understanding ofDrosophila meiosis due to combined cytologicaland genetic approaches. New techniques havepermitted the characterization of chromosomeposition and spindle formation in female meiosisI. The proteins encoded by the nod and ncdgenes, two genes known to be needed for theproper partitioning of chromosomes lackingexchange events, have been identified and foundto be kinesin-like motors. The effects ofmutations in these genes on the spindle andchromosomes, together with the localization ofthe proteins, have yielded a model for themechanism of female meiosis I. In male meiosisI, the chromosomal regions responsible forhomolog pairing have been resolved to the levelof specific DNA sequences. This provides afoundation for elucidating the molecular basis ofmeiotic pairing. The cytological techniquesavailable in Drosophila also have permitted", "metadata": {}}
+{"_id": "1642727", "title": "", "text": "Effect of physical activity on cognitive function inolder adults at risk for Alzheimer disease: arandomized trial.CONTEXT Many observationalstudies have shown that physical activity reducesthe risk of cognitive decline; however, evidencefrom randomized trials is lacking. OBJECTIVE Todetermine whether physical activity reduces therate of cognitive decline among older adults atrisk. DESIGN AND SETTING Randomizedcontrolled trial of a 24-week physical activityintervention conducted between 2004 and 2007in metropolitan Perth, Western Australia.Assessors of cognitive function were blinded togroup membership. PARTICIPANTS We recruitedvolunteers who reported memory problems butdid not meet criteria for dementia. Threehundred eleven individuals aged 50 years orolder were screened for eligibility, 89 were noteligible, and 52 refused to participate. A total of170 participants were randomized and 138participants completed the 18-monthassessment. INTERVENTION Participants were", "metadata": {}}
+{"_id": "1649738", "title": "", "text": "Variants at 6q21 implicate PRDM1 in the etiologyof therapy-induced second malignancies afterHodgkin's lymphomaSurvivors of pediatricHodgkin's lymphoma are at risk for radiationtherapy–induced second malignant neoplasms(SMNs). We identified two variants atchromosome 6q21 associated with SMNs insurvivors of Hodgkin's lymphoma treated withradiation therapy as children but not as adults.The variants comprise a risk locus associatedwith decreased basal expression of PRDM1(encoding PR domain containing 1, with ZNFdomain) and impaired induction of the PRDM1protein after radiation exposure. These datasuggest a new gene-exposure interaction thatmay implicate PRDM1 in the etiology of radiationtherapy-induced SMNs.", "metadata": {}}
+{"_id": "1667063", "title": "", "text": "Long non-coding RNA profiling of humanlymphoid progenitor cells reveals transcriptionaldivergence of B cell and T cell lineagesToelucidate the transcriptional 'landscape' thatregulates human lymphoid commitment duringpostnatal life, we used RNA sequencing toassemble the long non-coding transcriptomeacross human bone marrow and thymicprogenitor cells spanning the earliest stages of Blymphoid and T lymphoid specification. Over3,000 genes encoding previously unknown longnon-coding RNAs (lncRNAs) were revealedthrough the analysis of these rare populations.Lymphoid commitment was characterized bylncRNA expression patterns that were highlystage specific and were more lineage specificthan those of protein-coding genes.Protein-coding genes co-expressed withneighboring lncRNA genes showed enrichmentfor ontologies related to lymphoid differentiation.The exquisite cell-type specificity of globallncRNA expression patterns independently", "metadata": {}}
+{"_id": "1669173", "title": "", "text": "The VTI family of SNARE proteins is necessaryfor plant viability and mediates different proteintransport pathways.The Arabidopsis genomecontains a family of v-SNAREs: VTI11, VTI12,and VTI13. Only VTI11 and VTI12 are expressedat appreciable levels. Although these twoproteins are 60% identical, they complementdifferent transport pathways when expressed inthe yeast vti1 mutant. VTI11 was identifiedrecently as the mutated gene in the shootgravitropic mutant zig. Here, we show that thevti11 zig mutant has defects in vascularpatterning and auxin transport. An ArabidopsisT-DNA insertion mutant, vti12, had a normalphenotype under nutrient-rich growth conditions.However, under nutrient-poor conditions, vti12showed an accelerated senescence phenotype,suggesting that VTI12 may play a role in theplant autophagy pathway. VTI11 and VTI12 alsowere able to substitute for each other in theirrespective SNARE complexes, and adouble-mutant cross between zig and vti12 was", "metadata": {}}
+{"_id": "1676568", "title": "", "text": "CLASPs link focal adhesion-associatedmicrotubule capture to localized exocytosis andadhesion site turnoverTurnover of integrin-basedfocal adhesions (FAs) with the extracellularmatrix (ECM) is essential for coordinated cellmovement. In collectively migrating humankeratinocytes, FAs assemble near the leadingedge, grow and mature as a result of contractileforces and disassemble underneath theadvancing cell body. We report that clustering ofmicrotubule-associated CLASP1 and CLASP2proteins around FAs temporally correlates withFA turnover. CLASPs and LL5β (also known asPHLDB2), which recruits CLASPs to FAs, facilitateFA disassembly. CLASPs are further required forFA-associated ECM degradation, and matrixmetalloprotease inhibition slows FA disassemblysimilarly to CLASP or PHLDB2 (LL5β) depletion.Finally, CLASP-mediated microtubule tethering atFAs establishes an FA-directed transportpathway for delivery, docking and localizedfusion of exocytic vesicles near FAs. We propose", "metadata": {}}
+{"_id": "1684489", "title": "", "text": "CHD4 Is a RanGTP-Dependent MAP thatStabilizes Microtubules and Regulates BipolarSpindle FormationBACKGROUND Production ofthe GTP-bound form of the Ran GTPase(RanGTP) around chromosomes induces spindleassembly by activating nuclear localization signal(NLS)-containing proteins. Several NLS proteinshave been identified as spindle assembly factors,but the complexity of the process led us tosearch for additional proteins with distinct rolesin spindle assembly. RESULTS We identify achromatin-remodeling ATPase, CHD4, as aRanGTP-dependent microtubule (MT)-associatedprotein (MAP). MT binding occurs via the regioncontaining an NLS and chromatin-bindingdomains. In Xenopus egg extracts and culturedcells, CHD4 largely dissociates from mitoticchromosomes and partially localizes to thespindle. Immunodepletion of CHD4 from eggextracts significantly reduces the quantity of MTsproduced around chromatin and prevents spindleassembly. CHD4 RNAi in both HeLa and", "metadata": {}}
+{"_id": "1686881", "title": "", "text": "Myocardial muscarinic receptor upregulation andnormal response to isoproterenol in denervatedhearts by familial amyloidpolyneuropathy.BACKGROUND Patients withfamilial amyloid polyneuropathy, a rarehereditary form of amyloidosis, have progressiveautonomic neuropathy. The disease usually doesnot induce heart failure but is associated withsudden death, conduction disturbances, and anincreased risk of complications duringanesthesia. Although cardiac sympatheticdenervation has been clearly demonstrated, thepostsynaptic status of the cardiac autonomicnervous system remains unelucidated. METHODSAND RESULTS Twenty-one patients were studied(age, 39+/-11 years; normal coronary arteries;left ventricular ejection fraction 68+/-9%). Toevaluate the density and affinity constants ofmyocardial muscarinic receptors, PET with(11)C-MQNB (methylquinuclidinyl benzilate), aspecific hydrophilic antagonist, was used.Cardiac beta-receptor functional efficiency was", "metadata": {}}
+{"_id": "1686997", "title": "", "text": "6-phosphogluconate dehydrogenase linksoxidative PPP, lipogenesis and tumor growth byinhibiting LKB1-AMPK signalingThe oxidativepentose phosphate pathway (PPP) contributes totumour growth, but the precise contribution of6-phosphogluconate dehydrogenase (6PGD), thethird enzyme in this pathway, to tumorigenesisremains unclear. We found that suppression of6PGD decreased lipogenesis and RNAbiosynthesis and elevated ROS levels in cancercells, attenuating cell proliferation and tumourgrowth. 6PGD-mediated production ofribulose-5-phosphate (Ru-5-P) inhibits AMPKactivation by disrupting the active LKB1 complex,thereby activating acetyl-CoA carboxylase 1 andlipogenesis. Ru-5-P and NADPH are thought tobe precursors in RNA biosynthesis andlipogenesis, respectively; thus, our findingsprovide an additional link between the oxidativePPP and lipogenesis through Ru-5-P-dependentinhibition of LKB1-AMPK signalling. Moreover, weidentified and developed 6PGD inhibitors,", "metadata": {}}
+{"_id": "1695604", "title": "", "text": "Plant Nuclear RNA Polymerase IV Mediates siRNAand DNA Methylation-DependentHeterochromatin FormationAll eukaryotes havethree nuclear DNA-dependent RNA polymerases,namely, Pol I, II, and III. Interestingly, plantshave catalytic subunits for a fourth nuclearpolymerase, Pol IV. Genetic and biochemicalevidence indicates that Pol IV does notfunctionally overlap with Pol I, II, or III and isnonessential for viability. However, disruption ofthe Pol IV catalytic subunit genes NRPD1 orNRPD2 inhibits heterochromatin association intochromocenters, coincident with losses in cytosinemethylation at pericentromeric 5S gene clustersand AtSN1 retroelements. Loss of CG, CNG, andCNN methylation in Pol IV mutants implicates apartnership between Pol IV and themethyltransferase responsible for RNA-directedde novo methylation. Consistent with thishypothesis, 5S gene and AtSN1 siRNAs areessentially eliminated in Pol IV mutants. Thedata suggest that Pol IV helps produce siRNAs", "metadata": {}}
+{"_id": "1701063", "title": "", "text": "Sema3A regulates bone-mass accrual throughsensory innervationsSemaphorin 3A (Sema3A) isa diffusible axonal chemorepellent that has animportant role in axon guidance. Previous studieshave demonstrated that Sema3a−/− mice havemultiple developmental defects due to abnormalneuronal innervations. Here we show in micethat Sema3A is abundantly expressed in bone,and cell-based assays showed that Sema3Aaffected osteoblast differentiation in acell-autonomous fashion. Accordingly,Sema3a−/− mice had a low bone mass due todecreased bone formation. However,osteoblast-specific Sema3A-deficient mice(Sema3acol1−/− and Sema3aosx−/�� mice) hadnormal bone mass, even though the expressionof Sema3A in bone was substantially decreased.In contrast, mice lacking Sema3A in neurons(Sema3asynapsin−/− and Sema3anestin−/−mice) had low bone mass, similar to Sema3a−/−mice, indicating that neuron-derived Sema3A isresponsible for the observed bone abnormalities", "metadata": {}}
+{"_id": "1709625", "title": "", "text": "Direct lineage reprogramming: strategies,mechanisms, and applications.The direct lineagereprogramming of one specialized cell type intoanother using defined factors has fundamentallyre-shaped traditional concepts regarding theepigenetic stability of differentiated cells. Withthe rapid increase in cell types generatedthrough direct conversion in recent years, thisstrategy has become a promising approach forproducing functional cells. Here, we reviewrecent advances in lineage reprogramming,including the identification of novelreprogramming factors, underlying molecularmechanisms, strategies for generatingfunctionally mature cells, and assays forcharacterizing induced cells. We also discussprogress toward the application of lineagereprogramming and the major future challengesfor this strategy.", "metadata": {}}
+{"_id": "1710116", "title": "", "text": "Converging Intracranial Markers of ConsciousAccessWe compared conscious and nonconsciousprocessing of briefly flashed words using a visualmasking procedure while recording intracranialelectroencephalogram (iEEG) in ten patients.Nonconscious processing of masked words wasobserved in multiple cortical areas, mostly withinan early time window (<300 ms), accompaniedby induced gamma-band activity, but withoutcoherent long-distance neural activity,suggesting a quickly dissipating feedforwardwave. In contrast, conscious processing ofunmasked words was characterized by theconvergence of four distinct neurophysiologicalmarkers: sustained voltage changes, particularlyin prefrontal cortex, large increases in spectralpower in the gamma band, increases inlong-distance phase synchrony in the beta range,and increases in long-range Granger causality.We argue that all of those measures providedistinct windows into the same distributed stateof conscious processing. These results have a", "metadata": {}}
+{"_id": "1711571", "title": "", "text": "Hyperglycemia is associated with increased bonemineral density and decreased trabecular bonescore in elderly Japanese men: The Fujiwara-kyoosteoporosis risk in men (FORMEN)study.PURPOSE Patients with type 2 diabetesmellitus (T2DM) have an increased fracture riskdespite having higher areal bone mineral density(aBMD). This study aimed to clarify theassociation between glycemic and insulinresistance status and bone microarchitecture,and whether pentosidine and bone turnovermarkers play any roles in the association.METHODS A total of 2012 community-dwellingmen aged ≥65years completed baselinemeasurements of spine aBMD, fasting plasmaglucose (FPG) and serum insulin, hemoglobinA1c (HbA1c), osteocalcin, type I procollagenN-terminal propeptide, type I collagen C-terminalcrosslinking telopeptide, tartrate-resistant acidphosphatase isoenzyme 5b, pentosidine, heightand weight and an interview regarding pastdisease history. Homeostasis model", "metadata": {}}
+{"_id": "1727042", "title": "", "text": "Matrix Remodeling Promotes PulmonaryHypertension through FeedbackMechanoactivation of the YAP/TAZ-miR-130/301Circuit.Pulmonary hypertension (PH) is a deadlyvascular disease with enigmatic molecularorigins. We found that vascular extracellularmatrix (ECM) remodeling and stiffening are earlyand pervasive processes that promote PH. Inmultiple pulmonary vascular cell types, such ECMstiffening induced the microRNA-130/301 familyvia activation of the co-transcription factors YAPand TAZ. MicroRNA-130/301 controlled aPPAR?-APOE-LRP8 axis, promoting collagendeposition and LOX-dependent remodeling andfurther upregulating YAP/TAZ via amechanoactive feedback loop. In turn, ECMremodeling controlled pulmonary vascular cellcrosstalk via such mechanotransduction,modulation of secreted vasoactive effectors, andregulation of associated microRNA pathways. Invivo, pharmacologic inhibition ofmicroRNA-130/301, APOE, or LOX activity", "metadata": {}}
+{"_id": "1727493", "title": "", "text": "Exosomal transfer of stroma-derived miR21confers paclitaxel resistance in ovarian cancercells through targeting APAF1Advanced ovariancancer usually spreads to the visceral adiposetissue of the omentum. However, the omentalstromal cell-derived molecular determinants thatmodulate ovarian cancer growth have not beencharacterized. Here, using next-generationsequencing technology, we identify significantlyhigher levels of microRNA-21 (miR21) isomiRNAsin exosomes and tissue lysates isolated fromcancer-associated adipocytes (CAAs) andfibroblasts (CAFs) than in those from ovariancancer cells. Functional studies reveal that miR21is transferred from CAAs or CAFs to the cancercells, where it suppresses ovarian cancerapoptosis and confers chemoresistance bybinding to its direct novel target, APAF1. Thesedata suggest that the malignant phenotype ofmetastatic ovarian cancer cells can be altered bymiR21 delivered by exosomes derived fromneighbouring stromal cells in the omental tumour", "metadata": {}}
+{"_id": "1733337", "title": "", "text": "Age-related changes in kynurenic acid productionin rat brain.Two separate in vitro assays wereused to examine the biosynthesis of the broadspectrum excitatory amino acid receptorantagonist kynurenic acid (KYNA) during the lifespan of the adult rat. Assessment of KYNA'sanabolic enzyme kynurenine aminotransferaserevealed steady increases between 3 and 24months of age in all five brain regions examined.No changes were observed in the liver. Thechanges were particularly pronounced in thecortex and in the striatum where enzyme activityincreased three-fold during the period studied.KYNA production from its bioprecursorL-kynurenine was also investigated in tissueslices and was found to be significantly enhancedin the cortex and hippocampus of old animals.The effect of depolarizing agents or sodiumreplacement was virtually identical in tissuesfrom young and old rats. These data, which arein excellent agreement with reports on anage-dependent increase of KYNA concentration in", "metadata": {}}
+{"_id": "1744097", "title": "", "text": "The polycomb group protein Suz12 is requiredfor embryonic stem cell differentiation.Polycombgroup (PcG) proteins form multiproteincomplexes, called Polycomb repressivecomplexes (PRCs). PRC2 contains the PcGproteins EZH2, SUZ12, and EED and repressestranscription through methylation of lysine (K)27 of histone H3 (H3). Suz12 is essential forPRC2 activity and its inactivation results in earlylethality of mouse embryos. Here, wedemonstrate that Suz12(-/-) mouse embryonicstem (ES) cells can be established and expandedin tissue culture. The Suz12(-/-) ES cells arecharacterized by global loss of H3K27trimethylation (H3K27me3) and higherexpression levels of differentiation-specificgenes. Moreover, Suz12(-/-) ES cells areimpaired in proper differentiation, resulting in alack of repression of ES cell markers as well asactivation of differentiation-specific genes.Finally, we demonstrate that the PcGs areactively recruited to several genes during ES cell", "metadata": {}}
+{"_id": "1744752", "title": "", "text": "The 1.9 A structure of a proteasome-11Sactivator complex and implications forproteasome-PAN/PA700interactions.Proteasomes are cylindricalstructures that function in multiple cellularprocesses by degrading a wide variety ofcytosolic and nuclear proteins. Substrate accessand product release from the enclosed catalyticchamber occurs through axial pores that areopened by activator complexes. Here, we reporthigh-resolution structures of wild-type andmutant archaeal proteasomes bound to theactivator PA26. These structures support theproposal that an ordered open conformation isrequired for proteolysis and that its formationcan be triggered by outward displacement ofsurrounding residues. The structures andassociated biochemical assays reveal themechanism of binding, which involves aninteraction between the PA26 C terminus and aconserved lysine. Surprisingly, biochemicalobservations implicate an equivalent interaction", "metadata": {}}
+{"_id": "1748921", "title": "", "text": "Innate Immune and Chemically TriggeredOxidative Stress Modifies TranslationalFidelityTranslational fidelity, essential for proteinand cell function, requires accurate transfer RNA(tRNA) aminoacylation. Purified aminoacyl-tRNAsynthetases exhibit a fidelity of one error per10,000 to 100,000 couplings. The accuracy oftRNA aminoacylation in vivo is uncertain,however, and might be considerably lower. Herewe show that in mammalian cells, approximately1% of methionine (Met) residues used in proteinsynthesis are aminoacylated tonon-methionyl-tRNAs. Remarkably,Met-misacylation increases up to tenfold uponexposing cells to live or non-infectious viruses,toll-like receptor ligands or chemically inducedoxidative stress. Met is misacylated to specificnon-methionyl-tRNA families, and theseMet-misacylated tRNAs are used in translation.Met-misacylation is blocked by an inhibitor ofcellular oxidases, implicating reactive oxygenspecies (ROS) as the misacylation trigger.", "metadata": {}}
+{"_id": "1754001", "title": "", "text": "Yeast sirtuins and the regulation of aging.Thesirtuins are a phylogenetically conserved familyof NAD(+) -dependent protein deacetylases thatconsume one molecule of NAD(+) for everydeacetylated lysine side chain. Their requirementfor NAD(+) potentially makes them prone toregulation by fluctuations in NAD(+) orbiosynthesis intermediates, thus linking them tocellular metabolism. The Sir2 protein fromSaccharomyces cerevisiae is the founding sirtuinfamily member and has been well characterizedas a histone deacetylase that functions intranscriptional silencing of heterochromatindomains and as a pro-longevity factor forreplicative life span (RLS), defined as thenumber of times a mother cell divides (buds)before senescing. Deleting SIR2 shortens RLS,while increased gene dosage causes extension.Furthermore, Sir2 has been implicated inmediating the beneficial effects of caloricrestriction (CR) on life span, not only in yeast,but also in higher eukaryotes. While this", "metadata": {}}
+{"_id": "1759213", "title": "", "text": "The effect of combination treatment withaliskiren and blockers of the renin-angiotensinsystem on hyperkalaemia and acute kidneyinjury: systematic review andmeta-analysisOBJECTIVE To examine the safetyof using aliskiren combined with agents used toblock the renin-angiotensin system. DESIGNSystematic review and meta-analysis ofrandomised controlled trials. DATA SOURCESMedline, Embase, the Cochrane Library, and twotrial registries, published up to 7 May 2011.STUDY SELECTION Published and unpublishedrandomised controlled trials that comparedcombined treatment using aliskiren andangiotensin converting enzyme inhibitors orangiotensin receptor blockers with monotherapyusing these agents for at least four weeks andthat provided numerical data on the adverseevent outcomes of hyperkalaemia and acutekidney injury. A random effects model was usedto calculate pooled risk ratios and 95%confidence intervals for these outcomes.", "metadata": {}}
+{"_id": "1769799", "title": "", "text": "The ins and outs of DNA transfer inbacteria.Transformation and conjugation permitthe passage of DNA through the bacterialmembranes and represent dominant modes forthe transfer of genetic information betweenbacterial cells or between bacterial andeukaryotic cells. As such, they are responsiblefor the spread of fitness-enhancing traits,including antibiotic resistance. Both processesusually involve the recognition ofdouble-stranded DNA, followed by the transfer ofsingle strands. Elaborate molecular machines areresponsible for negotiating the passage ofmacromolecular DNA through the layers of thecell surface. All or nearly all the machinecomponents involved in transformation andconjugation have been identified, and here wepresent models for their roles in DNA transport.", "metadata": {}}
+{"_id": "1771079", "title": "", "text": "Synaptic islands defined by the territory of asingle astrocyte.In the mammalian brain,astrocytes modulate neuronal function, in part,by synchronizing neuronal firing and coordinatingsynaptic networks. Little, however, is knownabout how this is accomplished from a structuralstandpoint. To investigate the structural basis ofastrocyte-mediated neuronal synchrony andsynaptic coordination, the three-dimensionalrelationships between cortical astrocytes andneurons was investigated. Using a transgenicand viral approach to label astrocytes withenhanced green fluorescent protein, weperformed a three-dimensional reconstruction ofastrocytes from tissue sections or live animals invivo. We found that cortical astrocytes occupynonoverlapping territories similar to thosedescribed in the hippocampus. Usingimmunofluorescence labeling of neuronalsomata, a single astrocyte enwraps on averagefour neuronal somata with an upper limit ofeight. Single-neuron dye-fills allowed us to", "metadata": {}}
+{"_id": "1780819", "title": "", "text": "Role of DNA Methylation and Epigenetic Silencingof HAND2 in Endometrial CancerDevelopmentBACKGROUND Endometrial cancerincidence is continuing to rise in the wake of thecurrent ageing and obesity epidemics. Much ofthe risk for endometrial cancer development isinfluenced by the environment and lifestyle.Accumulating evidence suggests that theepigenome serves as the interface between thegenome and the environment and thathypermethylation of stem cell polycomb grouptarget genes is an epigenetic hallmark of cancer.The objective of this study was to determine thefunctional role of epigenetic factors inendometrial cancer development. METHODS ANDFINDINGS Epigenome-wide methylation analysisof >27,000 CpG sites in endometrial cancertissue samples (n = 64) and control samples (n= 23) revealed that HAND2 (a gene encoding atranscription factor expressed in the endometrialstroma) is one of the most commonlyhypermethylated and silenced genes in", "metadata": {}}
+{"_id": "1781626", "title": "", "text": "Socioeconomic factors, material inequalities, andperceived control in self-rated health:cross-sectional data from seven post-communistcountries.This study examined the associationbetween perceived control and severalsocioeconomic variables and self-rated health inseven post-communist countries (Russia,Estonia, Lithuania, Latvia, Hungary, Poland,Czech Republic). Questionnaire interviews wereused to collect data on self-rated health in thelast 12 months, education, marital status,perceived control based on nine questions, andmaterial deprivation based on availability of food,clothing and heating. For each population, twoecological measures of material inequalities wereavailable: an inequality score estimated from thesurvey data as the distance between the 90thand 10th percentiles of material deprivation, andGini coefficient from published sources. Data on5330 men and women aged 20-60 wereanalysed. Prevalence of poor health (worse thanaverage) varied between 8% in Czechs and 19%", "metadata": {}}
+{"_id": "1782201", "title": "", "text": "Integrin αvβ3/c-src “Oncogenic Unit” PromotesAnchorage-independence and TumorProgressionIntegrins regulateadhesion-dependent growth, survival andinvasion of tumor cells. In particular, expressionof integrin alpha(v)beta(3) is associated withprogression of a variety of human tumors. Herewe reveal a previously undescribedadhesion-independent role for integrinalpha(v)beta(3) in pancreatic cancer and othercarcinomas. Specifically, alpha(v)beta(3)expressed in carcinoma cells enhancedanchorage-independent tumor growth in vitroand increased lymph node metastases in vivo.These effects required recruitment of c-Src to thebeta(3) integrin cytoplasmic tail, leading to c-Srcactivation, Crk-associated substrate (CAS)phosphorylation and tumor cell survival that,unexpectedly, was independent of cell adhesionor focal adhesion kinase (FAK) activation.Pharmacological blockade of c-Src kinase activityor decreased expression of endogenous", "metadata": {}}
+{"_id": "1791637", "title": "", "text": "Genomewide Analysis of PRC1 and PRC2Occupancy Identifies Two Classes of BivalentDomainsIn embryonic stem (ES) cells, bivalentchromatin domains with overlapping repressive(H3 lysine 27 tri-methylation) and activating (H3lysine 4 tri-methylation) histone modificationsmark the promoters of more than 2,000 genes.To gain insight into the structure and function ofbivalent domains, we mapped key histonemodifications and subunits ofPolycomb-repressive complexes 1 and 2 (PRC1and PRC2) genomewide in human and mouse EScells by chromatin immunoprecipitation, followedby ultra high-throughput sequencing. We findthat bivalent domains can be segregated into twoclasses -- the first occupied by both PRC2 andPRC1 (PRC1-positive) and the second specificallybound by PRC2 (PRC2-only). PRC1-positivebivalent domains appear functionally distinct asthey more efficiently retain lysine 27tri-methylation upon differentiation, showstringent conservation of chromatin state, and", "metadata": {}}
+{"_id": "1791714", "title": "", "text": "Spatiotemporal regulation ofepithelial-mesenchymal transition is essential forsquamous cell carcinomametastasis.Epithelial-mesenchymal transition(EMT) is implicated in converting stationaryepithelial tumor cells into motile mesenchymalcells during metastasis. However, theinvolvement of EMT in metastasis is stillcontroversial, due to the lack of a mesenchymalphenotype in human carcinoma metastases.Using a spontaneous squamous cell carcinomamouse model, we show that activation of theEMT-inducing transcription factor Twist1 issufficient to promote carcinoma cells to undergoEMT and disseminate into blood circulation.Importantly, in distant sites, turning off Twist1 toallow reversion of EMT is essential fordisseminated tumor cells to proliferate and formmetastases. Our study demonstrates in vivo therequirement of \"reversible EMT\" in tumormetastasis and may resolve the controversy onthe importance of EMT in carcinoma metastasis.", "metadata": {}}
+{"_id": "1797622", "title": "", "text": "Control of Apoptosis by Asymmetric CellDivisionAsymmetric cell division and apoptosis(programmed cell death) are two fundamentalprocesses that are important for thedevelopment and function of multicellularorganisms. We have found that the processes ofasymmetric cell division and apoptosis can befunctionally linked. Specifically, we show thatasymmetric cell division in the nematodeCaenorhabditis elegans is mediated by apathway involving three genes, dnj-11 MIDA1,ces-2 HLF, and ces-1 Snail, that directly controlthe enzymatic machinery responsible forapoptosis. Interestingly, the MIDA1-like proteinGlsA of the alga Volvox carteri, as well as theSnail-related proteins Snail, Escargot, andWorniu of Drosophila melanogaster, havepreviously been implicated in asymmetric celldivision. Therefore, C. elegans dnj-11 MIDA1,ces-2 HLF, and ces-1 Snail may be componentsof a pathway involved in asymmetric cell divisionthat is conserved throughout the plant and", "metadata": {}}
+{"_id": "1800734", "title": "", "text": "CXCR2 mediates NADPH oxidase–independentneutrophil extracellular trap formation in cysticfibrosis airway inflammationUpon activation,neutrophils release DNA fibers decorated withantimicrobial proteins, forming neutrophilextracellular traps (NETs). Although NETs arebactericidal and contribute to innate hostdefense, excessive NET formation has beenlinked to the pathogenesis of autoinflammatorydiseases. However, the mechanisms regulatingNET formation, particularly during chronicinflammation, are poorly understood. Here weshow that the G protein–coupled receptor(GPCR) CXCR2 mediates NET formation.Downstream analyses showed thatCXCR2-mediated NET formation wasindependent of NADPH oxidase and involved Srcfamily kinases. We show the pathophysiologicalrelevance of this mechanism in cystic fibrosislung disease, characterized by chronicneutrophilic inflammation. We found abundantNETs in airway fluids of individuals with cystic", "metadata": {}}
+{"_id": "1805641", "title": "", "text": "Modelling the Impact of Artemisinin CombinationTherapy and Long-Acting Treatments on MalariaTransmission IntensityBACKGROUND Artemisininderivatives used in recently introducedcombination therapies (ACTs) for Plasmodiumfalciparum malaria significantly lower patientinfectiousness and have the potential to reducepopulation-level transmission of the parasite.With the increased interest in malariaelimination, understanding the impact ontransmission of ACT and other antimalarial drugswith different pharmacodynamics becomes a keyissue. This study estimates the reduction intransmission that may be achieved byintroducing different types of treatment forsymptomatic P. falciparum malaria in endemicareas. METHODS AND FINDINGS We developed amathematical model to predict the potentialimpact on transmission outcomes of introducingACT as first-line treatment for uncomplicatedmalaria in six areas of varying transmissionintensity in Tanzania. We also estimated the", "metadata": {}}
+{"_id": "1818578", "title": "", "text": "Systems metabolic engineering of Escherichiacoli for L-threonine productionAmino-acidproducers have traditionally been developed byrepeated random mutagenesis owing to thedifficulty in rationally engineering the complexand highly regulated metabolic network. Here,we report the development of the geneticallydefined L-threonine overproducing Escherichiacoli strain by systems metabolic engineering.Feedback inhibitions of aspartokinase I and III(encoded by thrA and lysC, respectively) andtranscriptional attenuation regulations (located inthrL) were removed. Pathways for Thrdegradation were removed by deleting tdh andmutating ilvA. The metA and lysA genes weredeleted to make more precursors available forThr biosynthesis. Further target genes to beengineered were identified by transcriptomeprofiling combined with in silico flux responseanalysis, and their expression levels weremanipulated accordingly. The final engineered E.coli strain was able to produce Thr with a high", "metadata": {}}
+{"_id": "1831916", "title": "", "text": "Association Between ADHD and Obesity: ASystematic Review andMeta-Analysis.OBJECTIVE Impulsivity andinattention related to attention deficithyperactivity disorder (ADHD) may increase foodintake and, consequently, weight gain. However,findings on the association betweenobesity/overweight and ADHD are mixed. Theauthors conducted a meta-analysis to estimatethis association. METHOD A broad range ofdatabases was searched through Aug. 31, 2014.Unpublished studies were also obtained. Studyquality was rated with the Newcastle-OttawaScale. Random-effects models were used.RESULTS Forty-two studies that included a totalof 728,136 individuals (48,161 ADHD subjects;679,975 comparison subjects) were retained. Asignificant association between obesity andADHD was found for both children (oddsratio=1.20, 95% CI=1.05-1.37) and adults(odds ratio=1.55, 95% CI=1.32-1.81). Thepooled prevalence of obesity was increased by", "metadata": {}}
+{"_id": "1834762", "title": "", "text": "Amyloid-DNA Composites of Bacterial BiofilmsStimulate Autoimmunity.Research on the humanmicrobiome has established that commensal andpathogenic bacteria can influence obesity,cancer, and autoimmunity through mechanismsmostly unknown. We found that a component ofbacterial biofilms, the amyloid protein curli,irreversibly formed fibers with bacterial DNAduring biofilm formation. This interactionaccelerated amyloid polymerization and createdpotent immunogenic complexes that activatedimmune cells, including dendritic cells, toproduce cytokines such as type I interferons,which are pathogenic in systemic lupuserythematosus (SLE). When given systemically,curli-DNA composites triggered immuneactivation and production of autoantibodies inlupus-prone and wild-type mice. We also foundthat the infection of lupus-prone mice withcurli-producing bacteria triggered higherautoantibody titers compared to curli-deficientbacteria. These data provide a mechanism by", "metadata": {}}
+{"_id": "1836154", "title": "", "text": "Comprehensive genomic characterization defineshuman glioblastoma genes and corepathwaysHuman cancer cells typically harbourmultiple chromosomal aberrations, nucleotidesubstitutions and epigenetic modifications thatdrive malignant transformation. The CancerGenome Atlas ( TCGA) pilot project aims toassess the value of large- scale multi-dimensional analysis of these molecularcharacteristics in human cancer and to providethe data rapidly to the research community. Herewe report the interim integrative analysis of DNAcopy number, gene expression and DNAmethylation aberrations in 206 glioblastomas -the most common type of primary adult braincancer - and nucleotide sequence aberrations in91 of the 206 glioblastomas. This analysisprovides new insights into the roles of ERBB2,NF1 and TP53, uncovers frequent mutations ofthe phosphatidylinositol- 3- OH kinase regulatorysubunit gene PIK3R1, and provides a networkview of the pathways altered in the development", "metadata": {}}
+{"_id": "1840993", "title": "", "text": "LY2405319, an Engineered FGF21 Variant,Improves the Metabolic Status of DiabeticMonkeysFibroblast growth factor 21 (FGF21) is anovel metabolic regulator that represents apromising target for the treatment of severalmetabolic diseases. Administration ofrecombinant wild type FGF21 to diabetic animalsleads to a dramatic improvement in glycaemiaand ameliorates other systemic measures ofmetabolic health. Here we report thepharmacologic outcomes observed in non-humanprimates upon administration of a recentlydescribed FGF21 analogue, LY2405319 (LY).Diabetic rhesus monkeys were treatedsubcutaneously with LY once daily for a period ofseven weeks. The doses of LY used were 3, 9and 50 mg/kg each delivered in an escalatingfashion with washout measurements taken at 2,4, 6 and 8 weeks following the final LY dose. LYtherapy led to a dramatic and rapid lowering ofseveral important metabolic parametersincluding glucose, body weight, insulin,", "metadata": {}}
+{"_id": "1848452", "title": "", "text": "Epigenetic Control of Stem Cell Potential duringHomeostasis, Aging, and Disease.Stem celldecline is an important cellular driver ofaging-associated pathophysiology in multipletissues. Epigenetic regulation is central toestablishing and maintaining stem cell function,and emerging evidence indicates that epigeneticdysregulation contributes to the altered potentialof stem cells during aging. Unlike terminallydifferentiated cells, the impact of epigeneticdysregulation in stem cells is propagated beyondself; alterations can be heritably transmitted todifferentiated progeny, in addition to beingperpetuated and amplified within the stem cellpool through self-renewal divisions. This Reviewfocuses on recent studies examining epigeneticregulation of tissue-specific stem cells inhomeostasis, aging, and aging-related disease.", "metadata": {}}
+{"_id": "1852826", "title": "", "text": "Host–Parasite Interactions and the Evolution ofGene ExpressionInteractions between hosts andparasites provide an ongoing source of selectionthat promotes the evolution of a variety offeatures in the interacting species. Here, we usea genetically explicit mathematical model toexplore how patterns of gene expression evolveat genetic loci responsible for host resistance andparasite infection. Our results reveal the strikingyet intuitive conclusion that gene expressionshould evolve along very different trajectories inthe two interacting species. Specifically, hostresistance loci should frequently evolve toco-express alleles, whereas parasite infection locishould evolve to express only a single allele. Thisresult arises because hosts that co-expressresistance alleles are able to recognize and cleara greater diversity of parasite genotypes. By thesame token, parasites that co-express antigen orelicitor alleles are more likely to be recognizedand cleared by the host, and this favours theexpression of only a single allele. Our model", "metadata": {}}
+{"_id": "1855679", "title": "", "text": "A crucial role for interleukin (IL)-1 in theinduction of IL-17–producing T cells that mediateautoimmune encephalomyelitisIt was recentlydemonstrated that interleukin (IL)-23–drivenIL-17–producing (ThIL-17) T cells mediateinflammatory pathology in certain autoimmunediseases. We show that the induction ofantigen-specific ThIL-17 cells, but not T helper(Th)1 or Th2 cells, by immunization withantigens and adjuvants is abrogated in IL-1receptor type I–deficient (IL-1RI−/−) mice.Furthermore, the incidence of experimentalautoimmune encephalomyelitis (EAE) wassignificantly lower in IL-1RI−/− compared withwild-type mice, and this correlated with a failureto induce autoantigen-specific ThIL-17 cells,whereas induction of Th1 and Th2 responses wasnot substantially different. However, EAE wasinduced in IL-1RI−/− mice by adoptive transferof autoantigen-specific cells from wild-type micewith EAE. IL-23 alone did not induce IL-17production by T cells from IL-1RI−/− mice, and", "metadata": {}}
+{"_id": "1866911", "title": "", "text": "Aberrant luminal progenitors as the candidatetarget population for basal tumor development inBRCA1 mutation carriersBasal-like breast cancersarising in women carrying mutations in theBRCA1 gene, encoding the tumor suppressorprotein BRCA1, are thought to develop from themammary stem cell. To explore early cellularchanges that occur in BRCA1 mutation carriers,we have prospectively isolated distinct epithelialsubpopulations from normal mammary tissueand preneoplastic specimens from individualsheterozygous for a BRCA1 mutation. We describethree epithelial subsets including basalstem/progenitor, luminal progenitor and matureluminal cells. Unexpectedly, we found that breasttissue from BRCA1 mutation carriers harbors anexpanded luminal progenitor population thatshows factor-independent growth in vitro.Moreover, gene expression profiling revealedthat breast tissue heterozygous for a BRCA1mutation and basal breast tumors were moresimilar to normal luminal progenitor cells than", "metadata": {}}
+{"_id": "1871230", "title": "", "text": "Getting to the site of inflammation: the leukocyteadhesion cascade updatedNeutrophilrecruitment, lymphocyte recirculation andmonocyte trafficking all require adhesion andtransmigration through blood-vessel walls. Thetraditional three steps of rolling, activation andfirm adhesion have recently been augmentedand refined. Slow rolling, adhesionstrengthening, intraluminal crawling andparacellular and transcellular migration are nowrecognized as separate, additional steps. Inneutrophils, a second activation pathway hasbeen discovered that does not require signallingthrough G-protein-coupled receptors and thesignalling steps leading to integrin activation arebeginning to emerge. This Review focuses onnew aspects of one of the central paradigms ofinflammation and immunity — the leukocyteadhesion cascade.", "metadata": {}}
+{"_id": "1871499", "title": "", "text": "Genome-wide loss of 5-hmC is a novel epigeneticfeature of Huntington'sdisease.5-Hydroxymethylcytosine (5-hmC) mayrepresent a new epigenetic modification ofcytosine. While the dynamics of 5-hmC duringneurodevelopment have recently been reported,little is known about its genomic distribution andfunction(s) in neurodegenerative diseases suchas Huntington's disease (HD). We here observeda marked reduction of the 5-hmC signal inYAC128 (yeast artificial chromosome transgenewith 128 CAG repeats) HD mouse brain tissueswhen compared with age-matched wild-type(WT) mice, suggesting a deficiency of 5-hmCreconstruction in HD brains during postnataldevelopment. Genome-wide distribution analysisof 5-hmC further confirmed the diminishment ofthe 5-hmC signal in striatum and cortex inYAC128 HD mice. General genomic features of5-hmC are highly conserved, not being affectedby either disease or brain regions. Intriguingly,we have identified disease-specific (YAC128", "metadata": {}}
+{"_id": "1886551", "title": "", "text": "Planning for Postdisaster ResiliencyThe focus ofthis article is planning for resiliency in theaftermath of a catastrophe. First, the authorsoffer their conception of planning for resiliency asa goal for recovering communities, and thebenefits of planning in efforts to create moreresilient places. Next, they discuss major issuesassociated with planning for postdisasterrecovery, including barriers posed by federal andstate governments to planning for resiliency, thepromise and risks of compact urban form modelsfor guiding rebuilding, and the failure to involvecitizens in planning for disasters. Finally, theydiscuss lessons from prior research that addressthese issues and policy recommendations thatfoster predisaster recovery planning for resilientcommunities.", "metadata": {}}
+{"_id": "1887056", "title": "", "text": "Increased stress-induced inflammatoryresponses in male patients with majordepression and increased early lifestress.OBJECTIVE The authors sought todetermine innate immune system activationfollowing psychosocial stress in patients withmajor depression and increased early life stress.METHOD Plasma interleukin (IL)-6, lymphocytesubsets, and DNA binding of nuclear factor(NF)-kB in peripheral blood mononuclear cellswere compared in medically healthy malesubjects with current major depression andincreased early life stress (N=14) versusnondepressed male comparison subjects (N=14)before and after completion of the Trier SocialStress Test. RESULTS Trier Social StressTest-induced increases in IL-6 and NF-kappaBDNA-binding were greater in major depressionpatients with increased early life stress andindependently correlated with depressionseverity, but not early life stress. Natural killer(NK) cell percentages also increased following", "metadata": {}}
+{"_id": "1889358", "title": "", "text": "KIF3A/B: a heterodimeric kinesin superfamilyprotein that works as a microtubule plusend-directed motor for membrane organelletransportWe cloned a new member of the murinebrain kinesin superfamily, KIF3B, and found thatits amino acid sequence is highly homologousbut not identical to KIF3A, which we previouslycloned and named KIF3 (47% identical). KIF3B islocalized in various organ tissues and developingneurons of mice and accumulates withanterogradely moving membranous organellesafter ligation of nerve axons.Immunoprecipitation assay of the brain revealedthat KIF3B forms a complex with KIF3A andthree other high molecular weight(approximately 100 kD)-associated polypeptides,called the kinesin superfamily-associated protein3 (KAP3). In vitro reconstruction usingbaculovirus expression systems showed thatKIF3A and KIF3B directly bind with each other inthe absence of KAP3. The recombinant KIF3A/Bcomplex (approximately 50-nm rod with two", "metadata": {}}
+{"_id": "1897324", "title": "", "text": "A genetic screen identifies an LKB1–MARKsignalling axis controlling the Hippo–YAPpathwayThe Hippo–YAP pathway is an emergingsignalling cascade involved in the regulation ofstem cell activity and organ size. To identifycomponents of this pathway, we performed anRNAi-based kinome screen in human cells. Ourscreen identified several kinases not previouslyassociated with Hippo signalling that controlmultiple cellular processes. One of the hits,LKB1, is a common tumour suppressor whosemechanism of action is only partially understood.We demonstrate that LKB1 acts through itssubstrates of the microtubule affinity-regulatingkinase family to regulate the localization of thepolarity determinant Scribble and the activity ofthe core Hippo kinases. Our data also indicatethat YAP is functionally important for the tumoursuppressive effects of LKB1. Our results identifya signalling axis that links YAP activation withLKB1 mutations, and have implications for thetreatment of LKB1-mutant human malignancies.", "metadata": {}}
+{"_id": "1900152", "title": "", "text": "Beyond melanoma: inhibiting the PD-1/PD-L1pathway in solid tumors.Immune checkpointinhibitors have been identified as breakthroughtreatment in melanoma given its dramaticresponse to PD-1/PD-L1 blockade. This is likelyto extend to many other cancers as hundreds ofclinical trials are being conducted or proposedusing this exciting modality of therapy in avariety of malignancies. While immunecheckpoint inhibitors have been extensivelystudied in melanoma and more recently in lungcancer, little is known regarding immunecheckpoint blockade in other cancers. Thisreview will focus on the tumor immunemicroenvironment, the expression of PD-1/PD-L1and the effect of immune modulation using PD-1or PD-L1 inhibitors in patients with head andneck, prostate, urothelial, renal, breast,gastrointestinal and lung cancers.", "metadata": {}}
+{"_id": "1904291", "title": "", "text": "Partitioning the symptoms of hypoglycaemiausing multi-sample confirmatory factoranalysisThe allocation of hypoglycaemicsymptoms to autonomie or neuroglycopenicgroups tends to occur on an a priori basis. Inview of the practical need for clear symptommarkers of hypoglycaemia more scientificapproaches must be pursued. Substantialevidence is presented from two large scalestudies we performed which support a threefactor model of hypoglycaemic symptomatology,based on the statistical associations discoveredamong symptoms reported by diabetic patients.Study 1 involved 295 insulin-treated outpatientsand found that 11 key hypoglycaemic symptomssegregated into three clear factors: autonomie(sweating, palpitation, shaking and hunger)neuroglycopenic (confusion, drowsiness, oddbehaviour, speech difficulty and incoordination),and malaise (nausea and headache). The threefactors were validated on a separate group of303 insulin-treated diabetic out-patients.", "metadata": {}}
+{"_id": "1905095", "title": "", "text": "Extracellular vesicles from human cardiacprogenitor cells inhibit cardiomyocyte apoptosisand improve cardiac function after myocardialinfarction.AIMS Recent evidence suggests thatcardiac progenitor cells (CPCs) may improvecardiac function after injury. The underlyingmechanisms are indirect, but their mediatorsremain unidentified. Exosomes and othersecreted membrane vesicles, hereaftercollectively referred to as extracellular vesicles(EVs), act as paracrine signalling mediators.Here, we report that EVs secreted by humanCPCs are crucial cardioprotective agents.METHODS AND RESULTS CPCs were derivedfrom atrial appendage explants from patientswho underwent heart valve surgery.CPC-conditioned medium (CM) inhibitedapoptosis in mouse HL-1 cardiomyocytic cells,while enhancing tube formation in humanumbilical vein endothelial cells. These effectswere abrogated by depleting CM of EVs. Theywere reproduced by EVs secreted by CPCs, but", "metadata": {}}
+{"_id": "1907601", "title": "", "text": "Increased Adipocyte O2 Consumption TriggersHIF-1α, Causing Inflammation and InsulinResistance in ObesityAdipose tissue hypoxia andinflammation have been causally implicated inobesity-induced insulin resistance. Here, wereport that, early in the course of high-fat diet(HFD) feeding and obesity, adipocyte respirationbecomes uncoupled, leading to increased oxygenconsumption and a state of relative adipocytehypoxia. These events are sufficient to triggerHIF-1α induction, setting off the chronic adiposetissue inflammatory response characteristic ofobesity. At the molecular level, these eventsinvolve saturated fatty acid stimulation of theadenine nucleotide translocase 2 (ANT2), aninner mitochondrial membrane protein, whichleads to the uncoupled respiratory state. Geneticor pharmacologic inhibition of either ANT2 orHIF-1α can prevent or reverse thesepathophysiologic events, restoring a state ofinsulin sensitivity and glucose tolerance. Theseresults reveal the sequential series of events in", "metadata": {}}
+{"_id": "1910120", "title": "", "text": "Lpcat3-dependent production of arachidonoylphospholipids is a key determinant of triglyceridesecretionThe role of specific phospholipids (PLs)in lipid transport has been difficult to assess dueto an inability to selectively manipulatemembrane composition in vivo. Here we showthat the phospholipid remodeling enzymelysophosphatidylcholine acyltransferase 3(Lpcat3) is a critical determinant of triglyceride(TG) secretion due to its unique ability tocatalyze the incorporation of arachidonate intomembranes. Mice lacking Lpcat3 in the intestinefail to thrive during weaning and exhibitenterocyte lipid accumulation and reducedplasma TGs. Mice lacking Lpcat3 in the livershow reduced plasma TGs, hepatosteatosis, andsecrete lipid-poor very low-density lipoprotein(VLDL) lacking arachidonoyl PLs. Mechanisticstudies indicate that Lpcat3 activity impactsmembrane lipid mobility in living cells,suggesting a biophysical basis for therequirement of arachidonoyl PLs in lipidating", "metadata": {}}
+{"_id": "1914588", "title": "", "text": "Characterization of a single-strandedDNA-binding protein from Pseudomonasaeruginosa PAO1.Single-stranded DNA-bindingprotein (SSB) plays an important role in DNAmetabolism, such as in DNA replication, repair,and recombination, and is essential for cellsurvival. We characterized the single-strandedDNA (ssDNA)-binding properties of Pseudomonasaeruginosa PAO1 SSB (PaSSB) by usingfluorescence quenching measurements andelectrophoretic mobility shift analysis (EMSA).Analysis of purified PaSSB by gel filtrationchromatography revealed a stable tetramer insolution. In fluorescence titrations, PaSSB bound22-32 nucleotides (nt) per tetramer dependingon salt concentration. Using EMSA, wecharacterized the stoichiometry of PaSSBcomplexed with a series of ssDNAhomopolymers, and the size of the binding sitewas determined to be 29 ± 1 nt. Furthermore,EMSA results indicated that the dissociationconstants of PaSSB for the first tetramer were", "metadata": {}}
+{"_id": "1917068", "title": "", "text": "Primary cilia and coordination of receptortyrosine kinase (RTK) signalling.Primary cilia aremicrotubule-based sensory organelles thatcoordinate signalling pathways in cell-cyclecontrol, migration, differentiation and othercellular processes critical during developmentand for tissue homeostasis. Accordingly, defectsin assembly or function of primary cilia lead to aplethora of developmental disorders andpathological conditions now known asciliopathies. In this review, we summarize thecurrent status of the role of primary cilia incoordinating receptor tyrosine kinase (RTK)signalling pathways. Further, we presentpotential mechanisms of signalling crosstalk andnetworking in the primary cilium and discuss howdefects in ciliary RTK signalling are linked tohuman diseases and disorders.", "metadata": {}}
+{"_id": "1921218", "title": "", "text": "Detecting and targeting tumor relapse by itsresistance to innate effectors at earlyrecurrenceTumor recurrence represents a majorclinical challenge. Our data show that emergentrecurrent tumors acquire a phenotype radicallydifferent from that of their originating primarytumors. This phenotype allows them to evade ahost-derived innate immune response elicited bythe progression from minimal residual disease(MRD) to actively growing recurrence. Screeningfor this innate response predicted accurately inwhich mice recurrence would occur. Prematureinduction of recurrence resensitized MRD to theprimary therapy, suggesting a possible paradigmshift for clinical treatment of dormant disease inwhich the current expectant approach is replacedwith active attempts to uncover MRD beforeevolution of the escape phenotype is complete.By combining screening with second-linetreatments targeting innate insensitivity, up to100% of mice that would have otherwiserelapsed were cured. These data may open new", "metadata": {}}
+{"_id": "1922901", "title": "", "text": "Forces in Tissue Morphogenesis andPatterningDuring development, mechanicalforces cause changes in size, shape, number,position, and gene expression of cells. They aretherefore integral to any morphogeneticprocesses. Force generation by actin-myosinnetworks and force transmission throughadhesive complexes are two self-organizingphenomena driving tissue morphogenesis.Coordination and integration of forces bylong-range force transmission andmechanosensing of cells within tissues producelarge-scale tissue shape changes. Extrinsicmechanical forces also control tissue patterningby modulating cell fate specification anddifferentiation. Thus, the interplay betweentissue mechanics and biochemical signalingorchestrates tissue morphogenesis andpatterning in development.", "metadata": {}}
+{"_id": "1933281", "title": "", "text": "CD169+ MACROPHAGES PRESENT LIPIDANTIGENS TO MEDIATE EARLY ACTIVATION OFINVARIANT NKT CELLS IN LYMPHNODESInvariant natural killer T cells (iNKT cells)are involved in the host defense againstmicrobial infection. Although it is known thatiNKT cells recognize glycolipids presented byCD1d, how and where they encounter antigen invivo remains unclear. Here we used multiphotonmicroscopy to visualize the dynamics andactivation of iNKT cells in lymph nodes. Afterantigen administration, iNKT cells becameconfined in a CD1d-dependent manner in closeproximity to subcapsular sinus CD169(+)macrophages. These macrophages retained,internalized and presented lipid antigen and wererequired for iNKT cell activation, cytokineproduction and population expansion. Thus,CD169(+) macrophages can act as trueantigen-presenting cells controlling early iNKTcell activation and favoring the fast initiation ofimmune responses.", "metadata": {}}
+{"_id": "1941721", "title": "", "text": "Oxygen Metabolism Causes Chromosome Breaksand Is Associated with the Neuronal ApoptosisObserved in DNA Double-Strand Break RepairMutantsCells deficient in a major DNAdouble-strand break repair pathway(nonhomologous DNA end joining [NHEJ]) haveincreased spontaneous chromosome breaks;however, the source of these chromosomebreaks has remained undefined. Here, we showthat the observed spontaneous chromosomebreaks are partially suppressed by reducing thecellular oxygen tension. Conversely, elevatingthe level of reactive oxygen species byoverexpressing the antioxidant enzymesuperoxide dismutase 1 (SOD1), in a transgenicmouse, increases chromosome breakage. Theeffect of SOD1 can also be modulated by cellularoxygen tension. The elevated chromosomebreakage correlates histologically with asignificant increase in the amount of neuronalcell death in Ku86(-/-) SOD1 transgenic embryosover that seen in Ku86(-/-) embryos. Therefore,", "metadata": {}}
+{"_id": "1944452", "title": "", "text": "Insertional mutagenesis in gene therapy andstem cell biology.PURPOSE OF REVIEW Recentpreclinical and clinical studies revealed that thesemirandom insertion of transgenes intochromosomal DNA of hematopoietic cells mayinduce clonal competition, which potentially mayeven trigger leukemia or sarcoma. Insertionalmutagenesis caused by gene vectors has thusled to major uncertainty among those developingadvanced hematopoietic cell therapies. Thisreview summarizes novel studies of underlyingmechanisms; these studies have demonstratedthe possibility of improved gene vector biosafetyand generated new insights into stem cellbiology. RECENT FINDINGS The characteristicinsertion pattern of various retroviral gene vectorsystems may be explained by properties of theviral integrase and associated cellular cofactors.Cell culture assays and animal models, includingdisease-specific and cancer-prone mousemodels, are emerging that reveal thecontributions of vector features and systemic", "metadata": {}}
+{"_id": "1946610", "title": "", "text": "Markets, voucher subsidies and free netscombine to achieve high bed net coverage inrural TanzaniaBACKGROUND Tanzania has awell-developed network of commercial ITNretailers. In 2004, the government introduced avoucher subsidy for pregnant women and, in mid2005, helped distribute free nets to under-fivesin small number of districts, including Rufiji onthe southern coast, during a child healthcampaign. Contributions of these multipleinsecticide-treated net delivery strategiesexisting at the same time and place to coveragein a poor rural community were assessed.METHODS Cross-sectional household survey in6,331 members of randomly selected 1,752households of 31 rural villages of DemographicSurveillance System in Rufiji district, SouthernTanzania was conducted in 2006. A questionnairewas administered to every consentingrespondent about net use, treatment status anddelivery mechanism. FINDINGS Net use was62.7% overall, 87.2% amongst infants (0 to 1", "metadata": {}}
+{"_id": "1958440", "title": "", "text": "Human chorionic gonadotropin levels in maternalblood in late pregnancy: relation to birthweight,sex and condition of the infant at birth.A total of527 blood samples was obtained from anunselected population of women between 36 and40 weeks gestation. Serum human chorionicgonadotropin (hCG) levels were measured usinga specific radioimmunoassay for the beta1-subunit of hCG. Serum hCG levels were higherin primigravidae and in women carrying femalefetuses. They were also related to thebirthweight of the child and to the occurrence offetal distress.", "metadata": {}}
+{"_id": "1964163", "title": "", "text": "Brain-Specific Phosphorylation of MeCP2Regulates Activity-Dependent Bdnf Transcription,Dendritic Growth, and Spine MaturationMutationsor duplications in MECP2 cause Rett and Rett-likesyndromes, neurodevelopmental disorderscharacterized by mental retardation, motordysfunction, and autistic behaviors. MeCP2 isexpressed in many mammalian tissues andfunctions as a global repressor of transcription;however, the molecular mechanisms by whichMeCP2 dysfunction leads to the neural-specificphenotypes of RTT remain poorly understood.Here, we show that neuronal activity andsubsequent calcium influx trigger the de novophosphorylation of MeCP2 at serine 421 (S421)by a CaMKII-dependent mechanism. MeCP2S421 phosphorylation is induced selectively inthe brain in response to physiological stimuli.Significantly, we find that S421 phosphorylationcontrols the ability of MeCP2 to regulate dendriticpatterning, spine morphogenesis, and theactivity-dependent induction of Bdnf", "metadata": {}}
+{"_id": "1967017", "title": "", "text": "A Candidate Gene Approach Identifies theTRAF1/C5 Region as a Risk Factor forRheumatoid ArthritisCorrection for:    KurreemanFAS, Padyukov L, Marques RB, Schrodi SJ,Seddighzadeh M, et al. (2007) A Candidate GeneApproach Identifies the TRAF1/C5 Region as aRisk Factor for Rheumatoid Arthritis. PLoS Med4(9): e278.doi:10.1371/journal.pmed.0040278    In Table1, the allele ratio in column eight (Allele Ratiosb:Cases, Controls) refers to allele A: allele B andnot allele1:allele2 as described in footnote b,with Allele A being the Susceptibility Allele asdenoted in column seven. The footnote shouldread:    bNumber of alleles were compared incases versus controls: allele A: allele B cases,allele A: allele B controls. Allele A refers to thesusceptibility alleles as given in column seven.", "metadata": {}}
+{"_id": "1967410", "title": "", "text": "Potential use of γ-secretase modulators in thetreatment of Alzheimer disease.Althoughsignificant progress has occurred in the past 20years regarding our understanding of Alzheimerdisease pathogenesis, we have yet to identifydisease-modifying therapeutics capable ofsubstantially altering the clinical course of thisprevalent neurodegenerative disease. In thisshort review, we discuss 2 approaches that arecurrently being tested clinically (γ-secretaseinhibition and γ-secretase modulation) andemphasize the significant differences betweenthese 2 therapeutic approaches. We also discusscertain genetic- and biomarker-basedtranslational and clinical trial paradigms that mayassist in developing a useful therapeutic agent.", "metadata": {}}
+{"_id": "1970884", "title": "", "text": "Rational design of a flavivirus vaccine byabolishing viral RNA 2'-O methylation.Virusesthat replicate in the cytoplasm cannot access thehost nuclear capping machinery. These viruseshave evolved viral methyltransferase(s) tomethylate N-7 and 2'-O cap of their RNA;alternatively, they \"snatch\" host mRNA cap toform the 5' end of viral RNA. The function of 2'-Omethylation of viral RNA cap is to mimic cellularmRNA and to evade host innate immunerestriction. A cytoplasmic virus defective in 2'-Omethylation is replicative, but its viral RNA lacks2'-O methylation and is recognized andeliminated by the host immune response. Such amutant virus could be rationally designed as alive attenuated vaccine. Here, we use Japaneseencephalitis virus (JEV), an importantmosquito-borne flavivirus, to prove this novelvaccine concept. We show that JEVmethyltransferase is responsible for both N-7and 2'-O cap methylations as well as evasion ofhost innate immune response. Recombinant", "metadata": {}}
+{"_id": "1974176", "title": "", "text": "Fruit consumption and risk of type 2 diabetes:results from three prospective longitudinal cohortstudiesOBJECTIVE To determine whetherindividual fruits are differentially associated withrisk of type 2 diabetes. DESIGN Prospectivelongitudinal cohort study. SETTING Healthprofessionals in the United States.PARTICIPANTS 66,105 women from the Nurses'Health Study (1984-2008), 85,104 women fromthe Nurses' Health Study II (1991-2009), and36,173 men from the Health ProfessionalsFollow-up Study (1986-2008) who were free ofmajor chronic diseases at baseline in thesestudies. MAIN OUTCOME MEASURE Incidentcases of type 2 diabetes, identified through selfreport and confirmed by supplementaryquestionnaires. RESULTS During 3,464,641person years of follow-up, 12,198 participantsdeveloped type 2 diabetes. After adjustment forpersonal, lifestyle, and dietary risk factors ofdiabetes, the pooled hazard ratio of type 2diabetes for every three servings/week of total", "metadata": {}}
+{"_id": "1976183", "title": "", "text": "OncomiR-196 promotes an invasive phenotype inoral cancer through the NME4-JNK-TIMP1-MMPsignaling pathwayBACKGROUND MicroRNA-196(miR-196), which is highly up-regulated in oralcancer cells, has been reported to be aberrantlyexpressed in several cancers; however, thesignificance of miR-196 in oral cancer has not yetbeen addressed. METHODS Cellular functions inresponse to miR-196 modulation were examined,including cell growth, migration, invasion andradio/chemosensitivity. Algorithm-based studieswere used to identify the regulatory target ofmiR-196. The miR-196 target gene anddownstream molecular mechanisms wereconfirmed by RT-qPCR, western blot, luciferasereporter and confocal microscopy analyses.miR-196 expression was determined in pairedcancer and adjacent normal tissues from oralcancer patients. RESULTS Both miR-196a andmiR-196b were highly over-expressed in thecancer tissue and correlated with lymph nodemetastasis (P = 0.001 and P = 0.006,", "metadata": {}}
+{"_id": "1982286", "title": "", "text": "Reverse engineering of TLX oncogenictranscriptional networks identifies RUNX1 astumor suppressor in T-ALLThe TLX1 and TLX3transcription factor oncogenes have a key role inthe pathogenesis of T cell acute lymphoblasticleukemia (T-ALL). Here we used reverseengineering of global transcriptional networks todecipher the oncogenic regulatory circuitcontrolled by TLX1 and TLX3. This systemsbiology analysis defined T cell leukemiahomeobox 1 (TLX1) and TLX3 as masterregulators of an oncogenic transcriptional circuitgoverning T-ALL. Notably, a network structureanalysis of this hierarchical network identifiedRUNX1 as a key mediator of the T-ALL inducedby TLX1 and TLX3 and predicted atumor-suppressor role for RUNX1 in T celltransformation. Consistent with these results, weidentified recurrent somatic loss-of-functionmutations in RUNX1 in human T-ALL. Overall,these results place TLX1 and TLX3 at the top ofan oncogenic transcriptional network controlling", "metadata": {}}
+{"_id": "1986482", "title": "", "text": "The Impact of the New WHO AntiretroviralTreatment Guidelines on HIV Epidemic Dynamicsand Cost in South AfricaBACKGROUND SinceNovember 2009, WHO recommends that adultsinfected with HIV should initiate antiretroviraltherapy (ART) at CD4+ cell counts of ≤350cells/µl rather than ≤200 cells/µl. South Africadecided to adopt this strategy for pregnant andTB co-infected patients only. We estimated theimpact of fully adopting the new WHO guidelineson HIV epidemic dynamics and associated costs.METHODS AND FINDING We used an establishedmodel of the transmission and control of HIV inspecified sexual networks and healthcaresettings. We quantified the model to representHlabisa subdistrict, KwaZulu-Natal, South Africa.We predicted the HIV epidemic dynamics,number on ART and program costs under thenew guidelines relative to treating patients at≤200 cells/µl for the next 30 years. During thefirst five years, the new WHO treatmentguidelines require about 7% extra annual", "metadata": {}}
+{"_id": "1991105", "title": "", "text": "ER-associated mitochondrial division links thedistribution of mitochondria and mitochondrialDNA in yeastMitochondrial division is importantfor mitochondrial distribution and function.Recent data have demonstrated thatER-mitochondria contacts mark mitochondrialdivision sites, but the molecular basis andfunctions of these contacts are not understood.Here we show that in yeast, the ER-mitochondriatethering complex, ERMES, and the highlyconserved Miro GTPase, Gem1, are spatially andfunctionally linked to ER-associatedmitochondrial division. Gem1 acts as a negativeregulator of ER-mitochondria contacts, anactivity required for the spatial resolution anddistribution of newly generated mitochondrialtips following division. Previous data havedemonstrated that ERMES localizes with a subsetof actively replicating mitochondrial nucleoids.We show that mitochondrial division is spatiallylinked to nucleoids and that a majority of thesenucleoids segregate prior to division, resulting in", "metadata": {}}
+{"_id": "1996292", "title": "", "text": "BMI-1 Autoantibody as a New PotentialBiomarker for Cervical CarcinomaBMI-1 isoverexpressed in a variety of cancers, which canelicit an immune response leading to theinduction of autoantibodies. However, BMI-1autoantibody as a biomarker has seldom beenstudied with the exception of nasopharyngealcarcinoma. Whether BMI-1 autoantibodies can beused as a biomarker for cervical carcinoma isunclear. In this study,BMI-1 proteins wereisolated by screening of a T7 phage cDNA libraryfrom mixed cervical carcinoma tissues. Weanalyzed BMI-1 autoantibody levels in serumsamples from 67 patients with cervical carcinomaand 65 controls using ELISA and immunoblot.BMI-1 mRNA or protein levels wereover-expressed in cervical carcinoma cell lines.Immunoblot results exhibited increased BMI-1autoantibody levels in patient sera compared tonormal sera. Additionally, the results forantibody affinity assay showed that there was nodifference between cervical polyps and normal", "metadata": {}}
+{"_id": "2000038", "title": "", "text": "MicroRNAs can generate thresholds in targetgene expressionMicroRNAs (miRNAs) are short,highly conserved noncoding RNA molecules thatrepress gene expression in asequence-dependent manner. We performedsingle-cell measurements using quantitativefluorescence microscopy and flow cytometry tomonitor a target gene's protein expression in thepresence and absence of regulation by miRNA.We find that although the average level ofrepression is modest, in agreement with previouspopulation-based measurements, the repressionamong individual cells varies dramatically. Inparticular, we show that regulation by miRNAsestablishes a threshold level of target mRNAbelow which protein production is highlyrepressed. Near this threshold, proteinexpression responds sensitively to target mRNAinput, consistent with a mathematical model ofmolecular titration. These results show thatmiRNAs can act both as a switch and as afine-tuner of gene expression.", "metadata": {}}
+{"_id": "2014909", "title": "", "text": "Oncogenic mTOR signaling recruitsmyeloid-derived suppressor cells to promotetumor initiationMyeloid-derived suppressor cells(MDSCs) play critical roles in primary andmetastatic cancer progression. MDSC regulationis widely variable even among patientsharbouring the same type of malignancy, and themechanisms governing such heterogeneity arelargely unknown. Here, integrating humantumour genomics and syngeneic mammarytumour models, we demonstrate that mTORsignalling in cancer cells dictates a mammarytumour's ability to stimulate MDSC accumulationthrough regulating G-CSF. Inhibiting thispathway or its activators (for example, FGFR)impairs tumour progression, which is partiallyrescued by restoring MDSCs or G-CSF.Tumour-initiating cells (TICs) exhibit elevatedG-CSF. MDSCs reciprocally increase TICfrequency through activating Notch in tumourcells, forming a feedforward loop. Analyses ofprimary breast cancers and patient-derived", "metadata": {}}
+{"_id": "2015126", "title": "", "text": "Management of women who have a geneticpredisposition for breast cancer.Themanagement of women who have a geneticpredisposition for breast cancer requires carefulplanning. Women who have BRCA 1 and BRCA 2mutations are at increased risk for breast cancerand for other cancers as well, particularly ovariancancer. Screening, prophlyactic surgery, andchemoprevention are commonly utilizedstrategies in the management of these patients,and women may choose more than one of thesestrategies. No randomized prospective trialshave assessed the impact of these strategiesspecifically in mutation carriers. All patientsshould be informed that screening, prophylacticsurgery, and chemoprevention have the potentialfor harm as well as benefit.", "metadata": {}}
+{"_id": "2015929", "title": "", "text": "Astrocytes from Familial and Sporadic ALSPatients are Toxic to Motor NeuronsAmyotrophiclateral sclerosis (ALS) is a fatal motor neurondisease, with astrocytes implicated ascontributing substantially to motor neuron deathin familial (F)ALS. However, the proposed role ofastrocytes in the pathology of ALS derives in partfrom rodent models of FALS based upondominant mutations within the superoxidedismutase 1 (SOD1) gene, which account for<2% of all ALS cases. Their role in sporadic(S)ALS, which affects >90% of ALS patients,remains to be established. Using astrocytesgenerated from postmortem tissue from bothFALS and SALS patients, we show that astrocytesderived from both patient groups are similarlytoxic to motor neurons. We also demonstratethat SOD1 is a viable target for SALS, as itsknockdown significantly attenuatesastrocyte-mediated toxicity toward motorneurons. Our data highlight astrocytes as anon-cell autonomous component in SALS and", "metadata": {}}
+{"_id": "2028532", "title": "", "text": "High-intensity functional exercise program andprotein-enriched energy supplement for olderpersons dependent in activities of daily living: arandomised controlled trial.The aims of thisrandomised controlled trial were to determine ifa high-intensity functional exercise programimproves balance, gait ability, and lower-limbstrength in older persons dependent in activitiesof daily living and if an intake of protein-enrichedenergy supplement immediately after theexercises increases the effects of the training.One hundred and ninety-one older personsdependent in activities of daily living, living inresidential care facilities, and with a Mini-MentalState Examination (MMSE) score of ? 10participated. They were randomised to ahigh-intensity functional exercise program or acontrol activity, which included 29 sessions over3 months, as well as to protein-enriched energysupplement or placebo. Berg Balance Scale,self-paced and maximum gait speed, andone-repetition maximum in lower-limb strength", "metadata": {}}
+{"_id": "2030623", "title": "", "text": "Inhibition of fatty acid oxidation modulatesimmunosuppressive functions of myeloid-derivedsuppressor cells and enhances cancertherapiesMyeloid-derived suppressor cells(MDSC) promote tumor growth by inhibitingT-cell immunity and promoting malignant cellproliferation and migration. The therapeuticpotential of blocking MDSC in tumors has beenlimited by their heterogeneity, plasticity, andresistance to various chemotherapy agents.Recent studies have highlighted the role ofenergy metabolic pathways in the differentiationand function of immune cells; however, themetabolic characteristics regulating MDSCremain unclear. We aimed to determine theenergy metabolic pathway(s) used by MDSC,establish its impact on their immunosuppressivefunction, and test whether its inhibition blocksMDSC and enhances antitumor therapies. Usingseveral murine tumor models, we found thattumor-infiltrating MDSC (T-MDSC) increasedfatty acid uptake and activated fatty acid", "metadata": {}}
+{"_id": "2032877", "title": "", "text": "Predicting mortality of patients hospitalized foracutely exacerbated chronic obstructivepulmonary disease.PURPOSE To identify factorsaffecting the short-term prognosis of patientswith acutely exacerbated chronic obstructivepulmonary disease (COPD). PATIENTS ANDMETHODS The 590 patients having COPD asprimary disease who were hospitalized in thepneumology unit of a university hospital from1981 to 1990 were studied. A standardizedprotocol for the treatment of acutely exacerbatedCOPD was adopted for all the patients. Thepatient records were retrospectively analyzed bytwo observers, and 23 clinical and laboratoryvariables defining the patient status onadmission were collected. Age and arterial gasdata were also taken into account, and theoutcome mortality was recorded. Interobserverreproducibility was tested by computing thekappa coefficient and Spearman's rho fordichotomous and continuous variables,respectively. The relationship of clinical and", "metadata": {}}
+{"_id": "2033917", "title": "", "text": "Clathrin is required for the function of the mitoticspindleClathrin has an established function in thegeneration of vesicles that transfer membraneand proteins around the cell. The formation ofclathrin-coated vesicles occurs continuously innon-dividing cells, but is shut down duringmitosis, when clathrin concentrates at thespindle apparatus. Here, we show that clathrinstabilizes fibres of the mitotic spindle to aidcongression of chromosomes. Clathrin bound tothe spindle directly by the amino-terminaldomain of clathrin heavy chain. Depletion ofclathrin heavy chain using RNA interferenceprolonged mitosis; kinetochore fibres weredestabilized, leading to defective congression ofchromosomes to the metaphase plate andpersistent activation of the spindle checkpoint.Normal mitosis was rescued by clathrin triskeliabut not the N-terminal domain of clathrin heavychain, indicating that stabilization of kinetochorefibres was dependent on the unique structure ofclathrin. The importance of clathrin for normal", "metadata": {}}
+{"_id": "2039912", "title": "", "text": "The origin and neuronal function of in vivononsynaptic glutamate.Basal extracellularglutamate sampled in vivo is present inmicromolar concentrations in the extracellularspace outside the synaptic cleft, and neither theorigin nor the function of this glutamate isknown. This report reveals that blockade ofglutamate release from the cystine-glutamateantiporter produced a significant decrease (60%)in extrasynaptic glutamate levels in the ratstriatum, whereas blockade ofvoltage-dependent Na+ and Ca2+ channelsproduced relatively minimal changes (0-30%).This indicates that the primary origin of in vivoextrasynaptic glutamate in the striatum arisesfrom nonvesicular glutamate release by thecystine-glutamate antiporter. By measuring[35S]cystine uptake, it was shown that similar tovesicular release, the activity of thecystine-glutamate antiporter is negativelyregulated by group II metabotropic glutamatereceptors (mGluR2/3) via a cAMP-dependent", "metadata": {}}
+{"_id": "2042250", "title": "", "text": "Disease-associated functions of IL-33: the newkid in the IL-1 familyInterleukin-33 (IL-33), anewly described member of the IL-1 family, isexpressed by many cell types followingpro-inflammatory stimulation and is thought tobe released on cell lysis. The IL-33 receptor,consisting of ST2 and IL-1 receptor accessoryprotein, is also widely expressed, particularly byT helper 2 (TH2) cells and mast cells. IL-33 ishost-protective against helminth infection andreduces atherosclerosis by promoting TH2-typeimmune responses. However, IL-33 can alsopromote the pathogenesis of asthma byexpanding TH2 cells and mediate jointinflammation, atopic dermatitis and anaphylaxisby mast cell activation. Thus IL-33 could be anew target for therapeutic intervention across arange of diseases.", "metadata": {}}
+{"_id": "2048139", "title": "", "text": "Interferon alpha therapy for hepatitis C:treatment completion and response rates amongpatients with substance usedisordersBackgroundIndividuals with substanceuse disorders (SUDs) are at increased risk forhepatitis C viral infection (HCV), and few studieshave explored their treatment responsesempirically. The objective of this study was toassess interferon alpha therapy (IFN) completionand response rates among patients with HCVwho had a history of comorbid SUDs. More datais needed to inform treatment strategies andguidelines for these patients. Using a medicalrecord database, information was retrospectivelycollected on 307,437 veterans seen in theVeterans Integrated Service Network 20 (VISN20) of the Veterans Healthcare Administration(VHA) between 1998 and 2003. For patientstreated with any type of IFN (including regular orpegylated IFN) or combination therapy (IFN andribavirin) who had a known HCV genotype, IFNcompletion and response rates were compared", "metadata": {}}
+{"_id": "2052720", "title": "", "text": "Association between infection with Helicobacterpylori and risk of gastric cancer: evidence from aprospective investigation.OBJECTIVE Toinvestigate the association between gastriccancer and prior infection with Helicobacterpylori. DESIGN Case-control comparison ofprevalence of IgG antibodies to H pylori in bloodsamples collected prospectively, before diagnosisof gastric cancer in the cases. Presence of Hpylori antibody (greater than 10 microgramsIgG/ml) determined by enzyme linkedimmunosorbent assay (ELISA). SUBJECTS 29men with a subsequent diagnosis of gastriccancer and 116 aged matched controls selectedfrom over 22,000 middle aged men participatingin two ongoing cohort studies (the British UnitedProvident Association study and the Caerphillycollaborative heart disease study), who hadprovided blood samples during 1975-1982.RESULTS 20 of the 29 cases (69%) and 54 of the116 controls (47%) were positive for H pylorispecific antibody. The median specific IgG", "metadata": {}}
+{"_id": "2053540", "title": "", "text": "Oncostatin M and leukemia inhibitory factor donot use the same functional receptor inmice.Oncostatin M (OSM) and leukemiainhibitory factor (LIF) are members of theinterleukin-6 (IL-6) subfamily of cytokines thatuse a common signal transducer gp130. HumanOSM (hOSM) and LIF share a functionalhigh-affinity receptor that is composed of gp130and LIF receptor beta subunit (LIFRbeta). Asecond high-affinity receptor for hOSM wasrecently found to be formed by gp130 and thehOSM receptor beta subunit. However, thenature of murine OSM (mOSM) and its receptorshas remained unknown. Using the recentlycloned mOSM cDNA, we produced recombinantmOSM and studied its biological activity andreceptor structure. Murine hematopoietic celllines M1 and DA1.a, an embryonic stem cell lineCCE, and Ba/F3 transfectants expressing gp130and LIFRbeta responded to murine LIF (mLIF)and hOSM equally well, while these cellsresponded to mOSM only at a 30-fold to 100-fold", "metadata": {}}
+{"_id": "2056197", "title": "", "text": "Multifunctional in vivo vascular imaging usingnear-infrared II fluorescenceIn vivo real-timeepifluorescence imaging of mouse hind limbvasculatures in the second near-infrared region(NIR-II) is performed using single-walled carbonnanotubes as fluorophores. Both high spatial(\u000030 μm) and temporal (<200 ms per frame)resolution for small-vessel imaging are achievedat 1–3 mm deep in the hind limb owing to thebeneficial NIR-II optical window that affordsdeep anatomical penetration and low scattering.This spatial resolution is unattainable bytraditional NIR imaging (NIR-I) or microscopiccomputed tomography, and the temporalresolution far exceeds scanning microscopicimaging techniques. Arterial and venous vesselsare unambiguously differentiated using adynamic contrast-enhanced NIR-II imagingtechnique on the basis of their distincthemodynamics. Further, the deep tissuepenetration and high spatial and temporalresolution of NIR-II imaging allow for precise", "metadata": {}}
+{"_id": "2058909", "title": "", "text": "Colorectal cancer survival in socioeconomicgroups in England: variation is mainly in theshort term after diagnosis.UNLABELLED Theobjective of this study was to examinedifferences in cancer survival betweensocioeconomic groups in England, with particularattention to survival in the short term offollow-up. PATIENTS AND METHODS Individualsdiagnosed with colorectal cancer between 1996and 2004 in England were identified from cancerregistry records. Five-year cumulative relativesurvival and excess death rates were computed.RESULTS For colon cancer there was a very highexcess death rate in the first month of follow-up,and the excess death rate was highest in thesocioeconomically deprived groups. Insubsequent periods, excess mortality rates weremuch lower and there was less socioeconomicvariation. The pattern of variation in excessdeath rates was generally similar in rectal cancerbut the socioeconomic difference in death ratespersisted several years longer. If the excess", "metadata": {}}
+{"_id": "2060137", "title": "", "text": "Cardiac myocyte remodeling mediated byN-cadherin-dependentmechanosensing.Cell-to-cell adhesions arecrucial in maintaining the structural andfunctional integrity of cardiac cells. Little isknown about the mechanosensitivity andmechanotransduction of cell-to-cell interactions.Most studies of cardiac mechanotransduction andmyofibrillogenesis have focused oncell-extracellular matrix (ECM)-specificinteractions. This study assesses the direct roleof intercellular adhesion, specifically that ofN-cadherin-mediated mechanotransduction, onthe morphology and internal organization ofneonatal ventricular cardiac myocytes. Theresults show that cadherin-mediated cellattachments are capable of eliciting acytoskeletal network response similar to that ofintegrin-mediated force response andtransmission, affecting myofibrillar organization,myocyte shape, and cortical stiffness. Tractionforces mediated by N-cadherin were shown to be", "metadata": {}}
+{"_id": "2061878", "title": "", "text": "NEAT1: A novel cancer\u0000related longnon\u0000coding RNAAberrant overexpression of thelong non-coding RNA NEAT1 (nuclearparaspeckle assembly transcript 1) has beendocumented in different types of solid tumours,such as lung cancer, oesophageal cancer,colorectal cancer and hepatocellular carcinoma,in which its high levels are associated with poorprognosis. In contrast, NEAT1 is downregulatedin acute promyelocytic leukaemia where itpromotes leucocyte differentiation. In thisreview, we provide an overview of currentevidence concerning the oncogenic role andpotential clinical utilities of NEAT1. Furtherinvestigations are warranted to elucidate theupstream and downstream mechanisms ofNEAT1 overexpression.", "metadata": {}}
+{"_id": "2062382", "title": "", "text": "The Function and Therapeutic Potential of LongNon-coding RNAs in Cardiovascular Developmentand DiseaseThe popularization of genome-wideanalyses and RNA sequencing led to thediscovery that a large part of the humangenome, while effectively transcribed, does notencode proteins. Long non-coding RNAs haveemerged as critical regulators of gene expressionin both normal and disease states. Studies oflong non-coding RNAs expressed in the heart, incombination with gene association studies,revealed that these molecules are regulatedduring cardiovascular development and disease.Some long non-coding RNAs have beenfunctionally implicated in cardiacpathophysiology and constitute potentialtherapeutic targets. Here, we review the currentknowledge of the function of long non-codingRNAs in the cardiovascular system, with anemphasis on cardiovascular development andbiology, focusing on hypertension, coronaryartery disease, myocardial infarction, ischemia,", "metadata": {}}
+{"_id": "2078658", "title": "", "text": "Oct4 links multiple epigenetic pathways to thepluripotency networkOct4 is a well-knowntranscription factor that plays fundamental rolesin stem cell self-renewal, pluripotency, andsomatic cell reprogramming. However, limitedinformation is available on Oct4-associatedprotein complexes and their intrinsicprotein-protein interactions that dictate Oct4'scritical regulatory activities. Here we employedan improved affinity purification approachcombined with mass spectrometry to purify Oct4protein complexes in mouse embryonic stemcells (mESCs), and discovered many novel Oct4partners important for self-renewal andpluripotency of mESCs. Notably, we found thatOct4 is associated with multiplechromatin-modifying complexes withdocumented as well as newly proved functionalsignificance in stem cell maintenance andsomatic cell reprogramming. Our studyestablishes a solid biochemical basis for geneticand epigenetic regulation of stem cell", "metadata": {}}
+{"_id": "2086909", "title": "", "text": "Tet1 is dispensable for maintaining pluripotencyand its loss is compatible with embryonic andpostnatal development.The Tet family ofenzymes (Tet1/2/3) converts 5-methylcytosine(5mC) to 5-hydroxymethylcytosine (5hmC).Mouse embryonic stem cells (mESCs) highlyexpress Tet1 and have an elevated level of5hmC. Tet1 has been implicated in ESCmaintenance and lineage specification in vitrobut its precise function in development is notwell defined. To establish the role of Tet1 inpluripotency and development, we havegenerated Tet1 mutant mESCs and mice.Tet1(-/-) ESCs have reduced levels of 5hmC andsubtle changes in global gene expression, andare pluripotent and support development oflive-born mice in tetraploid complementationassay, but display skewed differentiation towardtrophectoderm in vitro. Tet1 mutant mice areviable, fertile, and grossly normal, though somemutant mice have a slightly smaller body size atbirth. Our data suggest that Tet1 loss leading to", "metadata": {}}
+{"_id": "2095573", "title": "", "text": "LDL-cholesterol concentrations: a genome-wideassociation studyBACKGROUND LDL cholesterolhas a causal role in the development ofcardiovascular disease. Improved understandingof the biological mechanisms that underlie themetabolism and regulation of LDL cholesterolmight help to identify novel therapeutic targets.We therefore did a genome-wide associationstudy of LDL-cholesterol concentrations.METHODS We used genome-wide associationdata from up to 11,685 participants withmeasures of circulating LDL-cholesterolconcentrations across five studies, including datafor 293 461 autosomal single nucleotidepolymorphisms (SNPs) with a minor allelefrequency of 5% or more that passed our qualitycontrol criteria. We also used data from a secondgenome-wide array in up to 4337 participantsfrom three of these five studies, with data for290,140 SNPs. We did replication studies in twoindependent populations consisting of up to 4979participants. Statistical approaches, including", "metadata": {}}
+{"_id": "2097256", "title": "", "text": "Population Density, Water Supply, and the Riskof Dengue Fever in Vietnam: Cohort Study andSpatial AnalysisBACKGROUND Aedes aegypti, themajor vector of dengue viruses, often breeds inwater storage containers used by householdswithout tap water supply, and occurs in highnumbers even in dense urban areas. Weanalysed the interaction between humanpopulation density and lack of tap water as acause of dengue fever outbreaks with the aim ofidentifying geographic areas at highest risk.METHODS AND FINDINGS We conducted anindividual-level cohort study in a population of75,000 geo-referenced households in Vietnamover the course of two epidemics, on the basis ofdengue hospital admissions (n = 3,013). Weapplied space-time scan statistics andmathematical models to confirm the findings. Weidentified a surprisingly narrow range of criticalhuman population densities between around3,000 to 7,000 people/km² prone to dengueoutbreaks. In the study area, this population", "metadata": {}}
+{"_id": "2099400", "title": "", "text": "Helicobacter pylori induces AGS cell motility andelongation via independent signalingpathways.Helicobacter pylori induces motogenicand cytoskeletal responses in gastric epithelialcells. We demonstrate that these responses canbe induced via independent signaling pathwaysthat often occur in parallel. The cagpathogenicity island appears to be nonessentialfor induction of motility, whereas the elongationphenotype depends on translocation andphosphorylation of CagA.", "metadata": {}}
+{"_id": "2107238", "title": "", "text": "The Sequence Alignment/Map format andSAMtoolsSUMMARY The SequenceAlignment/Map (SAM) format is a genericalignment format for storing read alignmentsagainst reference sequences, supporting shortand long reads (up to 128 Mbp) produced bydifferent sequencing platforms. It is flexible instyle, compact in size, efficient in random accessand is the format in which alignments from the1000 Genomes Project are released. SAMtoolsimplements various utilities for post-processingalignments in the SAM format, such as indexing,variant caller and alignment viewer, and thusprovides universal tools for processing readalignments. AVAILABILITYhttp://samtools.sourceforge.net.", "metadata": {}}
+{"_id": "2119889", "title": "", "text": "Characterization of two classes of small moleculeinhibitors of Arp2/3 complexPolymerization ofactin filaments directed by the actin-relatedprotein (Arp)2/3 complex supports many typesof cellular movements. However, questionsremain regarding the relative contributions ofArp2/3 complex versus other mechanisms ofactin filament nucleation to processes such aspath finding by neuronal growth cones; this isbecause of the lack of simple methods to inhibitArp2/3 complex reversibly in living cells. Here wedescribe two classes of small molecules that bindto different sites on the Arp2/3 complex andinhibit its ability to nucleate actin filaments.CK-0944636 binds between Arp2 and Arp3,where it appears to block movement of Arp2 andArp3 into their active conformation. CK-0993548inserts into the hydrophobic core of Arp3 andalters its conformation. Both classes ofcompounds inhibit formation of actin filamentcomet tails by Listeria and podosomes bymonocytes. Two inhibitors with different", "metadata": {}}
+{"_id": "2121272", "title": "", "text": "Stresses at the cell-to-substrate interface duringlocomotion of fibroblastsRecent technologicalimprovements in the elastic substrate methodmake it possible to produce spatially resolvedmeasurements of the tractions exerted by singlemotile cells. In this study we have applied thesedevelopments to produce maps of the tractionsexerted by 3T3 fibroblasts during steadylocomotion. The resulting images have a spatialresolution of approximately 5 micrometers and amaximum intensity of approximately 10(2)kdyn/cm2 (10(4) pN/micrometers2). We findthat the propulsive thrust for fibroblastlocomotion, approximately 0.2 dyn, is impartedto the substratum within 15 micrometers of theleading edge. These observations demonstratethat the lamellipodium of the fibroblast is able togenerate intense traction stress. The cell bodyand posterior seem to be mechanically passivestructures pulled forward entirely by this action.", "metadata": {}}
+{"_id": "2130391", "title": "", "text": "Cancer-associated adipocytes exhibit anactivated phenotype and contribute to breastcancer invasion.Early local tumor invasion inbreast cancer results in a likely encounterbetween cancer cells and mature adipocytes, butthe role of these fat cells in tumor progressionremains unclear. We show that murine andhuman tumor cells cocultivated with matureadipocytes exhibit increased invasive capacitiesin vitro and in vivo, using an originaltwo-dimensional coculture system. Likewise,adipocytes cultivated with cancer cells alsoexhibit an altered phenotype in terms ofdelipidation and decreased adipocyte markersassociated with the occurrence of an activatedstate characterized by overexpression ofproteases, including matrixmetalloproteinase-11, and proinflammatorycytokines [interleukin (IL)-6, IL-1β]. In the caseof IL-6, we show that it plays a key role in theacquired proinvasive effect by tumor cells.Equally important, we confirm the presence of", "metadata": {}}
+{"_id": "2138767", "title": "", "text": "Prevalence of cardiovascular disease risk factorin the Chinese population: the 2007-2008 ChinaNational Diabetes and Metabolic DisordersStudy.AIMS Cardiovascular disease (CVD) is nowthe most prevalent and debilitating diseaseaffecting the Chinese population. The goal of thepresent manuscript was to analysecardiovascular risk factors and the prevalence ofnon-fatal CVDs from data gathered from the2007-2008 China National Diabetes andMetabolic Disorders Study. METHODS ANDRESULTS A nationally representative sample of46 239 adults, 20 years of age or older, wasrandomly recruited using a multistage stratifieddesign method. Lifestyle factors, diagnosis ofCVD, stroke, diabetes, and family history of eachsubject were collected, and an oral glucosetolerance test or a standard meal test wasperformed. Various non-fatal CVDs werereported by the subjects. SUDAAN software wasused to perform all weighted statistical analyses,with P < 0.05 considered statistically significant.", "metadata": {}}
+{"_id": "2138843", "title": "", "text": "Microvascular and Macrovascular Complicationsof DiabetesDiabetes is a group of chronicdiseases characterized by hyperglycemia.Modern medical care uses a vast array of lifestyleand pharmaceutical interventions aimed atpreventing and controlling hyperglycemia. Inaddition to ensuring the adequate delivery ofglucose to the tissues of the body, treatment ofdiabetes attempts to decrease the likelihood thatthe tissues of the body are harmed byhyperglycemia. The importance of protecting thebody from hyperglycemia cannot be overstated;the direct and indirect effects on the humanvascular tree are the major source of morbidityand mortality in both type 1 and type 2 diabetes.Generally, the injurious effects of hyperglycemiaare separated into macrovascular complications(coronary artery disease, peripheral arterialdisease, and stroke) and microvascularcomplications (diabetic nephropathy,neuropathy, and retinopathy). It is important forphysicians to understand the relationship", "metadata": {}}
+{"_id": "2139357", "title": "", "text": "Involvement of S-nitrosylation of actin ininhibition of neurotransmitter release by nitricoxideBACKGROUND The role of the diffusiblemessenger nitric oxide (NO) in the regulation ofpain transmission is still a debate of matter,pro-nociceptive and/or anti-nociceptive.S-Nitrosylation, the reversible post-translationalmodification of selective cysteine residues inproteins, has emerged as an importantmechanism by which NO acts as a signalingmolecule. The occurrence of S-nitrosylation inthe spinal cord and its targets that may modulatepain transmission remain unclarified. The\"biotin-switch\" method and matrix-assisted laserdesorption/ionization time-of-flight massspectrometry were employed for identifyingS-nitrosylated proteins. RESULTS Here we showthat actin was a major protein S-nitrosylated inthe spinal cord by the NO donor,S-nitroso-N-acetyl-DL-penicillamine (SNAP).Interestingly, actin was S-nitrosylated, more inthe S2 fraction than in the P2 fraction of the", "metadata": {}}
+{"_id": "2140497", "title": "", "text": "Independent Association of Lobular Involutionand Mammographic Breast Density With BreastCancer RiskBACKGROUND Lobular involution, orage-related atrophy of breast lobules, isinversely associated with breast cancer risk, andmammographic breast density (MBD) ispositively associated with breast cancer risk.METHODS To evaluate whether lobular involutionand MBD are independently associated withbreast cancer risk in women with benign breastdisease, we performed a nested cohort studyamong women (n = 2666) with benign breastdisease diagnosed at Mayo Clinic betweenJanuary 1, 1985, and December 31, 1991 and amammogram available within 6 months of thediagnosis. Women were followed up for anaverage of 13.3 years to document any breastcancer incidence. Lobular involution wascategorized as none, partial, or complete;parenchymal pattern was classified using theWolfe classification as N1 (nondense), P1, P2(ductal prominence occupying <25%, or >25%", "metadata": {}}
+{"_id": "2140513", "title": "", "text": "Pleiotropy as a mechanism to stabilizecooperationMost genes affect many traits. Thisphenomenon, known as pleiotropy, is a majorconstraint on evolution because adaptive changein one trait may be prevented because it wouldcompromise other traits affected by the samegenes. Here we show that pleiotropy can have anunexpected effect and benefit one of the mostenigmatic of adaptations—cooperation. Aspectacular act of cooperation occurs in thesocial amoeba Dictyostelium discoideum, inwhich some cells die to form a stalk that holdsthe other cells aloft as reproductive spores. Wehave identified a gene, dimA, in D. discoideumthat has two contrasting effects. It is required toreceive the signalling molecule DIF-1 that causesdifferentiation into prestalk cells. Ignoring DIF-1and not becoming prestalk should allow cells tocheat by avoiding the stalk. However, we findthat in aggregations containing the wild-typecells, lack of the dimA gene results in exclusionfrom spores. This pleiotropic linkage of stalk and", "metadata": {}}
+{"_id": "2147704", "title": "", "text": "The homeobox gene goosecoid controls cellmigration in Xenopus embryos.Goosecoid (gsc),a homeobox gene expressed specifically in thedorsal blastopore lip of the Xenopus gastrula, isconsidered to play an important role inSpemann's organizer phenomenon. Lineagetracing and time-lapse microscopy were used tofollow the fate of embryonic cells microinjectedwith gsc mRNA. Microinjected gsc has non-cellautonomous effects, recruiting neighboringuninjected cells into a twinned dorsal axis.Ectopic expression of gsc mRNA in ventralblastomeres as well as overexpression of gsc indorsal blastomeres leads to cell movementtoward the anterior of the embryo. The resultssuggest a function for gsc in the control ofgastrulation movements in groups of cells, butnot in dissociated cells, and demonstrate that avertebrate homeobox gene can regulateregion-specific cell migration.", "metadata": {}}
+{"_id": "2151983", "title": "", "text": "Epigenetic switch involved in activation ofpioneer factor FOXA1-dependentenhancers.Transcription factors (TFs) bindspecifically to discrete regions of mammaliangenomes called cis-regulatory elements. Amongthose are enhancers, which play key roles inregulation of gene expression duringdevelopment and differentiation. Despite therecognized central regulatory role exerted bychromatin in control of TF functions, muchremains to be learned regarding the chromatinstructure of enhancers and how it is established.Here, we have analyzed on a genomic-scaleenhancers that recruit FOXA1, a pioneertranscription factor that triggers transcriptionalcompetency of these cis-regulatory sites.Importantly, we found that FOXA1 binds togenomic regions showing local DNAhypomethylation and that its cell-type-specificrecruitment to chromatin is linked to differentialDNA methylation levels of its binding sites. Usingneural differentiation as a model, we showed", "metadata": {}}
+{"_id": "2158500", "title": "", "text": "Leptin treatment ameliorates anxiety in ob/obobese mice.We investigated whether or notadministered leptin influences anxiety-likebehavior in ob/ob mice. Repeated intraperitonealadministrations of leptin were continued for 5days. Anxiety was assessed in the standardelevated plus maze. Body weight was measureddaily. Repeated administrations of leptinsignificantly increased the percentage of the totalnumber of entries in the open arms and thenumber of total entries. The body weight wassignificantly reduced by 13.2% after treatment.Leptin treatment ameliorated not only obesitybut also anxiety in ob/ob mice. Our resultsindicate that the treatment of obesity may leadto the solution of psychological problems.", "metadata": {}}
+{"_id": "2158516", "title": "", "text": "Predicting new molecular targets for knowndrugsAlthough drugs are intended to beselective, at least some bind to severalphysiological targets, explaining side effects andefficacy. Because many drug-targetcombinations exist, it would be useful to explorepossible interactions computationally. Here wecompared 3,665 US Food and DrugAdministration (FDA)-approved andinvestigational drugs against hundreds oftargets, defining each target by its ligands.Chemical similarities between drugs and ligandsets predicted thousands of unanticipatedassociations. Thirty were tested experimentally,including the antagonism of the beta(1) receptorby the transporter inhibitor Prozac, the inhibitionof the 5-hydroxytryptamine (5-HT) transporterby the ion channel drug Vadilex, and antagonismof the histamine H(4) receptor by the enzymeinhibitor Rescriptor. Overall, 23 new drug-targetassociations were confirmed, five of which werepotent (<100 nM). The physiological relevance of", "metadata": {}}
+{"_id": "2159648", "title": "", "text": "Bone loss and vascular calcification: Abi-directional interplay?Vascular calcification(VC) represents a recognized adverse predictorfor cardiovascular morbidity and mortality.Previously considered passive and degenerative,VC is now recognized as an active process thatresembles bone formation, and shares a numberof histopathological features, mineralcomposition, and initiation mechanisms withbone development and metabolism. Oxidativestress and inflammation are key factors in bothVC and osteoporosis (OP). Biochemical factorsknown to be primarily involved in the healthybone metabolism also regulate VC. Thesebiomarkers include vitamin D, osteoprotegerin,osteopontin, matrix Gla protein, cathepsin K,fibroblast growth factor-23, and fetuin-A. Abetter understanding of this highly controlledregulatory network, with multiple, nestedfeedback loops and cross talk between organs,may help to decrease the growing prevalence ofcalcific vasculopathy as well as OP in the aging", "metadata": {}}
+{"_id": "2177022", "title": "", "text": "Immobilized chemokine fields and solublechemokine gradients cooperatively shapemigration patterns of dendritic cells.Chemokinesorchestrate immune cell trafficking by elicitingeither directed or random migration and byactivating integrins in order to induce celladhesion. Analyzing dendritic cell (DC)migration, we showed that these distinct cellularresponses depended on the mode of chemokinepresentation within tissues. Thesurface-immobilized form of the chemokineCCL21, the heparan sulfate-anchoring ligand ofthe CC-chemokine receptor 7 (CCR7), causedrandom movement of DCs that was confined tothe chemokine-presenting surface because ittriggered integrin-mediated adhesion. Upondirect contact with CCL21, DCs truncated theanchoring residues of CCL21, thereby releasing itfrom the solid phase. Soluble CCL21 functionallyresembles the second CCR7 ligand, CCL19, whichlacks anchoring residues and forms solublegradients. Both soluble CCR7 ligands triggered", "metadata": {}}
+{"_id": "2192419", "title": "", "text": "Local proliferation dominates lesionalmacrophage accumulation inatherosclerosisDuring the inflammatory responsethat drives atherogenesis, macrophagesaccumulate progressively in the expandingarterial wall. The observation that circulatingmonocytes give rise to lesional macrophages hasreinforced the concept that monocyte infiltrationdictates macrophage buildup. Recent work hasindicated, however, that macrophageaccumulation does not depend on monocyterecruitment in some inflammatory contexts. Wetherefore revisited the mechanism underlyingmacrophage accumulation in atherosclerosis. Inmurine atherosclerotic lesions, we found thatmacrophages turn over rapidly, after 4 weeks.Replenishment of macrophages in theseexperimental atheromata depends predominantlyon local macrophage proliferation rather thanmonocyte influx. The microenvironmentorchestrates macrophage proliferation throughthe involvement of scavenger receptor A (SR-A).", "metadata": {}}
+{"_id": "2194320", "title": "", "text": "Enzymatically active lysosomal proteases areassociated with amyloid deposits in Alzheimerbrain.The formation of beta-amyloid in the brainsof individuals with Alzheimer disease requires theproteolytic cleavage of a membrane-associatedprecursor protein. The proteases that may beinvolved in this process have not yet beenidentified. Cathepsins are normally intracellularproteolytic enzymes associated with lysosomes;however, when sections from Alzheimer brainswere stained by antisera to cathepsin D andcathepsin B, high levels of immunoreactivitywere also detected in senile plaques.Extracellular sites of cathepsin immunoreactivitywere not seen in control brains fromage-matched individuals without neurologicdisease or from patients with Huntington diseaseor Parkinson disease. In situ enzymehistochemistry of cathepsin D and cathepsin B onsections of neocortex using synthetic peptidesand protein substrates showed that senileplaques contained the highest levels of", "metadata": {}}
+{"_id": "2205779", "title": "", "text": "Gastric juice miR-129 as a potential biomarkerfor screening gastric cancerMicroRNAs (miRNAs)play crucial roles during the occurrence anddevelopment of gastric cancer. Conventionalserological tests for screening gastric cancerhave limits on sensitivity and specificity. SeveralmiRNAs in peripheral blood have been used asbiomarkers of gastric cancer. However, most ofthese miRNAs are shared by several types ofcancer. Thanks to the tissue specificity of gastricjuice, here we examined the feasibility of usinggastric juice miR-129-1/2, which are aberrantlyexpressed in gastric cancer, to screen gastriccancer. Total of 141 gastric juices samples fromgastric cancer, gastric ulcer, atrophic gastritis,and minimal gastritis patients or subjects withnormal mucosa were collected by gastroscopy.The gastric juice miR-129-1/2 levels weredetected by quantitative reversetranscription-polymerase chain reaction. Areceiver operating characteristic (ROC) curvewas constructed for differentiating patients with", "metadata": {}}
+{"_id": "2211868", "title": "", "text": "Epidemiological expansion, structural studies,and clinical challenges of new β-lactamases fromgram-negative bacteria.β-Lactamase evolutionpresents to the infectious disease community amajor challenge in the treatment of infectionscaused by multidrug-resistant gram-negativebacteria. Because over 1,000 of these naturallyoccurring β-lactamases exist, attempts tocorrelate structure and function have becomedaunting. Although new enzymes in theextended-spectrum β-lactamase (ESBL) familiesare frequently identified, the older CTX-M-14 andCTX-M-15 enzymes have become the mostprevalent ESBLs in global surveillance.Carbapenemases with either serine-based orzinc-facilitated hydrolysis mechanisms are posingsome of the most critical problems. Mostgeographical regions now report KPC serinecarbapenemases and the metallo-β-lactamasesVIM, IMP, and NDM-1, even though NDM-1 wasonly recently identified. The rapid emergence ofthese newer enzymes, with multiple", "metadata": {}}
+{"_id": "2212067", "title": "", "text": "Robust synchronization of coupled circadian andcell cycle oscillators in single mammaliancellsCircadian cycles and cell cycles are twofundamental periodic processes with a period inthe range of 1 day. Consequently, couplingbetween such cycles can lead to synchronization.Here, we estimated the mutual interactionsbetween the two oscillators by time-lapseimaging of single mammalian NIH3T3 fibroblastsduring several days. The analysis of thousands ofcircadian cycles in dividing cells clearly indicatedthat both oscillators tick in a 1:1 mode-lockedstate, with cell divisions occurring tightly 5 hbefore the peak in circadian Rev-Erbα-YFPreporter expression. In principle, such synchronymay be caused by either unidirectional orbidirectional coupling. While gating of celldivision by the circadian cycle has been moststudied, our data combined with stochasticmodeling unambiguously show that the reversecoupling is predominant in NIH3T3 cells.Moreover, temperature, genetic, and", "metadata": {}}
+{"_id": "2225918", "title": "", "text": "Identification of a Brainstem Circuit ControllingFeedingHunger, driven by negative energybalance, elicits the search for and consumptionof food. While this response is in part mediatedby neurons in the hypothalamus, the role ofspecific cell types in other brain regions is lesswell defined. Here, we show that neurons in thedorsal raphe nucleus, expressing vesiculartransporters for GABA or glutamate (hereafter,DRNVgat and DRNVGLUT3 neurons), arereciprocally activated by changes in energybalance and that modulating their activity hasopposite effects on feeding-DRNVgat neuronsincrease, whereas DRNVGLUT3 neuronssuppress, food intake. Furthermore, modulationof these neurons in obese (ob/ob) micesuppresses food intake and body weight andnormalizes locomotor activity. Finally, usingmolecular profiling, we identify druggable targetsin these neurons and show that local infusion ofagonists for specific receptors on these neuronshas potent effects on feeding. These data", "metadata": {}}
+{"_id": "2236768", "title": "", "text": "Infection-induced NETosis is a dynamic processinvolving neutrophil multitasking invivoNeutrophil extracellular traps (NETs) arereleased as neutrophils die in vitro in a processrequiring hours, leaving a temporal gap thatinvasive microbes may exploit. Neutrophilscapable of migration and phagocytosis whileundergoing NETosis have not been documented.During Gram-positive skin infections, we directlyvisualized live polymorphonuclear cells (PMNs) invivo rapidly releasing NETs, which preventedsystemic bacterial dissemination. NETosisoccurred during crawling, thereby casting largeareas of NETs. NET-releasing PMNs developeddiffuse decondensed nuclei, ultimately becomingdevoid of DNA. Cells with abnormal nucleishowed unusual crawling behavior highlighted byerratic pseudopods and hyperpolarizationconsistent with the nucleus being a fulcrum forcrawling. A requirement for both Toll-likereceptor 2 and complement-mediatedopsonization tightly regulated NET release.", "metadata": {}}
+{"_id": "2242416", "title": "", "text": "Swim training suppresses tumor growth inmice.The present study was designed todetermine the effects of physical training on thedevelopment of cancer induced by the injectionof Ehrlich tumor cells in mice. Male Swiss micewere subjected to a swim training protocol (5days/wk for 6 wk, 1 h at 50% of maximalcapacity-trained groups) or remained sedentaryin their cages (sedentary groups). Theinoculation of Ehrlich tumor cells was performedat the end of the fourth week, and animals werekilled after 6 wk of training. Heart and solidtumor weights were recorded, and tumorvolumes were calculated. Portions of the tumorswere used for the evaluation of macrophagesand neutrophil accumulation or fixed in neutral10% buffered formalin for histological analysis.The tumor volume and weight were,respectively, approximately 270% and 280%greater in sedentary mice than in trained mice.Macrophage infiltration in the tumor tissue wassignificantly lower in trained mice (0.65 +/- 0.16", "metadata": {}}
+{"_id": "2248870", "title": "", "text": "Lung dendritic cells imprint T cell lung homingand promote lung immunity through thechemokine receptor CCR4T cell trafficking intothe lung is critical for lung immunity, but themechanisms that mediate T cell lung homing arenot well understood. Here, we show that lungdendritic cells (DCs) imprint T cell lung homing,as lung DC-activated T cells traffic moreefficiently into the lung in response to inhaledantigen and at homeostasis compared with Tcells activated by DCs from other tissues.Consequently, lung DC-imprinted T cells protectagainst influenza more effectively than do gutand skin DC-imprinted T cells. Lung DCs imprintthe expression of CCR4 on T cells, and CCR4contributes to T cell lung imprinting. LungDC-activated, CCR4-deficient T cells fail to trafficinto the lung as efficiently and to protect againstinfluenza as effectively as lung DC-activated,CCR4-sufficient T cells. Thus, lung DCs imprint Tcell lung homing and promote lung immunity inpart through CCR4.", "metadata": {}}
+{"_id": "2251426", "title": "", "text": "microRNAs: A Safeguard againstTurmoil?Emerging data suggest that microRNAs(miRNAs) are instrumental in a variety of stressresponses in addition to their more recognizedrole in development. Surprisingly, miRNAs, whichnormally suppress expression of targettranscripts, may become activators of expressionduring stress. This might be partially explainedby new interactions of miRNA/Argonautecomplexes with RNA-binding proteins thatrelocate from different subcellular compartmentsduring stress.", "metadata": {}}
+{"_id": "2260571", "title": "", "text": "Vascular smooth muscle cell calcification ismediated by regulated exosomesecretion.RATIONALE Matrix vesicles (MVs),secreted by vascular smooth muscle cells(VSMCs), form the first nidus for mineralizationand fetuin-A, a potent circulating inhibitor ofcalcification, is specifically loaded into MVs.However, the processes of fetuin-A intracellulartrafficking and MV biogenesis are poorlyunderstood. OBJECTIVE The objective of thisstudy is to investigate the regulation, and role, ofMV biogenesis in VSMC calcification. METHODSAND RESULTS Alexa488-labeled fetuin-A wasinternalized by human VSMCs, trafficked via theendosomal system, and exocytosed frommultivesicular bodies via exosome release.VSMC-derived exosomes were enriched with thetetraspanins CD9, CD63, and CD81, and theirrelease was regulated by sphingomyelinphosphodiesterase 3. Comparative proteomicsshowed that VSMC-derived exosomes werecompositionally similar to exosomes from other", "metadata": {}}
+{"_id": "2264455", "title": "", "text": "Vaccines against malariaThere is no licencedvaccine against any human parasitic disease andPlasmodium falciparum malaria, a major cause ofinfectious mortality, presents a great challengeto vaccine developers. This has led to theassessment of a wide variety of approaches tomalaria vaccine design and development,assisted by the availability of a safe challengemodel for small-scale efficacy testing of vaccinecandidates. Malaria vaccine development hasbeen at the forefront of assessing many newvaccine technologies including novel adjuvants,vectored prime-boost regimes and the concept ofcommunity vaccination to block malariatransmission. Most current vaccine candidatestarget a single stage of the parasite's life cycleand vaccines against the early pre-erythrocyticstages have shown most success. A protein inadjuvant vaccine, working through antibodiesagainst sporozoites, and viral vector vaccinestargeting the intracellular liver-stage parasitewith cellular immunity show partial efficacy in", "metadata": {}}
+{"_id": "2266471", "title": "", "text": "MicroRNA-21 is Induced by Rapamycin in a Modelof Tuberous Sclerosis (TSC) andLymphangioleiomyomatosis(LAM)Lymphangioleiomyomatosis (LAM), amultisystem disease of women, is manifest bythe proliferation of smooth muscle-like cells inthe lung resulting in cystic lung destruction.Women with LAM can also develop renalangiomyolipomas. LAM is caused by mutations inthe tuberous sclerosis complex genes (TSC1 orTSC2), resulting in hyperactive mammalianTarget of Rapamycin (mTOR) signaling. ThemTOR inhibitor, Rapamycin, stabilizes lungfunction in LAM and decreases the volume ofrenal angiomyolipomas, but lung functiondeclines and angiomyolipomas regrow whentreatment is discontinued, suggesting thatfactors induced by mTORC1 inhibition maypromote the survival of TSC2-deficient cells.Whether microRNA (miRNA, miR) signaling isinvolved in the response of LAM to mTORC1inhibition is unknown. We identified", "metadata": {}}
+{"_id": "2272614", "title": "", "text": "Reduced NF1 expression confers resistance toEGFR inhibition in lung cancer.Activatingmutations in the EGF receptor (EGFR) areassociated with clinical responsiveness to EGFRtyrosine kinase inhibitors (TKI), such as erlotiniband gefitinib. However, resistance eventuallyarises, often due to a second EGFR mutation,most commonly T790M. Through a genome-widesiRNA screen in a human lung cancer cell lineand analyses of murine mutant EGFR-driven lungadenocarcinomas, we found that erlotinibresistance was associated with reducedexpression of neurofibromin, the RASGTPase-activating protein encoded by the NF1gene. Erlotinib failed to fully inhibit RAS-ERKsignaling when neurofibromin levels werereduced. Treatment of neurofibromin-deficientlung cancers with a MAP-ERK kinase (MEK)inhibitor restored sensitivity to erlotinib. Lowlevels of NF1 expression were associated withprimary and acquired resistance of lungadenocarcinomas to EGFR TKIs in patients.", "metadata": {}}
+{"_id": "2274272", "title": "", "text": "Human IRGM induces autophagy to eliminateintracellular mycobacteria.Immunity-related p47guanosine triphosphatases (IRG) play a role indefense against intracellular pathogens. Wefound that the murine Irgm1 (LRG-47)guanosine triphosphatase induced autophagyand generated large autolysosomal organelles asa mechanism for the elimination of intracellularMycobacterium tuberculosis. We also identified afunction for a human IRG protein in the controlof intracellular pathogens and report that thehuman Irgm1 ortholog, IRGM, plays a role inautophagy and in the reduction of intracellularbacillary load.", "metadata": {}}
+{"_id": "2276126", "title": "", "text": "Implementation of a Clinical Pharmacy EducationProgram in a Teaching Hospital: ResidentOriented Documentation and InterventionTheaim of this study was to provide a clinicalpharmacy education program at MasihDaneshvari hospital, a University affiliatedhospital, located in Tehran, Iran. For thispurpose, the most common pharmacist involvedinterventions and aspects of potential fields forpharmacy students and residents education wasfirstly identified. Clinical pharmacy interventionsand drug information forms were filled during thestudy period, from January 2006 till January2007. Based on the results of this study, a totalnumber of 772 interventions were conductedduring the study year. Drug information had thehighest rate of 22.30% among all interventions,followed by dose adjustment, and therapeuticreduction or addition. The mean number ofmedications per patient was 8.62 ± 7.54. Inconclusion, it could be said that although in ourcountry the challenge for the pharmacy as a", "metadata": {}}
+{"_id": "2291922", "title": "", "text": "The surgical anatomy of the conductiontissues.On the basis of our collective experiencewe have reviewed the disposition of the cardiacconduction tissues as they might be observed bythe surgeon in both normal and abnormal hearts.The sinus node lies subepicardially in theterminal sulcus; because of its variable bloodsupply the entire superior cavoatrial junction is apotential danger area. There are nomorphologically discrete tracts extendingthrough the atrial tissues between sinus andatrioventricular nodes. The atrioventricular node,the atrial extent of the atrioventricularconduction axis, is contained exclusively withinthe triangle of Koch. The axis penetrates throughthe central fibrous body and branches on themuscular ventricular septum immediatelybeneath the interventricular component of themembranous septum. The landmarks to thesestructures are described as they might be seenthrough the right atrium, left atrium, and aorta.Consideration is then given to the surgical", "metadata": {}}
+{"_id": "2295434", "title": "", "text": "Agreement between an online dietaryassessment tool (myfood24) and aninterviewer-administered 24-h dietary recall inBritish adolescents aged 11-18 years.myfood24Is an online 24-h dietary assessment tooldeveloped for use among British adolescents andadults. Limited information is available regardingthe validity of using new technology in assessingnutritional intake among adolescents. Thus, arelative validation of myfood24 against aface-to-face interviewer-administered 24-hmultiple-pass recall (MPR) was conducted amongseventy-five British adolescents aged 11-18years. Participants were asked to completemyfood24 and an interviewer-administered MPRon the same day for 2 non-consecutive days atschool. Total energy intake (EI) and nutrientsrecorded by the two methods were comparedusing intraclass correlation coefficients (ICC),Bland-Altman plots (using between andwithin-individual information) and weighted κ toassess the agreement. Energy, macronutrients", "metadata": {}}
+{"_id": "2296264", "title": "", "text": "Modulation of cancer chemotherapy by greentea.Biochemical modulation has played animportant role in the development of cancerchemotherapy. We have directed our attention tothe intake of common beverages andinvestigated the effects of green tea and teacomponents on the antitumor activity ofdoxorubicin. We carried out the combinedtreatment of toxorubicin and green tea on Ehrlichascites carcinoma tumor-bearing mice. The oraladministration of green tea enhanced 2.5-foldthe inhibitory effects of doxorubicin on tumorgrowth. The Doxorubicin concentration in thetumor was increased by the combination ofgreen tea with doxorubicin. In contrast, theincrease in doxorubicin concentration was notobserved in normal tissues after green teacombination. Furthermore, the enhancement ofantitumor activity of doxorubicin induced bygreen tea was observed in M5076 ovariansarcoma, which has low sensitivity todoxorubicin. These results suggest that drinking", "metadata": {}}
+{"_id": "2316374", "title": "", "text": "Histone deacetylase 5 interacts with Krüppel-likefactor 2 and inhibits its transcriptional activity inendothelium.AIMS Vascular endothelialdysfunction and inflammation are hallmarks ofatherosclerosis. Krüppel-like factor 2 (KLF2) is akey mediator of anti-inflammatory andanti-atherosclerotic properties of theendothelium. However, little is known of themolecular mechanisms for regulating KLF2transcriptional activation. METHODS ANDRESULTS Here, we found that histonedeacetylase 5 (HDAC5) associates with KLF2 andrepresses KLF2 transcriptional activation. HDAC5resided with KLF2 in the nuclei of humanumbilical cord vein endothelial cells (HUVECs).Steady laminar flow attenuated the associationof HDAC5 with KLF2 via stimulating HDAC5phosphorylation-dependent nuclear export inHUVEC. We also mapped theKLF2-HDAC5-interacting domains and found thatthe N-terminal region of HDAC5 interacts withthe C-terminal domain of KLF2. Chromatin", "metadata": {}}
+{"_id": "2319305", "title": "", "text": "N348I in HIV-1 reverse transcriptase cancounteract the nevirapine-mediated bias towardRNase H cleavage during plus-strandinitiation.Drug resistance-associated mutationsin HIV-1 reverse transcriptase (RT) can affect thebalance between polymerase and ribonuclease H(RNase H) activities of the enzyme. We haverecently demonstrated that the N348I mutationin the connection domain causes selectivedissociation from RNase H-competentcomplexes, whereas the functional integrity ofthe polymerase-competent complex remainslargely unaffected. N348I has been associatedwith resistance to the non-nucleoside RT inhibitor(NNRTI), nevirapine; however, a possiblemechanism that links changes in RNase Hactivity to changes in NNRTI susceptibilityremains to be established. To address thisproblem, we consider recent findings suggestingthat NNRTIs may affect the orientation of RT onits nucleic acid substrate and increase RNase Hactivity. Here we demonstrate that RNase", "metadata": {}}
+{"_id": "2328272", "title": "", "text": "Cancer survivorship research: the challenge ofrecruiting adult long term cancer survivors froma cooperative clinical trials groupINTRODUCTIONWith the growing number of adult cancersurvivors, there is increasing need forinformation that links potential late and longterm effects with specific treatment regimens.Few adult cancer patients are treated on clinicaltrials; however, patients previously enrolled inthese trials are an important source ofinformation about treatment-related late effects.METHODS Focusing on colorectal cancersurvivors, we used the database from five phaseIII randomized clinical trials from the NationalSurgical Adjuvant Breast & Bowel Project(NSABP) to recruit and enroll long term survivorsin a study of late health outcomes and quality oflife. We describe the challenges to recruitment ofpatients more than 5 -20 years after treatment.RESULTS Sixty-five NSABP treatment sites wereinvited to enroll patients in the study. Sixtyparticipated with the potential to recruit 2,408", "metadata": {}}
+{"_id": "2335873", "title": "", "text": "Arylsulfatase B Improves Locomotor Functionafter Mouse Spinal Cord InjuryBacterialchondroitinase ABC (ChaseABC) has been usedto remove the inhibitory chondroitin sulfatechains from chondroitin sulfate proteoglycans toimprove regeneration after rodent spinal cordinjury. We hypothesized that the mammalianenzyme arylsulfatase B (ARSB) would alsoenhance recovery after mouse spinal cord injury.Application of the mammalian enzyme would bean attractive alternative to ChaseABC because ofits more robust chemical stability and reducedimmunogenicity. A one-time injection of humanARSB into injured mouse spinal cord eliminatedimmunoreactivity for chondroitin sulfates withinfive days, and up to 9 weeks after injury. After amoderate spinal cord injury, we observedimprovements of locomotor recovery assessedby the Basso Mouse Scale (BMS) in ARSB treatedmice, compared to the buffer-treated controlgroup, at 6 weeks after injection. After a severespinal cord injury, mice injected with equivalent", "metadata": {}}
+{"_id": "2338488", "title": "", "text": "The World Health Organization Adult ADHDSelf-Report Scale (ASRS): a short screeningscale for use in the generalpopulation.BACKGROUND A self-report screeningscale of adult attention-deficit/hyperactivitydisorder (ADHD), the World Health Organization(WHO) Adult ADHD Self-Report Scale (ASRS)was developed in conjunction with revision of theWHO Composite International DiagnosticInterview (CIDI). The current report presentsdata on concordance of the ASRS and of ashort-form ASRS screener with blind clinicaldiagnoses in a community sample. METHOD TheASRS includes 18 questions about frequency ofrecent DSM-IV Criterion A symptoms of adultADHD. The ASRS screener consists of six out ofthese 18 questions that were selected based onstepwise logistic regression to optimizeconcordance with the clinical classification. ASRSresponses were compared to blind clinical ratingsof DSM-IV adult ADHD in a sample of 154respondents who previously participated in the", "metadata": {}}
+{"_id": "2344892", "title": "", "text": "Human milk proresolving mediators stimulateresolution of acute inflammationHuman milkcontains nutrients and bioactive productsrelevant to infant development andimmunological protection. Here, we investigatedthe proresolving properties of milk using humanmilk lipid mediator isolates (HLMIs) anddetermined their impact on resolution programsin vivo and with human macrophages. HLMIsreduced the maximum neutrophil numbers(14.6±1.2 × 106–11.0±1.0 × 106 cells perexudate) and shortened the resolution interval(Ri; 50% neutrophil reduction) by 54%compared with peritonitis. Using rigorousliquid-chromatography tandem-massspectrometry (LC-MS-MS)-based lipid mediator(LM) metabololipidomics, we demonstrated thathuman milk possesses a proresolvingLM-specialized proresolving mediator (LM-SPM)signature profile, containing SPMs (e.g. resolvins(Rv), protectins (PDs), maresins (MaRs), andlipoxins (LXs)) at bioactive levels", "metadata": {}}
+{"_id": "2352142", "title": "", "text": "Cerebral perfusion and stroke.Stroke is aheterogeneous syndrome caused by multipledisease mechanisms, but all result in a disruptionof cerebral blood flow with subsequent tissuedamage. This review covers the mechanismsresponsible for regulation of the normal cerebralcirculation, and how they are disrupted indisease states. A central concept in treatingpatients with acute ischaemic stroke is theexistence of an ischaemic penumbra ofpotentially salvageable tissue, and the evidencefor its existence in humans is reviewed.", "metadata": {}}
+{"_id": "2356950", "title": "", "text": "Epigenetic regulation of miR-184 by MBD1governs neural stem cell proliferation anddifferentiation.Methyl-CpG binding protein 1(MBD1) regulates gene expression via a DNAmethylation-mediated epigenetic mechanism.We have previously demonstrated that MBD1deficiency impairs adult neural stem/progenitorcell (aNSC) differentiation and neurogenesis, butthe underlying mechanism was unclear. Here, weshow that MBD1 regulates the expression ofseveral microRNAs in aNSCs and, specifically,that miR-184 is directly repressed by MBD1. Highlevels of miR-184 promoted proliferation butinhibited differentiation of aNSCs, whereasinhibition of miR-184 rescued the phenotypesassociated with MBD1 deficiency. We furtherfound that miR-184 regulates the expression ofNumblike (Numbl), a known regulator of braindevelopment, by binding to the 3'-UTR of NumblmRNA and affecting its translation. Expression ofexogenous Numbl could rescue the aNSC defectsthat result from either miR-184 overexpression", "metadata": {}}
+{"_id": "2359152", "title": "", "text": "Landscape of genetic lesions in 944 patients withmyelodysplastic syndromesHigh-throughput DNAsequencing significantly contributed to diagnosisand prognostication in patients withmyelodysplastic syndromes (MDS). Wedetermined the biological and prognosticsignificance of genetic aberrations in MDS. Intotal, 944 patients with various MDS subtypeswere screened for known/putativemutations/deletions in 104 genes using targeteddeep sequencing and array-based genomichybridization. In total, 845/944 patients (89.5%)harbored at least one mutation (median, 3 perpatient; range, 0-12). Forty-seven genes weresignificantly mutated with TET2, SF3B1, ASXL1,SRSF2, DNMT3A, and RUNX1 mutated in >10%of cases. Many mutations were associated withhigher risk groups and/or blast elevation.Survival was investigated in 875 patients. Byunivariate analysis, 25/48 genes (resulting from47 genes tested significantly plus PRPF8)affected survival (P<0.05). The status of 14", "metadata": {}}
+{"_id": "2360905", "title": "", "text": "Integrated molecular genetic profiling ofpediatric high-grade gliomas reveals keydifferences with the adult disease.PURPOSE Todefine copy number alterations and geneexpression signatures underlying pediatrichigh-grade glioma (HGG). PATIENTS ANDMETHODS We conducted a high-resolutionanalysis of genomic imbalances in 78 de novopediatric HGGs, including seven diffuse intrinsicpontine gliomas, and 10 HGGs arising in childrenwho received cranial irradiation for a previouscancer using single nucleotide polymorphismmicroarray analysis. Gene expression wasanalyzed with gene expression microarrays for53 tumors. Results were compared with publiclyavailable data from adult tumors. RESULTSSignificant differences in copy number alterationsdistinguish childhood and adult glioblastoma.PDGFRA was the predominant target of focalamplification in childhood HGG, including diffuseintrinsic pontine gliomas, and gene expressionanalyses supported an important role for", "metadata": {}}
+{"_id": "2374637", "title": "", "text": "Gene set enrichment analysis: aknowledge-based approach for interpretinggenome-wide expression profiles.Althoughgenomewide RNA expression analysis hasbecome a routine tool in biomedical research,extracting biological insight from suchinformation remains a major challenge. Here, wedescribe a powerful analytical method calledGene Set Enrichment Analysis (GSEA) forinterpreting gene expression data. The methodderives its power by focusing on gene sets, thatis, groups of genes that share common biologicalfunction, chromosomal location, or regulation.We demonstrate how GSEA yields insights intoseveral cancer-related data sets, includingleukemia and lung cancer. Notably, wheresingle-gene analysis finds little similaritybetween two independent studies of patientsurvival in lung cancer, GSEA reveals manybiological pathways in common. The GSEAmethod is embodied in a freely availablesoftware package, together with an initial", "metadata": {}}
+{"_id": "2380002", "title": "", "text": "The evolution of RNAs with multiplefunctions.Increasing numbers of transcripts havebeen reported to transmit both protein-codingand regulatory information. Apart fromchallenging our conception of the gene, thisobservation raises the question as to what extentthis phenomenon occurs across the genome andhow and why such dual encoding of function hasevolved in the eukaryotic genome. To addressthis question, we consider the evolutionary pathof genes in the earliest forms of life on Earth,where it is generally regarded that proteinsevolved from a cellular machinery based entirelywithin RNA. This led to the domination ofprotein-coding genes in the genomes ofmicroorganisms, although it is likely that RNAnever lost its other capacities and functionalities,as evidenced by cis-acting riboswitches andUTRs. On the basis that the subsequent evolutionof a more sophisticated regulatory architectureto provide higher levels of epigenetic control andaccurate spatiotemporal expression in", "metadata": {}}
+{"_id": "2388819", "title": "", "text": "In Vitro–expanded Antigen-specific Regulatory TCells Suppress Autoimmune DiabetesThe lownumber of CD4+ CD25+ regulatory T cells(Tregs), their anergic phenotype, and diverseantigen specificity present major challenges toharnessing this potent tolerogenic population totreat autoimmunity and transplant rejection. Inthis study, we describe a robust method toexpand antigen-specific Tregs fromautoimmune-prone nonobese diabetic mice.Purified CD4+ CD25+ Tregs were expanded upto 200-fold in less than 2 wk in vitro using acombination of anti-CD3, anti-CD28, andinterleukin 2. The expanded Tregs express aclassical cell surface phenotype and function bothin vitro and in vivo to suppress effector T cellfunctions. Most significantly, small numbers ofantigen-specific Tregs can reverse diabetes afterdisease onset, suggesting a novel approach tocellular immunotherapy for autoimmunity.", "metadata": {}}
+{"_id": "2389574", "title": "", "text": "Stathmin overexpression identifies high-riskpatients and lymph node metastasis inendometrial cancer.PURPOSE Overexpression ofthe oncogen Stathmin has been linked toaggressive endometrial carcinoma and apotential for PI3Kinase inhibitors in this disease.We wanted to validate the prognostic value ofStathmin expression in a large prospectivemulticenter setting. As lymph node sampling ispart of current surgical staging, we also aimed totest if Stathmin expression in endometrialcurettage specimens could predict lymph nodemetastasis. EXPERIMENTAL DESIGN A total of1,076 endometrial cancer patients have beenrecruited from 10 centers to investigate thebiological tumor marker Stathmin in relation toclinicopathologic variables, including lymph nodestatus and survival. Stathminimmunohistochemical staining was carried out in477 hysterectomy and 818 curettage specimens.RESULTS Seventy-one percent of the patients (n= 763) were subjected to lymph node sampling,", "metadata": {}}
+{"_id": "2391552", "title": "", "text": "Statin prophylaxis and inflammatory mediatorsfollowing cardiopulmonary bypass: a systematicreviewINTRODUCTION Induction of aninflammatory response is thought to have asignificant role in the complications that followcardiopulmonary bypass (CPB). The statin drugsare increasingly being recognized as havingpotent anti-inflammatory effects and hence havepotential to influence an important mechanism ofinjury in CPB, although there is no currentconfirmation that this is indeed the case. Ourobjective was to systematically review ifpre-operative prophylactic statin therapy,compared with placebo or standard of care, candecrease the inflammatory response in peopleundergoing heart surgery with CPB. METHODSWe performed a systematic and comprehensiveliterature search for all randomized controlledtrials (RCTs) of open heart surgery with CPB inadults or children who received prophylacticstatin treatment prior to CPB, with reportedoutcomes which included markers of", "metadata": {}}
+{"_id": "2402323", "title": "", "text": "Array-based Comparative Genomic Hybridizationfor Genome-Wide Screening of DNA CopyNumber in Bladder TumorsGenome-wide copynumber profiles were characterized in 41 primarybladder tumors using array-based comparativegenomic hybridization (array CGH). In additionto previously identified alterations in largechromosomal regions, alterations were identifiedin many small genomic regions, some withhigh-level amplifications or homozygousdeletions. High-level amplifications weredetected for 192 genomic clones, mostfrequently at 6p22.3 (E2F3), 8p12 (FGFR1),8q22.2 (CMYC), 11q13 (CCND1, EMS1, INT2),and 19q13.1 (CCNE). Homozygous deletionswere detected in 51 genomic clones, with fourshowing deletions in more than one case: twoclones mapping to 9p21.3 (CDKN2A/p16, in ninecases), one at 8p23.1 (three cases), and one at11p13 (two cases). Significant correlations wereobserved between copy number gain of clonescontaining CCNE1 and gain of ERBB2, and", "metadata": {}}
+{"_id": "2405259", "title": "", "text": "Tet2 is required to resolve inflammation byrecruiting Hdac2 to specifically repressIL-6Epigenetic modifiers have fundamental rolesin defining unique cellular identity through theestablishment and maintenance oflineage-specific chromatin and methylationstatus. Several DNA modifications such as5-hydroxymethylcytosine (5hmC) are catalysedby the ten eleven translocation (Tet)methylcytosine dioxygenase family members,and the roles of Tet proteins in regulatingchromatin architecture and gene transcriptionindependently of DNA methylation have beengradually uncovered. However, the regulation ofimmunity and inflammation by Tet proteinsindependent of their role in modulating DNAmethylation remains largely unknown. Here weshow that Tet2 selectively mediates activerepression of interleukin-6 (IL-6) transcriptionduring inflammation resolution in innate myeloidcells, including dendritic cells and macrophages.Loss of Tet2 resulted in the upregulation of", "metadata": {}}
+{"_id": "2417551", "title": "", "text": "Control of immunity by the TNFR-relatedmolecule OX40 (CD134).TNFR/TNF superfamilymembers can control diverse aspects of immunefunction. Research over the past 10 years hasshown that one of the most important andprominent interactions in this family is thatbetween OX40 (CD134) and its partner OX40L(CD252). These molecules strongly regulateconventional CD4 and CD8 T cells, and morerecent data are highlighting their ability tomodulate NKT cell and NK cell function as well asto mediate cross-talk with professionalantigen-presenting cells and diverse cell typessuch as mast cells, smooth muscle cells, andendothelial cells. Additionally, OX40-OX40Linteractions alter the differentiation and activityof regulatory T cells. Blocking OX40L hasproduced strong therapeutic effects in multipleanimal models of autoimmune and inflammatorydisease, and, in line with a prospective clinicalfuture, reagents that stimulate OX40 signalingare showing promise as adjuvants for vaccination", "metadata": {}}
+{"_id": "2423940", "title": "", "text": "The Drosophila DHR96 nuclear receptor bindscholesterol and regulates cholesterolhomeostasis.Cholesterol homeostasis is requiredto maintain normal cellular function and avoidthe deleterious effects of hypercholesterolemia.Here we show that the Drosophila DHR96 nuclearreceptor binds cholesterol and is required for thecoordinate transcriptional response of genes thatare regulated by cholesterol and involved incholesterol uptake, trafficking, and storage.DHR96 mutants die when grown on low levels ofcholesterol and accumulate excess cholesterolwhen maintained on a high-cholesterol diet. Thecholesterol accumulation phenotype can beattributed to misregulation of npc1b, an orthologof the mammalian Niemann-Pick C1-like 1 geneNPC1L1, which is essential for dietary cholesteroluptake. These studies define DHR96 as a centralregulator of cholesterol homeostasis.", "metadata": {}}
+{"_id": "2424794", "title": "", "text": "A neuroimaging investigation of the associationbetween aerobic fitness, hippocampal volume,and memory performance in preadolescentchildren.Because children are becomingoverweight, unhealthy, and unfit, understandingthe neurocognitive benefits of an active lifestylein childhood has important public health andeducational implications. Animal research hasindicated that aerobic exercise is related toincreased cell proliferation and survival in thehippocampus as well as enhancedhippocampal-dependent learning and memory.Recent evidence extends this relationship toelderly humans by suggesting that high aerobicfitness levels in older adults are associated withincreased hippocampal volume and superiormemory performance. The present study aimedto further extend the link between fitness,hippocampal volume, and memory to a sampleof preadolescent children. To this end, magneticresonance imaging was employed to investigatewhether higher- and lower-fit 9- and 10-year-old", "metadata": {}}
+{"_id": "2425364", "title": "", "text": "Association between maternal serum25-hydroxyvitamin D level and pregnancy andneonatal outcomes: systematic review andmeta-analysis of observationalstudies.OBJECTIVE To assess the effect of25-hydroxyvitamin D (25-OHD) levels onpregnancy outcomes and birth variables. DESIGNSystematic review and meta-analysis. DATASOURCES Medline (1966 to August 2012),PubMed (2008 to August 2012), Embase (1980to August 2012), CINAHL (1981 to August2012), the Cochrane database of systematicreviews, and the Cochrane database ofregistered clinical trials. STUDY SELECTIONStudies reporting on the association betweenserum 25-OHD levels during pregnancy and theoutcomes of interest (pre-eclampsia, gestationaldiabetes, bacterial vaginosis, caesarean section,small for gestational age infants, birth weight,birth length, and head circumference). DATAEXTRACTION Two authors independentlyextracted data from original research articles,", "metadata": {}}
+{"_id": "2436602", "title": "", "text": "β-Adrenergic receptor antagonism preventsanxiety-like behavior and microglial reactivityinduced by repeated social defeat.Psychosocialstress is associated with altered immune functionand development of psychological disordersincluding anxiety and depression. Here we showthat repeated social defeat in mice increasedc-Fos staining in brain regions associated withfear and threat appraisal and promotedanxiety-like behavior in a β-adrenergicreceptor-dependent manner. Repeated socialdefeat also significantly increased the number ofCD11b(+)/CD45(high)/Ly6C(high) macrophagesthat trafficked to the brain. In addition, severalinflammatory markers were increased on thesurface of microglia (CD14, CD86, and TLR4) andmacrophages (CD14 and CD86) after socialdefeat. Repeated social defeat also increased thepresence of deramified microglia in the medialamygdala, prefrontal cortex, and hippocampus.Moreover, mRNA analysis of microglia indicatedthat repeated social defeat increased levels of", "metadata": {}}
+{"_id": "2437807", "title": "", "text": "In vitro differentiation of transplantable neuralprecursors from human embryonic stem cellsTheremarkable developmental potential andreplicative capacity of human embryonic stem(ES) cells promise an almost unlimited supply ofspecific cell types for transplantation therapies.Here we describe the in vitro differentiation,enrichment, and transplantation of neuralprecursor cells from human ES cells. Uponaggregation to embryoid bodies, differentiatingES cells formed large numbers of neuraltube–like structures in the presence of fibroblastgrowth factor 2 (FGF-2). Neural precursorswithin these formations were isolated byselective enzymatic digestion and further purifiedon the basis of differential adhesion. Followingwithdrawal of FGF-2, they differentiated intoneurons, astrocytes, and oligodendrocytes. Aftertransplantation into the neonatal mouse brain,human ES cell–derived neural precursors wereincorporated into a variety of brain regions,where they differentiated into both neurons and", "metadata": {}}
+{"_id": "2443495", "title": "", "text": "Characterization of prostaglandin E2 productionby Candida albicans.Candida albicans produceslipid metabolites that are functionally similar tohost prostaglandins. These studies, using massspectrometry, demonstrate that C. albicansproduces authentic prostaglandin E(2) (PGE(2))from arachidonic acid. Maximal PGE(2)production was achieved at 37 degrees C instationary-phase culture supernatants and incell-free lysates generated from stationary-phasecells. Interestingly, PGE(2) production isinhibited by both nonspecific cyclooxygenase andlipoxygenase inhibitors but not by inhibitorsspecific for the cyclooxygenase 2 isoenzyme. TheC. albicans genome does not possess acyclooxygenase homolog; however, severalgenes that may play a role in prostaglandinproduction from C. albicans were investigated. Itwas found that a C. albicans fatty aciddesaturase homolog (Ole2) and a multicopperoxidase homolog (Fet3) play roles inprostaglandin production, with ole2/ole2 and", "metadata": {}}
+{"_id": "2452989", "title": "", "text": "A global role for KLF1 in erythropoiesis revealedby ChIP-seq in primary erythroid cells.KLF1regulates a diverse suite of genes to directerythroid cell differentiation from bipotentprogenitors. To determine the localcis-regulatory contexts and transcription factornetworks in which KLF1 operates, we performedKLF1 ChIP-seq in the mouse. We found at least945 sites in the genome of E14.5 fetal livererythroid cells which are occupied byendogenous KLF1. Many of these recovered sitesreside in erythroid gene promoters such asHbb-b1, but the majority are distant to anyknown gene. Our data suggests KLF1 directlyregulates most aspects of terminal erythroiddifferentiation including production of alpha- andbeta-globin protein chains, heme biosynthesis,coordination of proliferation and anti-apoptoticpathways, and construction of the red cellmembrane and cytoskeleton by functioningprimarily as a transcriptional activator.Additionally, we suggest new mechanisms for", "metadata": {}}
+{"_id": "2454002", "title": "", "text": "KOBAS 2.0: a web server for annotation andidentification of enriched pathways anddiseasesHigh-throughput experimentaltechnologies often identify dozens to hundreds ofgenes related to, or changed in, a biological orpathological process. From these genes onewants to identify biological pathways that maybe involved and diseases that may be implicated.Here, we report a web server, KOBAS 2.0, whichannotates an input set of genes with putativepathways and disease relationships based onmapping to genes with known annotations. Itallows for both ID mapping and cross-speciessequence similarity mapping. It then performsstatistical tests to identify statisticallysignificantly enriched pathways and diseases.KOBAS 2.0 incorporates knowledge across 1327species from 5 pathway databases (KEGGPATHWAY, PID, BioCyc, Reactome and Panther)and 5 human disease databases (OMIM, KEGGDISEASE, FunDO, GAD and NHGRI GWASCatalog). KOBAS 2.0 can be accessed at", "metadata": {}}
+{"_id": "2460304", "title": "", "text": "Translocation of sickle cell erythrocytemicroRNAs into Plasmodium falciparum inhibitsparasite translation and contributes to malariaresistance.Erythrocytes carrying a varianthemoglobin allele (HbS), which causes sickle celldisease and resists infection by the malariaparasite Plasmodium falciparum. The molecularbasis of this resistance, which has long beenrecognized as multifactorial, remainsincompletely understood. Here we show that thedysregulated microRNA (miRNA) composition, ofeither heterozygous HbAS or homozygous HbSSerythrocytes, contributes to resistance against P.falciparum. During the intraerythrocytic life cycleof P. falciparum, a subset of erythrocyte miRNAstranslocate into the parasite. Two miRNAs,miR-451 and let-7i, were highly enriched inHbAS and HbSS erythrocytes, and these miRNAs,along with miR-223, negatively regulatedparasite growth. Surprisingly, we found thatmiR-451 and let-7i integrated into essentialparasite messenger RNAs and, via impaired", "metadata": {}}
+{"_id": "2462673", "title": "", "text": "CD28 and ITK signals regulate autoreactive T celltraffickingActivation of self-reactive T cells andtheir trafficking to target tissues leads toautoimmune organ destruction. Mice lacking theco-inhibitory receptor cytotoxic T lymphocyteantigen-4 (CTLA-4) develop fatal autoimmunitycharacterized by lymphocytic infiltration intononlymphoid tissues. Here, we demonstrate thatthe CD28 co-stimulatory pathway regulates thetrafficking of self-reactive Ctla4(-/-) T cells totissues. Concurrent ablation of theCD28-activated Tec family kinase ITK does notblock spontaneous T cell activation but insteadcauses self-reactive Ctla4(-/-) T cells toaccumulate in secondary lymphoid organs.Despite excessive spontaneous T cell activationand proliferation in lymphoid organs, Itk(-/-);Ctla4(-/-) mice are otherwise healthy, mountantiviral immune responses and exhibit a longlifespan. We propose that ITK specificallylicenses autoreactive T cells to enter tissues tomount destructive immune responses. Notably,", "metadata": {}}
+{"_id": "2466614", "title": "", "text": "Delayed and Accelerated Aging Share CommonLongevity Assurance MechanismsMutant dwarfand calorie-restricted mice benefit from healthyaging and unusually long lifespan. In contrast,mouse models for DNA repair-deficient progeroidsyndromes age and die prematurely. To identifymechanisms that regulate mammalian longevity,we quantified the parallels between thegenome-wide liver expression profiles of micewith those two extremes of lifespan. Contrary toexpectation, we find significant, genome-wideexpression associations between the progeroidand long-lived mice. Subsequent analysis ofsignificantly over-represented biologicalprocesses revealed suppression of the endocrineand energy pathways with increased stressresponses in both delayed and premature aging.To test the relevance of these processes innatural aging, we compared the transcriptomesof liver, lung, kidney, and spleen over the entiremurine adult lifespan and subsequentlyconfirmed these findings on an independent", "metadata": {}}
+{"_id": "2474731", "title": "", "text": "Arginine depletion as a mechanism for theimmune privilege of corneal allograftsThe corneais an immune privileged tissue. Since arginasehas been found to modulate T-cell function bydepleting arginine, we investigated theexpression of arginase in the cornea and itspossible role in immune privilege using a murinetransplant model. We found that both theendothelium and epithelium of murine corneasexpress functional arginase I, capable ofdown-regulating T-cell proliferation in an in vitroculture system. The administration of the specificarginase inhibitor N-hydroxy-nor-L-Arg torecipient mice resulted in an acceleratedrejection of allogeneic C57BL/6 (B6) cornealgrafts. In contrast, in vivo blockade of arginaseactivity had no effect in altering the course ofrejection of primary skin grafts that expresslittle, if any, arginase. In addition, the inhibitionof arginase did not alter systemic T-cellproliferation. These data show that arginase isfunctional in the cornea and contributes to the", "metadata": {}}
+{"_id": "2475059", "title": "", "text": "Once-a-day Concerta methylphenidate versusthree-times-daily methylphenidate in laboratoryand natural settings.OBJECTIVE Methylphenidate(MPH), the most commonly prescribed drug forattention-deficit/hyperactivity disorder (ADHD),has a short half-life, which necessitates multipledaily doses. The need for multiple dosesproduces problems with medicationadministration during school and after-schoolhours, and therefore with compliance. Previouslong-acting stimulants and preparations haveshown effects equivalent to twice-daily dosing ofMPH. This study tests the efficacy and durationof action, in natural and laboratory settings, ofan extended-release MPH preparation designedto last 12 hours and therefore be equivalent to3-times-daily dosing. METHODS Sixty-eightchildren with ADHD, 6 to 12 years old,participated in a within-subject, double-blindcomparison of placebo, immediate-release (IR)MPH 3 times a day (tid), and Concerta, aonce-daily MPH formulation. Three dosing levels", "metadata": {}}
+{"_id": "2479538", "title": "", "text": "Leaderless genes in bacteria: clue to theevolution of translation initiation mechanisms inprokaryotesBACKGROUND Shine-Dalgarno (SD)signal has long been viewed as the dominanttranslation initiation signal in prokaryotes.Recently, leaderless genes, which lack5'-untranslated regions (5'-UTR) on theirmRNAs, have been shown abundant in archaea.However, current large-scale in silico analyses oninitiation mechanisms in bacteria are mainlybased on the SD-led initiation way, other thanthe leaderless one. The study of leaderless genesin bacteria remains open, which causes uncertainunderstanding of translation initiationmechanisms for prokaryotes. RESULTS Here, westudy signals in translation initiation regions ofall genes over 953 bacterial and 72 archaealgenomes, then make an effort to construct anevolutionary scenario in view of leaderless genesin bacteria. With an algorithm designed toidentify multi-signal in upstream regions ofgenes for a genome, we classify all genes into", "metadata": {}}
+{"_id": "2481032", "title": "", "text": "Neuronal Sirt1 deficiency increases insulinsensitivity in both brain and peripheraltissues.Sirt1 is a NAD(+)-dependent class IIIdeacetylase that functions as a cellular energysensor. In addition to its well-characterizedeffects in peripheral tissues, emerging evidencesuggests that neuronal Sirt1 activity plays a rolein the central regulation of energy balance andglucose metabolism. To assess this idea, wegenerated Sirt1 neuron-specific knockout(SINKO) mice. On both standard chow and HFD,SINKO mice were more insulin sensitive thanSirt1(f/f) mice. Thus, SINKO mice had lowerfasting insulin levels, improved glucose toleranceand insulin tolerance, and enhanced systemicinsulin sensitivity during hyperinsulinemiceuglycemic clamp studies. Hypothalamic insulinsensitivity of SINKO mice was also increasedover controls, as assessed by hypothalamicactivation of PI3K, phosphorylation of Akt andFoxO1 following systemic insulin injection.Intracerebroventricular injection of insulin led to", "metadata": {}}
+{"_id": "2485101", "title": "", "text": "Candidate Causal Regulatory Effects byIntegration of Expression QTLs with ComplexTrait Genetic AssociationsThe recent success ofgenome-wide association studies (GWAS) is nowfollowed by the challenge to determine how thereported susceptibility variants mediate complextraits and diseases. Expression quantitative traitloci (eQTLs) have been implicated in diseaseassociations through overlaps between eQTLsand GWAS signals. However, the abundance ofeQTLs and the strong correlation structure (LD)in the genome make it likely that some of theseoverlaps are coincidental and not driven by thesame functional variants. In the present study,we propose an empirical methodology, which wecall Regulatory Trait Concordance (RTC) thataccounts for local LD structure and integrateseQTLs and GWAS results in order to reveal thesubset of association signals that are due to ciseQTLs. We simulate genomic regions of variousLD patterns with both a single or two causalvariants and show that our score outperforms", "metadata": {}}
+{"_id": "2488880", "title": "", "text": "Gender-dependent differences in outcome afterthe treatment of infection in hospitalizedpatients.CONTEXT While it is established thatmanagement strategies and outcomes differ bygender for many diseases, its effect on infectionhas not been adequately studied. OBJECTIVE Toinvestigate the role of gender among hospitalizedpatients treated for infection. DESIGNObservational cohort study conducted during a26-month period from December 1996 throughJanuary 1999. SETTING University-affiliatedhospital. PARTICIPANTS A total of 892 patients inthe surgical units of the hospital with 1470consecutive infectious episodes (782 in men and688 in women). MAIN OUTCOME MEASURESMortality during hospitalization by gender forinfection episodes overall and for specificinfectious sites, including lung, peritoneum,bloodstream, catheter, urine, surgical site, andskin/soft tissue. RESULTS Among all infections,there was no significant difference in mortalitybased on gender (men, 11.1% vs women,", "metadata": {}}
+{"_id": "2492146", "title": "", "text": "Comparative Safety of Targeted Therapies forMetastatic Colorectal Cancer between Elderly andYounger Patients: a Study Using theInternational PharmacovigilanceDatabaseMetastatic colorectal cancer (mCRC) isincreasingly treated using targeted therapies.Post-marketing safety of these agents isunderstudied, especially in the elderly. Thisstudy aimed to compare, according to age, theadverse drug reactions (ADRs) of targetedtherapies used for mCRC in real life. Anextraction of VigiBase, which contains WorldHealth Organization individual case safetyreports (ICSRs), was performed. All ADR reportswith aflibercept, bevacizumab, cetuximab,panitumumab, or regorafenib used in CRC wereconsidered. For all drugs, chi-square tests wereused to compare frequencies of serious ADRsbetween patients aged ≥75 and <75 years. Forselected ADRs and each drug, the drug-ADRassociation compared to other anticancer drugswas estimated through the proportional reporting", "metadata": {}}
+{"_id": "2494748", "title": "", "text": "CpG island methylation in premalignant stages ofgastric carcinoma.There are limited reports onmethylation analysis of the premalignant lesionsof gastric carcinoma thus far. This is despite thefact that gastric carcinoma is one of the tumorswith a high frequency of CpG islandhypermethylation. To determine the frequencyand timing of hypermethylation during multistepgastric carcinogenesis, non-neoplastic gastricmucosa (n = 118), adenomas (n = 61), andcarcinomas (n = 64) were analyzed for their p16,human Mut L homologue 1 (hMLH1),death-associated protein (DAP)-kinase,thromobospondin-1 (THBS1), and tissue inhibitorof metalloproteinase 3 (TIMP-3) methylationstatus using methylation-specific PCR. Threedifferent classes of methylation behaviors werefound in the five tested genes. DAP-kinase wasmethylated at a similar frequency in all fourstages, whereas hMLH1 and p16 weremethylated in cancer samples (20.3% and42.2%, respectively) more frequently than in", "metadata": {}}
+{"_id": "2496002", "title": "", "text": "Familial amyloidotic polyneuropathy: current andemerging treatment options fortransthyretin-mediated amyloidosisTransthyretinfamilial amyloid polyneuropathy (TTR-FAP) is afatal clinical disorder characterized byextracellular deposition of abnormal fibrilsderived from misfolded, normally solubletransthyretin (TTR) molecules. The disease ismost commonly caused by a point mutationwithin the TTR gene inherited in an autosomaldominant fashion. Over 100 of such mutationshave been identified, leading to destabilization ofthe physiological TTR tetramer. As a result,many monomers originate with a tendency forspontaneous conformational changes andself-aggregation. The main clinical feature ofTTR-FAP is progressive sensorimotor andautonomic neuropathy. In the beginning, thispolyneuropathy predominantly involves smallunmyelinated nerve fibers with the result ofdissociated sensory loss disproportionatelyaffecting sensation of pain and temperature.", "metadata": {}}
+{"_id": "2506153", "title": "", "text": "Invariant natural killer T cells: bridging innateand adaptive immunityCells of the innateimmune system interact with pathogens viaconserved pattern-recognition receptors,whereas cells of the adaptive immune systemrecognize pathogens through diverse,antigen-specific receptors that are generated bysomatic DNA rearrangement. Invariant naturalkiller T (iNKT) cells are a subset of lymphocytesthat bridge the innate and adaptive immunesystems. Although iNKT cells express T cellreceptors that are generated by somatic DNArearrangement, these receptors aresemi-invariant and interact with a limited set oflipid and glycolipid antigens, thus resembling thepattern-recognition receptors of the innateimmune system. Functionally, iNKT cells mostclosely resemble cells of the innate immunesystem, as they rapidly elicit their effectorfunctions following activation, and fail to developimmunological memory. iNKT cells can becomeactivated in response to a variety of stimuli and", "metadata": {}}
+{"_id": "2522977", "title": "", "text": "Olmesartan-based therapies: an effective way toimprove blood pressure control andcardiovascular protection.The main purpose inhypertension treatment is the reduction ofcardiovascular disease burden. Among differentfirst-line antihypertensive drug classes,angiotensin-receptor blockers are characterizedby their both good effectiveness and tolerability.Furthermore, the interruption of therenin-angiotensin cascade is related with severalbenefits in target organ protection andcardiovascular prevention. Among differentangiotensin-receptor blockers, olmesartan hasbeen examined in several trial of organprotection, showing improvements in severaldisease markers, such as microinflammation,regression of both plaque volume and vascularhypertrophy, as well as microalbuminuriaprevention. Olmesartan has been also widelyexamined in combination of eitherhydrochlorothiazide or amlodipine, as well aswith both drugs in a single-pill triple", "metadata": {}}
+{"_id": "2526777", "title": "", "text": "Manslaughter by Fake Artesunate in Asia—WillAfrica Be Next?Falciparum malaria kills, and itparticularly kills the rural poor. Artemisininderivatives, such as artesunate, are a vitalcomponent of Plasmodium falciparum malariatreatment and control in the face of globallyincreasing antimalarial drug resistance. Since1998 a worsening epidemic of sophisticatedcounterfeit “artesunate” tablets (containing noartesunate) has plagued mainland SoutheastAsia (see Figure S1). In some countries, most ofthe available artesunate is fake [ 1–5].Artemisinin derivatives are remarkably rapid intheir antimalarial effects, and they are very welltolerated. So where these medicines areavailable, they are sought after. But as they arerelatively expensive, a demand is created forcheaper versions amongst the poorest and mostvulnerable people, upon whom the counterfeitershave preyed–with fatal results.", "metadata": {}}
+{"_id": "2533768", "title": "", "text": "Workshop: endothelial cell dysfunction leading todiabetic nephropathy : focus on nitricoxide.Clinical manifestations of diabeticnephropathy are an expression of diabeticmicroangiopathy. This review revisits thepreviously proposed Steno hypothesis andadvances our hypothesis that development ofendothelial cell dysfunction represents a commonpathophysiological pathway of diabeticcomplications. Specifically, the ability of glucoseto scavenge nitric oxide is proposed as theinitiation phase of endothelial dysfunction.Gradual accumulation of advanced glycated endproducts and induction of plasminogen activatorinhibitor-1, resulting in the decreased expressionof endothelial nitric oxide synthase and reducedgeneration of nitric oxide, are proposed to bepathophysiologically critical for the maintenancephase of endothelial dysfunction. The proposedconceptual shift toward the role of endothelialdysfunction in diabetic complications mayprovide new strategies for their prevention.", "metadata": {}}
+{"_id": "2541699", "title": "", "text": "A nuclear Argonaute promotesmulti-generational epigenetic inheritance andgermline immortalityEpigenetic information isfrequently erased near the start of each newgeneration. In some cases, however, epigeneticinformation can be transmitted from parent toprogeny (multigenerational epigeneticinheritance). A particularly notable example ofthis type of epigenetic inheritance isdouble-stranded RNA-mediated gene silencing inCaenorhabditis elegans. This RNA-mediatedinterference (RNAi) can be inherited for morethan five generations. To understand thisprocess, here we conduct a genetic screen fornematodes defective in transmitting RNAisilencing signals to future generations. Thisscreen identified the heritable RNAi defective 1(hrde-1) gene. hrde-1 encodes an Argonauteprotein that associates with small interferingRNAs in the germ cells of progeny of animalsexposed to double-stranded RNA. In the nuclei ofthese germ cells, HRDE-1 engages the nuclear", "metadata": {}}
+{"_id": "2543135", "title": "", "text": "Autophagic programmed cell death by selectivecatalase degradation.Autophagy plays a centralrole in regulating important cellular functionssuch as cell survival during starvation andcontrol of infectious pathogens. Recently, it hasbeen shown that autophagy can induce cells todie; however, the mechanism of the autophagiccell death program is unclear. We now show thatcaspase inhibition leading to cell death by meansof autophagy involves reactive oxygen species(ROS) accumulation, membrane lipid oxidation,and loss of plasma membrane integrity.Inhibition of autophagy by chemical compoundsor knocking down the expression of keyautophagy proteins such as ATG7, ATG8, andreceptor interacting protein (RIP) blocks ROSaccumulation and cell death. The cause ofabnormal ROS accumulation is the selectiveautophagic degradation of the major enzymaticROS scavenger, catalase. Caspase inhibitiondirectly induces catalase degradation and ROSaccumulation, which can be blocked by", "metadata": {}}
+{"_id": "2547636", "title": "", "text": "Human epidermal stem cell function is regulatedby circadian oscillations.Human skin copes withharmful environmental factors that are circadianin nature, yet how circadian rhythms modulatethe function of human epidermal stem cells ismostly unknown. Here we show that in humanepidermal stem cells and their differentiatedcounterparts, core clock genes peak in asuccessive and phased manner, establishingdistinct temporal intervals during the 24 hr dayperiod. Each of these successive clock waves isassociated with a peak in the expression ofsubsets of transcripts that temporally segregatethe predisposition of epidermal stem cells torespond to cues that regulate their proliferationor differentiation, such as TGFβ and calcium.Accordingly, circadian arrhythmia profoundlyaffects stem cell function in culture and in vivo.We hypothesize that this intricate mechanismensures homeostasis by providing epidermalstem cells with environmentally relevanttemporal functional cues during the course of the", "metadata": {}}
+{"_id": "2559303", "title": "", "text": "Engraftment of engineered ES cell–derivedcardiomyocytes but not BM cells restorescontractile function to the infarctedmyocardiumCellular cardiomyoplasty is anattractive option for the treatment of severeheart failure. It is, however, still unclear andcontroversial which is the most promising cellsource. Therefore, we investigated and examinedthe fate and functional impact of bone marrow(BM) cells and embryonic stem cell (EScell)–derived cardiomyocytes aftertransplantation into the infarcted mouse heart.This proved particularly challenging for the EScells, as their enrichment into cardiomyocytesand their long-term engraftment andtumorigenicity are still poorly understood. Wegenerated transgenic ES cells expressingpuromycin resistance and enhanced greenfluorescent protein cassettes under control of acardiac-specific promoter. Puromycin selectionresulted in a highly purified (>99%)cardiomyocyte population, and the yield of", "metadata": {}}
+{"_id": "2565138", "title": "", "text": "Hyaluronan impairs vascular function and drugdelivery in a mouse model of pancreaticcancerOBJECTIVE Pancreatic ductaladenocarcinoma (PDA) is characterised bystromal desmoplasia and vascular dysfunction,which critically impair drug delivery. This studyexamines the role of an abundant extracellularmatrix component, the megadaltonglycosaminoglycan hyaluronan (HA), as a noveltherapeutic target in PDA. METHODS Using agenetically engineered mouse model of PDA, theauthors enzymatically depleted HA by a clinicallyformulated PEGylated human recombinant PH20hyaluronidase (PEGPH20) and examined tumourperfusion, vascular permeability and drugdelivery. The preclinical utility of PEGPH20 incombination with gemcitabine was assessed byshort-term and survival studies. RESULTSPEGPH20 rapidly and sustainably depleted HA,inducing the re-expansion of PDA blood vesselsand increasing the intratumoral delivery of twochemotherapeutic agents, doxorubicin and", "metadata": {}}
+{"_id": "2566674", "title": "", "text": "Ribose 2′-O-methylation provides a molecularsignature for the distinction of self and non-selfmRNA dependent on the RNA sensor Mda5The 5′cap structures of higher eukaryote mRNAs haveribose 2′-O-methylation. Likewise, many virusesthat replicate in the cytoplasm of eukaryoteshave evolved 2′-O-methyltransferases toautonomously modify their mRNAs. However, adefined biological role for 2′-O-methylation ofmRNA remains elusive. Here we show that2′-O-methylation of viral mRNA was criticallyinvolved in subverting the induction of type Iinterferon. We demonstrate that human andmouse coronavirus mutants lacking2′-O-methyltransferase activity induced higherexpression of type I interferon and were highlysensitive to type I interferon. Notably, theinduction of type I interferon by viruses deficientin 2′-O-methyltransferase was dependent on thecytoplasmic RNA sensor Mda5. This link betweenMda5-mediated sensing of viral RNA and2′-O-methylation of mRNA suggests that RNA", "metadata": {}}
+{"_id": "2575938", "title": "", "text": "Relationship between activity levels, aerobicfitness, and body fat in 8- to 10-yr-oldchildren.The relationships between children'sactivity, aerobic fitness, and fatness are unclear.Indirect estimates of activity, e.g., heart rate(HR) and recall, may mask any associations. Thepurpose of this study was to assess theserelationships by using the Tritrac-R3D, apedometer, and heart rate. Thirty-four children,ages 8-10 yr, participated in the study. TheTritrac and pedometer were worn for up to 6days. HR was measured for 1 day. Activitymeasured by Tritrac or pedometer correlatedpositively to fitness in the whole group (Tritrac, r= 0.66; pedometer, r = 0.59; P < 0.01) and inboys and girls separately (P < 0.05) andcorrelated negatively to fatness in the wholegroup (r = -0.42, P < 0.05). In contrast, HR didnot correlate significantly to fitness, and HR of>139 beats/min correlated positively to fatnessin girls (r = 0.64, P < 0.05). This suggests thatHR is misleading as a measure of activity. This", "metadata": {}}
+{"_id": "2576811", "title": "", "text": "Junctional actin assembly is mediated byFormin-like 2 downstream of Rac1Epithelialintegrity is vitally important, and its deregulationcauses early stage cancer. De novo formation ofan adherens junction (AJ) between singleepithelial cells requires coordinated, spatial actindynamics, but the mechanisms steering nascentactin polymerization for cell-cell adhesioninitiation are not well understood. Here weinvestigated real-time actin assembly duringdaughter cell-cell adhesion formation in humanbreast epithelial cells in 3D environments. Weidentify formin-like 2 (FMNL2) as beingspecifically required for actin assembly andturnover at newly formed cell-cell contacts aswell as for human epithelial lumen formation.FMNL2 associates with components of the AJcomplex involving Rac1 activity and the FMNL2 Cterminus. Optogenetic control of Rac1 in livingcells rapidly drove FMNL2 to epithelial cell-cellcontact zones. Furthermore, Rac1-induced actinassembly and subsequent AJ formation critically", "metadata": {}}
+{"_id": "2582169", "title": "", "text": "Inhibition of HDM2 and activation of p53 byribosomal protein L23.The importance ofcoordinating cell growth with proliferation hasbeen recognized for a long time. The molecularbasis of this relationship, however, is poorlyunderstood. Here we show that the ribosomalprotein L23 interacts with HDM2. The interactioninvolves the central acidic domain of HDM2 andan N-terminal domain of L23. L23 and L11,another HDM2-interacting ribosomal protein, cansimultaneously yet distinctly interact with HDM2together to form a ternary complex. We showthat, when overexpressed, L23 inhibitsHDM2-induced p53 polyubiquitination anddegradation and causes a p53-dependent cellcycle arrest. On the other hand, knocking downL23 causes nucleolar stress and triggerstranslocation of B23 from the nucleolus to thenucleoplasm, leading to stabilization andactivation of p53. Our data suggest that cellsmay maintain a steady-state level of L23 duringnormal growth; alternating the levels of L23 in", "metadata": {}}
+{"_id": "2587396", "title": "", "text": "Association of Blood Monocyte and PlateletMarkers with Carotid Artery Characteristics: TheAtherosclerosis Risk in Communities Carotid MRIStudyBackground: Atherosclerosis ischaracterized by infiltration of inflammatory cellsfrom circulating blood. Blood cell activation couldplay an important role in plaque formation.Methods: We analyzed the relationship betweenblood cellular markers and quantitative measuresof carotid wall components in 1,546 participantsfrom the ARIC (Atherosclerosis Risk inCommunities) Carotid MRI Study. Carotidimaging was performed using a gadoliniumcontrast-enhanced MRI and cellular phenotypingby flow cytometry. Results: Monocyte Toll-likereceptor (TLR)-2 is associated with largerplaques, while CD14, myeloperoxidase, andTLR-4 associate with smaller. Platelet CD40L isassociated with smaller plaques and thinnercaps, while P-selectin is associated with smallercore size. Conclusions: Blood cell activation issignificantly associated with atherosclerotic", "metadata": {}}
+{"_id": "2593298", "title": "", "text": "Vascular endothelial cadherin controls VEGFR-2internalization and signaling from intracellularcompartmentsReceptor endocytosis is afundamental step in controlling the magnitude,duration, and nature of cell signaling events.Confluent endothelial cells are contact inhibitedin their growth and respond poorly to theproliferative signals of vascular endothelialgrowth factor (VEGF). In a previous study, wefound that the association of vascular endothelialcadherin (VEC) with VEGF receptor (VEGFR) type2 contributes to density-dependent growthinhibition (Lampugnani, G.M., A. Zanetti, M.Corada, T. Takahashi, G. Balconi, F. Breviario, F.Orsenigo, A. Cattelino, R. Kemler, T.O. Daniel,and E. Dejana. 2003. J. Cell Biol. 161:793–804).In the present study, we describe the mechanismthrough which VEC reduces VEGFR-2 signaling.We found that VEGF induces theclathrin-dependent internalization of VEGFR-2.When VEC is absent or not engaged at junctions,VEGFR-2 is internalized more rapidly and", "metadata": {}}
+{"_id": "2601135", "title": "", "text": "Diversification in the HIV-1 EnvelopeHyper-variable Domains V2, V4, and V5 andHigher Probability of Transmitted/FounderEnvelope Glycosylation Favor the Developmentof Heterologous Neutralization BreadthA recentstudy of plasma neutralization breadth in HIV-1infected individuals at nine International AIDSVaccine Initiative (IAVI) sites reported that viralload, HLA-A*03 genotype, and subtype Cinfection were strongly associated with thedevelopment of neutralization breadth. Here, werefine the findings of that study by analyzing theimpact of the transmitted/founder (T/F) envelope(Env), early Env diversification, and autologousneutralization on the development of plasmaneutralization breadth in 21 participantsidentified during recent infection at two of thosesites: Kigali, Rwanda (n = 9) and Lusaka,Zambia (n = 12). Single-genome analysis offull-length T/F Env sequences revealed that all21 individuals were infected with a highlyhomogeneous population of viral variants, which", "metadata": {}}
+{"_id": "2601324", "title": "", "text": "Glycolytic oligodendrocytes maintain myelin andlong-term axonal integrityOligodendrocytes, themyelin-forming glial cells of the central nervoussystem, maintain long-term axonal integrity.However, the underlying support mechanismsare not understood. Here we identify a metaboliccomponent of axon–glia interactions bygenerating conditional Cox10 (protoheme IXfarnesyltransferase) mutant mice, in whicholigodendrocytes and Schwann cells fail toassemble stable mitochondrial cytochrome coxidase (COX, also known as mitochondrialcomplex IV). In the peripheral nervous system,Cox10 conditional mutants exhibit severeneuropathy with dysmyelination, abnormalRemak bundles, muscle atrophy and paralysis.Notably, perturbing mitochondrial respiration didnot cause glial cell death. In the adult centralnervous system, we found no signs ofdemyelination, axonal degeneration or secondaryinflammation. Unlike cultured oligodendrocytes,which are sensitive to COX inhibitors,", "metadata": {}}
+{"_id": "2603304", "title": "", "text": "Siglec-1 Is a Novel Dendritic Cell Receptor ThatMediates HIV-1 Trans-Infection ThroughRecognition of Viral MembraneGangliosidesDendritic cells (DCs) are essentialantigen-presenting cells for the induction ofimmunity against pathogens. However, HIV-1spread is strongly enhanced in clusters of DCsand CD4(+) T cells. Uninfected DCs captureHIV-1 and mediate viral transfer to bystanderCD4(+) T cells through a process termedtrans-infection. Initial studies identified theC-type lectin DC-SIGN as the HIV-1 bindingfactor on DCs, which interacts with the viralenvelope glycoproteins. Upon DC maturation,however, DC-SIGN is down-regulated, whileHIV-1 capture and trans-infection is stronglyenhanced via a glycoprotein-independent capturepathway that recognizes sialyllactose-containingmembrane gangliosides. Here we show that thesialic acid-binding Ig-like lectin 1 (Siglec-1,CD169), which is highly expressed on matureDCs, specifically binds HIV-1 and vesicles", "metadata": {}}
+{"_id": "2604063", "title": "", "text": "The composition of the gut microbiotathroughout life, with an emphasis on earlylifeThe intestinal microbiota has become arelevant aspect of human health. Microbialcolonization runs in parallel with immune systemmaturation and plays a role in intestinalphysiology and regulation. Increasing evidenceon early microbial contact suggest that humanintestinal microbiota is seeded before birth.Maternal microbiota forms the first microbialinoculum, and from birth, the microbial diversityincreases and converges toward an adult-likemicrobiota by the end of the first 3-5 years oflife. Perinatal factors such as mode of delivery,diet, genetics, and intestinal mucin glycosylationall contribute to influence microbial colonization.Once established, the composition of the gutmicrobiota is relatively stable throughout adultlife, but can be altered as a result of bacterialinfections, antibiotic treatment, lifestyle,surgical, and a long-term change in diet. Shifts inthis complex microbial system have been", "metadata": {}}
+{"_id": "2605032", "title": "", "text": "Intrauterine protein restriction combined withearly postnatal overfeeding was not associatedwith adult-onset obesity but produced glucoseintolerance by pancreatic dysfunctionWeinvestigated if whether intrauterine proteinrestriction in combination with overfeedingduring lactation would cause adult-onset obesityand metabolic disorders. After birth, litters fromdams fed with control (17% protein) and lowprotein (6% protein) diets were adjusted to asize of four (CO and LO groups, respectively) oreight (CC and LC groups, respectively) pups. Allof the offspring were fed a diet containing 12%protein from the time of weaning until they were90 d old. Compared to the CC and LC groups, theCO and LO groups had higher relative andabsolute food intakes, oxygen consumption andcarbon dioxide production; lower brown adiposetissue weight and lipid content and greaterweight gain and absolute and relative whiteadipose tissue weight and absolute lipid content.Compared with the CO and CC rats, the LC and", "metadata": {}}
+{"_id": "2608447", "title": "", "text": "Somatic coding mutations in human inducedpluripotent stem cellsDefined transcriptionfactors can induce epigenetic reprogramming ofadult mammalian cells into induced pluripotentstem cells. Although DNA factors are integratedduring some reprogramming methods, it isunknown whether the genome remainsunchanged at the single nucleotide level. Herewe show that 22 human induced pluripotentstem (hiPS) cell lines reprogrammed using fivedifferent methods each contained an average offive protein-coding point mutations in the regionssampled (an estimated six protein-coding pointmutations per exome). The majority of thesemutations were non-synonymous, nonsense orsplice variants, and were enriched in genesmutated or having causative effects in cancers.At least half of these reprogramming-associatedmutations pre-existed in fibroblast progenitors atlow frequencies, whereas the rest occurredduring or after reprogramming. Thus, hiPS cellsacquire genetic modifications in addition to", "metadata": {}}
+{"_id": "2613411", "title": "", "text": "Cell cycle, CDKs and cancer: a changingparadigmTumour-associated cell cycle defectsare often mediated by alterations incyclin-dependent kinase (CDK) activity.Misregulated CDKs induce unscheduledproliferation as well as genomic andchromosomal instability. According to currentmodels, mammalian CDKs are essential fordriving each cell cycle phase, so therapeuticstrategies that block CDK activity are unlikely toselectively target tumour cells. However, recentgenetic evidence has revealed that, whereasCDK1 is required for the cell cycle, interphaseCDKs are only essential for proliferation ofspecialized cells. Emerging evidence suggeststhat tumour cells may also require specificinterphase CDKs for proliferation. Thus, selectiveCDK inhibition may provide therapeutic benefitagainst certain human neoplasias.", "metadata": {}}
+{"_id": "2613775", "title": "", "text": "Sudden infant death syndrome.Despite declinesin prevalence during the past two decades,sudden infant death syndrome (SIDS) continuesto be the leading cause of death for infants agedbetween 1 month and 1 year in developedcountries. Behavioural risk factors identified inepidemiological studies include prone and sidepositions for infant sleep, smoke exposure, softbedding and sleep surfaces, and overheating.Evidence also suggests that pacifier use at sleeptime and room sharing without bed sharing areassociated with decreased risk of SIDS. Althoughthe cause of SIDS is unknown, immaturecardiorespiratory autonomic control and failure ofarousal responsiveness from sleep are importantfactors. Gene polymorphisms relating toserotonin transport and autonomic nervoussystem development might make affected infantsmore vulnerable to SIDS. Campaigns for riskreduction have helped to reduce SIDS incidenceby 50-90%. However, to reduce the incidenceeven further, greater strides must be made in", "metadata": {}}
+{"_id": "2613813", "title": "", "text": "Regulation of heterochromatic silencing andhistone H3 lysine-9 methylation byRNAi.Eukaryotic heterochromatin is characterizedby a high density of repeats and transposons, aswell as by modified histones, and influences bothgene expression and chromosome segregation.In the fission yeast Schizosaccharomycespombe, we deleted the argonaute, dicer, andRNA-dependent RNA polymerase gene homologs,which encode part of the machinery responsiblefor RNA interference (RNAi). Deletion results inthe aberrant accumulation of complementarytranscripts from centromeric heterochromaticrepeats. This is accompanied by transcriptionalde-repression of transgenes integrated at thecentromere, loss of histone H3 lysine-9methylation, and impairment of centromerefunction. We propose that double-stranded RNAarising from centromeric repeats targetsformation and maintenance of heterochromatinthrough RNAi.", "metadata": {}}
+{"_id": "2617858", "title": "", "text": "Conformational Changes during Pore Formationby the Perforin-Related ProteinPleurotolysinMembrane attackcomplex/perforin-like (MACPF) proteins comprisethe largest superfamily of pore-forming proteins,playing crucial roles in immunity andpathogenesis. Soluble monomers assemble intolarge transmembrane pores via conformationaltransitions that remain to be structurally andmechanistically characterised. Here we presentan 11 Å resolution cryo-electron microscopy(cryo-EM) structure of the two-part, fungal toxinPleurotolysin (Ply), together with crystalstructures of both components (the lipid bindingPlyA protein and the pore-forming MACPFcomponent PlyB). These data reveal a 13-foldpore 80 Å in diameter and 100 Å in height, witheach subunit comprised of a PlyB molecule atopa membrane bound dimer of PlyA. The resolutionof the EM map, together with biophysical andcomputational experiments, allowed confidentassignment of subdomains in a MACPF pore", "metadata": {}}
+{"_id": "2619579", "title": "", "text": "The widespread regulation of microRNAbiogenesis, function and decayMicroRNAs(miRNAs) are a large family ofpost-transcriptional regulators of geneexpression that are \u000021 nucleotides in lengthand control many developmental and cellularprocesses in eukaryotic organisms. Researchduring the past decade has identified majorfactors participating in miRNA biogenesis and hasestablished basic principles of miRNA function.More recently, it has become apparent thatmiRNA regulators themselves are subject tosophisticated control. Many reports over the pastfew years have reported the regulation of miRNAmetabolism and function by a range ofmechanisms involving numerous protein–proteinand protein–RNA interactions. Such regulationhas an important role in the context-specificfunctions of miRNAs.", "metadata": {}}
+{"_id": "2638387", "title": "", "text": "The cytidine deaminase CEM15 induceshypermutation in newly synthesized HIV-1DNAHigh mutation frequency during reversetranscription has a principal role in the geneticvariation of primate lentiviral populations. It isthe main driving force for the generation of drugresistance and the escape from immunesurveillance. G to A hypermutation is one of thecharacteristics of primate lentiviruses, as well asother retroviruses, during replication in vivo andin cell culture. The molecular mechanisms of thisprocess, however, remain to be clarified. Here,we demonstrate that CEM15 (also known asapolipoprotein B mRNA editing enzyme, catalyticpolypeptide-like 3G; APOBEC3G), an endogenousinhibitor of human immunodeficiency virus type1 (HIV-1) replication, is a cytidine deaminaseand is able to induce G to A hypermutation innewly synthesized viral DNA. This effect can becounteracted by the HIV-1 virion infectivityfactor (Vif). It seems that this viral DNA mutatoris a viral defence mechanism in host cells that", "metadata": {}}
+{"_id": "2647374", "title": "", "text": "Variants in the Toll-interacting protein gene areassociated with susceptibility to sepsis in theChinese Han populationINTRODUCTIONDeregulated or excessive host immuneresponses contribute to the pathogenesis ofsepsis. Toll-like receptor (TLR) signalingpathways and their negative regulators play apivotal role in the modulation of host immuneresponses and the development of sepsis. Theobjective of this study was to investigate theassociation of variants in the TLR signalingpathway genes and their negative regulatorgenes with susceptibility to sepsis in the ChineseHan population. METHODS Patients with severesepsis (n = 378) and healthy control subjects (n= 390) were enrolled. Five genes, namely TLR2,TLR4, TLR9, MyD88 and TOLLIP, wereinvestigated for their association with sepsissusceptibility by a tag single nucleotidepolymorphism (SNP) strategy. Twelve tag SNPswere selected based on the data of Chinese Hanin Beijing from the HapMap project and", "metadata": {}}
+{"_id": "2659805", "title": "", "text": "Children's estimates of food portion size: thedevelopment and evaluation of three portion sizeassessment tools for use with children.A numberof methods have been developed to assistsubjects in providing an estimate of portion sizebut their application in improving portion sizeestimation by children has not been investigatedsystematically. The aim was to develop portionsize assessment tools for use with children andto assess the accuracy of children's estimates ofportion size using the tools. The tools were foodphotographs, food models and an interactiveportion size assessment system (IPSAS).Children (n 201), aged 4-16 years, were suppliedwith known quantities of food to eat, in school.Food leftovers were weighed. Children estimatedthe amount of each food using each tool, 24 hafter consuming the food. The age-specificportion sizes represented were based on portionsizes consumed by children in a national survey.Significant differences were found between theaccuracy of estimates using the three tools.", "metadata": {}}
+{"_id": "2665425", "title": "", "text": "A 3D Map of the Yeast Kinetochore Reveals thePresence of Core and AccessoryCentromere-Specific HistoneThe budding yeastkinetochore is ~68 nm in length with a diameterslightly larger than a 25 nm microtubule. Thekinetochores from the 16 chromosomes areorganized in a stereotypic cluster encirclingcentral spindle microtubules. Quantitativeanalysis of the inner kinetochore cluster (Cse4,COMA) reveals structural features not apparentin singly attached kinetochores. The cluster ofCse4-containing kinetochores is physically largerperpendicular to the spindle axis relative to thecluster of Ndc80 molecules. If there was a singleCse4 (molecule or nucleosome) at thekinetochore attached to each microtubule plusend, the cluster of Cse4 would appeargeometrically identical to Ndc80. Thus, thestructure of the inner kinetochore at the surfaceof the chromosomes remains unsolved. We haveused point fluorescence microscopy andstatistical probability maps to deduce the", "metadata": {}}
+{"_id": "2665675", "title": "", "text": "American Society of Clinical Oncology policystatement: the role of the oncologist in cancerprevention and risk assessment.Oncologists havea critical opportunity to utilize risk assessmentand cancer prevention strategies to interrupt theinitiation or progression of cancer in cancersurvivors and individuals at high risk ofdeveloping cancer. Expanding knowledge aboutthe natural history and prognosis of cancerspositions oncologists to advise patients regardingthe risk of second malignancies andtreatment-related cancers. In addition, asrecognized experts in the full spectrum of cancercare, oncologists are afforded opportunities forinvolvement in community-based cancerprevention activities. Although oncologists arecurrently providing many cancer prevention andrisk assessment services to their patients,economic barriers exist, including inadequate orlack of insurance, that may compromise uniformpatient access to these services. Additionally,insufficient reimbursement for existing and", "metadata": {}}
+{"_id": "2679511", "title": "", "text": "The BLM helicase contributes to telomeremaintenance through processing oflate-replicating intermediate structuresWerner'ssyndrome (WS) and Bloom's syndrome (BS) arecancer predisposition disorders caused by loss offunction of the RecQ helicases WRN or BLM,respectively. BS and WS are characterized byreplication defects, hyperrecombination eventsand chromosomal aberrations, which arehallmarks of cancer. Inefficient replication of theG-rich telomeric strand contributes tochromosome aberrations in WS cells,demonstrating a link between WRN, telomeresand genomic stability. Herein, we provideevidence that BLM also contributes tochromosome-end maintenance. Telomere defects(TDs) are observed in BLM-deficient cells at anelevated frequency, which is similar to cellslacking a functional WRN helicase. Loss of bothhelicases exacerbates TDs and chromosomeaberrations, indicating that BLM and WRNfunction independently in telomere maintenance.", "metadata": {}}
+{"_id": "2682251", "title": "", "text": "Formation of a thymus from rat ES cells inxenogeneic nude mouse\u0000rat ESchimeras.Various conditions for differentiatingembryonic stem (ES) cells or induced pluripotentstem (iPS) cells into specific kinds of cell linesare under intensive investigation. However, theproduction of a functional organ with athree-dimensional structure from ES or iPS cellsis difficult to achieve in vitro. In the presentpaper, we describe the establishment of a greenfluorescent protein-expressing rat ES cell lineand production of mouse\u0000rat ES chimera byinjecting rat ES cells into mouse blastocysts. Therat ES cells contributed to various organs in thechimera, including germ cells. When we injectedES cells into blastocysts of nu/nu mice lacking athymus, the resultant chimeras produced thymusderived from rat ES cells in their bodies. Thechimeric animals may provide a method for thederivation of various organs from ES or iPS cells.", "metadata": {}}
+{"_id": "2682997", "title": "", "text": "Wnt/beta-catenin signaling is required for CNS,but not non-CNS, angiogenesis.Despite theimportance of CNS blood vessels, the molecularmechanisms that regulate CNS angiogenesis andblood-brain barrier (BBB) formation are largelyunknown. Here we analyze the role ofWnt/beta-catenin signaling in regulating theformation of CNS blood vessels. First, throughthe analysis of TOP-Gal Wnt reporter mice, weidentify that canonical Wnt/beta-cateninsignaling is specifically activated in CNS, but notnon-CNS, blood vessels during development.This activation correlates with the expression ofdifferent Wnt ligands by neural progenitor cells indistinct locations throughout the CNS, includingWnt7a and Wnt7b in ventral regions and Wnt1,Wnt3, Wnt3a, and Wnt4 in dorsal regions.Blockade of Wnt/beta-catenin signaling in vivospecifically disrupts CNS, but not non-CNS,angiogenesis. These defects include reduction invessel number, loss of capillary beds, and theformation of hemorrhagic vascular malformations", "metadata": {}}
+{"_id": "2686003", "title": "", "text": "Cyanidin-3-rutinoside, a natural polyphenolantioxidant, selectively kills leukemic cells byinduction of oxidative stress.Anthocyanins are agroup of naturally occurring phenolic compoundswidely available in fruits and vegetables inhuman diets. They have broad biologicalactivities including anti-mutagenesis andanticarcinogenesis, which are generallyattributed to their antioxidant activities. Westudied the effects and the mechanisms of themost common type of anthocyanins,cyanidin-3-rutinoside, in several leukemia andlymphoma cell lines. We found thatcyanidin-3-rutinoside extracted and purified fromthe black raspberry cultivar Jewel inducedapoptosis in HL-60 cells in a dose- andtime-dependent manner. Paradoxically, thiscompound induced the accumulation ofperoxides, which are involved in the induction ofapoptosis in HL-60 cells. In addition,cyanidin-3-rutinoside treatment resulted inreactive oxygen species (ROS)-dependent", "metadata": {}}
+{"_id": "2692522", "title": "", "text": "Gout-associated uric acid crystals activate theNALP3 inflammasomeDevelopment of the acuteand chronic inflammatory responses known asgout and pseudogout are associated with thedeposition of monosodium urate (MSU) orcalcium pyrophosphate dihydrate (CPPD)crystals, respectively, in joints and periarticulartissues. Although MSU crystals were firstidentified as the aetiological agent of gout in theeighteenth century and more recently as a‘danger signal’ released from dying cells, little isknown about the molecular mechanismsunderlying MSU- or CPPD-induced inflammation.Here we show that MSU and CPPD engage thecaspase-1-activating NALP3 (also calledcryopyrin) inflammasome, resulting in theproduction of active interleukin (IL)-1β andIL-18. Macrophages from mice deficient invarious components of the inflammasome suchas caspase-1, ASC and NALP3 are defective incrystal-induced IL-1β activation. Moreover, animpaired neutrophil influx is found in an in vivo", "metadata": {}}
+{"_id": "2701077", "title": "", "text": "Hematopoietic stem cell quiescence promoteserror-prone DNA repair and mutagenesis.Mostadult stem cells, including hematopoietic stemcells (HSCs), are maintained in a quiescent orresting state in vivo. Quiescence is widelyconsidered to be an essential protectivemechanism for stem cells that minimizesendogenous stress caused by cellular respirationand DNA replication. We demonstrate that HSCquiescence can also have detrimental effects. Wefound that HSCs have unique cell-intrinsicmechanisms ensuring their survival in responseto ionizing irradiation (IR), which includeenhanced prosurvival gene expression andstrong activation of p53-mediated DNA damageresponse. We show that quiescent andproliferating HSCs are equally radioprotected butuse different types of DNA repair mechanisms.We describe how nonhomologous end joining(NHEJ)-mediated DNA repair in quiescent HSCsis associated with acquisition of genomicrearrangements, which can persist in vivo and", "metadata": {}}
+{"_id": "2714623", "title": "", "text": "Recruitment of Nck by CD3\u0000 Reveals aLigand-Induced Conformational Change Essentialfor T Cell Receptor Signaling and SynapseFormationHow membrane receptors initiatesignal transduction upon ligand binding is amatter of intense scrutiny. The T cell receptorcomplex (TCR-CD3) is composed of TCRalpha/beta ligand binding subunits bound to theCD3 subunits responsible for signal transduction.Although it has long been speculated thatTCR-CD3 may undergo a conformational change,confirmation is still lacking. We present strongevidence that ligand engagement of TCR-CD3induces a conformational change that exposes aproline-rich sequence in CD3 epsilon and resultsin recruitment of the adaptor protein Nck. Thisoccurs earlier than and independently of tyrosinekinase activation. Finally, by interfering withNck-CD3 epsilon association in vivo, wedemonstrate that TCR-CD3 recruitment of Nck iscritical for maturation of the immune synapseand for T cell activation.", "metadata": {}}
+{"_id": "2721426", "title": "", "text": "Pseudo-Seq: Genome-Wide Detection ofPseudouridine Modifications in RNA.RNAmolecules contain a variety of chemicallydiverse, posttranscriptionally modified bases.The most abundant modified base found incellular RNAs, pseudouridine (Ψ), has recentlybeen mapped to hundreds of sites in mRNAs,many of which are dynamically regulated.Though the pseudouridine landscape has beendetermined in only a few cell types and growthconditions, the enzymes responsible for mRNApseudouridylation are universally conserved,suggesting many novel pseudouridylated sitesremain to be discovered. Here, we presentPseudo-seq, a technique that allows theidentification of sites of pseudouridylationgenome-wide with single-nucleotide resolution.In this chapter, we provide a detailed descriptionof Pseudo-seq. We include protocols for RNAisolation from Saccharomyces cerevisiae,Pseudo-seq library preparation, and dataanalysis, including descriptions of processing and", "metadata": {}}
+{"_id": "2722988", "title": "", "text": "The Mammalian EpigenomeChemicalmodifications to DNA and histone proteins form acomplex regulatory network that modulateschromatin structure and genome function. Theepigenome refers to the complete description ofthese potentially heritable changes across thegenome. The composition of the epigenomewithin a given cell is a function of geneticdeterminants, lineage, and environment. Withthe sequencing of the human genomecompleted, investigators now seek acomprehensive view of the epigenetic changesthat determine how genetic information is mademanifest across an incredibly varied backgroundof developmental stages, tissue types, anddisease states. Here we review current researchefforts, with an emphasis on large-scale studies,emerging technologies, and challenges ahead.", "metadata": {}}
+{"_id": "2727303", "title": "", "text": "Microtubule-associated histone deacetylase 6supports the calcium store sensor STIM1 inmediating malignant cellbehaviors.Stromal-interaction molecule 1(STIM1) is an endoplasmic reticulum Ca(2+)storage sensor that promotes cell growth,migration, and angiogenesis in breast andcervical cancers. Here, we report that themicrotubule-associated histone deacetylase 6(HDAC6) differentially regulates activation ofSTIM1-mediated store-operated Ca(2+) entry(SOCE) between cervical cancer cells and normalcervical epithelial cells. Confocal microscopy ofliving cells indicated that microtubule integritywas necessary for STIM1 trafficking to theplasma membrane and interaction with Orai1, anessential pore subunit of SOCE. Cancer cellsoverexpressed both STIM1 and Orai1 comparedwith normal cervical epithelial cells. HDAC6upregulation in cancer cells was accompanied byhypoacetylated α-tubulin. Tubastatin-A, aspecific HDAC6 inhibitor, inhibited STIM1", "metadata": {}}
+{"_id": "2734421", "title": "", "text": "The tumor necrosis factor family receptors RANKand CD40 cooperatively establish the thymicmedullary microenvironment andself-tolerance.Medullary thymic epithelial cells(mTECs) establish T cell self-tolerance throughthe expression of autoimmune regulator (Aire)and peripheral tissue-specific self-antigens.However, signals underlying mTEC developmentremain largely unclear. Here, we demonstratecrucial regulation of mTEC development byreceptor activator of NF-kappaB (RANK) andCD40 signals. Whereas only RANK signaling wasessential for mTEC development duringembryogenesis, in postnatal mice, cooperationbetween CD40 and RANK signals was requiredfor mTEC development to successfully establishthe medullary microenvironment. Ligation ofRANK or CD40 on fetal thymic stroma in vitroinduced mTEC development in a tumor necrosisfactor-associated factor 6 (TRAF6)-, NF-kappaBinducing kinase (NIK)-, and IkappaB kinase beta(IKKbeta)-dependent manner. These results", "metadata": {}}
+{"_id": "2739854", "title": "", "text": "Rare and common variants: twentyargumentsGenome-wide association studies havegreatly improved our understanding of thegenetic basis of disease risk. The fact that theytend not to identify more than a fraction of thespecific causal loci has led to divergence ofopinion over whether most of the variance ishidden as numerous rare variants of large effector as common variants of very small effect. HereI review 20 arguments for and against each ofthese models of the genetic basis of complextraits and conclude that both classes of effectcan be readily reconciled.", "metadata": {}}
+{"_id": "2754534", "title": "", "text": "DNA methylation status predicts celltype-specific enhancer activity.Cell-selectiveglucocorticoid receptor (GR) binding to distalregulatory elements is associated with celltype-specific regions of locally accessiblechromatin. These regions can either pre-exist inchromatin (pre-programmed) or be induced bythe receptor (de novo). Mechanisms that createand maintain these sites are not well understood.We observe a global enrichment of CpG densityfor pre-programmed elements, and implicatetheir demethylated state in the maintenance ofopen chromatin in a tissue-specific manner. Incontrast, sites that are actively opened by GR(de novo) are characterized by low CpG density,and form a unique class of enhancers devoid ofsuppressive effect of agglomeratedmethyl-cytosines. Furthermore, treatment withglucocorticoids induces rapid changes inmethylation levels at selected CpGs within denovo sites. Finally, we identify GR-bindingelements with CpGs at critical positions, and", "metadata": {}}
+{"_id": "2758012", "title": "", "text": "BLM helicase facilitates telomere replicationduring leading strand synthesis oftelomeresBased on its in vitro unwinding activityon G-quadruplex (G4) DNA, the Bloomsyndrome-associated helicase BLM is proposed toparticipate in telomere replication by aiding forkprogression through G-rich telomeric DNA. Singlemolecule analysis of replicated DNA (SMARD)was used to determine the contribution of BLMhelicase to telomere replication. In BLM-deficientcells, replication forks initiating from originswithin the telomere, which copy the G-richstrand by leading strand synthesis, movedslower through the telomere compared with theadjacent subtelomere. Fork progression throughthe telomere was further slowed in the presenceof a G4 stabilizer. Using a G4-specific antibody,we found that deficiency of BLM, or anotherG4-unwinding helicase, the Wernersyndrome-associated helicase WRN, resulted inincreased G4 structures in cells. Importantly,deficiency of either helicase led to greater", "metadata": {}}
+{"_id": "2762601", "title": "", "text": "Reflecting on 25 years with MYCJust over 25years ago, MYC, the human homologue of aretroviral oncogene, was identified. Since thattime, MYC research has been intense and theadvances impressive. On reflection, it isastonishing how each incremental insight intoMYC regulation and function has also had animpact on numerous biological disciplines,including our understanding of molecularoncogenesis in general. Here we chronicle themajor advances in our understanding of MYCbiology, and peer into the future of MYCresearch.", "metadata": {}}
+{"_id": "2774906", "title": "", "text": "Protective effects of exercise andphosphoinositide 3-kinase(p110alpha) signalingin dilated and hypertrophiccardiomyopathy.Physical activity protects againstcardiovascular disease, and physiological cardiachypertrophy associated with regular exercise isusually beneficial, in marked contrast topathological hypertrophy associated withdisease. The p110alpha isoform ofphosphoinositide 3-kinase (PI3K) plays a criticalrole in the induction of exercise-inducedhypertrophy. Whether it or other genes activatedin the athlete's heart might have an impact oncardiac function and survival in a setting of heartfailure is unknown. To examine whetherprogressive exercise training andPI3K(p110alpha) activity affect survival and/orcardiac function in two models of heart disease,we subjected a transgenic mouse model ofdilated cardiomyopathy (DCM) to swim training,genetically crossed cardiac-specific transgenicmice with increased or decreased", "metadata": {}}
+{"_id": "2787558", "title": "", "text": "The effect of cigarette smoking, alcoholconsumption and fruit and vegetableconsumption on IVF outcomes: a review andpresentation of original dataBACKGROUNDLifestyle factors including cigarette smoking,alcohol consumption and nutritional habitsimpact on health, wellness, and the risk ofchronic diseases. In the areas of in-vitrofertilization (IVF) and pregnancy, lifestyle factorsinfluence oocyte production, fertilization rates,pregnancy and pregnancy loss, while chronic,low-grade oxidative stress may underlie pooroutcomes for some IVF cases. METHODS Here,we review the current literature and presentsome original, previously unpublished data,obtained from couples attending the PIVETMedical Centre in Western Australia. RESULTSDuring the study, 80 % of females and 70 % ofmale partners completed a 1-week diarydocumenting their smoking, alcohol and fruit andvegetable intake. The subsequent clinicaloutcomes of their IVF treatment such as quantity", "metadata": {}}
+{"_id": "2810997", "title": "", "text": "Efficient Mitochondrial Genome Editing byCRISPR/Cas9The Clustered RegularlyInterspaced Short Palindromic Repeats(CRISPR)/Cas9 system has been widely used fornuclear DNA editing to generate mutations orcorrect specific disease alleles. Despite itsflexible application, it has not been determined ifCRISPR/Cas9, originally identified as a bacterialdefense system against virus, can be targeted tomitochondria for mtDNA editing. Here, we showthat regular FLAG-Cas9 can localize tomitochondria to edit mitochondrial DNA withsgRNAs targeting specific loci of themitochondrial genome. Expression of FLAG-Cas9together with gRNA targeting Cox1 and Cox3leads to cleavage of the specific mtDNA loci. Inaddition, we observed disruption of mitochondrialprotein homeostasis following mtDNA truncationor cleavage by CRISPR/Cas9. To overcomenonspecific distribution of FLAG-Cas9, we alsocreated a mitochondria-targeted Cas9(mitoCas9). This new version of Cas9 localizes", "metadata": {}}
+{"_id": "2817000", "title": "", "text": "Histone Variant H2A.Z Marks the 5′ Ends of BothActive and Inactive Genes in EuchromatinIn S.cerevisiae, histone variant H2A.Z is deposited ineuchromatin at the flanks of silentheterochromatin to prevent its ectopic spread.We show that H2A.Z nucleosomes are found atpromoter regions of nearly all genes ineuchromatin. They generally occur as twopositioned nucleosomes that flank anucleosome-free region (NFR) that contains thetranscription start site. Astonishingly, enrichmentat 5' ends is observed not only at activelytranscribed genes but also at inactive loci.Mutagenesis of a typical promoter revealed a 22bp segment of DNA sufficient to programformation of a NFR flanked by two H2A.Znucleosomes. This segment contains a bindingsite of the Myb-related protein Reb1 and anadjacent dT:dA tract. Efficient deposition ofH2A.Z is further promoted by a specific patternof histone H3 and H4 tail acetylation and thebromodomain protein Bdf1, a component of the", "metadata": {}}
+{"_id": "2820454", "title": "", "text": "Exercise and respiratory training improveexercise capacity and quality of life in patientswith severe chronic pulmonaryhypertension.BACKGROUND Pulmonaryhypertension (PH) is associated with restrictedphysical capacity, limited quality of life, and apoor prognosis because of right heart failure. Thepresent study is the first prospective randomizedstudy to evaluate the effects of exercise andrespiratory training in patients with severesymptomatic PH. METHODS AND RESULTS Thirtypatients with PH (21 women; mean age,50+/-13 years; mean pulmonary arterypressure, 50+/-15 mm Hg; mean World HealthOrganization [WHO] class, 2.9+/-0.5; pulmonaryarterial hypertension, n=23; chronicthromboembolic PH, n=7) on stabledisease-targeted medication were randomlyassigned to a control (n=15) and a primarytraining (n=15) group. Medication remainedunchanged during the study period. Primary endpoints were the changes from baseline to week", "metadata": {}}
+{"_id": "2824347", "title": "", "text": "HIV-1 regulation of latency in themonocyte-macrophage lineage and in CD4+ Tlymphocytes.The introduction in 1996 of theHAART raised hopes for the eradication of HIV-1.Unfortunately, the discovery of latent HIV-1reservoirs in CD4+ T cells and in themonocyte-macrophage lineage proved theoptimism to be premature. The long-lived HIV-1reservoirs constitute a major obstacle to theeradication of HIV-1. In this review, we focus onthe establishment and maintenance of HIV-1latency in the two major targets for HIV-1: theCD4+ T cells and the monocyte-macrophagelineage. Understanding the cell-type molecularmechanisms of establishment, maintenance, andreactivation of HIV-1 latency in these reservoirsis crucial for efficient therapeutic intervention. Acomplete viral eradication, the holy graal forclinicians, might be achieved by strategicinterventions targeting latently and productivelyinfected cells. We suggest that new approaches,such as the combination of different kinds of", "metadata": {}}
+{"_id": "2825340", "title": "", "text": "Effects of Electro-Acupuncture Therapy onPost-Stroke Depression in Patients with DifferentDegrees of Motor Function Impairments: a PilotStudy[Purpose] The present study examinedwhether electro-acupuncture therapy reducespost-stroke depression (PSD) and whether motorfunction impairments interact with the effects ofthe therapy. [Subjects] Twenty-eight PSDpatients were assessed and assigned to either agood or poor motor function group depending ontheir motor grade. [Methods] The BeckDepression Inventory (BDI), HamiltonDepression Rating Scale (HDRS) and ManualMuscle Test (MMT) were administered at thescreening and initial phases of the study, and atthe 4th, 8th, 12th and 16th week of the dailyelectro-acupuncture treatment. [Results] Theelectro-acupuncture treatment reduced PSD (asassessed by BDI and HDRS) of the patients. Inparticular, the depression of the good motorfunction group was significantly more reducedthan that of the poor motor function group. The", "metadata": {}}
+{"_id": "2825380", "title": "", "text": "T cell receptor ligation induces the formation ofdynamically regulated signaling assembliesTcellantigen receptor (TCR) ligation initiates tyrosinekinase activation, signaling complex assembly,and immune synapse formation. Here, westudied the kinetics and mechanics of signalingcomplex formation in live Jurkat leukemic T cellsusing signaling proteins fluorescently tagged withvariants of enhanced GFP (EGFP). Within secondsof contacting coverslips coated with stimulatoryantibodies, T cells developed small, dynamicallyregulated clusters which were enriched in theTCR, phosphotyrosine, ZAP-70, LAT, Grb2, Gads,and SLP-76, excluded the lipid raft markerenhanced yellow fluorescent protein–GPI, andwere competent to induce calcium elevations.LAT, Grb2, and Gads were transiently associatedwith the TCR. Although ZAP-70–containingclusters persisted for more than 20 min,photobleaching studies revealed that ZAP-70continuously dissociated from and returned tothese complexes. Strikingly, SLP-76 translocated", "metadata": {}}
+{"_id": "2828460", "title": "", "text": "Developmental heterogeneity of cardiacfibroblasts does not predict pathologicalproliferation and activation.RATIONALE Fibrosisis mediated partly by extracellularmatrix-depositing fibroblasts in the heart.Although these mesenchymal cells are reportedto have multiple embryonic origins, thefunctional consequence of this heterogeneity isunknown. OBJECTIVE We sought to validate apanel of surface markers to prospectively identifycardiac fibroblasts. We elucidated thedevelopmental origins of cardiac fibroblasts andcharacterized their corresponding phenotypes.We also determined proliferation rates of eachdevelopmental subset of fibroblasts afterpressure overload injury. METHODS ANDRESULTS We showed thatThy1(+)CD45(-)CD31(-)CD11b(-)Ter119(-) cellsconstitute the majority of cardiac fibroblasts. Wecharacterized these cells using flow cytometry,epifluorescence and confocal microscopy, andtranscriptional profiling (using reverse", "metadata": {}}
+{"_id": "2829179", "title": "", "text": "Pre-eclampsia: connecting angiogenic andmetabolic pathways.Pre-eclampsia is ahypertensive disease of pregnancy with aworldwide incidence of 5-8%. This reviewfocuses on recent developments in pre-eclampsiaresearch related to angiogenesis andmetabolism. We first address the 'angiogenicimbalance' theory, which hypothesizes thatpre-eclampsia results from an imbalance offactors that promote or antagonize angiogenesis,such as soluble fms-like tyrosine kinase (sFlt1),2-methoxyestradiol (2-ME) andcatechol-O-methyltransferase (COMT). Next, weanalyze the association between pre-eclampsiaand dysfunctional metabolism of bothhomocysteine and placental glycogen. We hopethat illuminating some of the various connectionsexisting between angiogenesis and metabolismin pre-eclampsia will facilitate the update orreconsideration of old models of pathogenesis.", "metadata": {}}
+{"_id": "2831620", "title": "", "text": "Protein Lysine Acetylated/Deacetylated Enzymesand the Metabolism-Related DiseasesLysineacetylation is a reversible posttranslationalmodifcation, an epigenetic phenomenon, referredto as transfer of an acetyl group from acetyl CoAto lysine e- amino group of targeted protein,which is modulated by acetyltransferases(histone/ lysine (K) acetyltransferases,HATs/KATs) and deacetylases (histone/lysine (K)deacetylases, HDACs/KDACs). Lysine acetylationregulates various metabolic processes, such asfatty acid oxidation, Krebs cycle, oxidativephosphorylation, angiogenesis and so on. Thusdisorders of lysine acetylation may be correlatedwith obesity, diabetes and cardiovasculardisease, which are termed as the metaboliccomplication. With accumulating studies onproteomic acetylation, lysine acetylation alsoinvolves in cell immune status and degenerativediseases, for example, Alzheimer’s disease andHuntington’s disease. This review primarilysummarizes the current studies of lysine", "metadata": {}}
+{"_id": "2832403", "title": "", "text": "Differential Specificity of Endocrine FGF19 andFGF21 to FGFR1 and FGFR4 in Complex withKLBBACKGROUND Recent studies suggest thatbetaKlotho (KLB) and endocrine FGF19 andFGF21 redirect FGFR signaling to regulation ofmetabolic homeostasis and suppression ofobesity and diabetes. However, the identity ofthe predominant metabolic tissue in which amajor FGFR-KLB resides that critically mediatesthe differential actions and metabolism effects ofFGF19 and FGF21 remain unclear.METHODOLOGY/PRINCIPAL FINDINGS Wedetermined the receptor and tissue specificity ofFGF21 in comparison to FGF19 by using direct,sensitive and quantitative binding kinetics, anddownstream signal transduction and expressionof early response gene upon administration ofFGF19 and FGF21 in mice. We found that FGF21binds FGFR1 with much higher affinity thanFGFR4 in presence of KLB; while FGF19 bindsboth FGFR1 and FGFR4 in presence of KLB withcomparable affinity. The interaction of FGF21", "metadata": {}}
+{"_id": "2837758", "title": "", "text": "Therapeutic efficacy of a multi-epitope vaccineagainst Helicobacter pylori infection in BALB/cmice model.Epitope vaccine is a promising optionfor therapeutic vaccination against Helicobacterpylori (H. pylori) infection. In this study, weconstructed a multi-epitope vaccine with fiveepitopes and mucosal adjuvant E. coli heat-labileenterotoxin B subunit (LTB) named HUepi-LTBand evaluated its therapeutic effect against H.pylori infection in BALB/c mice model. HUepi-LTBcontaining three Th epitopes from UreB and twoB cell epitopes from UreB and HpaA wasconstructed and expressed in E. coli. Oraltherapeutic immunization with HUepi-LTBsignificantly decreased H. pylori colonizationcompared with oral immunization with PBS, andthe protection was correlated withantigen-specific CD4+ T cells and IgG andmucosal IgA antibody responses. Thismulti-epitope vaccine may be a promisingvaccine candidate that may help to control H.pylori infection.", "metadata": {}}
+{"_id": "2841164", "title": "", "text": "DNA fragments in the blood plasma of cancerpatients: quantitations and evidence for theirorigin from apoptotic and necrotic cells.Increasedlevels of DNA fragments have frequently beenfound in the blood plasma of cancer patients.Published data suggest that only a fraction of theDNA in blood plasma is derived from cancer cells.However, it is not known how much of thecirculating DNA is from cancer or from noncancercells. By quantitative methylation-specific PCR ofthe promoter region of the CDKN2A tumorsuppressor gene, we were able to quantify thefraction of plasma DNA derived from tumor cells.In the plasma samples of 30 unselected cancerpatients, we detected quantities of tumor DNAfrom only 3% to as much as 93% of totalcirculating DNA. We investigated possible originsof nontumor DNA in the plasma and demonstratehere a contribution of T-cell DNA in a few casesonly. To investigate the possibility that plasmaDNA originates from apoptotic or necrotic cells,we performed studies with apoptotic", "metadata": {}}
+{"_id": "2842550", "title": "", "text": "Pharmacodynamics and pharmacokinetics ofeptifibatide in patients with acute coronarysyndromes: prospective analysis fromPURSUIT.BACKGROUND Platelet deposition andaggregation are central to the pathogenesis ofischemic complications of acute coronarysyndromes (ACS). Pharmacodynamic effects ofthe platelet glycoprotein IIb/IIIa antagonisteptifibatide have been delineated in healthysubjects but not in patients with ACS. Weassessed effects of eptifibatide on ex vivoplatelet aggregation in patients enrolled in thePlatelet glycoprotein IIb/IIIa in Unstable angina:Receptor Suppression Using Integrilin(eptifibatide) Therapy (PURSUIT) trial of ACS.METHODS AND RESULTS Patients were randomlyassigned to an intravenous bolus (180microgram/kg) and 72-hour infusion ofeptifibatide (2.0 microgram/kg per minute,n=48) or placebo (n=50). We assessedcorrelations of plasma eptifibatide levels withreceptor occupancy and inhibition of ex vivo", "metadata": {}}
+{"_id": "2844490", "title": "", "text": "Proinflammatory cytokines underlying theinflammation of Crohn's disease.PURPOSE OFREVIEW To encapsulate our currentunderstanding of the proinflammatory cytokinesresponsible for the inflammation underlyingCrohn's disease and the prospect of using thisinformation to devise therapy for this conditionbased on inhibition of these cytokines. RECENTFINDINGS Current research is shedding new lighton the role of both T helper cell (Th)1 and Th17responses in the pathogenesis of Crohn'sdisease. Initial studies conducted a decade agohighlighted the view that Crohn's diseaseinflammation is caused by aninterleukin-12-driven Th1 response, whichresulted in the generation of interferon-gamma,which then served as the main inflammatorymediator. In recent years, however, this viewhas been largely eclipsed by studies, conductedmainly in murine models, showing that a Th17response is the main cause of Crohn's diseaseinflammation through the production of", "metadata": {}}
+{"_id": "2844897", "title": "", "text": "STATISTICAL METHODS FOR ASSESSINGAGREEMENT BETWEEN TWO METHODS OFCLINICAL MEASUREMENTIn clinicalmeasurement comparison of a newmeasurement technique with an established oneis often needed to see whether they agreesufficiently for the new to replace the old. Suchinvestigations are often analysed inappropriately,notably by using correlation coefficients. The useof correlation is misleading. An alternativeapproach, based on graphical techniques andsimple calculations, is described, together withthe relation between this analysis and theassessment of repeatability.", "metadata": {}}
+{"_id": "2851611", "title": "", "text": "The multidrug ABC transporter BmrC/BmrD ofBacillus subtilis is regulated via aribosome-mediated transcriptional attenuationmechanismExpression of particular drugtransporters in response to antibiotic pressure isa critical element in the development of bacterialmultidrug resistance, and represents a seriousconcern for human health. To obtain a betterunderstanding of underlying regulatorymechanisms, we have dissected thetranscriptional activation of the ATP-bindingcassette (ABC) transporter BmrC/BmrD of theGram-positive model bacterium Bacillus subtilis.By using promoter-GFP fusions and live cell arraytechnology, we demonstrate a temporallycontrolled transcriptional activation of the bmrCDgenes in response to antibiotics that targetprotein synthesis. Intriguingly, bmrCDexpression only occurs during thelate-exponential and stationary growth stages,irrespective of the timing of the antibioticchallenge. We show that this is due to tight", "metadata": {}}
+{"_id": "2853291", "title": "", "text": "The neural crest is a source of mesenchymalstem cells with specialized hematopoietic stemcell niche functionMesenchymal stem cells(MSCs) and osteolineage cells contribute to thehematopoietic stem cell (HSC) niche in the bonemarrow of long bones. However, theirdevelopmental relationships remain unclear. Inthis study, we demonstrate that different MSCpopulations in the developing marrow of longbones have distinct functions. Proliferativemesoderm-derived nestin(-) MSCs participate infetal skeletogenesis and lose MSC activity soonafter birth. In contrast, quiescent neuralcrest-derived nestin(+) cells preserve MSCactivity, but do not generate fetal chondrocytes.Instead, they differentiate into HSCniche-forming MSCs, helping to establish theHSC niche by secreting Cxcl12. Perineuralmigration of these cells to the bone marrowrequires the ErbB3 receptor. The neonatalNestin-GFP(+) Pdgfrα(-) cell population alsocontains Schwann cell precursors, but does not", "metadata": {}}
+{"_id": "2853685", "title": "", "text": "Hotspots of aberrant epigenomic reprogrammingin human induced pluripotent stem cellsInducedpluripotent stem cells (iPSCs) offer immensepotential for regenerative medicine and studiesof disease and development. Somatic cellreprogramming involves epigenomicreconfiguration, conferring iPSCs withcharacteristics similar to embryonic stem (ES)cells. However, it remains unknown howcomplete the reestablishment of ES-cell-like DNAmethylation patterns is throughout the genome.Here we report the first whole-genome profiles ofDNA methylation at single-base resolution in fivehuman iPSC lines, along with methylomes of EScells, somatic cells, and differentiated iPSCs andES cells. iPSCs show significant reprogrammingvariability, including somatic memory andaberrant reprogramming of DNA methylation.iPSCs share megabase-scale differentiallymethylated regions proximal to centromeres andtelomeres that display incompletereprogramming of non-CG methylation, and", "metadata": {}}
+{"_id": "2867345", "title": "", "text": "Inheritance of coronary artery disease in men:an analysis of the role of the YchromosomeBACKGROUND A sexual dimorphismexists in the incidence and prevalence ofcoronary artery disease--men are morecommonly affected than are age-matchedwomen. We explored the role of the Ychromosome in coronary artery disease in thecontext of this sexual inequity. METHODS Wegenotyped 11 markers of the male-specificregion of the Y chromosome in 3233 biologicallyunrelated British men from three cohorts: theBritish Heart Foundation Family Heart Study(BHF-FHS), West of Scotland CoronaryPrevention Study (WOSCOPS), and CardiogenicsStudy. On the basis of this information, each Ychromosome was tracked back into one of 13ancient lineages defined as haplogroups. Wethen examined associations between common Ychromosome haplogroups and the risk ofcoronary artery disease in cross-sectionalBHF-FHS and prospective WOSCOPS. Finally, we", "metadata": {}}
+{"_id": "2883827", "title": "", "text": "Cytoscape 2.8: new features for data integrationand network visualizationUNLABELLED Cytoscapeis a popular bioinformatics package for biologicalnetwork visualization and data integration.Version 2.8 introduces two powerful newfeatures--Custom Node Graphics and AttributeEquations--which can be used jointly to greatlyenhance Cytoscape's data integration andvisualization capabilities. Custom Node Graphicsallow an image to be projected onto a node,including images generated dynamically or atremote locations. Attribute Equations provideCytoscape with spreadsheet-like functionality inwhich the value of an attribute is computeddynamically as a function of other attributes andnetwork properties. AVAILABILITY ANDIMPLEMENTATION Cytoscape is a desktop Javaapplication released under the Library Gnu PublicLicense (LGPL). Binary install bundles and sourcecode for Cytoscape 2.8 are available fordownload from http://cytoscape.org.", "metadata": {}}
+{"_id": "2888272", "title": "", "text": "Detection of Histone Modifications at SpecificGene Loci in Single Cells in HistologicalSectionsChromatin immunoprecipitation assayshave contributed greatly to our understanding ofthe role of histone modifications in generegulation. However, they do not permit analysiswith single-cell resolution, thus confoundinganalyses of heterogeneous cell populations. Herewe present a method that permits visualizationof histone modifications of single genomic lociwith single-cell resolution in formaldehyde-fixedparaffin-embedded tissue sections based oncombined use of in situ hybridization andproximity ligation assays. We show thatdimethylation of lysine 4 of histone H3(H3K4me2) at the MYH11 locus is restricted tothe smooth muscle cell (SMC) lineage in humanand mouse tissue sections and that the markpersists even in phenotypically modulated SMCin atherosclerotic lesions that show no detectableexpression of SMC marker genes. Thismethodology has promise for broad applications", "metadata": {}}
+{"_id": "2890952", "title": "", "text": "Mechanistic characterization of the sulfur-relaysystem for eukaryotic 2-thiouridine biogenesis attRNA wobble positionsThe wobble modification intRNAs, 5-methoxycarbonylmethyl-2-thiouridine(mcm(5)s(2)U), is required for the properdecoding of NNR codons in eukaryotes. The2-thio group confers conformational rigidity ofmcm(5)s(2)U by largely fixing the C3'-endoribose puckering, ensuring stable and accuratecodon-anticodon pairing. We have identified fivegenes in Saccharomyces cerevisiae, YIL008w(URM1), YHR111w (UBA4), YOR251c (TUM1),YNL119w (NCS2) and YGL211w (NCS6), that arerequired for 2-thiolation of mcm(5)s(2)U. An invitro sulfur transfer experiment revealed thatTum1p stimulated the cysteine desulfurase ofNfs1p, and accepted persulfide sulfurs fromNfs1p. URM1 is a ubiquitin-related modifier, andUBA4 is an E1-like enzyme involved in proteinurmylation. The carboxy-terminus of Urm1p wasactivated as an acyl-adenylate (-COAMP), thenthiocarboxylated (-COSH) by Uba4p. The", "metadata": {}}
+{"_id": "2891825", "title": "", "text": "High prevalence of asthma in cross countryskiers.OBJECTIVES To study the prevalence ofasthma (asthma symptoms and bronchialhyperresponsiveness) in Swedish cross countryskiers compared with non-skiers and monitorchanges in symptoms and bronchialhyperresponsiveness during the year. DESIGNCross sectional study during the winter skiseason and in the summer. SETTING Six skiclubs for élite skiers (total 47) in two differentareas of Sweden. SUBJECTS 42 élite crosscountry skiers and 29 non-skiing referents. MAINOUTCOME MEASURES Bronchial responsiveness,asthma symptoms, and lung function. RESULTSBronchial responsiveness was significantlygreater and asthma symptoms more prevalent inthe skiers than in the referents. There was nodifference in bronchial responsiveness withineither group between winter and summer. 15 ofthe 42 skiers used antiasthmatic drugs regularlyand 23 had a combination of asthma symptomsand hyperresponsive airways or physician", "metadata": {}}
+{"_id": "2904102", "title": "", "text": "Characterization of biochemical properties ofBacillus subtilis RecQ helicase.RecQ familyhelicases function as safeguards of the genome.Unlike Escherichia coli, the Gram-positiveBacillus subtilis bacterium possesses twoRecQ-like homologues, RecQ[Bs] and RecS,which are required for the repair of DNAdouble-strand breaks. RecQ[Bs] also binds to theforked DNA to ensure a smooth progression ofthe cell cycle. Here we present the firstbiochemical analysis of recombinant RecQ[Bs].RecQ[Bs] binds weakly to single-stranded DNA(ssDNA) and blunt-ended double-stranded DNA(dsDNA) but strongly to forked dsDNA. Theprotein exhibits a DNA-stimulated ATPaseactivity and ATP- and Mg(2+)-dependent DNAhelicase activity with a 3' \u0000 5' polarity. Molecularmodeling shows that RecQ[Bs] shares highsequence and structure similarity with E. coliRecQ. Surprisingly, RecQ[Bs] resembles thetruncated Saccharomyces cerevisiae Sgs1 andhuman RecQ helicases more than RecQ[Ec] with", "metadata": {}}
+{"_id": "2919030", "title": "", "text": "SOD1 Integrates Signals from Oxygen andGlucose to Repress RespirationCu/Zn superoxidedismutase (SOD1) is an abundant enzyme thathas been best studied as a regulator ofantioxidant defense. Using the yeastSaccharomyces cerevisiae, we report that SOD1transmits signals from oxygen and glucose torepress respiration. The mechanism involvesSOD1-mediated stabilization of two casein kinase1-gamma (CK1γ) homologs, Yck1p and Yck2p,required for respiratory repression. SOD1 binds aC-terminal degron we identified in Yck1p/Yck2pand promotes kinase stability by catalyzingsuperoxide conversion to peroxide. The effects ofSOD1 on CK1γ stability are also observed withmammalian SOD1 and CK1γ and in a human cellline. Therefore, in a single circuit, oxygen,glucose, and reactive oxygen can repressrespiration through SOD1/CK1γ signaling. Ourdata therefore may provide mechanistic insightinto how rapidly proliferating cells and manycancers accomplish glucose-mediated repression", "metadata": {}}
+{"_id": "2931832", "title": "", "text": "The prognostic impact of the platelet distributionwidth-to-platelet count ratio in patients withbreast cancerActivated platelets promote tumorcell growth, angiogenesis, and invasion. Plateletactivity can be inferred by platelet volumeindices (PVIs), which include platelet distributionwidth (PDW), mean platelet volume (MPV),platelet distribution width-to-platelet count ratio(PDW/P), and mean platelet volume-to-plateletcount ratio. Platelets and platelet-relatedmarkers, such as the platelet-to-lymphocyteratio, have been found to be significantprognostic factors in patients with breast cancer.However, the role of PVIs for predicting survivalin breast cancer remains unknown; hence, weperformed this retrospective analysis of 275patients with breast cancer. PVIs were comparedwith clinicopathological variables, and wereassessed to identify independent indicatorsassociated with disease-free survival (DFS) usingthe Cox proportional hazards model. An elevatedPDW/P significantly correlated with age and", "metadata": {}}
+{"_id": "2947124", "title": "", "text": "Persistent LCMV infection is controlled byblockade of type I interferon signaling.Duringpersistent viral infections, chronic immuneactivation, negative immune regulatorexpression, an elevated interferon signature, andlymphoid tissue destruction correlate withdisease progression. We demonstrated thatblockade of type I interferon (IFN-I) signalingusing an IFN-I receptor neutralizing antibodyreduced immune system activation, decreasedexpression of negative immune regulatorymolecules, and restored lymphoid architecture inmice persistently infected with lymphocyticchoriomeningitis virus. IFN-I blockade before andafter establishment of persistent virus infectionresulted in enhanced virus clearance and wasCD4 T cell-dependent. Hence, we demonstrate adirect causal link between IFN-I signaling,immune activation, negative immune regulatorexpression, lymphoid tissue disorganization, andvirus persistence. Our results suggest thattherapies targeting IFN-I may help control", "metadata": {}}
+{"_id": "2947540", "title": "", "text": "Lam6 Regulates the Extent of Contacts betweenOrganellesCommunication between organelles iscrucial for eukaryotic cells to function as onecoherent unit. An important means ofcommunication is through membrane contactsites, where two organelles come into closeproximity allowing the transport of lipids andsmall solutes between them. Contact sites aredynamic in size and can change in response toenvironmental or cellular stimuli; however, howthis is regulated has been unclear. Here, weshow that Saccharomyces cerevisiae Lam6resides in several central contact sites: ERMES(ER/mitochondria encounter structure), vCLAMP(vacuole and mitochondria patch), and NVJ(nuclear vacuolar junction). We show that Lam6is sufficient for expansion of contact sites underphysiological conditions and necessary forcoordination of contact site size. Given thatLam6 is part of a large protein family and isconserved in vertebrates, our work opensavenues for investigating the underlying", "metadata": {}}
+{"_id": "2958458", "title": "", "text": "Endocrine regulation of human fetal growth: therole of the mother, placenta, and fetus.Theenvironment in which the fetus develops iscritical for its survival and long-term health. Theregulation of normal human fetal growth involvesmany multidirectional interactions between themother, placenta, and fetus. The mother suppliesnutrients and oxygen to the fetus via theplacenta. The fetus influences the provision ofmaternal nutrients via the placental productionof hormones that regulate maternal metabolism.The placenta is the site of exchange betweenmother and fetus and regulates fetal growth viathe production and metabolism ofgrowth-regulating hormones such as IGFs andglucocorticoids. Adequate trophoblast invasion inearly pregnancy and increased uteroplacentalblood flow ensure sufficient growth of the uterus,placenta, and fetus. The placenta may respondto fetal endocrine signals to increase transport ofmaternal nutrients by growth of the placenta, byactivation of transport systems, and by", "metadata": {}}
+{"_id": "2973910", "title": "", "text": "Endothelial-to-mesenchymal transitioncontributes to cardiac fibrosisCardiac fibrosis,associated with a decreased extent ofmicrovasculature and with disruption of normalmyocardial structures, results from excessivedeposition of extracellular matrix, which ismediated by the recruitment of fibroblasts. Thesource of these fibroblasts is unclear and specificanti-fibrotic therapies are not currently available.Here we show that cardiac fibrosis is associatedwith the emergence of fibroblasts originatingfrom endothelial cells, suggesting anendothelial-mesenchymal transition (EndMT)similar to events that occur during formation ofthe atrioventricular cushion in the embryonicheart. Transforming growth factor-β1 (TGF-β1)induced endothelial cells to undergo EndMT,whereas bone morphogenic protein 7 (BMP-7)preserved the endothelial phenotype. Thesystemic administration of recombinant humanBMP-7 (rhBMP-7) significantly inhibited EndMTand the progression of cardiac fibrosis in mouse", "metadata": {}}
+{"_id": "2988714", "title": "", "text": "Coupled local translation and degradationregulate growth cone collapseLocal translationmediates axonal responses to Semaphorin3A(Sema3A) and other guidance cues. However,only a subset of the axonal proteome is locallysynthesized, whereas most proteins aretrafficked from the soma. The reason why onlyspecific proteins are locally synthesized isunknown. Here we show that local proteinsynthesis and degradation are linked events ingrowth cones. We find that growth cones exhibithigh levels of ubiquitination and that localsignalling pathways trigger the ubiquitinationand degradation of RhoA, a mediator ofSema3A-induced growth cone collapse. Inhibitionof RhoA degradation is sufficient to remove theprotein-synthesis requirement forSema3A-induced growth cone collapse. Inaddition to RhoA, we find that locally translatedproteins are the main targets of theubiquitin-proteasome system in growth cones.Thus, local protein degradation is a major feature", "metadata": {}}
+{"_id": "2991954", "title": "", "text": "Cdk11 is a RanGTP-dependent microtubulestabilization factor that regulates spindleassembly rateProduction of Ran-guanosinetriphosphate (GTP) around chromosomes induceslocal nucleation and plus end stabilization ofmicrotubules (MTs). The nuclear protein TPX2 isrequired for RanGTP-dependent MT nucleation.To find the MT stabilizer, we affinity purifynuclear localization signal (NLS)-containingproteins from Xenopus laevis egg extracts. ThisNLS protein fraction contains the MT stabilizationactivity. After further purification, we used massspectrometry to identify proteins in activefractions, including cyclin-dependent kinase 11(Cdk11). Cdk11 localizes on spindle poles andMTs in Xenopus culture cells and egg extracts.Recombinant Cdk11 demonstratesRanGTP-dependent MT stabilization activity,whereas a kinase-dead mutant does not.Inactivation of Cdk11 in egg extracts blocksRanGTP-dependent MT stabilization anddramatically decreases the spindle assembly", "metadata": {}}
+{"_id": "3001685", "title": "", "text": "Population dynamics of a pathogen: theconundrum of vivax malariaBuilding amathematical model of population dynamics ofpathogens within their host involvesconsiderations of factors similar to those inecology, as pathogens can prey on cells in thehost. But within the multicellular host, attackedcell types are integrated with other cellularsystems, which in turn intervene in the infection.For example, immune responses attempt tosense and then eliminate or contain pathogens,and homeostatic mechanisms try to compensatefor cell loss. This review focuses on modelingapplied to malarias, diseases caused bysingle-cell eukaryote parasites that infect redblood cells, with special concern given to vivaxmalaria, a disease often thought to be benign (ifsometimes incapacitating) because the parasiteonly attacks a small proportion of red blood cells,the very youngest ones. However, I will usemathematical modeling to argue that depletionof this pool of red blood cells can be disastrous to", "metadata": {}}
+{"_id": "3033830", "title": "", "text": "Identification and analysis of ribonuclease P andMRP RNA in a broad range of eukaryotesRNasesP and MRP are ribonucleoprotein complexesinvolved in tRNA and rRNA processing,respectively. The RNA subunits of these twoenzymes are structurally related to each otherand play an essential role in the enzymaticreaction. Both of the RNAs have a highlyconserved helical region, P4, which is importantin the catalytic reaction. We have used abioinformatics approach based on conservedelements to computationally analyze availablegenomic sequences of eukaryotic organisms andhave identified a large number of novel nuclearRNase P and MRP RNA genes. For MRP RNA forinstance, this investigation increases the numberof known sequences by a factor of three. Wepresent secondary structure models of many ofthe predicted RNAs. Although all sequences areable to fold into the consensus secondarystructure of P and MRP RNAs, a striking variationin size is observed, ranging from a Nosema", "metadata": {}}
+{"_id": "3034412", "title": "", "text": "Calcium absorption varies within the referencerange for serum 25-hydroxyvitaminD.BACKGROUND Calcium absorption is generallyconsidered to be impaired under conditions ofvitamin D deficiency, but the vitamin D statusthat fully normalizes absorption is not known forhumans. OBJECTIVE To quantify calciumabsorption at two levels of vitamin D repletion,using pharmacokinetic methods andcommercially marketed calcium supplements.DESIGN Two experiments performed in thespring of the year, one year apart. In the first, inwhich participants were pretreated with25-hydroxyvitamin D (25OHD), mean serum25OHD concentration was 86.5 nmol/L; and inthe other, with no pretreatment, mean serumconcentration was 50.2 nmol/L. Participantsreceived 500 mg oral calcium loads as a part of astandard low calcium breakfast. A low calciumlunch was provided at mid-day. Blood wasobtained fasting and at frequent intervals for 10to 12 hours thereafter. METHODS Relative", "metadata": {}}
+{"_id": "3038933", "title": "", "text": "Evolution of virulence in opportunisticpathogens: generalism, plasticity, andcontrolStandard virulence evolution theoryassumes that virulence factors are maintainedbecause they aid parasitic exploitation,increasing growth within and/or transmissionbetween hosts. An increasing number of studiesnow demonstrate that many opportunisticpathogens (OPs) do not conform to theseassumptions, with virulence factors maintainedinstead because of advantages in non-parasiticcontexts. Here we review virulence evolutiontheory in the context of OPs and highlight theimportance of incorporating environmentsoutside a focal virulence site. We illustrate thatvirulence selection is constrained by correlationsbetween these external and focal settings andpinpoint drivers of key environmentalcorrelations, with a focus on generalist strategiesand phenotypic plasticity. We end with asummary of key theoretical and empiricalchallenges to be met for a fuller understanding of", "metadata": {}}
+{"_id": "3052213", "title": "", "text": "Genome-Wide Profiling of H3K56 Acetylation andTranscription Factor Binding Sites in HumanAdipocytesThe growing epidemic of obesity andmetabolic diseases calls for a betterunderstanding of adipocyte biology. Theregulation of transcription in adipocytes isparticularly important, as it is a target for severaltherapeutic approaches. Transcriptionaloutcomes are influenced by both histonemodifications and transcription factor binding.Although the epigenetic states and binding sitesof several important transcription factors havebeen profiled in the mouse 3T3-L1 cell line, suchdata are lacking in human adipocytes. In thisstudy, we identified H3K56 acetylation sites inhuman adipocytes derived from mesenchymalstem cells. H3K56 is acetylated by CBP andp300, and deacetylated by SIRT1, all areproteins with important roles in diabetes andinsulin signaling. We found that while almost halfof the genome shows signs of H3K56 acetylation,the highest level of H3K56 acetylation is", "metadata": {}}
+{"_id": "3052642", "title": "", "text": "Detecting and characterizing circularRNAsCircular RNA transcripts were first identifiedin the early 1990s but knowledge of thesespecies has remained limited, as their studythrough traditional methods of RNA analysis hasbeen difficult. Now, novel bioinformaticapproaches coupled with biochemical enrichmentstrategies and deep sequencing have allowedcomprehensive studies of circular RNA species.Recent studies have revealed thousands ofendogenous circular RNAs in mammalian cells,some of which are highly abundant andevolutionarily conserved. Evidence is emergingthat some circRNAs might regulate microRNA(miRNA) function, and roles in transcriptionalcontrol have also been suggested. Therefore,study of this class of noncoding RNAs haspotential implications for therapeutic andresearch applications. We believe the key futurechallenge for the field will be to understand theregulation and function of these unusualmolecules.", "metadata": {}}
+{"_id": "3056682", "title": "", "text": "A classification of unstable anginarevisited.Unstable angina is a critical phase ofcoronary heart disease with widely variablesymptoms and prognosis. A decade ago, aclassification of unstable angina based on clinicalsymptoms was introduced. This system was thenvalidated by prospective clinical studies tocorrelate with the prognosis and was linked toangiographic and histological findings. It hasbeen used to categorize patients in many largeclinical trials. In recent years, thepathophysiological roles of platelet activation andinflammation in unstable angina have beenelucidated. Subsequently, improved markers ofmyocardial injury, acute-phase proteins, andhemostatic markers that may be associated withclinical outcomes have been identified.Particularly, cardiac-specific troponin T andtroponin I have been shown to represent thebest predictors of early risk in patients withangina at rest. Accordingly, it is suggested thatthe original classification be extended by", "metadata": {}}
+{"_id": "3067015", "title": "", "text": "Alcohol Intake and Blood Pressure: A SystematicReview Implementing a MendelianRandomization ApproachBACKGROUND Alcoholhas been reported to be a common andmodifiable risk factor for hypertension. However,observational studies are subject to confoundingby other behavioural and sociodemographicfactors, while clinical trials are difficult toimplement and have limited follow-up time.Mendelian randomization can provide robustevidence on the nature of this association by useof a common polymorphism in aldehydedehydrogenase 2 (ALDH2) as a surrogate formeasuring alcohol consumption. ALDH2 encodesa major enzyme involved in alcohol metabolism.Individuals homozygous for the null variant(*2*2) experience adverse symptoms whendrinking alcohol and consequently drinkconsiderably less alcohol than wild-typehomozygotes (*1*1) or heterozygotes. Wehypothesise that this polymorphism mayinfluence the risk of hypertension by affecting", "metadata": {}}
+{"_id": "3078080", "title": "", "text": "Rapid and Sensitive RT-QuIC Detection of HumanCreutzfeldt-Jakob Disease Using CerebrospinalFluidUNLABELLED Fast, definitive diagnosis ofCreutzfeldt-Jakob disease (CJD) is important inassessing patient care options and transmissionrisks. Real-time quaking-induced conversion(RT-QuIC) assays of cerebrospinal fluid (CSF)and nasal-brushing specimens are valuable indistinguishing CJD from non-CJD conditions buthave required 2.5 to 5 days. Here, an improvedRT-QuIC assay is described which identifiedpositive CSF samples within 4 to 14 h with betteranalytical sensitivity. Moreover, analysis of 11CJD patients demonstrated that while 7 wereRT-QuIC positive using the previous conditions,10 were positive using the new assay. In theseand further analyses, a total of 46 of 48 CSFsamples from sporadic CJD patients werepositive, while all 39 non-CJD patients werenegative, giving 95.8% diagnostic sensitivity and100% specificity. This second-generationRT-QuIC assay markedly improved the speed", "metadata": {}}
+{"_id": "3078550", "title": "", "text": "Wortmannin, a phosphoinositide 3-kinaseinhibitor, selectively enhances cytotoxicity ofreceptor-directed-toxin chimeras in vitro and invivo.BACKGROUND Generalized resistance ofsome neoplastic cell lines to treatment withligand-toxin chimeras has been attributed to anincreased rate of lysosomal uptake anddegradation following endocytosis of thechimera-receptor complex. Becausephosphoinositide 3-kinase (Pl 3-kinase) activityis known to play a role in intracellular trafficking,particularly from endosomes to lysosomes, wehypothesized that co-exposing cells to the Pl3-kinase inhibitor, wortmannin, might enhancecytotoxicity of ligand-toxin chimeras. METHODSIn vitro, cytotoxicity of five receptordirected-toxin chimeras (bFGF-SAP, bFGF-PE,aFGF-PE, HBEGF-SAP, bFGF-gelonin) and animmunotoxin (11A8-SAP) was examined in thepresence or absence of this Pl 3-kinase inhibitoragainst a panel of human neoplastic cell lines:SK-MEL-5 (melanoma), PA-1 (ovarian", "metadata": {}}
+{"_id": "3083927", "title": "", "text": "Chronic stress, glucocorticoid receptorresistance, inflammation, and disease risk.Wepropose a model wherein chronic stress results inglucocorticoid receptor resistance (GCR) that, inturn, results in failure to down-regulateinflammatory response. Here we test the modelin two viral-challenge studies. In study 1, weassessed stressful life events, GCR, and controlvariables including baseline antibody to thechallenge virus, age, body mass index (BMI),season, race, sex, education, and virus type in276 healthy adult volunteers. The volunteerswere subsequently quarantined, exposed to oneof two rhinoviruses, and followed for 5 d withnasal washes for viral isolation and assessmentof signs/symptoms of a common cold. In study2, we assessed the same control variables andGCR in 79 subjects who were subsequentlyexposed to a rhinovirus and monitored atbaseline and for 5 d after viral challenge for theproduction of local (in nasal secretions)proinflammatory cytokines (IL-1β, TNF-α, and", "metadata": {}}
+{"_id": "3085264", "title": "", "text": "Pituitary Adenylate Cyclase-ActivatingPolypeptide (PACAP), a Neuron-Derived PeptideRegulating Glial Glutamate Transport andMetabolismIn the brain, glutamatergicneurotransmission is terminated predominantlyby the rapid uptake of synaptically releasedglutamate into astrocytes through theNa(+)-dependent glutamate transporters GLT-1and GLAST and its subsequent conversion intoglutamine by the enzyme glutamine synthetase(GS). To date, several factors have beenidentified that rapidly alter glial glutamateuptake by post-translational modification ofglutamate transporters. The only conditionknown to affect the expression of glial glutamatetransporters and GS is the coculturing of gliawith neurons. We now demonstrate that neuronsregulate glial glutamate turnover via pituitaryadenylate cyclase-activating polypeptide(PACAP). In the cerebral cortex PACAP issynthesized by neurons and acts on thesubpopulation of astroglia involved in glutamate", "metadata": {}}
+{"_id": "3090454", "title": "", "text": "Factors influencing B lymphopoiesis afterallogeneic hematopoietic cell transplantation.In93 allograft recipients, the numbers of marrowB-cell precursors on days 80 and 365 correlatedwith the counts of circulating B cells, suggestingthat the posttransplantation B-cell deficiency isat least in part due to insufficient Blymphopoiesis. Factors that could affect Blymphopoiesis were evaluated. The number ofmarrow B-cell precursors on days 30 and 80 wasat least 4-fold lower in patients with grade 2 to 4acute graft-versus-host disease (GVHD)compared with patients with grade 0 to 1 acuteGVHD. The number of B-cell precursors on day365 was 18-fold lower in patients with extensivechronic GVHD compared with patients with no orlimited chronic GVHD. The number of B-cellprecursors was not related to CD34 cell dose,type of transplant (marrow versus blood stemcells), donor age, or patient age. It wasconcluded that posttransplantation B-celldeficiency results in part from inhibition of B", "metadata": {}}
+{"_id": "3093512", "title": "", "text": "Genetic variants rs1994016 and rs3825807 inADAMTS7 affect its mRNA expression inatherosclerotic occlusive peripheral arterialdiseaseAIM Peripheral artery disease (PAD) is avascular disease affecting peripheral circulation.Recently, genome-wide association studiesrevealed a relationship between single nucleotidepolymorphisms (SNPs) in ADAMTS7 (adisintegrin and metalloprotease withthrombospondin motif 7) and atherosclerosis. Inthis study, we aimed to determine ADAMTS7expression in peripheral blood mononuclear cells(PBMCs) and the frequency of ADAMTS7rs1994016 and rs3825807 polymorphisms in asample of Turkish patients with PAD, and toevaluate the association of matrixmetalloproteinase (MMP) levels with PADdevelopment. METHODS In this case-controlstudy, ADAMTS7mRNA and protein expressionwas determined using reverse transcriptionquantitative real-time polymerase chain reaction(RT-qPCR) and western blot, respectively, and", "metadata": {}}
+{"_id": "3095620", "title": "", "text": "Distinct Parietal and Temporal Pathways to theHomologues of Broca's Area in the MonkeyThehomologues of the two distinct architectonicareas 44 and 45 that constitute the anteriorlanguage zone (Broca's region) in the humanventrolateral frontal lobe were recentlyestablished in the macaque monkey. Althoughwe know that the inferior parietal lobule and thelateral temporal cortical region project to theventrolateral frontal cortex, we do not knowwhich of the several cortical areas found in thoseregions project to the homologues of Broca'sregion in the macaque monkey and by means ofwhich white matter pathways. We have used theautoradiographic method, which permits theestablishment of the cortical area from whichaxons originate (i.e., the site of injection), theprecise course of the axons in the white matter,and their termination within particular corticalareas, to examine the parietal and temporalconnections to area 44 and the two subdivisionsof area 45 (i.e., areas 45A and 45B). The results", "metadata": {}}
+{"_id": "3098821", "title": "", "text": "MIRA-seq for DNA methylation analysis of CpGislandsAIM To develop a reliable method forwhole genome analysis of DNA methylation.MATERIALS & METHODS Genome-scale analysisof DNA methylation includes affinity-basedapproaches such as enrichment usingmethyl-CpG-binding proteins. One of thesemethods, the methylated-CpG island recoveryassay (MIRA), is based on the high affinity of theMBD2b-MBD3L1 complex for CpG-methylatedDNA. Here we provide a detailed description ofMIRA and combine it with next generationsequencing platforms (MIRA-seq). RESULTS Weassessed the performance of MIRA-seq andcompared the data with whole genome bisulfitesequencing. CONCLUSION MIRA-seq is a reliable,genome-scale DNA methylation analysis platformfor scoring DNA methylation differences atCpG-rich genomic regions. The method is notlimited by primer or probe design and is costeffective.", "metadata": {}}
+{"_id": "3099497", "title": "", "text": "How many images are in an auditory scene?If anauditory scene consists of many spatiallyseparated sound sources, how many soundsources can be processed by the auditorysystem? Experiment I determined how manyspeech sources could be localized simultaneouslyon the azimuth plane. Different words wereplayed from multiple loudspeakers, and listenersreported the total number of sound sources andtheir individual locations. In experiment II theaccuracy of localizing one speech source in amixture of multiple speech sources wasdetermined. An extra sound source was added toan existing set of sound sources, and the taskwas to localize that extra source. In experimentIII the setup and task were the same as inexperiment I, except that the sounds were tones.The results showed that the maximum number ofsound sources that listeners could perceive waslimited to approximately four spatially separatedspeech signals and three for tonal signals. Thelocalization errors increased along with the", "metadata": {}}
+{"_id": "3105781", "title": "", "text": "Mobilization of intracellular copper stores by thectr2 vacuolar copper transporter.Copper plays anessential role in processes including signaling tothe transcription and protein traffickingmachinery, oxidative phosphorylation, ironmobilization, neuropeptide maturation, andnormal development. Whereas much is knownabout intracellular mobilization of ions such ascalcium, little information is available on howeukaryotic cells mobilize intracellular copperstores. We describe a mechanism by which theSaccharomyces cerevisiae Ctr2 protein providesbioavailable copper via mobilization ofintracellular copper stores. Whereas Ctr2 exhibitsstructural similarity to the Ctr1 plasmamembrane copper importer, microscopic andbiochemical fractionation studies localize Ctr2 tothe vacuole membrane. We demonstrate thatCtr2 mobilizes vacuolar copper stores in amanner dependent on amino acid residuesconserved between the Ctr1 and Ctr2 coppertransport family and that ctr2 Delta mutants", "metadata": {}}
+{"_id": "3107733", "title": "", "text": "Peroxisomes Are Signaling Platforms for AntiviralInnate ImmunityPeroxisomes have long beenestablished to play a central role in regulatingvarious metabolic activities in mammalian cells.These organelles act in concert withmitochondria to control the metabolism of lipidsand reactive oxygen species. However, whilemitochondria have emerged as an important siteof antiviral signal transduction, a role forperoxisomes in immune defense is unknown.Here, we report that the RIG-I-like receptor(RLR) adaptor protein MAVS is located onperoxisomes and mitochondria. We find thatperoxisomal and mitochondrial MAVS actsequentially to create an antiviral cellular state.Upon viral infection, peroxisomal MAVS inducesthe rapid interferon-independent expression ofdefense factors that provide short-termprotection, whereas mitochondrial MAVSactivates an interferon-dependent signalingpathway with delayed kinetics, which amplifiesand stabilizes the antiviral response. The", "metadata": {}}
+{"_id": "3112885", "title": "", "text": "Two-sided confidence intervals for the singleproportion: comparison of seven methods. Stat.MedSimple interval estimate methods forproportions exhibit poor coverage and canproduce evidently inappropriate intervals.Criteria appropriate to the evaluation of variousproposed methods include: closeness of theachieved coverage probability to its nominalvalue; whether intervals are located too close toor too distant from the middle of the scale;expected interval width; avoidance ofaberrations such as limits outside [0,1] or zerowidth intervals; and ease of use, whether bytables, software or formulae. Seven methods forthe single proportion are evaluated on 96,000parameter space points. Intervals based on tailareas and the simpler score methods arerecommended for use. In each case, methodsare available that aim to align either theminimum or the mean coverage with the nominal1 -alpha.", "metadata": {}}
+{"_id": "3113630", "title": "", "text": "Nuclear accumulation of HDAC4 in ATMdeficiency promotes neurodegeneration inataxia-telangiectasiaAtaxia telangiectasia is aneurodegenerative disease caused by mutationof the Atm gene. Here we report that ataxiatelangiectasia mutated (ATM) deficiency causesnuclear accumulation of histone deacetylase 4(HDAC4) in neurons and promotesneurodegeneration. Nuclear HDAC4 binds tochromatin, as well as to myocyte enhancer factor2A (MEF2A) and cAMP-responsive elementbinding protein (CREB), leading to histonedeacetylation and altered neuronal geneexpression. Blocking either HDAC4 activity or itsnuclear accumulation blunts theseneurodegenerative changes and rescues severalbehavioral abnormalities of ATM-deficient mice.Full rescue of the neurodegeneration, however,also requires the presence of HDAC4 in thecytoplasm, suggesting that the ataxiatelangiectasia phenotype results both from a lossof cytoplasmic HDAC4 as well as its nuclear", "metadata": {}}
+{"_id": "3118719", "title": "", "text": "Regulation and function of theE-cadherin/catenin complex in cells of themonocyte-macrophage lineage andDCs.E-cadherin is best characterized as adherensjunction protein, which through homotypicinteractions contributes to the maintenance ofthe epithelial barrier function. In epithelial cells,the cytoplasmic tail of E-cadherin forms adynamic complex with catenins and regulatesseveral intracellular signal transductionpathways, including Wnt/β-catenin, PI3K/Akt,Rho GTPase, and NF-κB signaling. Recentprogress uncovered a novel and critical role forthis adhesion molecule in mononuclearphagocyte functions. E-cadherin regulates thematuration and migration of Langerhans cells,and its ligation prevents the induction of atolerogenic state in bone marrow-deriveddendritic cells (DCs). In this respect, thefunctionality of β-catenin could be instrumentalin determining the balance betweenimmunogenicity and tolerogenicity of DCs in vitro", "metadata": {}}
+{"_id": "3127341", "title": "", "text": "Polymorphism and ligand dependent changes inhuman glucagon-like peptide-1 receptor(GLP-1R) function: allosteric rescue of loss offunction mutation.The glucagon-like peptide-1receptor (GLP-1R) is a key physiologicalregulator of insulin secretion and a majortherapeutic target for the treatment of type IIdiabetes. However, regulation of GLP-1R functionis complex with multiple endogenous peptidesthat interact with the receptor, includingfull-length (1-37) and truncated (7-37) forms ofGLP-1 that can exist in an amidated form(GLP-1(1-36)NH\u0000 and GLP-1(7-36)NH\u0000) andthe related peptide oxyntomodulin. In addition,the GLP-1R possesses exogenous agonists,including exendin-4, and the allostericmodulator, compound 2 (6,7-dichloro-2-methylsulfonyl-3-tert-butylaminoquinoxaline). Thecomplexity of this ligand-receptor system isfurther increased by the presence of severalsingle nucleotide polymorphisms (SNPs) that aredistributed across the receptor. We have", "metadata": {}}
+{"_id": "3140772", "title": "", "text": "Neuronal circuitry mechanism regulating adultquiescent neural stem cell fate decisionAdultneurogenesis arises from neural stem cells withinspecialized niches. Neuronal activity andexperience, presumably acting on this localniche, regulate multiple stages of adultneurogenesis, from neural progenitorproliferation to new neuron maturation, synapticintegration and survival. It is unknown whetherlocal neuronal circuitry has a direct impact onadult neural stem cells. Here we show that, inthe adult mouse hippocampus, nestin-expressingradial glia-like quiescent neural stem cells (RGLs)respond tonically to the neurotransmitterγ-aminobutyric acid (GABA) by means ofγ2-subunit-containing GABAA receptors. Clonalanalysis of individual RGLs revealed a rapid exitfrom quiescence and enhanced symmetricalself-renewal after conditional deletion of γ2.RGLs are in close proximity to terminalsexpressing 67-kDa glutamic acid decarboxylase(GAD67) of parvalbumin-expressing (PV+)", "metadata": {}}
+{"_id": "3150030", "title": "", "text": "Global vitamin D levels in relation to age,gender, skin pigmentation and latitude: anecologic meta-regression analysisWe performeda meta-analysis of cross-sectional studies onserum 25(OH)D status globally. Serum 25(OH)Dlevels on average were 54 nmol/l, were higher inwomen than men, and higher in Caucasians thanin non-Caucasians. There was no trend in serum25(OH)D level with latitude. Vitamin D deficiencywas widespread. We studied vitamin D status(expressed as serum 25-hydroxy-vitamin D[25(OH)D]) in native subjects worldwide.Meta-analysis and meta-regression of studiesreporting on 25(OH)D in healthy subjectsretrieved from Pubmed, Embase and Web ofScience using the terms “serum”,“25-hydroxy-vitamin D”, “cholecalciferol”, and“human”. A total of 394 studies were included.The mean 25(OH)D level was 54 nmol/l (95%CI: 52–57 nmol/l). Women had borderlinesignificantly higher 25(OH)D levels than men,and Caucasians had higher levels than", "metadata": {}}
+{"_id": "3152612", "title": "", "text": "Identification and characterization of a novelmonocyte/macrophage differentiation-dependentgene that is responsive to lipopolysaccharide,ceramide, and lysophosphatidylcholine.A noveldifferentiation-dependent cDNA (DIF-2) has beenisolated from human mononuclear phagocytes bydifferential display. The full-length cDNA wascloned and sequenced. DIF-2 consists of 156amino acids and has a predicted isoelectric pointof 8.84. The mRNA is expressed in freshlyisolated monocytes and is downregulatedsignificantly when monocytes are subjected todifferentiation. A similardifferentiation-dependent downregulation isobserved in normal hepatocytes compared toundifferentiated HepG2 cells. The mRNAexpression in monocytes is sensitive tolipopolysaccharide and ceramide which bothstrongly increase DIF-2 transcription, whilelysophosphatidylcholine results in a weakerupregulation of DIF-2 expression. A DIF-2homologous gene has been previously isolated", "metadata": {}}
+{"_id": "3153673", "title": "", "text": "A Novel 3-Hydroxysteroid Dehydrogenase ThatRegulates Reproductive Development andLongevityEndogenous small moleculemetabolites that regulate animal longevity areemerging as a novel means to influence healthand life span. In C. elegans, bile acid-likesteroids called the dafachronic acids (DAs)regulate developmental timing and longevitythrough the conserved nuclear hormone receptorDAF-12, a homolog of mammaliansterol-regulated receptors LXR and FXR. Usingmetabolic genetics, mass spectrometry, andbiochemical approaches, we identify newactivities in DA biosynthesis and characterize anevolutionarily conserved short chaindehydrogenase, DHS-16, as a novel3-hydroxysteroid dehydrogenase. Throughregulation of DA production, DHS-16 controlsDAF-12 activity governing longevity in responseto signals from the gonad. Our elucidation of C.elegans bile acid biosynthetic pathways revealsthe possibility of novel ligands as well as striking", "metadata": {}}
+{"_id": "3154880", "title": "", "text": "An Argonaute transports siRNAs from thecytoplasm to the nucleus.Ribonucleoproteincomplexes consisting of Argonaute-like proteinsand small regulatory RNAs function in a widerange of biological processes. Many of thesesmall regulatory RNAs are predicted to act, atleast in part, within the nucleus. We conducted agenetic screen to identify factors essential forRNA interference (RNAi) in nuclei ofCaenorhabditis elegans and identified theArgonaute protein NRDE-3. In the absence ofsmall interfering RNAs (siRNAs), NRDE-3 residesin the cytoplasm. NRDE-3 binds siRNAsgenerated by RNA-dependent RNA polymerasesacting on messenger RNA templates in thecytoplasm and redistributes to the nucleus.Nuclear redistribution of NRDE-3 requires afunctional nuclear localization signal, is requiredfor nuclear RNAi, and results in NRDE-3association with nuclear-localized nascenttranscripts. Thus, specific Argonaute proteins cantransport specific classes of small regulatory", "metadata": {}}
+{"_id": "3155374", "title": "", "text": "Phosphatidylinositol 4,5-Bisphosphate Functionsas a Second Messenger that RegulatesCytoskeleton–Plasma MembraneAdhesionBinding interactions between theplasma membrane and the cytoskeleton definecell functions such as cell shape, formation of cellprocesses, cell movement, and endocytosis. Herewe use optical tweezers tether forcemeasurements and show that plasma membranephosphatidylinositol 4,5-bisphosphate (PIP2)acts as a second messenger that regulates theadhesion energy between the cytoskeleton andthe plasma membrane. Receptor stimuli thathydrolyze PIP2 lowered adhesion energy, aprocess that could be mimicked by expressing PHdomains that sequester PIP2 or by targeting a5'-PIP2-phosphatase to the plasma membrane toselectively lower plasma membrane PIP2concentration. Our study suggests that plasmamembrane PIP2 controls dynamic membranefunctions and cell shape by locally increasing anddecreasing the adhesion between the", "metadata": {}}
+{"_id": "3155731", "title": "", "text": "Tissue-resident memory T cells: local specialistsin immune defenceT cells have crucial roles inprotection against infection and cancer. Althoughthe trafficking of memory T cells around the bodyis integral to their capacity to provide immuneprotection, studies have shown thatspecialization of some memory T cells intounique tissue-resident subsets gives the hostenhanced regional immunity. In recent years,there has been considerable progress in ourunderstanding of tissue-resident T celldevelopment and function, revealingmechanisms for enhanced protective immunitythat have the potential to influence rationalvaccine design. This Review discusses the majoradvances and the emerging concepts in this field,summarizes what is known about thedifferentiation and the protective functions oftissue-resident memory T cells in differenttissues in the body and highlights keyunanswered questions.", "metadata": {}}
+{"_id": "3173489", "title": "", "text": "Defective replication stress response inhibitslymphomagenesis and impairs lymphocytereconstitutionDNA replication stress promotesgenome instability in cancer. However, thecontribution of the replication stress response tothe development of malignancies remainsunresolved. The DNA replication stress responseprotein SMARCAL1 stabilizes DNA replicationforks and prevents replication fork collapse, acause of DNA breaks and apoptosis. While thefork regression/remodeling functions ofSMARCAL1 have been investigated, its in vivofunctions in replication stress and cancer areunclear. Using a gamma radiation (IR)-inducedreplication stress T-cell lymphoma mouse model,we observed a significant inhibition oflymphomagenesis in mice lacking one or bothalleles of Smarcal1. Notably, a quarter of theSmarcal1-deficient mice did not develop tumors.Moreover, hematopoietic stem/progenitor cells(HSPCs) and developing thymocytes inSmarcal1-deficient mice showed increased DNA", "metadata": {}}
+{"_id": "3174305", "title": "", "text": "Human DNA methylomes at base resolution showwidespread epigenomic differencesDNA cytosinemethylation is a central epigenetic modificationthat has essential roles in cellular processesincluding genome regulation, development anddisease. Here we present the first genome-wide,single-base-resolution maps of methylatedcytosines in a mammalian genome, from bothhuman embryonic stem cells and fetalfibroblasts, along with comparative analysis ofmessenger RNA and small RNA components ofthe transcriptome, several histone modifications,and sites of DNA–protein interaction for severalkey regulatory factors. Widespread differenceswere identified in the composition and patterningof cytosine methylation between the twogenomes. Nearly one-quarter of all methylationidentified in embryonic stem cells was in anon-CG context, suggesting that embryonic stemcells may use different methylation mechanismsto affect gene regulation. Methylation in non-CGcontexts showed enrichment in gene bodies and", "metadata": {}}
+{"_id": "3190689", "title": "", "text": "Laparoscopic adhesiolysis in patients with chronicabdominal pain: a blinded randomised controlledmulti-centre trial.BACKGROUND Laparoscopicadhesiolysis for chronic abdominal pain iscontroversial and is not evidence based. Weaimed to test our hypothesis that laparoscopicadhesiolysis leads to substantial pain relief andimprovement in quality of life in patients withadhesions and chronic abdominal pain.METHODS Patients had diagnostic laparoscopyfor chronic abdominal pain attributed toadhesions; other causes for their pain had beenexcluded. If adhesions were confirmed duringdiagnostic laparoscopy, patients were randomlyassigned either to laparoscopic adhesiolysis or notreatment. Treatment allocation was concealedfrom patients, and assessors were unaware ofpatients' treatment and outcome. Pain wasassessed for 1 year by visual analogue score(VAS) score (scale 0-100), pain change score,use of analgesics, and quality of life score.Analysis was by intention to treat. FINDINGS Of", "metadata": {}}
+{"_id": "3202143", "title": "", "text": "Insulin Signaling and Dietary RestrictionDifferentially Influence the Decline of Learningand Memory with AgeOf all the age-relateddeclines, memory loss is one of the mostdevastating. While conditions that increaselongevity have been identified, the effects ofthese longevity-promoting factors on learningand memory are unknown. Here we show thatthe C. elegans Insulin/IGF-1 receptor mutantdaf-2 improves memory performance early inadulthood and maintains learning ability betterwith age but, surprisingly, demonstrates noextension in long-term memory with age. Bycontrast, eat-2 mutants, a model of DietaryRestriction (DR), exhibit impaired long-termmemory in young adulthood but maintain thislevel of memory longer with age. We find thatcrh-1, the C. elegans homolog of the CREBtranscription factor, is required for long-termassociative memory, but not for learning orshort-term memory. The expression of crh-1declines with age and differs in the longevity", "metadata": {}}
+{"_id": "3203590", "title": "", "text": "Unique response pathways are established byallosteric interactions among nuclear hormonereceptorsHeterodimerization is a commonparadigm among eukaryotic transcription factors.The 9-cis retinoic acid receptor (RXR) serves as acommon heterodimerization partner for severalnuclear receptors, including the thyroid hormonereceptor (T3R) and retinoic acid receptor (RAR).This raises the question as to whether thesecomplexes possess dual hormonalresponsiveness. We devised a strategy toexamine the transcriptional properties of eachreceptor individually or when tethered to aheterodimeric partner. We find that the intrinsicbinding properties of RXR are masked inT3R-RXR and RAR-RXR heterodimers. Incontrast, RXR is active as a non-DNA-bindingcofactor with the NGFI-B/Nurr1 orphanreceptors. Heterodimerization of RXR withconstitutively active NGFI-B/Nurr1 creates anovel hormone-dependent complex. Thesefindings suggest that allosteric interactions", "metadata": {}}
+{"_id": "3205945", "title": "", "text": "Midlife and Late\u0000Life Vascular Risk Factors andWhite Matter Microstructural Integrity: TheAtherosclerosis Risk in CommunitiesNeurocognitive StudyBACKGROUND Diffusiontensor imaging measures of white matter (WM)microstructural integrity appear to provideearlier indication of WM injury than WMhyperintensities; however, risk factors for poorWM microstructural integrity have not beenestablished. Our study quantifies the associationbetween vascular risk factors in midlife and latelife with measures of late-life WM microstructuralintegrity. METHODS AND RESULTS We used datafrom 1851 participants in ARIC (AtherosclerosisRisk in Communities Study) who completed 3-Tmagnetic resonance imaging, including diffusiontensor imaging, as part of the ARICNeurocognitive Study (ARIC-NCS). We quantifiedthe association among lipids, glucose, and bloodpressure from the baseline ARIC visit(1987-1989, ages 44-65, midlife) and visit 5 ofARIC (2011-2013, ages 67-90, late life,", "metadata": {}}
+{"_id": "3210545", "title": "", "text": "KRAS gene amplification and overexpression butnot mutation associates with aggressive andmetastatic endometrial cancerBACKGROUNDThree quarter of endometrial carcinomas aretreated at early stage. Still, 15 to 20% of thesepatients experience recurrence, with little effectfrom systemic therapies. Homo sapiens v-Ki-ras2Kirsten rat sarcoma viral oncogenes homologue(KRAS) mutations have been reported to have animportant role in tumorigenesis for humancancers, but there is limited knowledge regardingclinical relevance of KRAS status in endometrialcarcinomas. METHODS We have performed acomprehensive and integrated characterisationof genome-wide expression related to KRASmutations and copy-number alterations inprimary- and metastatic endometrial carcinomalesions in relation to clinical and histopathologicaldata. A primary investigation set and clinicalvalidation set was applied, consisting of 414primary tumours and 61 metastatic lesionstotally. RESULTS Amplification and gain of KRAS", "metadata": {}}
+{"_id": "3215494", "title": "", "text": "Hyperhomocysteinemia and atheroscleroticvascular disease: pathophysiology, screening,and treatment. off.Hyperhomocysteinemia hasrecently been identified as an important riskfactor for atherosclerotic vascular disease. Thisarticle reviews homocysteine metabolism, causesof hyperhomocysteinemia, thepathophysiological findings of this disorder, andepidemiological studies of homocysteine andvascular disease. Screening forhyperhomocysteinemia should be considered forpatients at high risk for vascular disease orabnormalities of homocysteine metabolism. Forprimary prevention of vascular disease,treatment of patients with homocysteine levels of14 micromol/L or higher should be considered.For secondary prevention, treatment of patientswith homocysteine levels of 11 micromol/L orhigher should be considered. Treatment is mostconveniently administered as a folic acidsupplement (400-1000 microg) and ahigh-potency multivitamin that contains at least", "metadata": {}}
+{"_id": "3222122", "title": "", "text": "Best--worst scaling: What it can do for healthcare research and how to do it.Statements like\"quality of care is more highly valued thanwaiting time\" can neither be supported norrefuted by comparisons of utility parametersfrom a traditional discrete choice experiment(DCE). Best--worst scaling can overcome thisproblem because it asks respondents to performa different choice task. However, whilst thenature of the best--worst task is generallyunderstood, there are a number of issuesrelating to the design and analysis of abest--worst choice experiment that requirefurther exposition. This paper illustrates how toaggregate and analyse such data and using aquality of life pilot study demonstrates howricher insights can be drawn by the use ofbest--worst tasks.", "metadata": {}}
+{"_id": "3222187", "title": "", "text": "Genetic variants and non-genetic factors predictcirculating vitamin D levels in Hispanic andnon-Hispanic White women: the Breast CancerHealth Disparities Study.Genome-wideassociation studies (GWAS) have identifiedcommon polymorphisms in or near GC, CYP2R1,CYP24A1, and NADSYN1/DHCR7 genes to beassociated with circulating levels of25-hydroxyvitamin D [25(OH)D] in Europeanpopulations. To replicate these GWAS findings,we examined six selected polymorphisms fromthese regions and their relation with circulating25(OH)D levels in 1,605 Hispanic women (629U.S. Hispanics and 976 Mexicans) and 354non-Hispanic White (NHW) women. We alsoassessed the potential interactions betweenthese variants and known non-genetic predictorsof 25(OH)D levels, including body mass index(BMI), sunlight exposure and vitamin D intakefrom diet and supplements. The minor alleles ofthe two GC polymorphisms (rs7041 andrs2282679) were significantly associated with", "metadata": {}}
+{"_id": "3230361", "title": "", "text": "Generation and characterization of methyl-lysinehistone antibodies.Publisher Summary Thischapter summarizes the development andcharacterization of rabbit polyclonal antibodiesnamed histone that are directed against themethylated H3-K9 position. It provides protocolsfor peptide design, rabbit immunizations, andquality controls of methyl-lysine histoneantibodies, followed by their in vivocharacterization using indirect IF of inter-andmetaphase chromatin in wild-type (wt) andmutant mouse cells that are deficient for theSuv39h histone methyltransferases (HMTases).Histone amino-termini (tails) protrude from thenucleosome core and are subject to a variety ofpost-translational modifications, includingacetylation (on lysine residues), phosphorylation(on serine and threonine residues), methylation(on lysine and arginine residues), ubiquitination(on lysine residues), and ADP-ribosylation (onglutamic acid residues). In addition to theirstructural roles, histones play important", "metadata": {}}
+{"_id": "3230557", "title": "", "text": "The Hallmarks of AgingAging is characterized bya progressive loss of physiological integrity,leading to impaired function and increasedvulnerability to death. This deterioration is theprimary risk factor for major human pathologies,including cancer, diabetes, cardiovasculardisorders, and neurodegenerative diseases.Aging research has experienced anunprecedented advance over recent years,particularly with the discovery that the rate ofaging is controlled, at least to some extent, bygenetic pathways and biochemical processesconserved in evolution. This Review enumeratesnine tentative hallmarks that represent commondenominators of aging in different organisms,with special emphasis on mammalian aging.These hallmarks are: genomic instability,telomere attrition, epigenetic alterations, loss ofproteostasis, deregulated nutrient sensing,mitochondrial dysfunction, cellular senescence,stem cell exhaustion, and altered intercellularcommunication. A major challenge is to dissect", "metadata": {}}
+{"_id": "3270834", "title": "", "text": "A sensitive mass spectrometry platform identifiesmetabolic changes of life history traits in C.elegansAbnormal nutrient metabolism is ahallmark of aging, and the underlying geneticand nutritional framework is rapidly beinguncovered, particularly using C. elegans as amodel. However, the direct metabolicconsequences of perturbations in life history ofC. elegans remain to be clarified. Based onrecent advances in the metabolomics field, weoptimized and validated a sensitive massspectrometry (MS) platform for identification ofmajor metabolite classes in worms and applied itto study age and diet related changes. Using thisplatform that allowed detection of over 600metabolites in a sample of 2500 worms, weobserved marked changes in fatty acids, aminoacids and phospholipids during worm life history,which were independent from the germ-line.Worms underwent a striking shift in lipidmetabolism after early adulthood that was atleast partly controlled by the metabolic regulator", "metadata": {}}
+{"_id": "3272084", "title": "", "text": "Characterisation of antibiotic prescriptions foracute respiratory tract infections in Danishgeneral practice: a retrospective registry basedcohort studyInappropriate use of antibiotics iscontributing to the increasing rates ofantimicrobial resistance. Several Danishguidelines on antibiotic prescribing for acuterespiratory tract infections in general practicehave been issued to promote rational prescribingof antibiotics, however it is unclear if theserecommendations are followed. We aimed tocharacterise the pattern of antibioticprescriptions for patients diagnosed with acuterespiratory tract infections, by means ofelectronic prescriptions, labeled with clinicalindications, from Danish general practice. Acuterespiratory tract infections accounted for456,532 antibiotic prescriptions issued betweenJuly 2012 and June 2013. Pneumonia was themost common indication with 178,354prescriptions (39%), followed by acute tonsillitis(21%) and acute otitis media (19%). In total,", "metadata": {}}
+{"_id": "3285059", "title": "", "text": "Lack of Skeletal Muscle IL-6 Affects PyruvateDehydrogenase Activity at Rest and duringProlonged ExercisePyruvate dehydrogenase(PDH) plays a key role in the regulation ofskeletal muscle substrate utilization. IL-6 isproduced in skeletal muscle during exercise in aduration dependent manner and has beenreported to increase whole body fatty acidoxidation, muscle glucose uptake and decreasePDHa activity in skeletal muscle of fed mice. Theaim of the present study was to examinewhether muscle IL-6 contributes toexercise-induced PDH regulation in skeletalmuscle. Skeletal muscle-specific IL-6 knockout(IL-6 MKO) mice and floxed littermate controls(control) completed a single bout of treadmillexercise for 10, 60 or 120 min, with rested miceof each genotype serving as basal controls. Therespiratory exchange ratio (RER) was overallhigher (P<0.05) in IL-6 MKO than control miceduring the 120 min of treadmill exercise, whileRER decreased during exercise independent of", "metadata": {}}
+{"_id": "3285322", "title": "", "text": "Clinical and pathologic characteristics of patientswith BRCA-positive and BRCA-negative breastcancer.PURPOSE Mutations in the BRCA1 andBRCA2 genes confer greater risk of developingbreast cancer. We determined whether tumorpathologic features and clinical features differ inpatients with and without BRCA mutations.PATIENTS AND METHODS Tumor pathologicfeatures and clinical characteristics wereexamined in 491 women with breast cancer whounderwent genetic testing for BRCA mutationsbetween 1997 and 2006. A retrospective reviewof medical records was conducted to determineclinical characteristics including ethnicity, ageand clinical stage at diagnosis, age at parity,number of full-term pregnancies, use of oralcontraceptives and hormone replacementtherapy, and BRCA mutation status. Tumorpathology was reviewed to determine histologictype, tumor grade, and estrogen receptor,progesterone receptor, and HER-2/neu status.RESULTS Of the 491 patients with identified", "metadata": {}}
+{"_id": "3308636", "title": "", "text": "Interferons: Success in anti-viralimmunotherapy.The interferons (IFNs) areglycoproteins with strong antiviral activities thatrepresent one of the first lines of host defenseagainst invading pathogens. These proteins areclassified into three groups, Type I, II and IIIIFNs, based on the structure of their receptorson the cell surface. Due to their ability tomodulate immune responses, they have becomeattractive therapeutic options to control chronicvirus infections. In combination with other drugs,Type I IFNs are considered as \"standard of care\"in suppressing Hepatitis C (HCV) and Hepatitis B(HBV) infections, while Type III IFN hasgenerated encouraging results as a treatment forHCV infection in phase III clinical trials. However,though effective, using IFNs as a treatment isnot without the need for caution. IFNs are suchpowerful cytokines that affect a wide array of celltypes; as a result, patients usually experienceunpleasant symptoms, with a percentage ofpatients suffering system wide effects. Thus,", "metadata": {}}
+{"_id": "3315558", "title": "", "text": "Genetic analysis of human obesity in an Italiansample.An analysis of the genetic factors inobesity has been carried out on a sample ofnuclear families from Aosta (N. Italy). Thefamilies consisted of the parents and sibs of allelementary school children considered to beobese during a preliminary screening and asimilar sample of non-obese children and theirnuclear families. The numbers of such familieswere 67 and 112, respectively. Several testswere applied in order to examine the geneticcontribution to obesity, and in particular toinvestigate the presence of a dominant majorgene. Our conclusions are that genetic factorsare certainly present. Several analyses suggestthe presence of a dominant major gene withweak effect.", "metadata": {}}
+{"_id": "3321943", "title": "", "text": "The non-coding RNA landscape of humanhematopoiesis and leukemiaNon-coding RNAshave emerged as crucial regulators of geneexpression and cell fate decisions. However, theirexpression patterns and regulatory functionsduring normal and malignant humanhematopoiesis are incompletely understood.Here we present a comprehensive resourcedefining the non-coding RNA landscape of thehuman hematopoietic system. Based on highlyspecific non-coding RNA expression portraits perblood cell population, we identify uniquefingerprint non-coding RNAs-such as LINC00173in granulocytes-and assign these to criticalregulatory circuits involved in blood homeostasis.Following the incorporation of acute myeloidleukemia samples into the landscape, we furtheruncover prognostically relevant non-coding RNAstem cell signatures shared between acutemyeloid leukemia blasts and healthyhematopoietic stem cells. Our findings highlightthe importance of the non-coding transcriptome", "metadata": {}}
+{"_id": "3329824", "title": "", "text": "Incidence and risk of central nervous systemmetastases as site of first recurrence in patientswith HER2-positive breast cancer treated withadjuvant trastuzumab.BACKGROUND Centralnervous system (CNS) disease as the site of firstrelapse after exposure to adjuvant trastuzumabhas been reported. We carried outcomprehensive meta-analysis to determine therisk of CNS metastases as the first site ofrecurrence in patients with HER2-positive breastcancer who received adjuvant trastuzumab.METHODS Eligible studies include randomizedtrials of adjuvant trastuzumab administered for 1year to patients with HER2-positive breast cancerwho reported CNS metastases as first site ofdisease recurrence. Statistical analyses wereconducted to calculate the incidence, relative risk(RR), and 95% confidence intervals (CIs) usingfixed-effects inverse variance andrandom-effects models. RESULTS A total of 9020patients were included. The incidence of CNSmetastases as first site of disease recurrence in", "metadata": {}}
+{"_id": "3330111", "title": "", "text": "Neutrophils in the activation and regulation ofinnate and adaptive immunityNeutrophils havelong been viewed as the final effector cells of anacute inflammatory response, with a primary rolein the clearance of extracellular pathogens.However, more recent evidence has extendedthe functions of these cells. The newlydiscovered repertoire of effector molecules in theneutrophil armamentarium includes a broadarray of cytokines, extracellular traps andeffector molecules of the humoral arm of theinnate immune system. In addition, neutrophilsare involved in the activation, regulation andeffector functions of innate and adaptive immunecells. Accordingly, neutrophils have a crucial rolein the pathogenesis of a broad range of diseases,including infections caused by intracellularpathogens, autoimmunity, chronic inflammationand cancer.", "metadata": {}}
+{"_id": "3346812", "title": "", "text": "Functions of DNA methylation: islands, startsites, gene bodies and beyondDNA methylation isfrequently described as a 'silencing' epigeneticmark, and indeed this function of5-methylcytosine was originally proposed in the1970s. Now, thanks to improved genome-scalemapping of methylation, we can evaluate DNAmethylation in different genomic contexts:transcriptional start sites with or without CpGislands, in gene bodies, at regulatory elementsand at repeat sequences. The emerging picture isthat the function of DNA methylation seems tovary with context, and the relationship betweenDNA methylation and transcription is morenuanced than we realized at first. Improving ourunderstanding of the functions of DNAmethylation is necessary for interpreting changesin this mark that are observed in diseases suchas cancer.", "metadata": {}}
+{"_id": "3353748", "title": "", "text": "Metaplasia and transdifferentiation: from purebiology to the clinicTransformations from onetissue type to another make up a wellestablished set of phenomena that can beexplained by the principles of developmentalbiology. Although these phenomena might berare in nature, we can now imagine thepossibility of deliberately reprogramming cellsfrom one tissue type to another by manipulatingthe expression of transcription factors. Thisapproach could generate new therapies for manyhuman diseases.", "metadata": {}}
+{"_id": "3355397", "title": "", "text": "Pioglitazone Use and Risk of Bladder Cancer andOther Common Cancers in Persons WithDiabetes.IMPORTANCE Studies suggestpioglitazone use may increase risk of cancers.OBJECTIVE To examine whether pioglitazone usefor diabetes is associated with risk of bladder and10 additional cancers. DESIGN, SETTING, ANDPARTICIPANTS Cohort and nested case-controlanalyses among persons with diabetes. A bladdercancer cohort followed 193,099 persons aged 40years or older in 1997-2002 until December2012; 464 case patients and 464 matchedcontrols were surveyed about additionalconfounders. A cohort analysis of 10 additionalcancers included 236,507 persons aged 40 yearsor older in 1997-2005 and followed until June2012. Cohorts were from Kaiser PermanenteNorthern California. EXPOSURES Ever use,duration, cumulative dose, and time sinceinitiation of pioglitazone as time dependent.MAIN OUTCOMES AND MEASURES Incidentcancer, including bladder, prostate, female", "metadata": {}}
+{"_id": "3360421", "title": "", "text": "Embryonic stem cell lines from humanblastocysts: somatic differentiation in vitroWedescribe the derivation of pluripotent embryonicstem (ES) cells from human blastocysts. Twodiploid ES cell lines have been cultivated in vitrofor extended periods while maintainingexpression of markers characteristic ofpluripotent primate cells. Human ES cells expressthe transcription factor Oct-4, essential fordevelopment of pluripotential cells in the mouse.When grafted into SCID mice, both lines give riseto teratomas containing derivatives of all threeembryonic germ layers. Both cell linesdifferentiate in vitro into extraembryonic andsomatic cell lineages. Neural progenitor cells maybe isolated from differentiating ES cell culturesand induced to form mature neurons. Embryonicstem cells provide a model to study early humanembryology, an investigational tool for discoveryof novel growth factors and medicines, and apotential source of cells for use in transplantationtherapy.", "metadata": {}}
+{"_id": "3360428", "title": "", "text": "Multipoint Kras oncogene mutations potentiallyindicate mucinous carcinoma on the entirespectrum of mucinous ovarian neoplasmsKrasmutation is a common phenomenon in manyhuman neoplasms. We aimed to assess the Krasmutational status along the histologicalcontinuum from normal ovaries to thedevelopment of benign, borderline and malignantovarian mucinous neoplasms. We analyzed 41cases of malignant, 10 cases of borderline, 7cases of benign mucinous ovarian tumors and 7cases of normal ovarian tissue. The prevalence ofKras mutations in the normal ovary was 0.00%(n=0/7), while the prevalence in benign,borderline and malignant mucinous neoplasmswas 57.14% (n=4/7), 90.00% (n=9/10) and75.61% (n=31/41), respectively. Multiple Krasmutations were detected in 6 cases of mucinouscarcinoma, including 5 double mutations withG13D/V14I (n=1), G12V/G13S (n=1),G12D/G13S (n=3) and one triple mutation withA11V/G13N/V14I (n=1). We identified six cases", "metadata": {}}
+{"_id": "3367829", "title": "", "text": "Identification and distinct regulation of yeastTATA box-containing genes.Despite being one ofthe first eukaryotic transcriptional regulatoryelements identified, the sequence of a nativeTATA box and its significance remain elusive.Applying criteria associated with TATA boxes wequeried several Saccharomyces genomes andarrived at the consensus TATA(A/T)A(A/T)(A/G).Approximately 20% of yeast genes contain aTATA box. Strikingly, TATA box-containing genesare associated with responses to stress, arehighly regulated, and preferentially utilize SAGArather than TFIID when compared to TATA-lesspromoters. Transcriptional regulation in yeastappears to be mechanistically bipolar, possiblyreflecting a need to balance induciblestress-related responses with constitutivehousekeeping functions.", "metadata": {}}
+{"_id": "3376731", "title": "", "text": "IL6 derived from cancer-associated fibroblastspromotes chemoresistance via CXCR7 inesophageal squamous cell carcinomaVariousfactors and cellular components in the tumormicroenvironment are key drivers associatedwith drug resistance in many cancers. Here, weanalyzed the factors and molecular mechanismsinvolved in chemoresistance in patients withesophageal squamous cell carcinoma (ESCC). Wefound that interleukin 6 (IL6) derived mainlyfrom cancer-associated fibroblasts played themost important role in chemoresistance byupregulating C-X-C motif chemokine receptor 7(CXCR7) expression through signal transducerand activator of transcription 3/nuclear factor-κBpathway. CXCR7 knockdown resulted in theinhibition of IL6-induced proliferation andchemoresistance. In addition, CXCR7 silencingsignificantly decreased gene expressionassociated with stemness, chemoresistance andepithelial–mesenchymal transition andsuppressed the proliferation ability of ESCC cells", "metadata": {}}
+{"_id": "3391547", "title": "", "text": "Myelodysplastic syndromes: revisiting the role ofthe bone marrow microenvironment in diseasepathogenesisMyelodysplastic syndromes are aheterogeneous group of diseases characterizedby ineffective hematopoiesis and the propensityto leukemic transformation. Their pathogenesisis complex and likely depends on interplaybetween aberrant hematopoietic cells and theirmicroenvironment. How niche cells play a role indisease evolution is poorly defined, but thedelineation of the hematopoietic stem cell nicheand the ability to interrogate its role inhematopoietic disease in animal models havefurthered our insights in recent years. The datasupport a view in which the microenvironmentcan play an active role in the evolution ofmyelodysplasia and myeloproliferative disorders,thus providing further rationale to exploretherapeutic targeting ofmesenchymal–hematopoietic interactions inthese diseases.", "metadata": {}}
+{"_id": "3400973", "title": "", "text": "SMC complexes differentially compact mitoticchromosomes according to genomiccontextStructural maintenance of chromosomes(SMC) protein complexes are key determinantsof chromosome conformation. Using Hi-C andpolymer modelling, we study how cohesin andcondensin, two deeply conserved SMCcomplexes, organize chromosomes in thebudding yeast Saccharomyces cerevisiae. Thecanonical role of cohesin is to co-align sisterchromatids, while condensin generally compactsmitotic chromosomes. We find strikingly differentroles for the two complexes in budding yeastmitosis. First, cohesin is responsible forcompacting mitotic chromosome arms,independently of sister chromatid cohesion.Polymer simulations demonstrate that this rolecan be fully accounted for through cis-looping ofchromatin. Second, condensin is generallydispensable for compaction along chromosomearms. Instead, it plays a targeted rolecompacting the rDNA proximal regions and", "metadata": {}}
+{"_id": "3413083", "title": "", "text": "Patterns of chlamydia testing in different settingsand implications for wider STI diagnosis andcare: a probability sample survey of the BritishpopulationBACKGROUND Following widespreadrollout of chlamydia testing to non-specialist andcommunity settings in the UK, many individualsreceive a chlamydia test without being offeredcomprehensive STI and HIV testing. We assesssexual behaviour among testers in differentsettings with a view to understanding their needfor other STI diagnostic services. METHODS Aprobability sample survey of the Britishpopulation undertaken 2010-2012 (the thirdNational Survey of Sexual Attitudes andLifestyles). We analysed weighted data onchlamydia testing (past year), including locationof most recent test, and diagnoses (past 5 years)from individuals aged 16-44 years reporting atleast one sexual partner in the past year (4992women, 3406 men). RESULTS Of the 26.8%(95% CI 25.4% to 28.2%) of women and 16.7%(15.5% to 18.1%) of men reporting a chlamydia", "metadata": {}}
+{"_id": "3419709", "title": "", "text": "Treatment of nonalcoholic fatty liver disease:role of AMPK.Nonalcoholic fatty liver disease(NAFLD) is a growing worldwide epidemic and animportant risk factor for the development ofinsulin resistance, type 2 diabetes, nonalcoholicsteatohepatitis (NASH), and hepatic cellularcarcinoma (HCC). Despite the prevalence ofNAFLD, lifestyle interventions involving exerciseand weight loss are the only accepted treatmentsfor this disease. Over the last decade, numerousexperimental compounds have been shown toimprove NAFLD in preclinical animal models, andmany of these therapeutics have been shown toincrease the activity of the cellular energy sensorAMP-activated protein kinase (AMPK). BecauseAMPK activity is reduced by inflammation,obesity, and diabetes, increasing AMPK activityhas been viewed as a viable therapeutic strategyto improve NAFLD. In this review, we proposethree primary mechanisms by which AMPKactivation may improve NAFLD. In addition, weexamine the mechanisms by which AMPK is", "metadata": {}}
+{"_id": "3419802", "title": "", "text": "Microenvironment-dependent growth ofpre-neoplastic and malignant plasma cells inhumanized miceMost human cancers, includingmyeloma, are preceded by a precursor state.There is an unmet need for in vivo models tostudy the interaction of human preneoplasticcells in the bone marrow microenvironment withnon-malignant cells. Here, we geneticallyhumanized mice to permit the growth of primaryhuman preneoplastic and malignant plasma cellstogether with non-malignant cells in vivo.Growth was largely restricted to the bonemarrow, mirroring the pattern in patients withmyeloma. Xenografts captured the genomiccomplexity of parental tumors and revealedadditional somatic changes. Moreover,xenografts from patients with preneoplasticgammopathy showed progressive growth,suggesting that the clinical stability of theselesions may in part be due to growth controlsextrinsic to tumor cells. These data demonstratea new approach to investigate the entire", "metadata": {}}
+{"_id": "3430789", "title": "", "text": "Effect of activated charcoal hemoperfusion onrenal function in patients with paraquatpoisoning.The present study retrospectivelyanalyzed 19 patients diagnosed with paraquat(PQ) poisoning with the aim to investigate theeffect of activated charcoal hemoperfusion onrenal function and PQ elimination. The resultsindicated that 7 patients died and 12 survived.Non-oliguric renal failure occurred in all of the 7patients who died. Among the 12 survivingpatients, 10 had normal renal function and 2developed non-oliguric renal failure. There was alinear correlation between plasma and urineparaquat concentration prior to and duringactivated charcoal hemoperfusion. The equationparameters together with the correlationcoefficient on admission were as follows:Y=0.5820+1.7348X (R2=0.678; F=35.768;P<0.0001). The equation parameters togetherwith the correlation coefficient were as followsduring activated charcoal hemoperfusion:Y=0.6827+1.2649X (R2=0.626; F=50.308;", "metadata": {}}
+{"_id": "3435889", "title": "", "text": "Diabetes-induced effects on cardiomyocytes inchick embryonic heart micromass and mouseembryonic D3 differentiated stem cells.Diabetesmellitus during pregnancy is a considerablemedical challenge, since it is related to\u0000augmented morbidity and mortality concernsfor both the fetus \u0000and the pregnant woman.Records show that the etiology of diabetic\u0000embryopathy is complicated, as manyteratological factors might be involved \u0000in themechanisms of diabetes mellitus-inducedcongenital malformation. \u0000In this study, thepotential cardiotoxic effect of hyperglycemia withhyperketonemia was investigated by using two invitro models; primary chick embryoniccardiomyocytes and stem cell derivedcardiomyocytes, where adverse effects wererecorded in both systems. The cells wereevaluated by changes in beating activity, cellactivity, protein content, ROS production, DNAdamage and differentiating stem cell migration.The diabetic formulae used produced an increase", "metadata": {}}
+{"_id": "3437084", "title": "", "text": "Motion magnificationWe present motionmagnification, a technique that acts like amicroscope for visual motion. It can amplifysubtle motions in a video sequence, allowing forvisualization of deformations that wouldotherwise be invisible. To achieve motionmagnification, we need to accurately measurevisual motions, and group the pixels to bemodified. After an initial image registration step,we measure motion by a robust analysis offeature point trajectories, and segment pixelsbased on similarity of position, color, andmotion. A novel measure of motion similaritygroups even very small motions according tocorrelation over time, which often relates tophysical cause. An outlier mask marksobservations not explained by our layeredmotion model, and those pixels are simplyreproduced on the output from the originalregistered observations. The motion of anyselected layer may be magnified by auser-specified amount; texture synthesis fills-in", "metadata": {}}
+{"_id": "3441524", "title": "", "text": "Human TRPML1 channel structures in open andclosed conformationsTransient receptor potentialmucolipin 1 (TRPML1) is a Ca2+-releasing cationchannel that mediates the calcium signalling andhomeostasis of lysosomes. Mutations in TRPML1lead to mucolipidosis type IV, a severe lysosomalstorage disorder. Here we report two electroncryo-microscopy structures of full-length humanTRPML1: a 3.72-Å apo structure at pH 7.0 in theclosed state, and a 3.49-Å agonist-boundstructure at pH 6.0 in an open state. Severalaromatic and hydrophobic residues in pore helix1, helices S5 and S6, and helix S6 of aneighbouring subunit, form a hydrophobic cavityto house the agonist, suggesting a distinctagonist-binding site from that found in TRPV1, aTRP channel from a different subfamily. Theopening of TRPML1 is associated with distinctdilations of its lower gate together with a slightstructural movement of pore helix 1. Our workreveals the regulatory mechanism of TRPMLchannels, facilitates better understanding of TRP", "metadata": {}}
+{"_id": "3444507", "title": "", "text": "Integrative Genomics Viewer (IGV):high-performance genomics data visualizationand explorationData visualization is an essentialcomponent of genomic data analysis. However,the size and diversity of the data sets producedby today's sequencing and array-based profilingmethods present major challenges tovisualization tools. The Integrative GenomicsViewer (IGV) is a high-performance viewer thatefficiently handles large heterogeneous datasets, while providing a smooth and intuitive userexperience at all levels of genome resolution. Akey characteristic of IGV is its focus on theintegrative nature of genomic studies, withsupport for both array-based andnext-generation sequencing data, and theintegration of clinical and phenotypic data.Although IGV is often used to view genomic datafrom public sources, its primary emphasis is tosupport researchers who wish to visualize andexplore their own data sets or those fromcolleagues. To that end, IGV supports flexible", "metadata": {}}
+{"_id": "3446400", "title": "", "text": "Can genome engineering be used to targetcancer-associated enhancers?Transcriptionalmisregulation is involved in the development ofmany diseases, especially neoplastictransformation. Distal regulatory elements, suchas enhancers, play a major role in specifyingcell-specific transcription patterns in both normaland diseased tissues, suggesting that enhancersmay be prime targets for therapeuticintervention. By focusing on modulating generegulation mediated by cell type-specificenhancers, there is hope that normal epigeneticpatterning in an affected tissue could be restoredwith fewer side effects than observed withtreatments employing relatively nonspecificinhibitors such as epigenetic drugs. Newmethods employing genomic nucleases andsite-specific epigenetic regulators targeted tospecific genomic regions, using either artificialDNA-binding proteins or RNA-DNA interactions,may allow precise genome engineering atenhancers. However, this field is still in its", "metadata": {}}
+{"_id": "3462075", "title": "", "text": "Long\u0000Term Follow\u0000up of CD19 CAR Therapy inAcute Lymphoblastic LeukemiaBackgroundCD19\u0000specific chimeric antigen receptor (CAR) Tcells induce high rates of initial response amongpatients with relapsed B\u0000cell acutelymphoblastic leukemia (ALL) and long\u0000termremissions in a subgroup of patients. MethodsWe conducted a phase 1 trial involving adultswith relapsed B\u0000cell ALL who received aninfusion of autologous T cells expressing the19\u000028z CAR at the Memorial Sloan KetteringCancer Center (MSKCC). Safety and long\u0000termoutcomes were assessed, as were theirassociations with demographic, clinical, anddisease characteristics. Results A total of 53adults received 19\u000028z CAR T cells that weremanufactured at MSKCC. After infusion, severecytokine release syndrome occurred in 14 of 53patients (26%; 95% confidence interval [CI], 15to 40); 1 patient died. Complete remission wasobserved in 83% of the patients. At a medianfollow\u0000up of 29 months (range, 1 to 65), the", "metadata": {}}
+{"_id": "3464191", "title": "", "text": "Periosteum contains skeletal stem cells with highbone regenerative potential controlled byPeriostinBone regeneration relies on theactivation of skeletal stem cells (SSCs) that stillremain poorly characterized. Here, we show thatperiosteum contains SSCs with high boneregenerative potential compared to bone marrowstromal cells/skeletal stem cells (BMSCs) inmice. Although periosteal cells (PCs) and BMSCsare derived from a common embryonicmesenchymal lineage, postnatally PCs exhibitgreater clonogenicity, growth and differentiationcapacity than BMSCs. During bone repair, PCscan efficiently contribute to cartilage and bone,and integrate long-term after transplantation.Molecular profiling uncovers genes encodingPeriostin and other extracellular matrixmolecules associated with the enhancedresponse to injury of PCs. Periostin gene deletionimpairs PC functions and fracture consolidation.Periostin-deficient periosteum cannotreconstitute a pool of PCs after injury", "metadata": {}}
+{"_id": "3468459", "title": "", "text": "Metabolism strikes back: metabolic flux regulatescell signaling.Mammalian cells depend on growthfactor signaling to take up nutrients; however,coordination of glucose and glutamine uptakehas been a mystery. In this issue of Genes &Development, Wellen and colleagues (pp.2784-2799) show that glucose flux through thehexosamine biosynthesis pathway regulatesgrowth factor receptor glycosylation and enablesglutamine consumption. This mechanism ensuresthat cells do not engage in anabolic metabolismwhen nutrients are limiting, and highlights howsubstrate availability for protein modificationscan modulate cell signaling.", "metadata": {}}
+{"_id": "3471191", "title": "", "text": "Association of Pembrolizumab With TumorResponse and Survival Among Patients WithAdvanced Melanoma.IMPORTANCE Theprogrammed death 1 (PD-1) pathway limitsimmune responses to melanoma and can beblocked with the humanized anti-PD-1monoclonal antibody pembrolizumab. OBJECTIVETo characterize the association ofpembrolizumab with tumor response and overallsurvival among patients with advancedmelanoma. DESIGN, SETTINGS, ANDPARTICIPANTS Open-label, multicohort, phase1b clinical trials (enrollment, December2011-September 2013). Median duration offollow-up was 21 months. The study wasperformed in academic medical centers inAustralia, Canada, France, and the UnitedStates. Eligible patients were aged 18 years andolder and had advanced or metastaticmelanoma. Data were pooled from 655 enrolledpatients (135 from a nonrandomized cohort [n =87 ipilimumab naive; n = 48 ipilimumab treated]", "metadata": {}}
+{"_id": "3475317", "title": "", "text": "Inflammatory signaling in human Tuberculosisgranulomas is spatially organizedGranulomas arethe pathological hallmark of tuberculosis (TB).However, their function and mechanisms offormation remain poorly understood. Tounderstand the role of granulomas in TB, weanalyzed the proteomes of granulomas fromsubjects with tuberculosis in an unbiasedmanner. Using laser-capture microdissection,mass spectrometry and confocal microscopy, wegenerated detailed molecular maps of humangranulomas. We found that the centers ofgranulomas have a pro-inflammatoryenvironment that is characterized by thepresence of antimicrobial peptides, reactiveoxygen species and pro-inflammatoryeicosanoids. Conversely, the tissue surroundingthe caseum has a comparativelyanti-inflammatory signature. These findings areconsistent across a set of six human subjectsand in rabbits. Although the balance betweensystemic pro- and anti-inflammatory signals is", "metadata": {}}
+{"_id": "3493623", "title": "", "text": "Suppression of interferon-mediated anti-HBVresponse by single CpG methylation in the5′-UTR of TRIM22Objective Interferons (IFNs)mediate direct antiviral activity. They play acrucial role in the early host immune responseagainst viral infections. However, IFN therapy forHBV infection is less effective than for other viralinfections. Design We explored the cellulartargets of HBV in response to IFNs usingproteome-wide screening. Results UsingLC-MS/MS, we identified proteins downregulatedand upregulated by IFN treatment in HBV Xprotein (HBx)-stable and control cells. We foundseveral IFN-stimulated genes downregulated byHBx, including TRIM22, which is known as anantiretroviral protein. We demonstrated that HBxsuppresses the transcription of TRIM22 througha single CpG methylation in its 5′-UTR, whichfurther reduces the IFN regulatory factor-1binding affinity, thereby suppressing theIFN-stimulated induction of TRIM22. ConclusionsWe verified our findings using a mouse model,", "metadata": {}}
+{"_id": "3495456", "title": "", "text": "Developmental Analysis of Bone MarrowNeutrophils Reveals Populations Specialized inExpansion, Trafficking, and EffectorFunctionsSummary Neutrophils are specializedinnate cells that require constant replenishmentfrom proliferative bone marrow (BM) precursorsas a result of their short half\u0000life. Although it isestablished that neutrophils are derived from thegranulocyte\u0000macrophage progenitor (GMP), thedifferentiation pathways from GMP to functionalmature neutrophils are poorly defined. Usingmass cytometry (CyTOF) and cell\u0000cycle\u0000basedanalysis, we identified three neutrophil subsetswithin the BM: a committed proliferativeneutrophil precursor (preNeu) whichdifferentiates into non\u0000proliferating immatureneutrophils and mature neutrophils.Transcriptomic profiling and functional analysisrevealed that preNeu require the C/EBP&egr;transcription factor for their generation from theGMP, and their proliferative program issubstituted by a gain of migratory and effector", "metadata": {}}
+{"_id": "3504761", "title": "", "text": "TAK1-mediated autophagy and fatty acidoxidation prevent hepatosteatosis andtumorigenesis.The MAP kinase kinase kinaseTGFβ-activated kinase 1 (TAK1) is activated byTLRs, IL-1, TNF, and TGFβ and in turn activatesIKK-NF-κB and JNK, which regulate cell survival,growth, tumorigenesis, and metabolism. TAK1signaling also upregulates AMPK activity andautophagy. Here, we investigatedTAK1-dependent regulation of autophagy, lipidmetabolism, and tumorigenesis in the liver.Fasted mice with hepatocyte-specific deletion ofTak1 exhibited severe hepatosteatosis withincreased mTORC1 activity and suppression ofautophagy compared with their WT counterparts.TAK1-deficient hepatocytes exhibited suppressedAMPK activity and autophagy in response tostarvation or metformin treatment; however,ectopic activation of AMPK restored autophagy inthese cells. Peroxisome proliferator-activatedreceptor α (PPARα) target genes and β-oxidation,which regulate hepatic lipid degradation, were", "metadata": {}}
+{"_id": "3506723", "title": "", "text": "Formins at the Junction.The actin cytoskeletonand adhesion junctions are physically andfunctionally coupled at the cell-cell interfacebetween epithelial cells. The actin regulatorycomplex Arp2/3 has an established role in theturnover of junctional actin; however, the role offormins, the largest group of actin regulators, isless clear. Formins dynamically shape the actincytoskeleton and have various functions withincells. In this review we describe recent progresson how formins regulate actin dynamics atcell-cell contacts and highlight formin functionsduring polarized protein traffic necessary forepithelialization.", "metadata": {}}
+{"_id": "3512154", "title": "", "text": "CRISPR adaptation biases explain preference foracquisition of foreign DNACRISPR-Cas (clustered,regularly interspaced short palindromic repeatscoupled with CRISPR-associated proteins) is abacterial immunity system that protects againstinvading phages or plasmids. In the process ofCRISPR adaptation, short pieces of DNA('spacers') are acquired from foreign elementsand integrated into the CRISPR array. So far, ithas remained a mystery how spacers arepreferentially acquired from the foreign DNAwhile the self chromosome is avoided. Here weshow that spacer acquisition isreplication-dependent, and that DNA breaksformed at stalled replication forks promotespacer acquisition. Chromosomal hotspots ofspacer acquisition were confined by Chi sites,which are sequence octamers highly enriched onthe bacterial chromosome, suggesting that thesesites limit spacer acquisition from self DNA. Wefurther show that the avoidance of self ismediated by the RecBCD double-stranded DNA", "metadata": {}}
+{"_id": "3514072", "title": "", "text": "High-resolution mapping of open chromatin inthe rice genome.Gene expression is controlled bythe complex interaction of transcription factorsbinding to promoters and other regulatory DNAelements. One common characteristic of thegenomic regions associated with regulatoryproteins is a pronounced sensitivity to DNase Idigestion. We generated genome-widehigh-resolution maps of DNase I hypersensitive(DH) sites from both seedling and callus tissuesof rice (Oryza sativa). Approximately 25% of theDH sites from both tissues were found in putativepromoters, indicating that the vast majority ofthe gene regulatory elements in rice are notlocated in promoter regions. We found 58%more DH sites in the callus than in the seedling.For DH sites detected in both the seedling andcallus, 31% displayed significantly differentlevels of DNase I sensitivity within the twotissues. Genes that are differentially expressed inthe seedling and callus were frequentlyassociated with DH sites in both tissues. The", "metadata": {}}
+{"_id": "3514540", "title": "", "text": "Prospective study of body fat distribution and therisk of endometrial cancer.BACKGROUNDEpidemiologic studies have found that overallobesity is positively related to endometrialcancer (EC) risk. However, data assessing theassociation between body fat distribution andrisk of EC are still limited. METHODS We followed51,948 women who first reported waistcircumference (WC) and hip circumference in1986 in the Nurses' Health Study. Waist-to-hipratio (WHR) was calculated. RESULTS During 24years of follow-up, 449 incident invasive ECcases were diagnosed. In a multivariate analysiswithout adjusting for body mass index (BMI), therelative risks (RRs) for EC comparing extremecategories were 2.44 (95% confidence interval[CI] 1.72-3.45) for WC and 1.69 (95%CI=1.20-2.40) for WHR. However, afteradjustment of BMI, those positive associationswere substantially attenuated and no longersignificant; RR=1.08 (95% CI=0.69-1.67) forWC and 1.15 (95% CI=0.81-1.64) for WHR,", "metadata": {}}
+{"_id": "3524352", "title": "", "text": "Breast cancer clusters in the northeast UnitedStates: a geographic analysis.High breast cancermortality rates have been reported in thenortheastern part of the United States, withrecent attention focused on Long Island, NewYork. In this study, the authors investigatewhether the high breast cancer mortality isevenly spread over the Northeast, in the sensethat any observed clusters of deaths can beexplained by chance alone, or whether there areclusters of statistical significance. Demographicdata and age-specific breast cancer mortalityrates for women were obtained for all 244counties in 11 northeastern states and for theDistrict of Columbia for 1988-1992. A recentlydeveloped spatial scan statistic is used, whichsearches for clusters of cases without specifyingtheir size or location ahead of time, and whichtests for their statistical significance whileadjusting for the multiple testing inherent in sucha procedure. The basic analysis is adjusted forage, with further analyses examining how the", "metadata": {}}
+{"_id": "3531388", "title": "", "text": "CD200R/CD200 Inhibits Osteoclastogenesis: NewMechanism of Osteoclast Control byMesenchymal Stem Cells in HumanBonehomeostasis is maintained by the balancebetween bone-forming osteoblasts andbone-degrading osteoclasts. Osteoblasts have amesenchymal origin whereas osteoclasts belongto the myeloid lineage. Osteoclast and osteoblastcommunication occurs through soluble factorssecretion, cell-bone interaction and cell-cellcontact, which modulate their activities. CD200is an immunoglobulin superfamilly memberexpressed on various types of cells includingmesenchymal stem cells (MSCs). CD200 receptor(CD200R) is expressed on myeloid cells such asmonocytes/macrophages. We assume thatCD200 could be a new molecule involved in thecontrol of osteoclastogenesis and could play arole in MSC-osteoclast communication inhumans. In this study, we demonstrated thatsoluble CD200 inhibited the differentiation ofosteoclast precursors as well as their maturation", "metadata": {}}
+{"_id": "3545805", "title": "", "text": "Tumor-specific Th17-polarized cells eradicatelarge established melanoma.CD4+ T cells candifferentiate into multiple effector subsets, butthe potential roles of these subsets in anti-tumorimmunity have not been fully explored. Seekingto study the impact of CD4+ T cell polarizationon tumor rejection in a model mimicking humandisease, we generated a new MHC classII-restricted, T-cell receptor (TCR) transgenicmouse model in which CD4+ T cells recognize anovel epitope in tyrosinase-related protein 1(TRP-1), an antigen expressed by normalmelanocytes and B16 murine melanoma. Cellscould be robustly polarized into Th0, Th1, andTh17 subtypes in vitro, as evidenced by cytokine,chemokine, and adhesion molecule profiles andby surface markers, suggesting the potential fordifferential effector function in vivo. Contrary tothe current view that Th1 cells are mostimportant in tumor rejection, we found thatTh17-polarized cells better mediated destructionof advanced B16 melanoma. Their therapeutic", "metadata": {}}
+{"_id": "3552753", "title": "", "text": "Defining community acquired pneumoniaseverity on presentation to hospital: aninternational derivation and validationstudy.BACKGROUND In the assessment ofseverity in community acquired pneumonia(CAP), the modified British Thoracic Society(mBTS) rule identifies patients with severepneumonia but not patients who might besuitable for home management. A multicentrestudy was conducted to derive and validate apractical severity assessment model forstratifying adults hospitalised with CAP intodifferent management groups. METHODS Datafrom three prospective studies of CAP conductedin the UK, New Zealand, and the Netherlandswere combined. A derivation cohort comprising80% of the data was used to develop the model.Prognostic variables were identified usingmultiple logistic regression with 30 day mortalityas the outcome measure. The final model wastested against the validation cohort. RESULTS1068 patients were studied (mean age 64 years,", "metadata": {}}
+{"_id": "3553087", "title": "", "text": "Mitochondrial iron chelation amelioratescigarette-smoke induced bronchitis andemphysema in miceChronic obstructivepulmonary disease (COPD) is linked to bothcigarette smoking and genetic determinants. Wehave previously identified iron-responsiveelement-binding protein 2 (IRP2) as animportant COPD susceptibility gene and haveshown that IRP2 protein is increased in the lungsof individuals with COPD. Here we demonstratethat mice deficient in Irp2 were protected fromcigarette smoke (CS)-induced experimentalCOPD. By integrating RNA immunoprecipitationfollowed by sequencing (RIP-seq), RNAsequencing (RNA-seq), and gene expression andfunctional enrichment clustering analysis, weidentified Irp2 as a regulator of mitochondrialfunction in the lungs of mice. Irp2 increasedmitochondrial iron loading and levels ofcytochrome c oxidase (COX), which led tomitochondrial dysfunction and subsequentexperimental COPD. Frataxin-deficient mice,", "metadata": {}}
+{"_id": "3559136", "title": "", "text": "Cancer-Associated Fibroblasts Neutralize theAnti-tumor Effect of CSF1 Receptor Blockade byInducing PMN-MDSC Infiltration ofTumors.Tumor-associated macrophages (TAM)contribute to all aspects of tumor progression.Use of CSF1R inhibitors to target TAM istherapeutically appealing, but has had verylimited anti-tumor effects. Here, we haveidentified the mechanism that limited the effectof CSF1R targeted therapy. We demonstratedthat carcinoma-associated fibroblasts (CAF) aremajor sources of chemokines that recruitgranulocytes to tumors. CSF1 produced by tumorcells caused HDAC2-mediated downregulation ofgranulocyte-specific chemokine expression inCAF, which limited migration of these cells totumors. Treatment with CSF1R inhibitorsdisrupted this crosstalk and triggered a profoundincrease in granulocyte recruitment to tumors.Combining CSF1R inhibitor with a CXCR2antagonist blocked granulocyte infiltration oftumors and showed strong anti-tumor effects.", "metadata": {}}
+{"_id": "3566945", "title": "", "text": "Phenotypic deficits in the HIV-1 envelope areassociated with the maturation of a V2-directedbroadly neutralizing antibody lineageBroadlyneutralizing antibodies (bnAbs) to HIV-1 canevolve after years of an iterative process of virusescape and antibody adaptation that HIV-1vaccine design seeks to mimic. To enable this,properties that render HIV-1 envelopes (Env)capable of eliciting bnAb responses need to bedefined. Here, we followed the evolution of theV2 apex directed bnAb lineage VRC26 in theHIV-1 subtype C superinfected donor CAP256 toinvestigate the phenotypic changes of the viruspopulations circulating before and during theearly phases of bnAb induction. Longitudinalviruses that evolved from the VRC26-resistantprimary infecting (PI) virus, the VRC26-sensitivesuperinfecting (SU) virus and ensuing PI-SUrecombinants revealed substantial phenotypicchanges in Env, with a switch in Env propertiescoinciding with early resistance to VRC26.Decreased sensitivity of SU-like viruses to VRC26", "metadata": {}}
+{"_id": "3572885", "title": "", "text": "High somatic mutation and neoantigen burdenare correlated with decreased progression-freesurvival in multiple myelomaTumor-specificmutations can result in immunogenicneoantigens, both of which have been correlatedwith responsiveness to immune checkpointinhibitors in highly mutagenic cancers. However,early results of single-agent checkpoint inhibitorsin multiple myeloma (MM) have beenunderwhelming. Therefore, we sought tounderstand the relationship between mutationand neoantigen landscape of MM patients andresponsiveness to therapies. Somatic mutationburden, neoantigen load, and response totherapy were determined using interim data fromthe MMRF CoMMpass study (NCT01454297) on664 MM patients. In this population, the meansomatic and missense mutation loads were405.84(s=608.55) and 63.90(s=95.88)mutations per patient, respectively. There was apositive linear relationship between mutation andneoantigen burdens (R2=0.862). The average", "metadata": {}}
+{"_id": "3578380", "title": "", "text": "Postmarket Safety Events Among NovelTherapeutics Approved by the US Food and DrugAdministration Between 2001 and2010Importance Postmarket safety events ofnovel pharmaceuticals and biologics occur whennew safety risks are identified after initialregulatory approval of these therapeutics. Thesesafety events can change how novel therapeuticsare used in clinical practice and inform patientand clinician decision making. Objectives Tocharacterize the frequency of postmarket safetyevents among novel therapeutics approved bythe US Food and Drug Administration (FDA), andto examine whether any novel therapeuticcharacteristics known at the time of FDAapproval were associated with increased risk.Design and Setting Cohort study of all noveltherapeutics approved by the FDA betweenJanuary 1, 2001, and December 31, 2010,followed up through February 28, 2017.Exposures Novel therapeutic characteristicsknown at the time of FDA approval, including", "metadata": {}}
+{"_id": "3580005", "title": "", "text": "Who is where at risk for Chronic ObstructivePulmonary Disease? A spatial epidemiologicalanalysis of health insurance claims for COPD inNortheastern GermanyBACKGROUND Chronicobstructive pulmonary disease (COPD) has ahigh prevalence rate in Germany and a furtherincrease is expected within the next years.Although risk factors on an individual level arewidely understood, only little is known about thespatial heterogeneity and population-based riskfactors of COPD. Background knowledge aboutbroader, population-based processes could helpto plan the future provision of healthcare andprevention strategies more aligned to theexpected demand. The aim of this study is toanalyze how the prevalence of COPD variesacross northeastern Germany on the smallestspatial-scale possible and to identify thelocation-specific population-based risk factorsusing health insurance claims of the AOKNordost. METHODS To visualize the spatialdistribution of COPD prevalence at the level of", "metadata": {}}
+{"_id": "3583084", "title": "", "text": "Large intergenic non-coding RNA-RoR modulatesreprogramming of human induced pluripotentstem cellsThe conversion of lineage-committedcells to induced pluripotent stem cells (iPSCs) byreprogramming is accompanied by a globalremodeling of the epigenome, resulting in alteredpatterns of gene expression. Here wecharacterize the transcriptional reorganization oflarge intergenic non-coding RNAs (lincRNAs) thatoccurs upon derivation of human iPSCs andidentify numerous lincRNAs whose expression islinked to pluripotency. Among these, we definedten lincRNAs whose expression was elevated iniPSCs compared with embryonic stem cells,suggesting that their activation may promote theemergence of iPSCs. Supporting this, our resultsindicate that these lincRNAs are direct targets ofkey pluripotency transcription factors. Usingloss-of-function and gain-of-function approaches,we found that one such lincRNA (lincRNA-RoR)modulates reprogramming, thus providing a firstdemonstration for critical functions of lincRNAs in", "metadata": {}}
+{"_id": "3588621", "title": "", "text": "Extracellular vesicle isolation andcharacterization: toward clinical application.Twobroad categories of extracellular vesicles (EVs),exosomes and shed microvesicles (sMVs), whichdiffer in size distribution as well as protein andRNA profiles, have been described. EVs areknown to play key roles in cell-cellcommunication, acting proximally as well assystemically. This Review discusses the nature ofEV subtypes, strategies for isolating EVs fromboth cell-culture media and body fluids, andprocedures for quantifying EVs. We also discussproteins selectively enriched in exosomes andsMVs that have the potential for use as markersto discriminate between EV subtypes, as well asvarious applications of EVs in clinical diagnosis.", "metadata": {}}
+{"_id": "3590806", "title": "", "text": "Up-regulated NRIP2 in colorectal cancer initiatingcells modulates the Wnt pathway by targetingRORβBACKGROUND Colorectal cancer remainsone of the most common malignant tumorsworldwide. Colorectal cancer initiating cells(CCICs) are a small subpopulation responsiblefor malignant behaviors of colorectal cancer.Aberrant activation of the Wnt pathwaysregulates the self-renewal of CCIC. However, theunderlying mechanism(s) remain poorlyunderstood. METHODS Via retroviral libraryscreening, we identified NuclearReceptor-Interacting Protein 2 (NRIP2) as anovel interactor of the Wnt pathway fromenriched colorectal cancer colosphere cells. Theexpression levels of NRIP2 and retinoicacid-related orphan receptor β (RORβ) werefurther examined by FISH, qRT-PCR, IHC andWestern blot. NRIP2 overexpressed andknockdown colorectal cancer cells were producedto study the role of NRIP2 in Wnt pathway. Wealso verified the binding between NRIP2 and", "metadata": {}}
+{"_id": "3591070", "title": "", "text": "Speed Limits for Nonvesicular Intracellular SterolTransport.Sterol transport between theendoplasmic reticulum (ER) and plasmamembrane (PM) occurs by nonvesicularmechanisms requiring sterol transport proteins(STPs). Here we examine the idea that transportis enhanced at membrane contact sites wherethe ER is closely apposed to the PM. We concludethat sterol desorption from the membrane,rather than STP-mediated diffusion, is ratelimiting in the cellular context, so there is noapparent kinetic benefit to having STP-mediatedsterol transfer occur at contact sites. Contactsites may instead compartmentalize lipidsynthesis or transport machinery, providingopportunities for regulation.", "metadata": {}}
+{"_id": "3610080", "title": "", "text": "Misunderstandings in prescribing decisions ingeneral practice: qualitative study.OBJECTIVESTo identify and describe misunderstandingsbetween patients and doctors associated withprescribing decisions in general practice. DESIGNQualitative study. SETTING 20 general practicesin the West Midlands and south east England.PARTICIPANTS 20 general practitioners and 35consulting patients. MAIN OUTCOME MEASURESMisunderstandings between patients and doctorsthat have potential or actual adverseconsequences for taking medicine. RESULTS 14categories of misunderstanding were identifiedrelating to patient information unknown to thedoctor, doctor information unknown to thepatient, conflicting information, disagreementabout attribution of side effects, failure ofcommunication about doctor's decision, andrelationship factors. All the misunderstandingswere associated with lack of patients'participation in the consultation in terms of thevoicing of expectations and preferences or the", "metadata": {}}
+{"_id": "3610282", "title": "", "text": "Phase-plate cryo-EM structure of a biasedagonist-bound human GLP-1 receptor–GscomplexThe class B glucagon-like peptide-1(GLP-1) G protein-coupled receptor is a majortarget for the treatment of type 2 diabetes andobesity. Endogenous and mimetic GLP-1 peptidesexhibit biased agonism—a difference infunctional selectivity—that may provideimproved therapeutic outcomes. Here wedescribe the structure of the human GLP-1receptor in complex with the G protein-biasedpeptide exendin-P5 and a Gαs heterotrimer,determined at a global resolution of 3.3 Å. At theextracellular surface, the organization ofextracellular loop 3 and proximal transmembranesegments differs between our exendin-P5-boundstructure and previous GLP-1-bound GLP-1receptor structure. At the intracellular face, therewas a six-degree difference in the angle of theGαs–α5 helix engagement between structures,which was propagated across the G proteinheterotrimer. In addition, the structures differed", "metadata": {}}
+{"_id": "3613041", "title": "", "text": "Therapeutic equivalence of alendronate 70 mgonce-weekly and alendronate 10 mg daily in thetreatment of osteoporosis. AlendronateOnce-Weekly Study Group.Dosing convenience isa key element in the effective management ofany chronic disease, and is particularly importantin the long-term management of osteoporosis.Less frequent dosing with any medication mayenhance compliance, thereby maximizing theeffectiveness of therapy. Animal data support therationale that once-weekly dosing withalendronate 70 mg (7 times the daily oraltreatment dose) could provide similar efficacy todaily dosing with alendronate 10 mg due to itslong duration of effect in bone. In addition, dogstudies suggest that the potential for esophagealirritation, observed with daily oralbisphosphonates, may be substantially reducedwith once-weekly dosing. This dosing regimenwould provide patients with increasedconvenience and would be likely to enhancepatient compliance. We compared the efficacy", "metadata": {}}
+{"_id": "3616843", "title": "", "text": "Association of Toll-Like Receptor 4 on HumanMonocyte Subsets and VulnerabilityCharacteristics of Coronary Plaque as Assessedby 64-Slice Multidetector ComputedTomography.BACKGROUND Although Toll-likereceptor 4 (TLR-4) is involved in monocyteactivation in patients with accelerated forms ofatherosclerosis, the relationship between theexpression of TLR-4 on circulating monocytesand coronary plaque vulnerability has notpreviously been evaluated. We investigated thisrelationship using 64-slice multidetectorcomputed tomography (MDCT) in patients withstable angina pectoris (SAP).Methods andResults:We enrolled 65 patients with SAP whounderwent MDCT. Three monocyte subsets(CD14++CD16-, CD14++CD16+, andCD14+CD16+) and expression of TLR-4 weremeasured by flow cytometry. Intracoronaryplaques were assessed by 64-slice MDCT. Wedefined vulnerability of intracoronary plaquesaccording to the presence of positive remodeling", "metadata": {}}
+{"_id": "3619372", "title": "", "text": "Expandable Cardiovascular Progenitor CellsReprogrammed from Fibroblasts.Stem cell-basedapproaches to cardiac regeneration areincreasingly viable strategies for treating heartfailure. Generating abundant and functionalautologous cells for transplantation in such asetting, however, remains a significantchallenge. Here, we isolated a cell populationwith extensive proliferation capacity andrestricted cardiovascular differentiationpotentials during cardiac transdifferentiation ofmouse fibroblasts. These induced expandablecardiovascular progenitor cells (ieCPCs)proliferated extensively for more than 18passages in chemically defined conditions, with10(5) starting fibroblasts robustly producing10(16) ieCPCs. ieCPCs expressed cardiacsignature genes and readily differentiated intofunctional cardiomyocytes (CMs), endothelialcells (ECs), and smooth muscle cells (SMCs) invitro, even after long-term expansion. Whentransplanted into mouse hearts following", "metadata": {}}
+{"_id": "3619931", "title": "", "text": "Thyroid hormone inhibits lung fibrosis in mice byimproving epithelial mitochondrialfunctionThyroid hormone (TH) is critical for themaintenance of cellular homeostasis duringstress responses, but its role in lung fibrosis isunknown. Here we found that the activity andexpression of iodothyronine deiodinase 2 (DIO2),an enzyme that activates TH, were higher inlungs from patients with idiopathic pulmonaryfibrosis than in control individuals and werecorrelated with disease severity. We also foundthat Dio2-knockout mice exhibited enhancedbleomycin-induced lung fibrosis. Aerosolized THdelivery increased survival and resolved fibrosisin two models of pulmonary fibrosis in mice(intratracheal bleomycin and inducible TGF-β1).Sobetirome, a TH mimetic, also bluntedbleomycin-induced lung fibrosis. Afterbleomycin-induced injury, TH promotedmitochondrial biogenesis, improvedmitochondrial bioenergetics and attenuatedmitochondria-regulated apoptosis in alveolar", "metadata": {}}
+{"_id": "3621011", "title": "", "text": "Tenomodulin promotes human adipocytedifferentiation and beneficial visceral adiposetissue expansion.Proper regulation of energystorage in adipose tissue is crucial formaintaining insulin sensitivity and moleculescontributing to this process have not been fullyrevealed. Here we show that type IItransmembrane protein tenomodulin (TNMD) isupregulated in adipose tissue of insulin-resistantversus insulin-sensitive individuals, who werematched for body mass index (BMI). TNMDexpression increases in human preadipocytesduring differentiation, whereas silencing TNMDblocks adipogenesis. Upon high-fat diet feeding,transgenic mice overexpressing Tnmd developincreased epididymal white adipose tissue(eWAT) mass, and preadipocytes derived fromTnmd transgenic mice display greaterproliferation, consistent with elevatedadipogenesis. In Tnmd transgenic mice, lipogenicgenes are upregulated in eWAT, as is Ucp1 inbrown fat, while liver triglyceride accumulation is", "metadata": {}}
+{"_id": "3623127", "title": "", "text": "Evidence for a limit to human lifespanDriven bytechnological progress, human life expectancyhas increased greatly since the nineteenthcentury. Demographic evidence has revealed anongoing reduction in old-age mortality and a riseof the maximum age at death, which maygradually extend human longevity. Together withobservations that lifespan in various animalspecies is flexible and can be increased bygenetic or pharmaceutical intervention, theseresults have led to suggestions that longevitymay not be subject to strict, species-specificgenetic constraints. Here, by analysing globaldemographic data, we show that improvementsin survival with age tend to decline after age100, and that the age at death of the world’soldest person has not increased since the 1990s.Our results strongly suggest that the maximumlifespan of humans is fixed and subject to naturalconstraints.", "metadata": {}}
+{"_id": "3654468", "title": "", "text": "Effect of Oral Semaglutide Compared WithPlacebo and Subcutaneous Semaglutide onGlycemic Control in Patients With Type 2Diabetes: A Randomized Clinical TrialImportanceGlucagon-like peptide-1 (GLP-1) receptoragonists are effective therapies for the treatmentof type 2 diabetes and are all currently availableas an injection. Objectives To compare theeffects of oral semaglutide with placebo(primary) and open-label subcutaneoussemaglutide (secondary) on glycemic control inpatients with type 2 diabetes. Design, Setting,and Patients Phase 2, randomized,parallel-group, dosage-finding, 26-week trialwith 5-week follow-up at 100 sites (hospitalclinics, general practices, and clinical researchcenters) in 14 countries conducted betweenDecember 2013 and December 2014. Of 1106participants assessed, 632 with type 2 diabetesand insufficient glycemic control using diet andexercise alone or a stable dose of metforminwere randomized. Randomization was stratified", "metadata": {}}
+{"_id": "3662132", "title": "", "text": "Fast and accurate short read alignment withBurrows–Wheeler transformMOTIVATION Theenormous amount of short reads generated bythe new DNA sequencing technologies call for thedevelopment of fast and accurate read alignmentprograms. A first generation of hash table-basedmethods has been developed, including MAQ,which is accurate, feature rich and fast enoughto align short reads from a single individual.However, MAQ does not support gappedalignment for single-end reads, which makes itunsuitable for alignment of longer reads whereindels may occur frequently. The speed of MAQ isalso a concern when the alignment is scaled upto the resequencing of hundreds of individuals.RESULTS We implemented Burrows-WheelerAlignment tool (BWA), a new read alignmentpackage that is based on backward search withBurrows-Wheeler Transform (BWT), to efficientlyalign short sequencing reads against a largereference sequence such as the human genome,allowing mismatches and gaps. BWA supports", "metadata": {}}
+{"_id": "3662510", "title": "", "text": "The financial cost of doctors emigrating fromsub-Saharan Africa: human capitalanalysisOBJECTIVE To estimate the lostinvestment of domestically educated doctorsmigrating from sub-Saharan African countries toAustralia, Canada, the United Kingdom, and theUnited States. DESIGN Human capital costanalysis using publicly accessible data.SETTINGS Sub-Saharan African countries.PARTICIPANTS Nine sub-Saharan Africancountries with an HIV prevalence of 5% orgreater or with more than one million peoplewith HIV/AIDS and with at least one medicalschool (Ethiopia, Kenya, Malawi, Nigeria, SouthAfrica, Tanzania, Uganda, Zambia, andZimbabwe), and data available on the number ofdoctors practising in destination countries. MAINOUTCOME MEASURES The financial cost ofeducating a doctor (through primary, secondary,and medical school), assuming that migrationoccurred after graduation, using current countryspecific interest rates for savings converted to", "metadata": {}}
+{"_id": "3669694", "title": "", "text": "Chromatin modifying enzymes as modulators ofreprogrammingGeneration of induced pluripotentstem cells (iPSCs) by somatic cellreprogramming involves global epigeneticremodelling. Whereas several proteins are knownto regulate chromatin marks associated with thedistinct epigenetic states of cells before and afterreprogramming, the role of specificchromatin-modifying enzymes in reprogrammingremains to be determined. To address howchromatin-modifying proteins influencereprogramming, we used short hairpin RNAs(shRNAs) to target genes in DNA and histonemethylation pathways, and identified positiveand negative modulators of iPSC generation.Whereas inhibition of the core components of thepolycomb repressive complex 1 and 2, includingthe histone 3 lysine 27 methyltransferase EZH2,reduced reprogramming efficiency, suppressionof SUV39H1, YY1 and DOT1L enhancedreprogramming. Specifically, inhibition of theH3K79 histone methyltransferase DOT1L by", "metadata": {}}
+{"_id": "3672261", "title": "", "text": "Natural variation in the parameters of innateimmune cells is preferentially driven by geneticfactorsThe quantification and characterization ofcirculating immune cells provide key indicators ofhuman health and disease. To identify therelative effects of environmental and geneticfactors on variation in the parameters of innateand adaptive immune cells in homeostaticconditions, we combined standardized flowcytometry of blood leukocytes and genome-wideDNA genotyping of 1,000 healthy, unrelatedpeople of Western European ancestry. We foundthat smoking, together with age, sex and latentinfection with cytomegalovirus, were the mainnon-genetic factors that affected variation inparameters of human immune cells.Genome-wide association studies of 166immunophenotypes identified 15 loci thatshowed enrichment for disease-associatedvariants. Finally, we demonstrated that theparameters of innate cells were more stronglycontrolled by genetic variation than were those", "metadata": {}}
+{"_id": "3680979", "title": "", "text": "The transcriptional program, functionalheterogeneity, and clinical targeting of mastcellsMast cells are unique tissue-residentimmune cells that express an array of receptorsthat can be activated by several extracellularcues, including antigen-immunoglobulin E (IgE)complexes, bacteria, viruses, cytokines,hormones, peptides, and drugs. Mast cellsconstitute a small population in tissues, but theirextraordinary ability to respond rapidly byreleasing granule-stored and newly mademediators underpins their importance in healthand disease. In this review, we document thebiology of mast cells and introduce new conceptsand opinions regarding their role in humandiseases beyond IgE-mediated allergic responsesand antiparasitic functions. We bring to lightrecent discoveries and developments in mast cellresearch, including regulation of mast cellfunctions, differentiation, survival, and novelmouse models. Finally, we highlight the currentand future opportunities for therapeutic", "metadata": {}}
+{"_id": "3684342", "title": "", "text": "LIN28B enhanced tumorigenesis in anautochthonous KRASG12V-driven lung carcinomamouse modelLIN28B is a RNA-binding proteinregulating predominantly let-7 microRNAs withessential functions in inflammation, woundhealing, embryonic stem cells, and cancer.LIN28B expression is associated with tumorinitiation, progression, resistance, and pooroutcome in several solid cancers, including lungcancer. However, the functional role of LIN28B,especially in non-small cell lungadenocarcinomas, remains elusive. Here, weinvestigated the effects of LIN28B expression onlung tumorigenesis using LIN28B transgenicoverexpression in an autochthonousKRASG12V-driven mouse model. We found thatLIN28B overexpression significantly increasedthe number of CD44+/CD326+ tumor cells,upregulated VEGF-A and miR-21 and promotedtumor angiogenesis andepithelial-to-mesenchymal transition (EMT)accompanied by enhanced AKT phosphorylation", "metadata": {}}
+{"_id": "3690068", "title": "", "text": "Cost-effectiveness comparison between topicalsilver sulfadiazine and enclosed silver dressingfor partial-thickness burn treatment.Thestandard treatment of partial-thickness burnsincludes topical silver products such as silversulfadiazine (SSD) cream and enclosed dressingsincluding silver-impregnated foam (Mepilex Ag;Molnlycke Health Care, Gothenburg, Sweden)and silver-laden sheets (Aquacel Ag; ConvaTec,Skillman, NJ). The current state of health care islimited by resources, with an emphasis onevidence-based outcomes and cost-effectivetreatments. This study includes a decisionanalysis with an incremental cost-utility ratiocomparing enclosed silver dressings with SSD inpartial-thickness burn patients with TBSA lessthan 20%. A comprehensive literature reviewwas conducted to identify clinically relevanthealth states in partial-thickness burn patients.These health states include successful healing,infection, and noninfected delayed healingrequiring either surgery or conservative", "metadata": {}}
+{"_id": "3692112", "title": "", "text": "Randomized clinical study of Hydrofiber dressingwith silver or silver sulfadiazine in themanagement of partial-thickness burns.Thisprospective, randomized study comparedprotocols of care using either AQUACEL AgHydrofiber (ConvaTec, a Bristol-Myers Squibbcompany, Skillman, NJ) dressing with silver (n =42) or silver sulfadiazine (n = 42) for up to 21days in the management of partial-thicknessburns covering 5% to 40% body surface area(BSA). AQUACEL Ag dressing was associatedwith less pain and anxiety during dressingchanges, less burning and stinging during wear,fewer dressing changes, less nursing time, andfewer procedural medications. Silver sulfadiazinewas associated with greater flexibility and easeof movement. Adverse events, includinginfection, were comparable between treatmentgroups. The AQUACEL Ag dressing protocoltended to have lower total treatment costs(Dollars 1040 vs. Dollars 1180) and a greaterrate of re-epithelialization (73.8% vs 60.0%),", "metadata": {}}
+{"_id": "3698758", "title": "", "text": "Hepatitis C virus and blood transfusion: past andpresent risks.The risk of HCV transmission byblood and blood products has been greatlyreduced since the early 1980's. Selection ofnon-remunerated donors, donor selection toprevent HIV transmission, initial surrogatetesting in some regions, and introduction ofanti-HCV testing have all contributed to this. ALTsurrogate testing has become obsolete since theintroduction of anti-HCV testing. The residual riskof HCV transmission due to donations in theanti-HCV window period at present is about 1 in100 000 transfusions of cellular products, andtransmission of HCV by plasma products treatedwith modern inactivation methods such assolvent-detergent treatment, has not beenreported. Hemovigilance programmes, which arepresently being installed, will provide more dataon the safety of blood transfusion. Introductionof HCV nucleic amplification technology (NAT) asa quality control of manufacturing pools forplasma products or as a form of blood donor", "metadata": {}}
+{"_id": "3701541", "title": "", "text": "p62/SQSTM1 by Binding to Vitamin D ReceptorInhibits Hepatic Stellate Cell Activity, Fibrosis,and Liver Cancer.Hepatic stellate cells (HSCs)play critical roles in liver fibrosis andhepatocellular carcinoma (HCC). Vitamin Dreceptor (VDR) activation in HSCs inhibits liverinflammation and fibrosis. We found thatp62/SQSTM1, a protein upregulated in liverparenchymal cells but downregulated inHCC-associated HSCs, negatively controls HSCactivation. Total body or HSC-specific p62ablation potentiates HSCs and enhancesinflammation, fibrosis, and HCC progression. p62directly interacts with VDR and RXR promotingtheir heterodimerization, which is critical forVDR:RXR target gene recruitment. Loss of p62 inHSCs impairs the repression of fibrosis andinflammation by VDR agonists. Thisdemonstrates that p62 is a negative regulator ofliver inflammation and fibrosis through its abilityto promote VDR signaling in HSCs, whoseactivation supports HCC.", "metadata": {}}
+{"_id": "3707035", "title": "", "text": "Developing criteria for evaluation ofgeroprotectors as a key stage toward translationto the clinicIn the coming decades, a massiveshift in the aging segment of the population willhave major social and economic consequencesaround the world. One way to offset this increaseis to expedite the development ofgeroprotectors, substances that slow aging,repair age-associated damage and extendhealthy lifespan, or healthspan. While over 200geroprotectors are now reported in modelorganisms and some are in human use forspecific disease indications, the path towarddetermining whether they affect aging in humansremains obscure. Translation to the clinic ishampered by multiple issues including absenceof a common set of criteria to define, select, andclassify these substances, given the complexityof the aging process and their enormousdiversity in mechanism of action. Translationalresearch efforts would benefit from the formationof a scientific consensus on the following: the", "metadata": {}}
+{"_id": "3710557", "title": "", "text": "β-Catenin Signaling and Roles in LiverHomeostasis, Injury, andTumorigenesis.β-catenin (encoded by CTNNB1)is a subunit of the cell surface cadherin proteincomplex that acts as an intracellular signaltransducer in the WNT signaling pathway;alterations in its activity have been associatedwith the development of hepatocellularcarcinoma and other liver diseases. Other thanWNT, additional signaling pathways also canconverge at β-catenin. β-catenin also interactswith transcription factors such as T-cell factor,forkhead box protein O, and hypoxia induciblefactor 1α to regulate the expression of targetgenes. We discuss the role of β-catenin inmetabolic zonation of the adult liver. β-cateninalso regulates the expression of genes thatcontrol metabolism of glucose, nutrients, andxenobiotics; alterations in its activity maycontribute to the pathogenesis of nonalcoholicsteatohepatitis. Alterations in β-catenin signalingmay lead to activation of hepatic stellate cells,", "metadata": {}}
+{"_id": "3716075", "title": "", "text": "The global burden of dengue: an analysis fromthe Global Burden of Disease Study2013.BACKGROUND Dengue is the mostcommon arbovirus infection globally, but itsburden is poorly quantified. We estimateddengue mortality, incidence, and burden for theGlobal Burden of Disease Study 2013. METHODSWe modelled mortality from vital registration,verbal autopsy, and surveillance data using theCause of Death Ensemble Modelling tool. Wemodelled incidence from officially reported cases,and adjusted our raw estimates forunder-reporting based on published estimates ofexpansion factors. In total, we had 1780country-years of mortality data from 130countries, 1636 country-years of dengue casereports from 76 countries, and expansion factorestimates for 14 countries. FINDINGS Weestimated an average of 9221 dengue deaths peryear between 1990 and 2013, increasing from alow of 8277 (95% uncertainty estimate 5353-10649) in 1992, to a peak of 11 302 (6790-13 722)", "metadata": {}}
+{"_id": "3720107", "title": "", "text": "Formin-mediated actin polymerization at cell–celljunctions stabilizes E-cadherin and maintainsmonolayer integrity during woundrepairCadherin-mediated cell-cell adhesion isrequired for epithelial tissue integrity inhomeostasis, during development, and in tissuerepair. E-cadherin stability depends on F-actin,but the mechanisms regulating actinpolymerization at cell-cell junctions remainpoorly understood. Here we investigated a rolefor formin-mediated actin polymerization atcell-cell junctions. We identify mDia1 and Fmnl3as major factors enhancing actin polymerizationand stabilizing E-cadherin at epithelial junctions.Fmnl3 localizes to adherens junctionsdownstream of Src and Cdc42 and its depletionleads to a reduction in F-actin and E-cadherin atjunctions and a weakening of cell-cell adhesion.Of importance, Fmnl3 expression is up-regulatedand junctional localization increases duringcollective cell migration. Depletion of Fmnl3 ormDia1 in migrating monolayers results in", "metadata": {}}
+{"_id": "3727986", "title": "", "text": "A mechanically active heterotypicE-cadherin/N-cadherin adhesion enablesfibroblasts to drive cancer cellinvasionCancer-associated fibroblasts (CAFs)promote tumour invasion and metastasis. Weshow that CAFs exert a physical force on cancercells that enables their collective invasion. Forcetransmission is mediated by a heterophilicadhesion involving N-cadherin at the CAFmembrane and E-cadherin at the cancer cellmembrane. This adhesion is mechanically active;when subjected to force it triggers β-cateninrecruitment and adhesion reinforcementdependent on α-catenin/vinculin interaction.Impairment of E-cadherin/N-cadherin adhesionabrogates the ability of CAFs to guide collectivecell migration and blocks cancer cell invasion.N-cadherin also mediates repolarization of theCAFs away from the cancer cells. In parallel,nectins and afadin are recruited to the cancercell/CAF interface and CAF repolarization isafadin dependent. Heterotypic junctions between", "metadata": {}}
+{"_id": "3730196", "title": "", "text": "Long non-coding RNA HOTTIP promotes BCL-2expression and induces chemoresistance in smallcell lung cancer by sponging miR-216aDespiteprogress in treatment of small cell lung cancer(SCLC), its multidrug chemoresistance and poorprognosis still remain. Recently, we globallyassessed long non-coding RNAs (lncRNAs) forcontributions to SCLC chemoresistance usingmicroarray data, in vitro and in vivo assays. Herewe reported that HOTTIP, encoding a lncRNAthat is frequently amplified in SCLC, wasassociated with SCLC cell chemosensitivity,proliferation, and poor prognosis of SCLCpatients. Moreover, mechanistic investigationsshowed that HOTTIP functioned as an oncogenein SCLC progression by binding miR-216a andabrogating its tumor-suppressive function in thissetting. On the other hand, HOTTIP increasedthe expression of anti-apoptotic factor BCL-2,another important target gene of miR-216a, andjointly enhanced chemoresistance of SCLC byregulating BCL-2. Taken together, our study", "metadata": {}}
+{"_id": "3743071", "title": "", "text": "GSDS 2.0: an upgraded gene featurevisualization serverUNLABELLED : Visualizinggenes' structure and annotated features helpsbiologists to investigate their function andevolution intuitively. The Gene Structure DisplayServer (GSDS) has been widely used by morethan 60 000 users since its first publication in2007. Here, we reported the upgraded GSDS 2.0with a newly designed interface, supports formore types of annotation features and formats,as well as an integrated visual editor for editingthe generated figure. Moreover, a user-specifiedphylogenetic tree can be added to facilitatefurther evolutionary analysis. The full sourcecode is also available for downloading.AVAILABILITY AND IMPLEMENTATION Webserver and source code are freely available athttp://gsds.cbi.pku.edu.cn. CONTACTgaog@mail.cbi.pku.edu.cn orgsds@mail.cbi.pku.edu.cn   SUPPLEMENTARYINFORMATION Supplementary data are availableat Bioinformatics online.", "metadata": {}}
+{"_id": "3748310", "title": "", "text": "SLP-65 regulates immunoglobulin light chaingene recombination through thePI(3)K-PKB-Foxo pathwayAlthough the essentialrole of the adaptor protein SLP-65 in pre-B celldifferentiation is established, the molecularmechanism underlying its function is poorlyunderstood. In this study, we uncover a linkbetween SLP-65–dependent signaling and thephosphoinositide-3-OH kinase (PI(3)K)–proteinkinase B (PKB)–Foxo pathway. We show that theforkhead box transcription factor Foxo3apromotes light chain rearrangement in pre-Bcells. Our data suggest that PKB suppresses lightchain recombination by phosphorylating Foxoproteins, whereas reconstitution of SLP-65function counteracts PKB activation andpromotes Foxo3a and Foxo1 activity in pre-Bcells. Together, these data illuminate a molecularfunction of SLP-65 and identify a key role forFoxo proteins in the regulation of light chainrecombination, receptor editing and B cellselection.", "metadata": {}}
+{"_id": "3752408", "title": "", "text": "A case-mix classification system for explaininghealthcare costs using administrative data inItaly.BACKGROUND The Italian National HealthService (NHS) provides universal coverage to allcitizens, granting primary and hospital care witha copayment system for outpatient and drugservices. Financing of Local Health Trusts (LHTs)is based on a capitation system adjusted only forage, gender and area of residence. We applied arisk-adjustment system (Johns Hopkins AdjustedClinical Groups System, ACG® System) in orderto explain health care costs using routinelycollected administrative data in the VenetoRegion (North-eastern Italy). METHODS Allresidents in the Veneto Region were included inthe study. The ACG system was applied toclassify the regional population based on thefollowing information sources for the year 2015:Hospital Discharges, Emergency Room visits,Chronic disease registry for copaymentexemptions, ambulatory visits, medications, theHome care database, and drug prescriptions.", "metadata": {}}
+{"_id": "3756384", "title": "", "text": "EpCAM-regulated intramembrane proteolysisinduces a cancer stem cell-like gene signature inhepatitis B virus-infectedhepatocytes.BACKGROUND & AIMS Hepatocytesin which the hepatitis B virus (HBV) is replicatingexhibit loss of the chromatin modifying polycombrepressive complex 2 (PRC2), resulting inre-expression of specific, cellular PRC2-repressedgenes. Epithelial cell adhesion molecule (EpCAM)is a PRC2-repressed gene, normally expressed inhepatic progenitors, but re-expressed in hepaticcancer stem cells (hCSCs). Herein, weinvestigated the functional significance of EpCAMre-expression in HBV-mediatedhepatocarcinogenesis. METHODS Employingmolecular approaches (transfections,fluorescence-activated cell sorting,immunoblotting, qRT-PCR), we investigated therole of EpCAM-regulated intramembraneproteolysis (RIP) in HBV replicating cells in vitro,and in liver tumors from HBV X/c-myc mice andchronically HBV infected patients. RESULTS", "metadata": {}}
+{"_id": "3758260", "title": "", "text": "Parathyroid Hormone Directs Bone MarrowMesenchymal Cell Fate.Intermittent PTHadministration builds bone mass and preventsfractures, but its mechanism of action is unclear.We genetically deleted the PTH/PTHrP receptor(PTH1R) in mesenchymal stem cells usingPrx1Cre and found low bone formation, increasedbone resorption, and high bone marrow adiposetissue (BMAT). Bone marrow adipocytes tracedto Prx1 and expressed classic adipogenicmarkers and high receptor activator of nuclearfactor kappa B ligand (Rankl) expression. RANKLlevels were also elevated in bone marrowsupernatant and serum, but undetectable inother adipose depots. By cell sorting,Pref1+RANKL+ marrow progenitors were twiceas great in mutant versus control marrow.Intermittent PTH administration to control micereduced BMAT significantly. A similar finding wasnoted in male osteoporotic patients. Thus,marrow adipocytes exhibit osteogenic andadipogenic characteristics, are uniquely", "metadata": {}}
+{"_id": "3761017", "title": "", "text": "Metformin attenuates blood-brain barrierdisruption in mice following middle cerebralartery occlusionBACKGROUND Metformin, awidely used hypoglycemic drug, reduces strokeincidence and alleviates chronic inflammation inclinical trials. However, the effect of metformin inischemic stroke is unclear. Here, we investigatedthe effect of metformin on ischemic stroke inmice and further explored the possibleunderlying mechanisms. METHODS Ninety-eightadult male CD-1 mice underwent 90-minutetransient middle cerebral artery occlusion(tMCAO). Metformin (200 mg/kg) wasadministrated for up to 14 days. Neurobehavioraloutcomes, brain infarct volume, inflammatoryfactors, blood-brain barrier (BBB) permeabilityand AMPK signaling pathways were evaluatedfollowing tMCAO. Oxygen glucose deprivationwas performed on bEND.3 cells to explore themechanisms of metformin in inhibitinginflammatory signaling pathways. RESULTSInfarct volume was reduced in metformin-treated", "metadata": {}}
+{"_id": "3765739", "title": "", "text": "Epstein-Barr Virus nuclear antigen 1 (EBNA1)confers resistance to apoptosis in EBV-positiveB-lymphoma cells through up-regulation ofsurvivin.Resistance to apoptosis is an importantcomponent of the overall mechanism whichdrives the tumorigenic process. EBV is aubiquitous human gamma-herpesvirus whichpreferentially establishes latent infection in viralinfected B-lymphocytes. EBNA1 is typicallyexpressed in most forms of EBV-positivemalignancies and is important for replication ofthe latent episome in concert with replication ofthe host cells. Here, we investigate the effects ofEBNA1 on survivin up-regulation in EBV-infectedhuman B-lymphoma cells. We present evidencewhich demonstrates that EBNA1 forms a complexwith Sp1 or Sp1-like proteins bound to theircis-element at the survivin promoter. Thisenhances the activity of the complex andup-regulates survivin. Knockdown of survivin andEBNA1 showed enhanced apoptosis in infectedcells and thus supports a role for EBNA1 in", "metadata": {}}
+{"_id": "3770726", "title": "", "text": "Microfluidic platform to evaluate migration ofcells from patients with DYT1dystonia.BACKGROUND Microfluidic platforms forquantitative evaluation of cell biologic processesallow low cost and time efficient research studiesof biological and pathological events, such asmonitoring cell migration by real-time imaging.In healthy and disease states, cell migration iscrucial in development and wound healing, aswell as to maintain the body's homeostasis. NEWMETHOD The microfluidic chambers allow precisemeasurements to investigate whether fibroblastscarrying a mutation in the TOR1A gene,underlying the hereditary neurologicdisease--DYT1 dystonia, have decreasedmigration properties when compared to controlcells. RESULTS We observed that fibroblastsfrom DYT1 patients showed abnormalities inbasic features of cell migration, such as reducedvelocity and persistence of movement.COMPARISON WITH EXISTING METHOD Themicrofluidic method enabled us to demonstrate", "metadata": {}}
+{"_id": "3770750", "title": "", "text": "Sugar-sweetened beverages and weight gain inchildren and adults: a systematic review andmeta-analysis.BACKGROUND The relationbetween sugar-sweetened beverages (SSBs) andbody weight remains controversial. OBJECTIVEWe conducted a systematic review andmeta-analysis to summarize the evidence inchildren and adults. DESIGN We searchedPubMed, EMBASE, and Cochrane databasesthrough March 2013 for prospective cohortstudies and randomized controlled trials (RCTs)that evaluated the SSB-weight relation. Separatemeta-analyses were conducted in children andadults and for cohorts and RCTs by usingrandom- and fixed-effects models. RESULTSThirty-two original articles were included in ourmeta-analyses: 20 in children (15 cohort studies,n = 25,745; 5 trials, n = 2772) and 12 in adults(7 cohort studies, n = 174,252; 5 trials, n =292). In cohort studies, one daily servingincrement of SSBs was associated with a 0.06(95% CI: 0.02, 0.10) and 0.05 (95% CI: 0.03,", "metadata": {}}
+{"_id": "3773719", "title": "", "text": "The tumorigenic potential of pluripotent stemcells: What can we do to minimize it?Humanpluripotent stem cells (hPSCs) have the potentialto fundamentally change the way that we goabout treating and understanding humandisease. Despite this extraordinary potential,these cells also have an innate capability to formtumors in immunocompromised individuals whenthey are introduced in their pluripotent state.Although current therapeutic strategies involvetransplantation of only differentiated hPSCderivatives, there is still a concern thattransplanted cell populations could contain asmall percentage of cells that are not fullydifferentiated. In addition, these cells have beenfrequently reported to acquire genetic alterationsthat, in some cases, are associated with certaintypes of human cancers. Here, we try toseparate the panic from reality and rationallyevaluate the true tumorigenic potential of thesecells. We also discuss a recent study examiningthe effect of culture conditions on the genetic", "metadata": {}}
+{"_id": "3776162", "title": "", "text": "Epidemiology of sepsis and septic shock incritical care units: comparison between sepsis-2and sepsis-3 populations using a national criticalcare databaseBackground New sepsis and septicshock definitions could change the epidemiologyof sepsis because of differences in criteria. Wetherefore compared the sepsis populationsidentified by the old and new definitions.Methods We used a high-quality, national,intensive care unit (ICU) database of 654 918consecutive admissions to 189 adult ICUs inEngland, from January 2011 to December 2015.Primary outcome was acute hospital mortality.We compared old (Sepsis-2) and new (Sepsis-3)incidence, outcomes, trends in outcomes, andpredictive validity of sepsis and septic shockpopulations. Results From among 197 724Sepsis-2 severe sepsis and 197 142 Sepsis-3sepsis cases, we identified 153 257 Sepsis-2septic shock and 39 262 Sepsis-3 septic shockcases. The extrapolated population incidence ofSepsis-3 sepsis and Sepsis-3 septic shock was", "metadata": {}}
+{"_id": "3788528", "title": "", "text": "Thymic expression of the golli-myelin basicprotein gene in the SJL/J mouseThe T cellantigen-specific repertoire is thought to beshaped by thymic expression of self molecules.Since a myelin basic protein (MBP)-like gene(golli-MBP) has been reported to be expressedby cells of the immune system, the present studywas undertaken to determine whether thegolli-MBP gene was expressed in the mousethymus and, if so, to characterize transcripts ofthis gene in this organ. Using exon-specificprimers for MBP and golli-MBP, cDNA fromthymus and other tissues was amplified, and theamplified products analyzed by Southern blottingwith exon-specific oligonucleotide probes. Theamplified products were subcloned, and theinserts characterized by DNA sequencing. Thethymic transcripts were found to containgolli-MBP exons 1, 2, 3, 5A, 5B, 5C, 6, 7, 8, and11.", "metadata": {}}
+{"_id": "3790895", "title": "", "text": "Urine microRNAs as biomarkers for bladdercancer: a diagnostic meta-analysisBACKGROUNDThe diagnostic value of microRNA (miRNA)detection in patients with bladder cancer (BCa) iscontroversial. We performed a diagnosticmeta-analysis to evaluate current evidence onthe use of miRNA assays to diagnose BCa.METHODS We systematically searched PubMed,Embase, and Web of Science for studiespublished before March 31, 2015. The pooledsensitivity, specificity, positive and negativelikelihood ratios, diagnostic odds ratio, and areaunder the curve (AUC) were calculated toevaluate the overall test performance. Subgroupanalyses were used to explore thebetween-study heterogeneity. Deeks' funnel plotasymmetry test was used to test publicationbias. We applied the software of RevMan 5.2 andStata 11.0 to the meta-analysis. RESULTS A totalof 23 studies from nine articles were included inthe meta-analysis, with a total of 719 patientsand 494 controls. The pooled sensitivity and", "metadata": {}}
+{"_id": "3801693", "title": "", "text": "Elevated Plasma Transforming Growth Factor&bgr;1 Levels Predict the Development ofHypertension in Normotensives: The 14-YearFollow-Up StudyBACKGROUND Transforminggrowth factor β1 (TGF-β1) is a multifunctionalcytokine. There is growing evidence that TGF-β1is involved in the pathogenesis of hypertensionand the development of target organ damage inhypertensives. Although several studies haveshown that TGF-β1 induced vascular hypertrophyand remodelling in various vascular diseases,there are no longitudinal data on hypertension inthe epidemiological studies. The present studytested the hypothesis whether elevated TGF-β1levels can predict the development ofhypertension. METHODS In 2002-2004, 528subjects received health examinations in Ukutown, southwestern Japan. We examined bloodpressure (BP), body mass index, and blood test.Data on fasting plasma TGF-β1 were obtainedfrom 528 individuals. Of these, 149normotensives (BP <140/90 mm Hg without", "metadata": {}}
+{"_id": "3805841", "title": "", "text": "MYC Disrupts the Circadian Clock and Metabolismin Cancer Cells.The MYC oncogene encodes MYC,a transcription factor that binds the genomethrough sites termed E-boxes (5'-CACGTG-3'),which are identical to the binding sites of theheterodimeric CLOCK-BMAL1 master circadiantranscription factor. Hence, we hypothesized thatectopic MYC expression perturbs the clock byderegulating E-box-driven components of thecircadian network in cancer cells. We report herethat deregulated expression of MYC or N-MYCdisrupts the molecular clock in vitro by directlyinducing REV-ERBα to dampen expression andoscillation of BMAL1, and this could be rescuedby knockdown of REV-ERB. REV-ERBα expressionpredicts poor clinical outcome for N-MYC-drivenhuman neuroblastomas that have diminishedBMAL1 expression, and re-expression of ectopicBMAL1 in neuroblastoma cell lines suppressestheir clonogenicity. Further, ectopic MYCprofoundly alters oscillation of glucosemetabolism and perturbs glutaminolysis. Our", "metadata": {}}
+{"_id": "3823862", "title": "", "text": "Integrated maps in quail (Coturnix japonica)confirm the high degree of synteny conservationwith chicken (Gallus gallus) despite 35 millionyears of divergenceBackgroundBy comparing thequail genome with that of chicken, chromosomerearrangements that have occurred in these twogalliform species over 35 million years ofevolution can be detected. From a more practicalpoint of view, the definition of conservedsyntenies helps to predict the position of genesin quail, based on information taken from thechicken sequence, thus enhancing the utility ofthis species in biological studies through a betterknowledge of its genome structure. Amicrosatellite and an Amplified Fragment LengthPolymorphism (AFLP) genetic map werepreviously published for quail, as well ascomparative cytogenetic data with chicken formacrochromosomes. Quail genomics will benefitfrom the extension and the integration of thesemaps. ResultsThe integrated linkage mappresented here is based on segregation analysis", "metadata": {}}
+{"_id": "3825472", "title": "", "text": "Cadherin activity is required for activity-inducedspine remodelingNeural activity induces theremodeling of pre- and postsynaptic membranes,which maintain their apposition through celladhesion molecules. Among them, N-cadherin isredistributed, undergoes activity-dependentconformational changes, and is required forsynaptic plasticity. Here, we show thatdepolarization induces the enlargement of thewidth of spine head, and that cadherin activity isessential for this synaptic rearrangement.Dendritic spines visualized with green fluorescentprotein in hippocampal neurons showed anexpansion by the activation of AMPA receptor, sothat the synaptic apposition zone may beexpanded. N-cadherin-venus fusion proteinlaterally dispersed along the expanding spinehead. Overexpression of dominant-negativeforms of N-cadherin resulted in the abrogation ofthe spine expansion. Inhibition of actinpolymerization with cytochalasin D abolished thespine expansion. Together, our data suggest that", "metadata": {}}
+{"_id": "3825750", "title": "", "text": "Aliskiren combined with losartan in type 2diabetes and nephropathy.BACKGROUNDDiabetic nephropathy is the leading cause ofend-stage renal disease in developed countries.We evaluated the renoprotective effects of dualblockade of the renin-angiotensin-aldosteronesystem by adding treatment with aliskiren, anoral direct renin inhibitor, to treatment with themaximal recommended dose of losartan (100 mgdaily) and optimal antihypertensive therapy inpatients who had hypertension and type 2diabetes with nephropathy. METHODS Weenrolled 599 patients in this multinational,randomized, double-blind study. After a3-month, open-label, run-in period during whichpatients received 100 mg of losartan daily,patients were randomly assigned to receive 6months of treatment with aliskiren (150 mg dailyfor 3 months, followed by an increase in dosageto 300 mg daily for another 3 months) orplacebo, in addition to losartan. The primaryoutcome was a reduction in the ratio of albumin", "metadata": {}}
+{"_id": "3828508", "title": "", "text": "Overweight in Celiac Disease: Prevalence,Clinical Characteristics, and Effect of aGluten-Free DietBACKGROUND:It is wellestablished that a minority of celiac patientspresent with “classic” symptoms due tomalabsorption. However, few studies havefocussed on the distribution of body mass index(BMI) in celiac populations and its relationship toclinical characteristics, or on its response totreatment. METHODS:We reviewed BMImeasurements and other clinical andpathological characteristics from a database of371 celiac patients diagnosed over a 10-yr periodand seen by a single gastroenterologist. Toassess response to gluten exclusion, wecompared BMI at diagnosis and after 2 yrtreatment in patients with serological support fordietary compliance. RESULTS:Mean BMI was24.6 kg/m2 (range 16.3–43.5). Seventeenpatients (5%) were underweight (BMI <18.5),211 (57%) were normal, and 143 (39%) wereoverweight (BMI ≥25), including 48 (13% of all", "metadata": {}}
+{"_id": "3829232", "title": "", "text": "Structural Studies of a Four-MBT Repeat ProteinMBTD1BACKGROUND The Polycomb group (PcG)of proteins is a family of importantdevelopmental regulators. The respectivemembers function as large protein complexesinvolved in establishment and maintenance oftranscriptional repression of developmentalcontrol genes. MBTD1, Malignant Brain Tumordomain-containing protein 1, is one such PcGprotein. MBTD1 contains four MBT repeats.METHODOLOGY/PRINCIPAL FINDINGS We havedetermined the crystal structure of MBTD1(residues 130-566aa covering the 4 MBTrepeats) at 2.5 A resolution by X-raycrystallography. The crystal structure of MBTD1reveals its similarity to another four-MBT-repeatprotein L3MBTL2, which binds lower methylatedlysine histones. Fluorescence polarizationexperiments confirmed that MBTD1 preferentiallybinds mono- and di-methyllysine histonepeptides, like L3MBTL1 and L3MBTL2. All knownMBT-peptide complex structures characterized to", "metadata": {}}
+{"_id": "3831884", "title": "", "text": "Glutamine supports pancreatic cancer growththrough a Kras-regulated metabolicpathwayCancer cells have metabolicdependencies that distinguish them from theirnormal counterparts. Among these dependenciesis an increased use of the amino acid glutamineto fuel anabolic processes. Indeed, the spectrumof glutamine-dependent tumours and themechanisms whereby glutamine supports cancermetabolism remain areas of active investigation.Here we report the identification of anon-canonical pathway of glutamine use inhuman pancreatic ductal adenocarcinoma(PDAC) cells that is required for tumour growth.Whereas most cells use glutamatedehydrogenase (GLUD1) to convertglutamine-derived glutamate intoα-ketoglutarate in the mitochondria to fuel thetricarboxylic acid cycle, PDAC relies on a distinctpathway in which glutamine-derived aspartate istransported into the cytoplasm where it can beconverted into oxaloacetate by aspartate", "metadata": {}}
+{"_id": "3835423", "title": "", "text": "CD4+ T cell help guides formation of CD103+lung-resident memory CD8+ T cells duringinfluenza viral infection.Tissue-resident memoryT (Trm) cells provide enhanced protectionagainst infection at mucosal sites. Here we foundthat CD4(+) T cells are important for theformation of functional lung-resident CD8(+) Tcells after influenza virus infection. In theabsence of CD4(+) T cells, CD8(+) T cellsdisplayed reduced expression of CD103 (Itgae),were mislocalized away from airway epithelia,and demonstrated an impaired ability to recruitCD8(+) T cells to the lung airways uponheterosubtypic challenge. CD4(+) T cell-derivedinterferon-γ was necessary for generatinglung-resident CD103(+) CD8(+) Trm cells.Furthermore, expression of the transcriptionfactor T-bet was increased in \"unhelped\" lungTrm cells, and a reduction in T-bet rescuedCD103 expression in the absence of CD4(+) Tcell help. Thus, CD4(+) T cell-dependent signalsare important to limit expression of T-bet and", "metadata": {}}
+{"_id": "3840043", "title": "", "text": "Inhibition of Apoptosis Overcomes Stage-RelatedCompatibility Barriers to Chimera Formation inMouse Embryos.Cell types more advanced indevelopment than embryonic stem cells, such asEpiSCs, fail to contribute to chimeras wheninjected into pre-implantation-stage blastocysts,apparently because the injected cells undergoapoptosis. Here we show that transientpromotion of cell survival through expression ofthe anti-apoptotic gene BCL2 enables EpiSCs andSox17+ endoderm progenitors to integrate intoblastocysts and contribute to chimeric embryos.Upon injection into blastocyst, BCL2-expressingEpiSCs contributed to all bodily tissues inchimeric animals while Sox17+ endodermprogenitors specifically contributed in aregion-specific fashion to endodermal tissues. Inaddition, BCL2 expression enabled rat EpiSCs tocontribute to mouse embryonic chimeras,thereby forming interspecies chimeras that couldsurvive to adulthood. Our system thereforeprovides a method to overcome cellular", "metadata": {}}
+{"_id": "3845894", "title": "", "text": "Computational and Statistical Analyses of AminoAcid Usage and Physico-Chemical Properties ofthe Twelve Late Embryogenesis AbundantProtein ClassesLate Embryogenesis AbundantProteins (LEAPs) are ubiquitous proteinsexpected to play major roles in desiccationtolerance. Little is known about their structure -function relationships because of the scarcity of3-D structures for LEAPs. The previous buildingof LEAPdb, a database dedicated to LEAPs fromplants and other organisms, led to theclassification of 710 LEAPs into 12non-overlapping classes with distinct properties.Using this resource, numerous physico-chemicalproperties of LEAPs and amino acid usage byLEAPs have been computed and statisticallyanalyzed, revealing distinctive features for eachclass. This unprecedented analysis allowed arigorous characterization of the 12 LEAP classes,which differed also in multiple structural andphysico-chemical features. Although most LEAPscan be predicted as intrinsically disordered", "metadata": {}}
+{"_id": "3847200", "title": "", "text": "Direct Reprogramming of Hepatic Myofibroblastsinto Hepatocytes In Vivo Attenuates LiverFibrosis.Direct induction of induced hepatocytes(iHeps) from fibroblasts holds potential as astrategy for regenerative medicine but until nowhas only been shown in culture settings. Here,we describe in vivo iHep formation usingtranscription factor induction and genetic fatetracing in mouse models of chronic liver disease.We show that ectopic expression of thetranscription factors FOXA3, GATA4, HNF1A, andHNF4A from a polycistronic lentiviral vectorconverts mouse myofibroblasts into cells with ahepatocyte phenotype. In vivo expression of thesame set of transcription factors from a p75neurotrophin receptor peptide (p75NTRp)-taggedadenovirus enabled the generation ofhepatocyte-like cells from myofibroblasts infibrotic mouse livers and reduced liver fibrosis.We have therefore been able to convertpro-fibrogenic myofibroblasts in the liver intohepatocyte-like cells with positive functional", "metadata": {}}
+{"_id": "3848469", "title": "", "text": "Epithelial to Mesenchymal Transition by TGFβ-1Induction Increases Stemness Characteristics inPrimary Non Small Cell Lung Cancer CellLineBACKGROUND Cancer Stem Cells (CSCs)hypothesis asserts that only a small subset ofcells within a tumour is capable of both tumourinitiation and sustainment. TheEpithelial-Mesenchymal Transition (EMT) is anembryonic developmental program that is oftenactivated during cancer invasion and metastasis.The aim of this study is to shed light on therelationship between EMT and CSCs by usingLC31 lung cancer primary cell line. MATERIALSAND METHODS A549 and LC31 cell lines weretreated with 2 ng/ml TGFβ-1 for 30 days, and 80days, respectively. To evaluate EMT,morphological changes were assessed by lightmicroscopy, immunofluorescence and cytometryfor following markers: cytokeratins, e-cadherin,CD326 (epithelial markers) and CD90, andvimentin (mesenchymal markers). Moreover,RT-PCR for Slug, Twist and β-catenin genes were", "metadata": {}}
+{"_id": "3849194", "title": "", "text": "Dnmt3a and Dnmt3b Associate with Enhancersto Regulate Human Epidermal Stem CellHomeostasis.The genome-wide localization andfunction of endogenous Dnmt3a and Dnmt3b inadult stem cells are unknown. Here, we showthat in human epidermal stem cells, the twoproteins bind in a histone H3K36me3-dependentmanner to the most active enhancers and arerequired to produce their associated enhancerRNAs. Both proteins prefer super-enhancersassociated to genes that either define theectodermal lineage or establish the stem cell anddifferentiated states. However, Dnmt3a andDnmt3b differ in their mechanisms of enhancerregulation: Dnmt3a associates with p63 tomaintain high levels of DNA hydroxymethylationat the center of enhancers in a Tet2-dependentmanner, whereas Dnmt3b promotes DNAmethylation along the body of the enhancer.Depletion of either protein inactivates theirtarget enhancers and profoundly affectsepidermal stem cell function. Altogether, we", "metadata": {}}
+{"_id": "3851329", "title": "", "text": "CDK inhibitors in cancer therapy: what isnext?The pursuit for drugs that inhibitcyclin-dependent kinases (CDKs) has been anintense area of research for more than 15 years.The first-generation inhibitors, Flavopiridol andCY-202, are in late-stage clinical trials, but so farhave demonstrated only modest activity. Severalsecond-generation inhibitors are now in clinicaltrials. Future approaches to determine clinicalbenefit need to incorporate both the lessonslearned from these early compounds andinformation recently obtained from the geneticanalysis of CDKs in preclinical models. Here wediscuss key concepts that should be consideredwhen validating the clinical utility of CDKinhibitors in cancer therapy.", "metadata": {}}
+{"_id": "3858268", "title": "", "text": "Lipid Desaturation Is a Metabolic Marker andTherapeutic Target of Ovarian Cancer StemCells.Lack of sensitive single-cell analysis toolshas limited the characterization of metabolicactivity in cancer stem cells. Byhyperspectral-stimulated Raman scatteringimaging of single living cells and massspectrometry analysis of extracted lipids, wereport here significantly increased levels ofunsaturated lipids in ovarian cancer stem cells(CSCs) as compared to non-CSCs. Higher lipidunsaturation levels were also detected inCSC-enriched spheroids compared to monolayercultures of ovarian cancer cell lines or primarycells. Inhibition of lipid desaturases effectivelyeliminated CSCs, suppressed sphere formation invitro, and blocked tumor initiation capacity invivo. Mechanistically, we demonstrate thatnuclear factor κB (NF-κB) directly regulates theexpression levels of lipid desaturases, andinhibition of desaturases blocks NF-κB signaling.Collectively, our findings reveal that increased", "metadata": {}}
+{"_id": "3863543", "title": "", "text": "Mesenchymal Inflammation Drives GenotoxicStress in Hematopoietic Stem Cells and PredictsDisease Evolution in HumanPre-leukemia.Mesenchymal niche cells may drivetissue failure and malignant transformation inthe hematopoietic system, but the underlyingmolecular mechanisms and relevance to humandisease remain poorly defined. Here, we showthat perturbation of mesenchymal cells in amouse model of the pre-leukemic disorderShwachman-Diamond syndrome (SDS) inducesmitochondrial dysfunction, oxidative stress, andactivation of DNA damage responses inhematopoietic stem and progenitor cells. Massiveparallel RNA sequencing of highly purifiedmesenchymal cells in the SDS mouse model anda range of human pre-leukemic syndromesidentified p53-S100A8/9-TLR inflammatorysignaling as a common driving mechanism ofgenotoxic stress. Transcriptional activation ofthis signaling axis in the mesenchymal nichepredicted leukemic evolution and", "metadata": {}}
+{"_id": "3866315", "title": "", "text": "Novel Functional Sets of Lipid-Derived Mediatorswith Antiinflammatory Actions Generated fromOmega-3 Fatty Acids via Cyclooxygenase2–Nonsteroidal Antiinflammatory Drugs andTranscellular ProcessingAspirin therapy inhibitsprostaglandin biosynthesis without directly actingon lipoxygenases, yet via acetylation ofcyclooxygenase 2 (COX-2) it leads to bioactivelipoxins (LXs) epimeric at carbon 15 (15-epi-LX,also termed aspirin-triggered LX [ATL]). Here,we report that inflammatory exudates from micetreated with ω-3 polyunsaturated fatty acid andaspirin (ASA) generate a novel array of bioactivelipid signals. Human endothelial cells withupregulated COX-2 treated with ASA convertedC20:5 ω-3 to 18R-hydroxyeicosapentaenoic acid(HEPE) and 15R-HEPE. Each was used bypolymorphonuclear leukocytes to generateseparate classes of novel trihydroxy-containingmediators, including 5-series 15R-LX5 and5,12,18R-triHEPE. These new compounds provedto be potent inhibitors of human", "metadata": {}}
+{"_id": "3868322", "title": "", "text": "Cholesteryl Ester Transfer Protein (CETP)Polymorphisms Affect mRNA Splicing, HDLLevels, and Sex-Dependent CardiovascularRiskPolymorphisms in and around theCholesteryl Ester Transfer Protein (CETP) genehave been associated with HDL levels, risk forcoronary artery disease (CAD), and response totherapy. The mechanism of action of thesepolymorphisms has yet to be defined. We usedmRNA allelic expression and splice isoformmeasurements in human liver tissues to identifythe genetic variants affecting CETP levels. AllelicCETP mRNA expression ratios in 56 human liverswere strongly associated with several variants2.5-7 kb upstream of the transcription start site(e.g., rs247616 p = 6.4 × 10(-5), allelefrequency 33%). In addition, a commonalternatively spliced CETP isoform lacking exon 9(Δ9), has been shown to prevent CETP secretionin a dominant-negative manner. The Δ 9expression ranged from 10 to 48% of total CETPmRNA in 94 livers. Increased formation of this", "metadata": {}}
+{"_id": "3870062", "title": "", "text": "6-Sulphated Chondroitins Have a PositiveInfluence on Axonal RegenerationChondroitinsulphate proteoglycans (CSPGs) upregulated inthe glial scar inhibit axon regeneration via theirsulphated glycosaminoglycans (GAGs).Chondroitin 6-sulphotransferase-1 (C6ST-1) isupregulated after injury leading to an increase in6-sulphated GAG. In this study, we ask if thisincrease in 6-sulphated GAG is responsible forthe increased inhibition within the glial scar, orwhether it represents a partial reversion to thepermissive embryonic state dominated by6-sulphated glycosaminoglycans (GAGs). UsingC6ST-1 knockout mice (KO), we studiedpost-injury changes in chondroitinsulphotransferase (CSST) expression and theeffect of chondroitin 6-sulphates on both centraland peripheral axon regeneration. After CNSinjury, wild-type animals (WT) showed anincrease in mRNA for C6ST-1, C6ST-2 andC4ST-1, but KO did not upregulate any CSSTs.After PNS injury, while WT upregulated C6ST-1,", "metadata": {}}
+{"_id": "3874000", "title": "", "text": "Tissue Mechanics Orchestrate Wnt-DependentHuman Embryonic Stem CellDifferentiation.Regenerative medicine ispredicated on understanding the mechanismsregulating development and applying theseconditions to direct stem cell fate.Embryogenesis is guided by cell-cell andcell-matrix interactions, but it is unclear howthese physical cues influence stem cells inculture. We used human embryonic stem cells(hESCs) to examine whether mechanical featuresof the extracellular microenvironment coulddifferentially modulate mesoderm specification.We found that, on a hydrogel-based compliantmatrix, hESCs accumulate β-catenin at cell-celladhesions and show enhanced Wnt-dependentmesoderm differentiation. Mechanistically,Src-driven ubiquitination of E-cadherin byCbl-like ubiquitin ligase releases P120-catenin tofacilitate transcriptional activity of β-catenin,which initiates and reinforces mesodermdifferentiation. By contrast, on a stiff hydrogel", "metadata": {}}
+{"_id": "3878434", "title": "", "text": "Predictive performance of the quick SequentialOrgan Failure Assessment score as a screeningtool for sepsis, mortality, and intensive care unitadmission in patients with febrile neutropeniaInSepsis-3, the quick Sequential Organ FailureAssessment (qSOFA) score was developed ascriteria to use for recognizing patients who mayhave poor outcomes. This study was performedto evaluate the predictive performance of theqSOFA score as a screening tool for sepsis,mortality, and intensive care unit (ICU)admission in patients with febrile neutropenia(FN). We also tried to compare its performancewith that of the systemic inflammatory responsesyndrome (SIRS) criteria and MultinationalAssociation of Supportive Care in Cancer(MASCC) score for FN. We used a prospectivelycollected adult FN data registry. The qSOFA andSIRS scores were calculated retrospectivelyusing the preexisting data. The primary outcomewas the development of sepsis. The secondaryoutcomes were ICU admission and 28-day", "metadata": {}}
+{"_id": "3882374", "title": "", "text": "LIN28 Regulates Stem Cell Metabolism andConversion to Primed Pluripotency.TheRNA-binding proteins LIN28A and LIN28B playcritical roles in embryonic development,tumorigenesis, and pluripotency, but their exactfunctions are poorly understood. Here, we showthat, like LIN28A, LIN28B can function effectivelywith NANOG, OCT4, and SOX2 in reprogrammingto pluripotency and that reactivation of bothendogenous LIN28A and LIN28B loci are requiredfor maximal reprogramming efficiency. In humanfibroblasts, LIN28B is activated early duringreprogramming, while LIN28A is activated laterduring the transition to bona fide inducedpluripotent stem cells (iPSCs). In murine cells,LIN28A and LIN28B facilitate conversion fromnaive to primed pluripotency. Proteomic andmetabolomic analysis highlighted roles for LIN28in maintaining the low mitochondrial functionassociated with primed pluripotency and inregulating one-carbon metabolism, nucleotidemetabolism, and histone methylation. LIN28", "metadata": {}}
+{"_id": "3883485", "title": "", "text": "Genetic Drift Can Compromise MitochondrialReplacement by Nuclear Transfer in HumanOocytes.Replacement of mitochondria throughnuclear transfer between oocytes of two differentwomen has emerged recently as a strategy forpreventing inheritance of mtDNA diseases.Although experiments in human oocytes haveshown effective replacement, the consequencesof small amounts of mtDNA carryover have notbeen studied sufficiently. Using humanmitochondrial replacement stem cell lines, weshow that, even though the low levels ofheteroplasmy introduced into human oocytes bymitochondrial carryover during nuclear transferoften vanish, they can sometimes instead resultin mtDNA genotypic drift and reversion to theoriginal genotype. Comparison of cells withidentical oocyte-derived nuclear DNA butdifferent mtDNA shows that either mtDNAgenotype is compatible with the nucleus and thatdrift is independent of mitochondrial function.Thus, although functional replacement of the", "metadata": {}}
+{"_id": "3893473", "title": "", "text": "TAL effectors are remote controls for geneactivation.TAL (transcription activator-like)effectors constitute a novel class of DNA-bindingproteins with predictable specificity. They areemployed by Gram-negative plant-pathogenicbacteria of the genus Xanthomonas whichtranslocate a cocktail of different effectorproteins via a type III secretion system (T3SS)into plant cells where they serve as virulencedeterminants. Inside the plant cell, TALs localizeto the nucleus, bind to target promoters, andinduce expression of plant genes. DNA-bindingspecificity of TALs is determined by a centraldomain of tandem repeats. Each repeat confersrecognition of one base pair (bp) in the DNA.Rearrangement of repeat modules allows designof proteins with desired DNA-bindingspecificities. Here, we summarize how TALspecificity is encoded, first structural data andfirst data on site-specific TAL nucleases.", "metadata": {}}
+{"_id": "3896759", "title": "", "text": "Vascular heterogeneity and specialization indevelopment and diseaseBlood and lymphaticvessels pervade almost all body tissues and havenumerous essential roles in physiology anddisease. The inner lining of these networks isformed by a single layer of endothelial cells,which is specialized according to the needs of thetissue that it supplies. Whereas the generalmechanisms of blood and lymphatic vesseldevelopment are being defined with increasingmolecular precision, studies of the processes ofendothelial specialization remain mostlydescriptive. Recent insights from genetic animalmodels illuminate how endothelial cells interactwith each other and with their tissueenvironment, providing paradigms for vesseltype- and organ-specific endothelialdifferentiation. Delineating these governingprinciples will be crucial for understanding howtissues develop and maintain, and how theirfunction becomes abnormal in disease.", "metadata": {}}
+{"_id": "3898784", "title": "", "text": "Association of Intracerebral Hemorrhage AmongPatients Taking Non–Vitamin K Antagonist vsVitamin K Antagonist Oral Anticoagulants WithIn-Hospital MortalityImportance Althoughnon–vitamin K antagonist oral anticoagulants(NOACs) are increasingly used to preventthromboembolic disease, there are limited dataon NOAC-related intracerebral hemorrhage(ICH). Objective To assess the associationbetween preceding oral anticoagulant use(warfarin, NOACs, and no oral anticoagulants[OACs]) and in-hospital mortality among patientswith ICH. Design, Setting, and ParticipantsRetrospective cohort study of 141 311 patientswith ICH admitted from October 2013 toDecember 2016 to 1662 Get With TheGuidelines–Stroke hospitals. ExposuresAnticoagulation therapy before ICH, defined asany use of OACs within 7 days prior to hospitalarrival. Main Outcomes and Measures In-hospitalmortality. Results Among 141 311 patients withICH (mean [SD] age, 68.3 [15.3] years; 48.1%", "metadata": {}}
+{"_id": "3899896", "title": "", "text": "Elevated red blood cell distribution widthcontributes to poor prognosis in patientsundergoing resection for nonmetastatic rectalcancerSeveral studies have reported thatelevated red blood cell distribution width (RDW)was associated with the poor prognosis ofdifferent kinds of cancers. The aim of this studywas to investigate the prognostic role of RDW inpatients undergoing resection for nonmetastaticrectal cancer. We retrospectively reviewed adatabase of 625 consecutive patients whounderwent curative resection for nonmetastaticrectal cancer at our institution from January2009 to December 2014. The cutoff value ofRDW was calculated by receiver-operatingcharacteristic curve. The results demonstratedthat patients in high RDW-cv group had a loweroverall survival (OS) (P = .018) and disease-freesurvival (P = .004). We also observed thatpatients in high RDW-sd group were associatedwith significantly lower OS (P = .033), whereasthe disease-free survival (DFS) was not", "metadata": {}}
+{"_id": "3903084", "title": "", "text": "Health workers cohort study: methods and studydesign.Objective: To examine different healthoutcomes that are associated with specificlifestyle and genetic factors. Materials andmethods: From March 2004 to April 2006, asample of employees from three different healthand academic institutions, as well as their familymembers, were enrolled in the study afterproviding informed consent. At baseline andfollow-up (2010-2013), participants completed aself-administered questionnaire, a physicalexamination, and provided blood samples.Results: A total of 10 729 participants aged 6 to94 years were recruited at baseline. Of these,70% were females, and 50% were from theMexican Social Security Institute. Nearly 42% ofthe adults in the sample were overweight, while20% were obese. Conclusion: Our study canoffer new insights into disease mechanisms andprevention through the analysis of risk factorinformation in a large sample of Mexicans.", "metadata": {}}
+{"_id": "3912660", "title": "", "text": "Aberrant pro-atrial natriureticpeptide/corin/natriuretic peptide receptorsignaling is present in maternal vascularendothelium in preeclampsia.OBJECTIVE Corin isa serine protease that converts pro-atrialnatriuretic peptide (pro-ANP) to atrial natriureticpeptide (ANP), a cardiac hormone that regulatessalt-water balance and blood pressure. ANP isdegraded by natriuretic peptide receptor (NPR).This study was to determine if aberrantpro-ANP/corin/NPR signaling is present inmaternal vascular system in preeclampsia.STUDY DESIGN Maternal venous blood wasobtained from 197 pregnant women (84normotensive, 16 complicated with chronichypertension (CHT), 11 mild and 86 severepreeclampsia). Plasma corin and pro-ANPconcentrations were measured by enzyme-linkedimmunosorbent assay. Maternal subcutaneousfat tissue was obtained from 12 pregnant womenwith cesarean section delivery (6 normotensiveand 6 preeclampsia). Vascular ANP and its", "metadata": {}}
+{"_id": "3929361", "title": "", "text": "Optimising Strategies for Plasmodium falciparumMalaria Elimination in Cambodia: Primaquine,Mass Drug Administration and ArtemisininResistanceBACKGROUND Malaria eliminationrequires a variety of approaches individuallyoptimized for different transmission settings. Arecent field study in an area of low seasonaltransmission in South West Cambodiademonstrated dramatic reductions in malariaparasite prevalence following both mass drugadministration (MDA) and high treatmentcoverage of symptomatic patients withartemisinin-piperaquine plus primaquine. Thisstudy employed multiple combined strategiesand it was unclear what contribution each madeto the reductions in malaria. METHOD ANDFINDINGS A mathematical model fitted to thetrial results was used to assess the effects of thevarious components of these interventions,design optimal elimination strategies, andexplore their interactions with artemisininresistance, which has recently been discovered in", "metadata": {}}
+{"_id": "3930020", "title": "", "text": "Role of the Parasite-Derived Prostaglandin D2 inthe Inhibition of Epidermal Langerhans CellMigration during SchistosomiasisInfectionEpidermal Langerhans cells (LCs) play akey role in immune defense mechanisms and innumerous immunological disorders. In thisreport, we show that percutaneous infection ofC57BL/6 mice with the helminth parasiteSchistosoma mansoni leads to the activation ofLCs but, surprisingly, to their retention in theepidermis. Moreover, using an experimentalmodel of LC migration induced by tumor necrosisfactor (TNF)-α, we show that parasitestransiently impair the departure of LCs from theepidermis and their subsequent accumulation asdendritic cells in the draining lymph nodes. Theinhibitory effect is mediated by soluble lipophilicfactors released by the parasites and not byhost-derived antiinflammatory cytokines, such asinterleukin-10. We find that prostaglandin(PG)D2, but not the other major eicosanoidsproduced by the parasites, specifically impedes", "metadata": {}}
+{"_id": "3935126", "title": "", "text": "Axicabtagene Ciloleucel CAR T\u0000Cell Therapy inRefractory Large B\u0000Cell LymphomaBackgroundIn a phase 1 trial, axicabtagene ciloleucel(axi\u0000cel), an autologous anti\u0000CD19 chimericantigen receptor (CAR) T\u0000cell therapy, showedefficacy in patients with refractory large B\u0000celllymphoma after the failure of conventionaltherapy. Methods In this multicenter, phase 2trial, we enrolled 111 patients with diffuse largeB\u0000cell lymphoma, primary mediastinal B\u0000celllymphoma, or transformed follicular lymphomawho had refractory disease despite undergoingrecommended prior therapy. Patients received atarget dose of 2×106 anti\u0000CD19 CAR T cells perkilogram of body weight after receiving aconditioning regimen of low\u0000dosecyclophosphamide and fludarabine. The primaryend point was the rate of objective response(calculated as the combined rates of completeresponse and partial response). Secondary endpoints included overall survival, safety, andbiomarker assessments. Results Among the 111", "metadata": {}}
+{"_id": "3943235", "title": "", "text": "Beta adrenergic blockade decreases theimmunomodulatory effects of social disruptionstressDuring physiological or psychologicalstress, catecholamines produced by thesympathetic nervous system (SNS) regulate theimmune system. Previous studies report that theactivation of β-adrenergic receptors (βARs)mediates the actions of catecholamines andincreases pro-inflammatory cytokine productionin a number of different cell types. The impact ofthe SNS on the immune modulation of socialdefeat has not been examined. The followingstudies were designed to determine whether SNSactivation during social disruption stress (SDR)influences anxiety-like behavior as well as theactivation, priming, and glucocorticoid resistanceof splenocytes after social stress. CD-1 micewere exposed to one, three, or six cycles of SDRand HPLC analysis of the plasma and spleenrevealed an increase in catecholamines. After sixcycles of SDR the open field test was used tomeasure behaviors characteristic of anxiety and", "metadata": {}}
+{"_id": "3944632", "title": "", "text": "Stereotactic radiosurgery plus whole-brainradiation therapy vs stereotactic radiosurgeryalone for treatment of brain metastases: arandomized controlled trial.CONTEXT In patientswith brain metastases, it is unclear whetheradding up-front whole-brain radiation therapy(WBRT) to stereotactic radiosurgery (SRS) hasbeneficial effects on mortality or neurologicfunction compared with SRS alone. OBJECTIVETo determine if WBRT combined with SRS resultsin improvements in survival, brain tumor control,functional preservation rate, and frequency ofneurologic death. DESIGN, SETTING, ANDPATIENTS Randomized controlled trial of 132patients with 1 to 4 brain metastases, each lessthan 3 cm in diameter, enrolled at 11 hospitals inJapan between October 1999 and December2003. INTERVENTIONS Patients were randomlyassigned to receive WBRT plus SRS (65 patients)or SRS alone (67 patients). MAIN OUTCOMEMEASURES The primary end point was overallsurvival; secondary end points were brain tumor", "metadata": {}}
+{"_id": "3952288", "title": "", "text": "RANK signals from CD4+3− inducer cellsregulate development of Aire-expressingepithelial cells in the thymicmedullaAire-expressing medullary thymicepithelial cells (mTECs) play a key role inpreventing autoimmunity by expressingtissue-restricted antigens to help purge theemerging T cell receptor repertoire ofself-reactive specificities. Here we demonstrate anovel role for a CD4+3− inducer cell population,previously linked to development of organizedsecondary lymphoid structures and maintenanceof T cell memory in the functional regulation ofAire-mediated promiscuous gene expression inthe thymus. CD4+3− cells are closely associatedwith mTECs in adult thymus, and in fetal thymustheir appearance is temporally linked with theappearance of Aire+ mTECs. We show thatRANKL signals from this cell promote thematuration of RANK-expressing CD80−Aire−mTEC progenitors into CD80+Aire+ mTECs, andthat transplantation of RANK-deficient thymic", "metadata": {}}
+{"_id": "3960385", "title": "", "text": "Proteomic approach to characterize biochemistryof meat quality defects.Proteomics can be usedto characterize quality defects including pale,soft, and exudative (PSE) meat (pork andpoultry), woody broiler breast meat, reddishcatfish fillets, meat toughness, and beefmyoglobin oxidation. PSE broiler meat wascharacterized by 15 proteins that differed inabundance in comparison to normal broilerbreast meat, and eight proteins weredifferentially expressed in woody breast meat incomparison to normal breast meat. Hemoglobinwas the only protein that was differentiallyexpressed between red and normal catfish fillets.However, inducing low oxygen and/or heat stressconditions to catfish fillets did not lead to theproduction of red fillets. Proteomic data providedinformation pertaining to the protein differencesthat exist in meat quality defects. However,these data need to be evaluated in conjunctionwith information pertaining to genetics, nutrition,environment of the live animal, muscle to meat", "metadata": {}}
+{"_id": "3973445", "title": "", "text": "Phosphorylation of Janus kinase 1 (JAK1) byAMP-activated protein kinase (AMPK) linksenergy sensing to anti-inflammatorysignalingAdenosine 5′-monophosphate–activatedprotein kinase (AMPK) is a pivotal regulator ofmetabolism at cellular and organismal levels.AMPK also suppresses inflammation. We foundthat pharmacological activation of AMPK rapidlyinhibited the Janus kinase (JAK)–signaltransducer and activator of transcription (STAT)pathway in various cells. In vitro kinase assaysrevealed that AMPK directly phosphorylated tworesidues (Ser515 and Ser518) within the Srchomology 2 domain of JAK1. Activation of AMPKenhanced the interaction between JAK1 and14-3-3 proteins in cultured vascular endothelialcells and fibroblasts, an effect that required thepresence of Ser515 and Ser518 and wasabolished in cells lacking AMPK catalyticsubunits. Mutation of Ser515 and Ser518abolished AMPK-mediated inhibition of JAK-STATsignaling stimulated by either the sIL-6Rα/IL-6", "metadata": {}}
+{"_id": "3981033", "title": "", "text": "IAP antagonists induce anti-tumor immunity inmultiple myelomaThe cellular inhibitors ofapoptosis (cIAP) 1 and 2 are amplified in about3% of cancers and have been identified inmultiple malignancies as being potentialtherapeutic targets as a result of their role in theevasion of apoptosis. Consequently,small-molecule IAP antagonists, such as LCL161,have entered clinical trials for their ability toinduce tumor necrosis factor (TNF)-mediatedapoptosis of cancer cells. However, cIAP1 andcIAP2 are recurrently homozygously deleted inmultiple myeloma (MM), resulting in constitutiveactivation of the noncanonical nuclear factor(NF)-κB pathway. To our surprise, we observedrobust in vivo anti-myeloma activity of LCL161 ina transgenic myeloma mouse model and inpatients with relapsed-refractory MM, where theaddition of cyclophosphamide resulted in amedian progression-free-survival of 10 months.This effect was not a result of direct induction oftumor cell death, but rather of upregulation of", "metadata": {}}
+{"_id": "3981244", "title": "", "text": "Psychobiological Protective Factors Modifying theAssociation Between Age and Sexual Health inMen: Findings From the Men’s Health 40+StudySexual health severely decreases with age.For males older than 40 years, erectiledysfunction (ED) is the most common sexualdisorder. Although physical and psychologicalrisk factors for ED have been identified,protective factors are yet to be determined. Todate, no study has examined endocrine andpsychosocial factors in parallel with regard totheir modifying effect on the age-relatedincrease in ED. Two hundred and seventy-oneself-reporting healthy men aged between 40 and75 years provided both psychometric data onsexual function and a set of potentialpsychosocial protective factors, and salivasamples for the analysis of steroid hormones andproinflammatory cytokines. Around 35% of theparticipants reported at least a mild form of ED.Direct associations with ED were identified forperceived general health, emotional support,", "metadata": {}}
+{"_id": "3981613", "title": "", "text": "Patient-derived induced pluripotent stem cells incancer research and precision oncologyTogetherwith recent advances in the processing andculture of human tissue, bioengineering,xenotransplantation and genome editing,Induced pluripotent stem cells (iPSCs) present arange of new opportunities for the study ofhuman cancer. Here we discuss the mainadvantages and limitations of iPSC modeling,and how the method intersects with otherpatient-derived models of cancer, such asorganoids, organs-on-chips and patient-derivedxenografts (PDXs). We highlight theopportunities that iPSC models can providebeyond those offered by existing systems andanimal models and present current challengesand crucial areas for future improvementstoward wider adoption of this technology.", "metadata": {}}
+{"_id": "3981729", "title": "", "text": "Structural basis for sequence-specific recognitionof DNA by TAL effectors.TAL (transcriptionactivator-like) effectors, secreted byphytopathogenic bacteria, recognize host DNAsequences through a central domain of tandemrepeats. Each repeat comprises 33 to 35conserved amino acids and targets a specificbase pair by using two hypervariable residues[known as repeat variable diresidues (RVDs)] atpositions 12 and 13. Here, we report the crystalstructures of an 11.5-repeat TAL effector in bothDNA-free and DNA-bound states. Each TALrepeat comprises two helices connected by ashort RVD-containing loop. The 11.5 repeatsform a right-handed, superhelical structure thattracks along the sense strand of DNA duplex,with RVDs contacting the major groove. The 12thresidue stabilizes the RVD loop, whereas the13th residue makes a base-specific contact.Understanding DNA recognition by TAL effectorsmay facilitate rational design of DNA-bindingproteins with biotechnological applications.", "metadata": {}}
+{"_id": "3984231", "title": "", "text": "Caveolin-1 deletion exacerbates cardiacinterstitial fibrosis by promoting M2 macrophageactivation in mice after myocardialinfarction.Adverse remodeling followingmyocardial infarction (MI) leading to heart failureis driven by an imbalanced resolution ofinflammation. The macrophage cell is animportant control of post-MI inflammation, asmacrophage subtypes secrete mediators toeither promote inflammation and extend injury(M1 phenotype) or suppress inflammation andpromote scar formation (M2 phenotype). Wehave previously shown that the absence ofcaveolin-1 (Cav1), a membrane scaffoldingprotein, is associated with adverse cardiacremodeling in mice, but the mechanismsresponsible remain to be elucidated. We explorehere the role of Cav1 in the activation ofmacrophages using wild type C57BL6/J (WT) andCav1(tm1Mls/J) (Cav1(-/-)) mice. Byechocardiography, cardiac function wascomparable between WT and Cav1(-/-) mice at", "metadata": {}}
+{"_id": "3986403", "title": "", "text": "Lipid hydroperoxide measurement by oxidationof Fe2+ in the presence of xylenol orange.Comparison with the TBA assay and aniodometric methodStudy of the role ofhydroperoxides and lipid peroxidation in diseaserequires simple and sensitive methods for directhydroperoxide measurement. We report on atechnique for measuring hydroperoxide whichrelies upon the rapid hydroperoxide-mediatedoxidation of Fe2+ under acidic conditions. Fe3+forms a chromophore with xylenol orange whichabsorbs strongly at 560 nm, yielding an apparentE560 (for H2O2, butyl hydroperoxide andcumene hydroperoxide) of 4.3×104 M−1 cm−1.The assay was validated in a study of liposomallipid peroxidation and shown to give resultscomparable with those obtained by an iodometricmethod or by measuring conjugated dienes. Theassay involving thiobarbituric acid, bycomparison, underestimates lipid peroxidationand does not measure hydroperoxideper se.", "metadata": {}}
+{"_id": "4020950", "title": "", "text": "Roles of exosomes in cardioprotection.Exosomesare extracellular vesicles of endosomal originwhich have emerged as key mediators ofintercellular communication. All major cardiaccell types-including cardiomyocytes, endothelialcells, and fibroblasts-release exosomes thatmodulate cellular functions. Exosomes releasedfrom human cardiac progenitor cells (CPCs) arecardioprotective and improve cardiac functionafter myocardial infarction to an extentcomparable with that achieved by their parentcells. Cardiac progenitor cell-derived exosomesare enriched in cardioprotective microRNAs,particularly miR-146a-3p. Circulating exosomesmediate remote ischaemic preconditioning.Moreover, they currently are being investigatedas diagnostic markers. The discovery thatcell-derived extracellular signalling organellesmediate the paracrine effects of stem cellssuggests that cell-free strategies could supplantcell transplantation. This review discussesemerging roles of exosomes in cardiovascular", "metadata": {}}
+{"_id": "4036038", "title": "", "text": "The rate of change in declining steroidhormones: a new parameter of healthy aging inmen?Research on healthy aging in men hasincreasingly focused on age-related hormonalchanges. Testosterone (T) decline is primarilyinvestigated, while age-related changes in othersex steroids (dehydroepiandrosterone [DHEA],estradiol [E2], progesterone [P]) are mostlyneglected. An integrated hormone parameterreflecting aging processes in men has yet to beidentified. 271 self-reporting healthy menbetween 40 and 75 provided both psychometricdata and saliva samples for hormone analysis.Correlation analysis between age and sexsteroids revealed negative associations for thefour sex steroids (T, DHEA, E2, and P). Principalcomponent analysis including ten salivaryanalytes identified a principal component mainlyunifying the variance of the four sex steroidhormones. Subsequent principal componentanalysis including the four sex steroids extractedthe principal component of declining steroid", "metadata": {}}
+{"_id": "4037034", "title": "", "text": "Development of a novel helper-dependentadenovirus-Epstein-Barr virus hybrid system forthe stable transformation of mammaliancells.Epstein-Barr virus (EBV) episomes arestably maintained in permissive proliferating celllines due to EBV nuclear antigen 1 (EBNA-1)protein-mediated replication and segregation.Previous studies showed the ability of EBVepisomes to confer long-term transgeneexpression and correct genetic defects indeficient cells. To achieve quantitative delivery ofEBV episomes in vitro and in vivo, we developeda binary helper-dependent adenovirus(HDA)-EBV hybrid system that consists of oneHDA vector for the expression of Crerecombinase and a second HDA vector thatcontains all of the sequences for the EBVepisome flanked by loxP sites. Upon coinfectionof cells, Cre expressed from the first vectorrecombined loxP sites on the second vector. Theresulting circular EBV episomes expressed atransgene and contained the EBV-derived family", "metadata": {}}
+{"_id": "4067274", "title": "", "text": "Spliceosome assembly pathways for differenttypes of alternative splicing converge duringcommitment to splice site pairing in the Acomplex.Differential splice site pairingestablishes alternative splicing patterns resultingin the generation of multiple mRNA isoforms.This process is carried out by the spliceosome,which is activated by a series of sequentialstructural rearrangements of its five coresnRNPs. To determine when splice sites becomefunctionally paired, we carried out a series ofkinetic trap experiments using pre-mRNAs thatundergo alternative 5' splice site selection oralternative exon inclusion. We show thatcommitment to splice site pairing in both casesoccurs in the A complex, which is characterizedby the ATP-dependent association of the U2snRNP with the branch point. Interestingly, thetiming of splice site pairing is independent of theintron or exon definition modes of splice siterecognition. Using the ATP analog ATPgammaS,we showed that ATP hydrolysis is required for", "metadata": {}}
+{"_id": "4085204", "title": "", "text": "Transcripts of the MHM region on the chicken Zchromosome accumulate as non-coding RNA inthe nucleus of female cells adjacent to theDMRT1 locusThe male hypermethylated (MHM)region, located near the middle of the short armof the Z chromosome of chickens, consists ofapproximately 210 tandem repeats of a BamHI2.2-kb sequence unit. Cytosines of the CpGdinucleotides of this region are extensivelymethylated on the two Z chromosomes in themale but much less methylated on the single Zchromosome in the female. The state ofmethylation of the MHM region is establishedafter fertilization by about the 1-day embryonicstage. The MHM region is transcribed only in thefemale from the particular strand intoheterogeneous, high molecular-mass,non-coding RNA, which is accumulated at the siteof transcription, adjacent to the DMRT1 locus, inthe nucleus. The transcriptional silence of theMHM region in the male is most likely caused bythe CpG methylation, since treatment of the", "metadata": {}}
+{"_id": "4138659", "title": "", "text": "Macropinocytosis of protein is an amino acidsupply route in Ras-transformedcellsMacropinocytosis is a highly conservedendocytic process by which extracellular fluidand its contents are internalized into cellsthrough large, heterogeneous vesicles known asmacropinosomes. Oncogenic Ras proteins havebeen shown to stimulate macropinocytosis butthe functional contribution of this uptakemechanism to the transformed phenotyperemains unknown. Here we show thatRas-transformed cells use macropinocytosis totransport extracellular protein into the cell. Theinternalized protein undergoes proteolyticdegradation, yielding amino acids includingglutamine that can enter central carbonmetabolism. Accordingly, the dependence ofRas-transformed cells on free extracellularglutamine for growth can be suppressed by themacropinocytic uptake of protein. Consistentwith macropinocytosis representing an importantroute of nutrient uptake in tumours, its", "metadata": {}}
+{"_id": "4162857", "title": "", "text": "Linking Splicing to Pol II Transcription StabilizesPre-mRNAs and Influences Splicing PatternsRNAprocessing is carried out in close proximity to thesite of transcription, suggesting a regulatory linkbetween transcription and pre-mRNA splicing.Using an in vitro transcription/splicing assay, wedemonstrate that an association of RNApolymerase II (Pol II) transcription andpre-mRNA splicing is required for efficient geneexpression. Pol II-synthesized RNAs containingfunctional splice sites are protected from nucleardegradation, presumably because the localconcentration of the splicing machinery issufficiently high to ensure its association overinteractions with nucleases. Furthermore, theprocess of transcription influences alternativesplicing of newly synthesized pre-mRNAs.Because other RNA polymerases do not providesimilar protection from nucleases, and their RNAproducts display altered splicing patterns, thelink between transcription and RNA processing isRNA Pol II-specific. We propose that the", "metadata": {}}
+{"_id": "4164929", "title": "", "text": "The emerging role of skeletal muscleextracellular matrix remodelling in obesity andexercise.Skeletal muscle extracellular matrixremodelling has been proposed as a new featureassociated with obesity and metabolicdysfunction. Exercise training improves musclefunction in obesity, which may be mediated byregulatory effects on the muscle extracellularmatrix. This review examined available literatureon skeletal muscle extracellular matrixremodelling during obesity and the effects ofexercise. A non-systematic literature review wasperformed on PubMed of publications from 1970to 2015. A total of 37 studies from humans andanimals were retained. Studies reported overallincreases in gene and protein expression ofdifferent types of collagen, growth factors andenzymatic regulators of the skeletal muscleextracellular matrix in obesity. Only two studiesinvestigated the effects of exercise on skeletalmuscle extracellular matrix during obesity, withboth suggesting a regulatory effect of exercise.", "metadata": {}}
+{"_id": "4200695", "title": "", "text": "Effect of specific exercise strategy on need forsurgery in patients with subacromialimpingement syndrome: randomised controlledstudyOBJECTIVE To evaluate if a specificexercise strategy, targeting the rotator cuff andscapula stabilisers, improves shoulder functionand pain more than unspecific exercises inpatients with subacromial impingementsyndrome, thereby decreasing the need forarthroscopic subacromial decompression.DESIGN Randomised, participant and singleassessor blinded, controlled study. SETTINGDepartment of orthopaedics in a Swedishuniversity hospital. PARTICIPANTS 102 patientswith long standing (over six months) persistentsubacromial impingement syndrome in whomearlier conservative treatment had failed,recruited through orthopaedic specialists.INTERVENTIONS The specific exercise strategyconsisted of strengthening eccentric exercises forthe rotator cuff and concentric/eccentricexercises for the scapula stabilisers in", "metadata": {}}
+{"_id": "4231060", "title": "", "text": "Nucleotide sequence of an avian sarcoma virusoncogene (src) and proposed amino acidsequence for gene productThe transforming gene(src) of avian sarcoma virus (ASV) and adjacentregions of the viral genome have been isolatedby molecular cloning of viral DNA. Theirnucleotide sequence encompasses the whole ofsrc and the portion of the gene env that encodesgp 37, one of two glycoproteins found in the viralenvelope. Src encodes a single, hydrophobicprotein with structural features that conform toprevious descriptions of the gene product(pp60src). It appears that a single viral protein isresponsible for both the initiation andmaintenance of neoplastic transformation byavian sarcoma virus. Neither src nor its productbear any obvious structural relationship toseveral other viral oncogenes and their encodedproteins. Src is flanked by a repeated nucleotidesequence that may facilitate frequent deletion ofthe gene from the viral genome.", "metadata": {}}
+{"_id": "4246523", "title": "", "text": "Issues in design and interpretation of MDR-TBclinical trials: report of the first Global MDR-TBClinical Trials Landscape MeetingRecognizing thatthe current MDR-TB regimen is suboptimal andbased on low-quality evidence, the GlobalMDR-TB Clinical Trials Landscape Meeting washeld in December, 2014 to strategize aboutcoordination of research and development of newtreatment regimens for this disease that affectsmillions of people worldwide every year. Sixtyinternational experts on multidrug-resistanttuberculosis (MDR-TB) met in Washington D.C.and Cape Town, South Africa to consider keyMDR-TB trial-related issues, including:standardization of definitions; clinical trialcapacity building and; regimens optimized tofoster compliance, avoid the emergence ofresistance and have clinical relevance for specialpopulations, including children and thoseco-infected with HIV. Underpinning all of this isthe generation of a sufficient evidence base tofacilitate regulatory approval and improved", "metadata": {}}
+{"_id": "4254064", "title": "", "text": "Para-aortic splanchnopleura from early mouseembryos contains B1a cellprogenitorsDEFINITIVE erythropoiesis in birdsoriginates from stem cells that emerge in thesplanchnopleural mesoderm near the embryonicaorta1–4. The yolk sac is still generally held tobe the unique provider of haematopoietic stemcells during mammalian ontogeny5, althoughthere may be an alternative intraembryonicsource of stem cells in the mouse fetus6,7. Herewe search for a possible non-yolk-sac source ofstem cells by grafting intraembryonicsplanchnopleura from 10- to 18-somite mouseembryos into adult immunodeficient SCID mice.We find significant amounts of donor-derivedserum IgM, normal numbers of IgM-secretingplasma cells, and the Bla (IgMabrightB220dullCD5+) cell subset to be fullyreconstituted by donor progenitors 3 to 6 monthsafter engraftment. The haematogenic capacityrevealed in our experiments is present in apreviously unrecognized site, the earliest", "metadata": {}}
+{"_id": "4256553", "title": "", "text": "Establishment in culture of pluripotential cellsfrom mouse embryosPluripotential cells arepresent in a mouse embryo until at least an earlypost-implantation stage, as shown by their abilityto take part hi the formation of chimaericanimals1 and to form teratocarcinomas2. Untilnow it has not been possible to establishprogressively growing cultures of these cells invitro, and cell lines have only been obtained afterteratocarcinoma formation in vivo. We reporthere the establishment in tissue culture ofpluripotent cell lines which have been isolateddirectly from in vitro cultures of mouseblastocysts. These cells are able to differentiateeither in vitro or after innoculation into a mouseas a tumour in vivo. They have a normalkaryotype.", "metadata": {}}
+{"_id": "4270992", "title": "", "text": "MHC class II interaction with CD4 mediated by aregion analogous to the MHC class I binding sitefor CD8INTERACTIONS between majorhistocompatibility complex (MHC) molecules andthe CD4 or CDS coreceptors have a major role inintrathymic T-cell selection1. On mature T cells,each of these two glycoproteins is associatedwith a class-specific bias in MHC moleculerecognition by the T-cell receptor. CD4+ T cellsrespond to antigen in association with MHC classII molecules and CD8+ T cells respond to antigenin association with MHC class I molecules.Physical interaction between the CD4/MHC classII molecules and CD8/MHC class I molecules hasbeen demonstrated by cell adhesion assay2–5,and a binding site for CDS on class I has beenidentified6,7. Here we demonstrate that a regionof the MHC class IIβ-chain β2 domain,structurally analogous to the CDS-binding loop inthe MHC class I α3 domain, is critical for functionwith both mouse and human CD4.", "metadata": {}}
+{"_id": "4283694", "title": "", "text": "Instability and decay of the primary structure ofDNAAlthough DNA is the carrier of geneticinformation, it has limited chemical stability.Hydrolysis, oxidation and nonenzymaticmethylation of DNA occur at significant ratesinvivo, and are counteracted by specific DNA repairprocesses. The spontaneous decay of DNA islikely to be a major factor in mutagenesis,carcinogenesis and ageing, and also sets limitsfor the recovery of DNA fragments from fossils.", "metadata": {}}
+{"_id": "4300851", "title": "", "text": "Single-cell proteomic analysis of S. cerevisiaereveals the architecture of biological noiseAmajor goal of biology is to provide a quantitativedescription of cellular behaviour. This task,however, has been hampered by the difficulty inmeasuring protein abundances and theirvariation. Here we present a strategy that pairshigh-throughput flow cytometry and a library ofGFP-tagged yeast strains to monitor rapidly andprecisely protein levels at single-cell resolution.Bulk protein abundance measurements of>2,500 proteins in rich and minimal mediaprovide a detailed view of the cellular responseto these conditions, and capture many changesnot observed by DNA microarray analyses. Oursingle-cell data argue that noise in proteinexpression is dominated by the stochasticproduction/destruction of messenger RNAs.Beyond this global trend, there are dramaticprotein-specific differences in noise that arestrongly correlated with a protein's mode oftranscription and its function. For example,", "metadata": {}}
+{"_id": "4303075", "title": "", "text": "Direct conversion of fibroblasts to functionalneurons by defined factorsCellular differentiationand lineage commitment are considered to berobust and irreversible processes duringdevelopment. Recent work has shown thatmouse and human fibroblasts can bereprogrammed to a pluripotent state with acombination of four transcription factors. Thisraised the question of whether transcriptionfactors could directly induce other definedsomatic cell fates, and not only anundifferentiated state. We hypothesized thatcombinatorial expression ofneural-lineage-specific transcription factors coulddirectly convert fibroblasts into neurons. Startingfrom a pool of nineteen candidate genes, weidentified a combination of only three factors,Ascl1, Brn2 (also called Pou3f2) and Myt1l, thatsuffice to rapidly and efficiently convert mouseembryonic and postnatal fibroblasts intofunctional neurons in vitro. These inducedneuronal (iN) cells express multiple", "metadata": {}}
+{"_id": "4303939", "title": "", "text": "Inflammasome-mediated dysbiosis regulatesprogression of NAFLD and obesityNon-alcoholicfatty liver disease (NAFLD) is the hepaticmanifestation of metabolic syndrome and theleading cause of chronic liver disease in theWestern world. Twenty per cent of NAFLDindividuals develop chronic hepatic inflammation(non-alcoholic steatohepatitis, NASH) associatedwith cirrhosis, portal hypertension andhepatocellular carcinoma, yet the causes ofprogression from NAFLD to NASH remainobscure. Here, we show that the NLRP6 andNLRP3 inflammasomes and the effector proteinIL-18 negatively regulate NAFLD/NASHprogression, as well as multiple aspects ofmetabolic syndrome via modulation of the gutmicrobiota. Different mouse models reveal thatinflammasome-deficiency-associated changes inthe configuration of the gut microbiota areassociated with exacerbated hepatic steatosisand inflammation through influx of TLR4 andTLR9 agonists into the portal circulation, leading", "metadata": {}}
+{"_id": "4305576", "title": "", "text": "Chromatin remodelling at promoters suppressesantisense transcriptionChromatin allows theeukaryotic cell to package its DNA efficiently. Tounderstand how chromatin structure is controlledacross the Saccharomyces cerevisiae genome,we have investigated the role of theATP-dependent chromatin remodelling complexIsw2 in positioning nucleosomes. We find thatIsw2 functions adjacent to promoter regionswhere it repositions nucleosomes at the interfacebetween genic and intergenic sequences.Nucleosome repositioning by Isw2 is directionaland results in increased nucleosome occupancyof the intergenic region. Loss of Isw2 activityleads to inappropriate transcription, resulting inthe generation of both coding and noncodingtranscripts. Here we show that Isw2 repositionsnucleosomes to enforce directionality ontranscription by preventing transcriptioninitiation from cryptic sites. Our analyses revealhow chromatin is organized on a global scale andadvance our understanding of how transcription", "metadata": {}}
+{"_id": "4306711", "title": "", "text": "The Human Mitochondrial DEAD-Box ProteinDDX28 Resides in RNA Granules and Functions inMitoribosome Assembly.Human mitochondrialribosomes are specialized in the synthesis of 13proteins, which are fundamental components ofthe oxidative phosphorylation system. Thepathway of mitoribosome biogenesis, thecompartmentalization of the process, and factorsinvolved remain largely unknown. Here, we haveidentified the DEAD-box protein DDX28 as anRNA granule component essential for thebiogenesis of the mitoribosome large subunit(mt-LSU). DDX28 interacts with the 16S rRNAand the mt-LSU. RNAi-mediated DDX28 silencingin HEK293T cells does not affect mitochondrialmRNA stability or 16S rRNA processing ormodification. However, it leads to reduced levelsof 16S rRNA and mt-LSU proteins, impairedmt-LSU assembly, deeply attenuatedmitochondrial protein synthesis, and consequentfailure to assemble oxidative phosphorylationcomplexes. Our findings identify DDX28 as", "metadata": {}}
+{"_id": "4311206", "title": "", "text": "Conversion of Adult Pancreatic α-cells to β-cellsAfter Extreme β-cell LossPancreaticinsulin-producing beta-cells have a long lifespan,such that in healthy conditions they replicatelittle during a lifetime. Nevertheless, they showincreased self-duplication after increasedmetabolic demand or after injury (that is,beta-cell loss). It is not known whether adultmammals can differentiate (regenerate) newbeta-cells after extreme, total beta-cell loss, asin diabetes. This would indicate differentiationfrom precursors or another heterologous(non-beta-cell) source. Here we show beta-cellregeneration in a transgenic model ofdiphtheria-toxin-induced acute selectivenear-total beta-cell ablation. If given insulin, themice survived and showed beta-cell massaugmentation with time. Lineage-tracing to labelthe glucagon-producing alpha-cells beforebeta-cell ablation tracked large fractions ofregenerated beta-cells as deriving fromalpha-cells, revealing a previously disregarded", "metadata": {}}
+{"_id": "4312169", "title": "", "text": "Driver mutations in histone H3.3 and chromatinremodelling genes in paediatricglioblastomaGlioblastoma multiforme (GBM) is alethal brain tumour in adults and children.However, DNA copy number and gene expressionsignatures indicate differences between adultand paediatric cases. To explore the geneticevents underlying this distinction, we sequencedthe exomes of 48 paediatric GBM samples.Somatic mutations in the H3.3-ATRX-DAXXchromatin remodelling pathway were identified in44% of tumours (21/48). Recurrent mutations inH3F3A, which encodes thereplication-independent histone 3 variant H3.3,were observed in 31% of tumours, and led toamino acid substitutions at two critical positionswithin the histone tail (K27M, G34R/G34V)involved in key regulatory post-translationalmodifications. Mutations in ATRX(α-thalassaemia/mental retardation syndromeX-linked) and DAXX (death-domain associatedprotein), encoding two subunits of a chromatin", "metadata": {}}
+{"_id": "4313478", "title": "", "text": "Translational control of intron splicing ineukaryotesMost eukaryotic genes are interruptedby non-coding introns that must be accuratelyremoved from pre-messenger RNAs to producetranslatable mRNAs. Splicing is guided locally byshort conserved sequences, but genes typicallycontain many potential splice sites, and themechanisms specifying the correct sites remainpoorly understood. In most organisms, shortintrons recognized by the intron definitionmechanism cannot be efficiently predicted solelyon the basis of sequence motifs. In multicellulareukaryotes, long introns are recognized throughexon definition and most genes produce multiplemRNA variants through alternative splicing. Thenonsense-mediated mRNA decay (NMD) pathwaymay further shape the observed sets of variantsby selectively degrading those containingpremature termination codons, which arefrequently produced in mammals. Here we showthat the tiny introns of the ciliate Parameciumtetraurelia are under strong selective pressure to", "metadata": {}}
+{"_id": "4319174", "title": "", "text": "Alternatively activated macrophages producecatecholamines to sustain adaptivethermogenesisAll homeotherms usethermogenesis to maintain their core bodytemperature, ensuring that cellular functions andphysiological processes can continue in coldenvironments. In the prevailing model ofthermogenesis, when the hypothalamus sensescold temperatures it triggers sympatheticdischarge, resulting in the release ofnoradrenaline in brown adipose tissue and whiteadipose tissue. Acting via the β(3)-adrenergicreceptors, noradrenaline induces lipolysis inwhite adipocytes, whereas it stimulates theexpression of thermogenic genes, such asPPAR-γ coactivator 1a (Ppargc1a), uncouplingprotein 1 (Ucp1) and acyl-CoA synthetaselong-chain family member 1 (Acsl1), in brownadipocytes. However, the precise nature of allthe cell types involved in this efferent loop is notwell established. Here we report in mice anunexpected requirement for the interleukin-4", "metadata": {}}
+{"_id": "4319844", "title": "", "text": "Alternative Lengthening of Telomeres Mediatedby Mitotic DNA Synthesis Engages Break-InducedReplication Processes.Alternative lengthening oftelomeres (ALT) is a telomerase-independenttelomere maintenance mechanism that occurs ina subset of cancers. By analyzingtelomerase-positive cells and their human TERCknockout-derived ALT human cell lines, we showthat ALT cells harbor more fragile telomeresrepresenting telomere replication problems.ALT-associated replication defects trigger mitoticDNA synthesis (MiDAS) at telomeres in aRAD52-dependent, but RAD51-independent,manner. Telomeric MiDAS is a conservative DNAsynthesis process, potentially mediated bybreak-induced replication, similar to type II ALTsurvivors in Saccharomyces cerevisiaeReplication stresses induced by ectopiconcogenic expression of cyclin E,G-quadruplexes, or R-loop formation facilitatethe ALT pathway and lead to telomere clustering,a hallmark of ALT cancers. The TIMELESS/TIPIN", "metadata": {}}
+{"_id": "4320111", "title": "", "text": "Light acts directly on organs and cells in cultureto set the vertebrate circadian clock.Theexpression of clock genes in vertebrates iswidespread and not restricted to classical clockstructures. The expression of the Clock gene inzebrafish shows a strong circadian oscillation inmany tissues in vivo and in culture, showing thatendogenous oscillators exist in peripheralorgans. A defining feature of circadian clocks isthat they can be set or entrained to local time,usually by the environmental light-dark cycle. Animportant question is whether peripheraloscillators are entrained to local time by signalsfrom central pacemakers such as the eyes or arethemselves directly light-responsive. Here weshow that the peripheral organ clocks ofzebrafish are set by light-dark cycles in culture.We also show that a zebrafish-derived cell linecontains a circadian oscillator, which is alsodirectly light entrained.", "metadata": {}}
+{"_id": "4320424", "title": "", "text": "Small molecule inhibition of the KRAS–PDEδinteraction impairs oncogenic KRAS signallingTheKRAS oncogene product is considered a majortarget in anticancer drug discovery. However,direct interference with KRAS signalling has notyet led to clinically useful drugs. Correctlocalization and signalling by farnesylated KRASis regulated by the prenyl-binding protein PDEδ,which sustains the spatial organization of KRASby facilitating its diffusion in the cytoplasm. Herewe report that interfering with binding ofmammalian PDEδ to KRAS by means of smallmolecules provides a novel opportunity tosuppress oncogenic RAS signalling by altering itslocalization to endomembranes. Biochemicalscreening and subsequent structure-based hitoptimization yielded inhibitors of the KRAS–PDEδinteraction that selectively bind to theprenyl-binding pocket of PDEδ with nanomolaraffinity, inhibit oncogenic RAS signalling andsuppress in vitro and in vivo proliferation ofhuman pancreatic ductal adenocarcinoma cells", "metadata": {}}
+{"_id": "4321295", "title": "", "text": "Evolution of novel cooperative swarming in thebacterium Myxococcus xanthusCooperationamong individuals is necessary for evolutionarytransitions to higher levels of biologicalorganization. In such transitions, groups ofindividuals at one level (such as single cells)cooperate to form selective units at a higherlevel (such as multicellular organisms). Thoughthe evolution of cooperation is difficult to observedirectly in higher eukaryotes, microorganisms dooffer such an opportunity. Here we report theevolution of novel cooperative behaviour inexperimental lineages of the bacteriumMyxococcus xanthus. Wild-type strains of M.xanthus exhibit socially dependent swarmingacross soft surfaces by a mechanism known as‘S-motility’ that requires the presence ofextracellular type IV pili. In lineages of M.xanthus unable to make pili, a new mechanisticbasis for cooperative swarming evolved. Evolvedswarming is mediated, at least in part, byenhanced production of an extracellular fibril", "metadata": {}}
+{"_id": "4321947", "title": "", "text": "Exon duplication and divergence in the humanpreproglucagon geneGlucagon is a 29-amino acidpancreatic hormone which counteracts the bloodglucose-lowering action of insulin by stimulatinghepatic glycogenolysis and gluconeogenesis1.The structure of the hamster pancreatic glucagonprecursor has recently been determined from thesequence of a cloned cDNA2. Hamsterpreproglucagon is a 180-amino acid proteinwhich contains five functional regions; a signal orpre-peptide, an NH2-terminal peptide (alsocalled glicentin-related pancreatic peptide,GRPP), glucagon, and two carboxy-terminalglucagon-like peptides (GLP-1 and GLP-2). Thesequences of two non-allelic anglerfishpancreatic glucagon precursors3–5 have alsobeen determined and their organization is similarbut not identical to the hamster protein; theylack the polypeptide segment corresponding tohamster GLP-2. The presence of three regionspossessing internal homology, that is, glucagon,GLP-1 and GLP-2, within proglucagon, and the", "metadata": {}}
+{"_id": "4323425", "title": "", "text": "BH1 and BH2 domains of Bcl-2 are required forinhibition of apoptosis and heterodimerizationwith BaxBCL-2 was isolated from the t(14;18)chromosomal breakpoint in follicular B-celllymphoma1–3. Bcl-2 has the unique oncogenicrole of extending cell survival by inhibiting avariety of apoptotic deaths4–13. An emergingfamily of Bcl-2 -related proteins share two highlyconserved regions14–20 referred to here asBcl-2 homology 1 and 2 (BH1 and BH2) domains(Fig. 1). This includes Bax which heterodimerizeswith Bcl-2 and when overexpressed counteractsBcl-214. We report here that site-specificmutagenesis of Bcl-2 establishes the twodomains as novel dimerization motifs.Substitu-tion of Gly 145 in BHl domain or Trp188 in BH2 domain completely abrogated Bcl-2'sdeath-repressor activity in inter-leukin-3deprivation, γ-irradiation andglucocorticoid-induced apoptosis. Mutations thataffected Bcl-2's function also disrupted itsheterodimerization with Bax, yet still permitted", "metadata": {}}
+{"_id": "4323449", "title": "", "text": "KAP1 controls endogenous retroviruses inembryonic stem cellsMore than forty per cent ofthe mammalian genome is derived fromretroelements, of which about one-quarter areendogenous retroviruses (ERVs). Some are stillactive, notably in mice the highly polymorphicearly transposon (ETn)/MusD and intracisternalA-type particles (IAP). ERVs are transcriptionallysilenced during early embryogenesis by histoneand DNA methylation (and reviewed in ref. 7),although the initiators of this process, which isessential to protect genome integrity, remainlargely unknown. KAP1 (KRAB-associated protein1, also known as tripartite motif-containingprotein 28, TRIM28) represses genes byrecruiting the histone methyltransferaseSETDB1, heterochromatin protein 1 (HP1) andthe NuRD histone deacetylase complex, but fewof its physiological targets are known. Two linesof evidence suggest that KAP1-mediatedrepression could contribute to the control ofERVs: first, KAP1 can trigger permanent gene", "metadata": {}}
+{"_id": "4324278", "title": "", "text": "The TOR signalling pathway controls nuclearlocalization of nutrient-regulated transcriptionfactors.The rapamycin-sensitive TOR signallingpathway in Saccharomyces cerevisiae activates acell-growth program in response to nutrientssuch as nitrogen and carbon. The TOR1 andTOR2 kinases (TOR) control cytoplasmic proteinsynthesis and degradation through theconserved TAP42 protein. Upon phosphorylationby TOR, TAP42 binds and possibly inhibits type2A and type-2A-related phosphatases; however,the mechanism by which TOR controls nuclearevents such as global repression ofstarvation-specific transcription is unknown.Here we show that TOR prevents transcription ofgenes expressed upon nitrogen limitation bypromoting the association of the GATAtranscription factor GLN3 with the cytoplasmicprotein URE2. The binding of GLN3 to URE2requires TOR-dependent phosphorylation ofGLN3. Phosphorylation and cytoplasmic retentionof GLN3 are also dependent on the TOR effector", "metadata": {}}
+{"_id": "4325137", "title": "", "text": "Inhibition of pluripotential embryonic stem celldifferentiation by purified polypeptidesMurineembryonic stem (ES) cells are pluripotent celllines established directly from the earlyembryo1,2 which can contribute differentiatedprogeny to all adult tissues, including thegerm-cell lineage3, after re-incorporation intothe normal embryo. They provide both a cellularvector for the generation of transgenic animals4and a useful system for the identification ofpolypeptide factors controlling differentiationprocesses in early development5. In particular,medium conditioned by Buffalo rat liver cellscontains a polypeptide factor, ES celldifferentiation inhibitory activity (DIA), whichspecifically suppresses the spontaneousdifferentiation of ES cells in vitro, therebypermitting their growth as homogeneous stemcell populations in the absence of heterologousfeeder cells6. ES cell pluripotentiality, includingthe ability to give rise to functional gametes, ispreserved after prolonged culture in Buffalo rat", "metadata": {}}
+{"_id": "4325398", "title": "", "text": "Pancreatic cancer genomes reveal aberrations inaxon guidance pathway genesPancreatic canceris a highly lethal malignancy with few effectivetherapies. We performed exome sequencing andcopy number analysis to define genomicaberrations in a prospectively accrued clinicalcohort (n = 142) of early (stage I and II)sporadic pancreatic ductal adenocarcinoma.Detailed analysis of 99 informative tumoursidentified substantial heterogeneity with 2,016non-silent mutations and 1,628 copy-numbervariations. We define 16 significantly mutatedgenes, reaffirming known mutations (KRAS,TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1Aand SF3B1), and uncover novel mutated genesincluding additional genes involved in chromatinmodification (EPC1 and ARID2), DNA damagerepair (ATM) and other mechanisms (ZIM2,MAP2K4, NALCN, SLC16A4 and MAGEA6).Integrative analysis with in vitro functional dataand animal models provided supportive evidencefor potential roles for these genetic aberrations", "metadata": {}}
+{"_id": "4326318", "title": "", "text": "Rejuvenation of aged progenitor cells byexposure to a young systemic environmentThedecline of tissue regenerative potential is ahallmark of ageing and may be due toage-related changes in tissue-specific stem cells.A decline in skeletal muscle stem cell (satellitecell) activity due to a loss of Notch signallingresults in impaired regeneration of aged muscle.The decline in hepatic progenitor cell proliferationowing to the formation of a complex involvingcEBP-α and the chromatin remodelling factorbrahma (Brm) inhibits the regenerative capacityof aged liver. To examine the influence ofsystemic factors on aged progenitor cells fromthese tissues, we established parabiotic pairings(that is, a shared circulatory system) betweenyoung and old mice (heterochronic parabioses),exposing old mice to factors present in youngserum. Notably, heterochronic parabiosisrestored the activation of Notch signalling as wellas the proliferation and regenerative capacity ofaged satellite cells. The exposure of satellite cells", "metadata": {}}
+{"_id": "4335423", "title": "", "text": "Continuous single-cell imaging of bloodgeneration from haemogenic endotheliumDespitedecades of research, the identity of the cellsgenerating the first haematopoietic cells inmammalian embryos is unknown. Indeed,whether blood cells arise from mesodermal cells,mesenchymal progenitors, bipotentendothelial–haematopoietic precursors orhaemogenic endothelial cells remainscontroversial. Proximity of endothelial and bloodcells at sites of embryonic haematopoiesis, aswell as their similar gene expression, led to thehypothesis of the endothelium generating blood.However, owing to lacking technology it hasbeen impossible to observe blood cell emergencecontinuously at the single-cell level, and thepostulated existence of haemogenic endothelialcells remains disputed. Here, using new imagingand cell-tracking methods, we show thatembryonic endothelial cells can be haemogenic.By continuous long-term single-cell observationof mouse mesodermal cells generating", "metadata": {}}
+{"_id": "4335599", "title": "", "text": "Formation of germ-line chimaeras fromembryo-derived teratocarcinoma cell linesTherecent availability in culture of embryo-derivedpluripotential cells which exhibit both a normalkaryotype and a high differentiative ability1–3has encouraged us to assess the potential ofthese cells to form functional germ cells followingtheir incorporation into chimaeric mice. Wereport here the results of blastocyst injectionstudies using three independently isolated XYembryo-derived cell lines (EK.CP1, EK.CC1.1 andEKCC1.2) which produce a very high proportion(>50%) of live-born animals that are overtlychimaeric. Seven chimaeric male mice, derivedfrom these three lines, have, so far, proved to befunctional germ-line chimaeras.", "metadata": {}}
+{"_id": "4336849", "title": "", "text": "Chloroquine resistance not linked to mdr-likegenes in a Plasmodium falciparumcrossCHLOROQUINE is thought to act againstfalciparum malaria by accumulating in the acidvesicles of the parasite and interfering with theirfunction1\u00004. Parasites resistant to chloroquineexpel the drug rapidly in an unaltered form,thereby reducing levels of accumulation in thevesicles5. The discovery that verapamil partiallyreverses chloroquine resistance in vitro 6 led tothe proposal that efflux may involve anATP-driven P-glycoprotein pump similar to that inmammalian multidrug-resistant (mdr) tumor celllines. Indeed, Plasmodium falciparum contains atleast two mdr-like genes7,8, one of which hasbeen suggested to confer the chloroquineresistant (CQR) phenotype7,9,10. To determineif either of these genes is linked to chloroquineresistance, we performed a genetic crossbetween CQR and chloroquine-susceptible (CQS)clones of P. falciparum. Examination of 16independent recombinant progeny indicated that", "metadata": {}}
+{"_id": "4340358", "title": "", "text": "Identification of a cold receptor reveals a generalrole for TRP channels in thermosensationThecellular and molecular mechanisms that enableus to sense cold are not well understood.Insights into this process have come from theuse of pharmacological agents, such as menthol,that elicit a cooling sensation. Here we havecharacterized and cloned a menthol receptorfrom trigeminal sensory neurons that is alsoactivated by thermal stimuli in the cool to coldrange. This cold- and menthol-sensitive receptor,CMR1, is a member of the TRP family ofexcitatory ion channels, and we propose that itfunctions as a transducer of cold stimuli in thesomatosensory system. These findings, togetherwith our previous identification of theheat-sensitive channels VR1 and VRL-1,demonstrate that TRP channels detecttemperatures over a wide range and are theprincipal sensors of thermal stimuli in themammalian peripheral nervous system.", "metadata": {}}
+{"_id": "4340509", "title": "", "text": "Surface mechanics mediate pattern formation inthe developing retinaPattern formation ofbiological structures involves organizing differenttypes of cells into a spatial configuration. In thisstudy, we investigate the physical basis ofbiological patterning of the Drosophila retina invivo. We demonstrate that E- and N-cadherinsmediate apical adhesion between retina epithelialcells. Differential expression of N-cadherin withina sub-group of retinal cells (cone cells) causesthem to form an overall shape that minimizestheir surface contact with surrounding cells. Thecells within this group, in both normal andexperimentally manipulated conditions, packtogether in the same way as soap bubbles do.The shaping of the cone cell group and packingof its components precisely imitate the physicaltendency for surfaces to be minimized. Thus,simple patterned expression of N-cadherinresults in a complex spatial pattern of cells owingto cellular surface mechanics.", "metadata": {}}
+{"_id": "4343437", "title": "", "text": "Role of inscuteable in orienting asymmetric celldivisions in DrosophilaDrosophila neuroblastsand epithelial cells in the procephalic neurogenicregion divide perpendicular to the surface, andsegregate the proteins Numb and Prospero intothe basal daughter cell. We demonstrate herethat orientation of the mitotic spindle and correctlocalization of Numb and Prospero in these cellsrequire the inscuteable gene. Moreover, ectopicexpression of inscuteable in other epithelial cellsleads to spindle reorientation. The Inscuteableprotein localizes to the apical cell cortex beforemitosis, suggesting that Inscuteable functions inestablishing polarity for asymmetric cell division.", "metadata": {}}
+{"_id": "4343811", "title": "", "text": "Specific interference by ingested dsRNA.Agenetic interference phenomenon in thenematode Caenorhabditis elegans has beendescribed in which expression of an individualgene can be specifically reduced bymicroinjecting a corresponding fragment ofdouble-stranded (ds) RNA. One striking featureof this process is a spreading effect: interferencein a broad region of the animal is observedfollowing the injection of dsRNA into theextracellular body cavity. Here we show that C.elegans can respond in a gene-specific mannerto dsRNA encountered in the environment. C.elegans normally feed on bacteria, ingesting andgrinding them in the pharynx and subsequentlyabsorbing bacterial contents in the gut. We findthat Escherichia coli bacteria expressing dsRNAscan confer specific interference effects on thenematode larvae that feed on them.", "metadata": {}}
+{"_id": "4345315", "title": "", "text": "Bacterial RNA and small antiviral compoundsactivate caspase-1 throughcryopyrin/Nalp3Missense mutations in the CIAS1gene cause three autoinflammatory disorders:familial cold autoinflammatory syndrome,Muckle–Wells syndrome and neonatal-onsetmultiple-system inflammatory disease. Cryopyrin(also called Nalp3), the product of CIAS1, is amember of the NOD-LRR protein family that hasbeen linked to the activation of intracellular hostdefence signalling pathways. Cryopyrin forms amulti-protein complex termed ‘theinflammasome’, which contains theapoptosis-associated speck-like protein (ASC)and caspase-1, and promotes caspase-1activation and processing of pro-interleukin(IL)-1β (ref. 4). Here we show the effect ofcryopyrin deficiency on inflammasome functionand immune responses. Cryopyrin and ASC areessential for caspase-1 activation and IL-1β andIL-18 production in response to bacterial RNAand the imidazoquinoline compounds R837 and", "metadata": {}}
+{"_id": "4345605", "title": "", "text": "Control of cortical GABA circuitry development byNrg1 and ErbB4 signallingSchizophrenia is acomplex disorder that interferes with thefunction of several brain systems required forcognition and normal social behaviour. Althoughthe most notable clinical aspects of the diseaseonly become apparent during late adolescence orearly adulthood, many lines of evidence suggestthat schizophrenia is a neurodevelopmentaldisorder with a strong genetic component.Several independent studies have identifiedneuregulin 1 (NRG1) and its receptor ERBB4 asimportant risk genes for schizophrenia, althoughtheir precise role in the disease process remainsunknown. Here we show that Nrg1 and ErbB4signalling controls the development of inhibitorycircuitries in the mammalian cerebral cortex bycell-autonomously regulating the connectivity ofspecific GABA (γ-aminobutyric acid)-containinginterneurons. In contrast to the prevalent view,which supports a role for these genes in theformation and function of excitatory synapses", "metadata": {}}
+{"_id": "4345757", "title": "", "text": "Obesity as a medical problem.Obesity is now socommon within the world's population that it isbeginning to replace undernutrition andinfectious diseases as the most significantcontributor to ill health. In particular, obesity isassociated with diabetes mellitus, coronary heartdisease, certain forms of cancer, andsleep-breathing disorders. Obesity is defined bya body-mass index (weight divided by square ofthe height) of 30 kg m(-2) or greater, but thisdoes not take into account the morbidity andmortality associated with more modest degreesof overweight, nor the detrimental effect ofintra-abdominal fat. The global epidemic ofobesity results from a combination of geneticsusceptibility, increased availability ofhigh-energy foods and decreased requirementfor physical activity in modern society. Obesityshould no longer be regarded simply as acosmetic problem affecting certain individuals,but an epidemic that threatens global well being.", "metadata": {}}
+{"_id": "4346436", "title": "", "text": "Nonlinear Elasticity in Biological GelsUnlike mostsynthetic materials, biological materials oftenstiffen as they are deformed. This nonlinearelastic response, critical for the physiologicalfunction of some tissues, has been documentedsince at least the 19th century, but the molecularstructure and the design principles responsiblefor it are unknown. Current models for thisresponse require geometrically complex orderedstructures unique to each material. In this Articlewe show that a much simpler molecular theoryaccounts for strain stiffening in a wide range ofmolecularly distinct biopolymer gels formed frompurified cytoskeletal and extracellular proteins.This theory shows that systems of semi-flexiblechains such as filamentous proteins arranged inan open crosslinked meshwork invariably stiffenat low strains without the need for a specificarchitecture or multiple elements with differentintrinsic stiffnesses.", "metadata": {}}
+{"_id": "4346731", "title": "", "text": "Live-cell delamination counterbalances epithelialgrowth to limit tissue overcrowdingThedevelopment and maintenance of an epitheliumrequires finely balanced rates of growth and celldeath. However, the mechanical and biochemicalmechanisms that ensure proper feedback controlof tissue growth, which when deregulatedcontribute to tumorigenesis, are poorlyunderstood. Here we use the fly notum as amodel system to identify a novel process ofcrowding-induced cell delamination that balancesgrowth to ensure the development ofwell-ordered cell packing. In crowded regions ofthe tissue, a proportion of cells undergo a serialloss of cell–cell junctions and a progressive lossof apical area, before being squeezed out bytheir neighbours. This path of delamination isrecapitulated by a simple computational model ofepithelial mechanics, in which stochastic cell lossrelieves overcrowding as the system tendstowards equilibrium. We show that this processof delamination is mechanistically distinct from", "metadata": {}}
+{"_id": "4347374", "title": "", "text": "Broad antiretroviral defence by humanAPOBEC3G through lethal editing of nascentreverse transcriptsViral replication usuallyrequires that innate intracellular lines of defencebe overcome, a task usually accomplished byspecialized viral gene products. The virioninfectivity factor (Vif) protein of humanimmunodeficiency virus (HIV) is required duringthe late stages of viral production to counter theantiviral activity of APOBEC3G (apolipoprotein BmRNA-editing enzyme, catalytic polypeptide-like3G; also known as CEM15), a protein expressednotably in human T lymphocytes. Whenproduced in the presence of APOBEC3G,vif-defective virus is non-infectious. APOBEC3Gis closely related to APOBEC1, the centralcomponent of an RNA-editing complex thatdeaminates a cytosine residue in apoBmessenger RNA. APOBEC family members alsohave potent DNA mutator activity through dCdeamination; however, whether the editingpotential of APOBEC3G has any relevance to HIV", "metadata": {}}
+{"_id": "4350400", "title": "", "text": "Generation of cell polarity in plants linksendocytosis, auxin distribution and cell fatedecisionsDynamically polarized membraneproteins define different cell boundaries and havean important role in intercellularcommunication—a vital feature of multicellulardevelopment. Efflux carriers for the signallingmolecule auxin from the PIN family arelandmarks of cell polarity in plants and have acrucial involvement in auxindistribution-dependent development includingembryo patterning, organogenesis and tropisms.Polar PIN localization determines the direction ofintercellular auxin flow, yet the mechanismsgenerating PIN polarity remain unclear. Here weidentify an endocytosis-dependent mechanism ofPIN polarity generation and analyse itsdevelopmental implications. Real-time PINtracking showed that after synthesis, PINs areinitially delivered to the plasma membrane in anon-polar manner and their polarity isestablished by subsequent endocytic recycling.", "metadata": {}}
+{"_id": "4353857", "title": "", "text": "Congenital leptin deficiency is associated withsevere early-onset obesity in humans.Theextreme obesity of the obese (ob/ob) mouse isattributable to mutations in the gene encodingleptin, an adipocyte-specific secreted proteinwhich has profound effects on appetite andenergy expenditure. We know of no equivalentevidence regarding leptin's role in the control offat mass in humans. We have examined twoseverely obese children who are members of thesame highly consanguineous pedigree. Theirserum leptin levels were very low despite theirmarkedly elevated fat mass and, in both, ahomozygous frame-shift mutation involving thedeletion of a single guanine nucleotide in codon133 of the gene for leptin was found. The severeobesity found in these congenitallyleptin-deficient subjects provides the first geneticevidence that leptin is an important regulator ofenergy balance in humans.", "metadata": {}}
+{"_id": "4361990", "title": "", "text": "Targeting of cell-surface β-amyloid precursorprotein to lysosomes: alternative processing intoamyloid-bearing fragmentsPROGRESSIVEcerebral deposition of the amyloid β-peptide isan early and invariant feature of Alzheimer'sdisease. The β-peptide is released by proteolyticcleavages from the β-amyloid precursor protein(βAPP)1, a membrane-spanning glycoproteinexpressed in most mammalian cells. Normalsecretion of βAPP involves a cleavage in theβ-peptide region2-3, releasing the solubleextramembranous portion4,5 and retaining a10K C-terminal fragment in the membrane6.Because this secretory pathway precludesβ-amyloid formation, we searched for analternative proteolytic processing pathway thatcan generate β-peptide-bearing fragments fromfull-length β APP. Incubation of living humanendothelial cells with a βAPP antibody revealedreinternalization of mature βAPP from the cellsurface and its targeting toendosomes/lysosomes. After cell-surface", "metadata": {}}
+{"_id": "4362729", "title": "", "text": "A keratin cytoskeletal protein regulates proteinsynthesis and epithelial cell growthCell growth,an increase in mass and size, is a highlyregulated cellular event. The Akt/mTOR(mammalian target of rapamycin) signallingpathway has a central role in the control ofprotein synthesis and thus the growth of cells,tissues and organisms. A striking example of aphysiological context requiring rapid cell growthis tissue repair in response to injury. Here weshow that keratin 17, an intermediate filamentprotein rapidly induced in wounded stratifiedepithelia, regulates cell growth through bindingto the adaptor protein 14-3-3σ. Mouse skinkeratinocytes lacking keratin 17 (ref. 4) showdepressed protein translation and are of smallersize, correlating with decreased Akt/mTORsignalling activity. Other signalling kinases havenormal activity, pointing to the specificity of thisdefect. Two amino acid residues located in theamino-terminal head domain of keratin 17 arerequired for the serum-dependent relocalization", "metadata": {}}
+{"_id": "4363526", "title": "", "text": "Co-crystal structure of the HNF-3/fork headDNA-recognition motif resembles histone H5Thethree-dimensional structure of an HNF-3/forkhead DNA-recognition motif complexed with DNAhas been determined by X-ray crystallography at2.5 \u0000 resolution. This α/β protein binds B-DNAas a monomer, through interactions with theDNA backbone and through both direct andwater-mediated major and minor groove basecontacts, inducing a 13° bend. The transcriptionfactor fold is very similar to the structure ofhistone H5. In its amino-terminal half, threeα-helices adopt a compact structure thatpresents the third helix to the major groove. Theremainder of the protein includes a twisted,antiparallel β-structure and random coil thatinteracts with the minor groove.", "metadata": {}}
+{"_id": "4364884", "title": "", "text": "A Mechanism Linking Extra Centrosomes toChromosomal InstabilityChromosomal instability(CIN) is a hallmark of many tumours andcorrelates with the presence of extracentrosomes. However, a direct mechanistic linkbetween extra centrosomes and CIN has notbeen established. It has been proposed thatextra centrosomes generate CIN by promotingmultipolar anaphase, a highly abnormal divisionthat produces three or more aneuploid daughtercells. Here we use long-term live-cell imaging todemonstrate that cells with multiple centrosomesrarely undergo multipolar cell divisions, and theprogeny of these divisions are typically inviable.Thus, multipolar divisions cannot explainobserved rates of CIN. In contrast, we observethat CIN cells with extra centrosomes routinelyundergo bipolar cell divisions, but display asignificantly increased frequency of laggingchromosomes during anaphase. To define themechanism underlying this mitotic defect, wegenerated cells that differ only in their", "metadata": {}}
+{"_id": "4366738", "title": "", "text": "Haematopoietic stem cells and early lymphoidprogenitors occupy distinct bone marrownichesAlthough haematopoietic stem cells(HSCs) are commonly assumed to reside within aspecialized microenvironment, or niche, mostpublished experimental manipulations of the HSCniche have affected the function of diverserestricted progenitors. This raises thefundamental question of whether HSCs andrestricted progenitors reside within distinct,specialized niches or whether they share acommon niche. Here we assess the physiologicalsources of the chemokine CXCL12 for HSC andrestricted progenitor maintenance.Cxcl12(DsRed) knock-in mice (DsRed-Express2recombined into the Cxcl12 locus) showed thatCxcl12 was primarily expressed by perivascularstromal cells and, at lower levels, by endothelialcells, osteoblasts and some haematopoietic cells.Conditional deletion of Cxcl12 fromhaematopoietic cells or nestin-cre-expressingcells had little or no effect on HSCs or restricted", "metadata": {}}
+{"_id": "4373433", "title": "", "text": "Broad neutralization coverage of HIV by multiplehighly potent antibodiesBroadly neutralizingantibodies against highly variable viral pathogensare much sought after to treat or protect againstglobal circulating viruses. Here we probed theneutralizing antibody repertoires of four humanimmunodeficiency virus (HIV)-infected donorswith remarkably broad and potent neutralizingresponses and rescued 17 new monoclonalantibodies that neutralize broadly across clades.Many of the new monoclonal antibodies arealmost tenfold more potent than the recentlydescribed PG9, PG16 and VRC01 broadlyneutralizing monoclonal antibodies and 100-foldmore potent than the original prototype HIVbroadly neutralizing monoclonal antibodies. Themonoclonal antibodies largely recapitulate theneutralization breadth found in thecorresponding donor serum and many recognizenovel epitopes on envelope (Env) glycoproteingp120, illuminating new targets for vaccinedesign. Analysis of neutralization by the full", "metadata": {}}
+{"_id": "4373445", "title": "", "text": "Coordination of Rho GTPase activities during cellprotrusionThe GTPases Rac1, RhoA and Cdc42act together to control cytoskeleton dynamics.Recent biosensor studies have shown that allthree GTPases are activated at the front ofmigrating cells, and biochemical evidencesuggests that they may regulate one another:Cdc42 can activate Rac1 (ref. 8), and Rac1 andRhoA are mutually inhibitory. However, theirspatiotemporal coordination, at the seconds andsingle-micrometre dimensions typical ofindividual protrusion events, remains unknown.Here we examine GTPase coordination in mouseembryonic fibroblasts both through simultaneousvisualization of two GTPase biosensors and usinga 'computational multiplexing' approach capableof defining the relationships between multipleprotein activities visualized in separateexperiments. We found that RhoA is activated atthe cell edge synchronous with edgeadvancement, whereas Cdc42 and Rac1 areactivated 2 micro-m behind the edge with a", "metadata": {}}
+{"_id": "4378885", "title": "", "text": "Understanding mechanisms underlying humangene expression variation with RNAsequencingUnderstanding the geneticmechanisms underlying natural variation in geneexpression is a central goal of both medical andevolutionary genetics, and studies of expressionquantitative trait loci (eQTLs) have become animportant tool for achieving this goal. Althoughall eQTL studies so far have assayed messengerRNA levels using expression microarrays, recentadvances in RNA sequencing enable the analysisof transcript variation at unprecedentedresolution. We sequenced RNA from 69lymphoblastoid cell lines derived from unrelatedNigerian individuals that have been extensivelygenotyped by the International HapMap Project.By pooling data from all individuals, wegenerated a map of the transcriptional landscapeof these cells, identifying extensive use ofunannotated untranslated regions and more than100 new putative protein-coding exons. Usingthe genotypes from the HapMap project, we", "metadata": {}}
+{"_id": "4380004", "title": "", "text": "Mesenchymal and haematopoietic stem cellsform a unique bone marrow nicheThe cellularconstituents forming the haematopoietic stemcell (HSC) niche in the bone marrow are unclear,with studies implicating osteoblasts, endothelialand perivascular cells. Here we demonstrate thatmesenchymal stem cells (MSCs), identified usingnestin expression, constitute an essential HSCniche component. Nestin+ MSCs contain all thebone-marrow colony-forming-unit fibroblasticactivity and can be propagated as non-adherent‘mesenspheres’ that can self-renew and expandin serial transplantations. Nestin+ MSCs arespatially associated with HSCs and adrenergicnerve fibres, and highly express HSCmaintenance genes. These genes, and otherstriggering osteoblastic differentiation, areselectively downregulated during enforced HSCmobilization or β3 adrenoreceptor activation.Whereas parathormone administration doublesthe number of bone marrow nestin+ cells andfavours their osteoblastic differentiation, in vivo", "metadata": {}}
+{"_id": "4380287", "title": "", "text": "Response to self antigen imprints regulatorymemory in tissuesImmune homeostasis intissues is achieved through a delicate balancebetween pathogenic T-cell responses directed attissue-specific antigens and the ability of thetissue to inhibit these responses. Themechanisms by which tissues and the immunesystem communicate to establish and maintainimmune homeostasis are currently unknown.Clinical evidence suggests that chronic orrepeated exposure to self antigen within tissuesleads to an attenuation of pathologicalautoimmune responses, possibly as a means tomitigate inflammatory damage and preservefunction. Many human organ-specificautoimmune diseases are characterized by theinitial presentation of the disease being the mostsevere, with subsequent flares being of lesserseverity and duration. In fact, these diseasesoften spontaneously resolve, despite persistenttissue autoantigen expression. In the practice ofantigen-specific immunotherapy, allergens or self", "metadata": {}}
+{"_id": "4380451", "title": "", "text": "Reprogramming of human somatic cells topluripotency with defined factorsPluripotencypertains to the cells of early embryos that cangenerate all of the tissues in the organism.Embryonic stem cells are embryo-derived celllines that retain pluripotency and representinvaluable tools for research into themechanisms of tissue formation. Recently,murine fibroblasts have been reprogrammeddirectly to pluripotency by ectopic expression offour transcription factors (Oct4, Sox2, Klf4 andMyc) to yield induced pluripotent stem (iPS)cells. Using these same factors, we have derivediPS cells from fetal, neonatal and adult humanprimary cells, including dermal fibroblastsisolated from a skin biopsy of a healthy researchsubject. Human iPS cells resemble embryonicstem cells in morphology and gene expressionand in the capacity to form teratomas inimmune-deficient mice. These data demonstratethat defined factors can reprogramme humancells to pluripotency, and establish a method", "metadata": {}}
+{"_id": "4381486", "title": "", "text": "Haematopoietic stem cells do not asymmetricallysegregate chromosomes or retain BrdUStem cellsare proposed to segregate chromosomesasymmetrically during self-renewing divisions sothat older (‘immortal’) DNA strands are retainedin daughter stem cells whereas newlysynthesized strands segregate to differentiatingcells. Stem cells are also proposed to retain DNAlabels, such as 5-bromo-2-deoxyuridine (BrdU),either because they segregate chromosomesasymmetrically or because they divide slowly.However, the purity of stem cells amongBrdU-label-retaining cells has not beendocumented in any tissue, and the ‘immortalstrand hypothesis’ has not been tested in asystem with definitive stem cell markers. Herewe tested these hypotheses in haematopoieticstem cells (HSCs), which can be highly purifiedusing well characterized markers. Weadministered BrdU to newborn mice, micetreated with cyclophosphamide and granulocytecolony-stimulating factor, and normal adult mice", "metadata": {}}
+{"_id": "4385779", "title": "", "text": "Circadian Clocks in Human Red BloodCellsCircadian (\u000024 hour) clocks arefundamentally important for coordinatedphysiology in organisms as diverse ascyanobacteria and humans. All current models ofthe molecular circadian clockwork in eukaryoticcells are based on transcription-translationfeedback loops. Non-transcriptional mechanismsin the clockwork have been difficult to study inmammalian systems. We circumvented theseproblems by developing novel assays usinghuman red blood cells, which have no nucleus(or DNA) and therefore cannot performtranscription. Our results show that transcriptionis not required for circadian oscillations inhumans, and that non-transcriptional eventsseem to be sufficient to sustain cellular circadianrhythms. Using red blood cells, we found thatperoxiredoxins, highly conserved antioxidantproteins, undergo \u000024-hour redox cycles, whichpersist for many days under constant conditions(that is, in the absence of external cues).", "metadata": {}}
+{"_id": "4387484", "title": "", "text": "G-protein-coupled receptor of Kaposi'ssarcoma-associated herpesvirus is a viraloncogene and angiogenesis activator.TheKaposi's sarcoma-associated herpesvirus(KSHV/HHV8) is a gamma-2 herpesvirus that isimplicated in the pathogenesis of Kaposi'ssarcoma and of primary effusion B-celllymphomas (PELs). KSHV infects malignant andprogenitor cells of Kaposi's sarcoma and PEL, itencodes putative oncogenes and genes that maycause Kaposi's sarcoma pathogenesis bystimulating angiogenesis. The G-protein-coupledreceptor encoded by an open reading frame (ORF74) of KSHV is expressed in Kaposi's sarcomalesions and in PEL and stimulates signallingpathways linked to cell proliferation in aconstitutive (agonist-independent) way. Here weshow that signalling by this KSHVG-protein-coupled receptor leads to celltransformation and tumorigenicity, and induces aswitch to an angiogenic phenotype mediated byvascular endothelial growth factor, an", "metadata": {}}
+{"_id": "4387494", "title": "", "text": "Therapeutic potential of GSK-J4, a histonedemethylase KDM6B/JMJD3 inhibitor, for acutemyeloid leukemiaPURPOSE Acute myeloidleukemia (AML) is a heterogeneous disease withpoor outcomes. Despite increased evidenceshows that dysregulation of histone modificationcontributes to AML, specific drugs targeting keyhistone modulators are not applied in the clinicaltreatment of AML. Here, we investigated whethertargeting KDM6B, the demethylase oftri-methylated histone H3 lysine 27(H3K27me3), has a therapeutic potential forAML. METHODS A KDM6B-specific inhibitor,GSK-J4, was applied to treat the primary cellsfrom AML patients and AML cell lines in vitro andin vivo. RNA-sequencing was performed to revealthe underlying mechanisms of inhibiting KDM6Bfor the treatment of AML. RESULTS Here weobserved that the mRNA expression of KDM6Bwas up-regulated in AML and positivelycorrelated with poor survival. Treatment withGSK-J4 increased the global level of H3K27me3", "metadata": {}}
+{"_id": "4387784", "title": "", "text": "Structure of the proton-gated urea channel fromthe gastric pathogen Helicobacter pyloriHalf theworld's population is chronically infected withHelicobacter pylori, causing gastritis, gastriculcers and an increased incidence of gastricadenocarcinoma. Its proton-gatedinner-membrane urea channel, HpUreI, isessential for survival in the acidic environment ofthe stomach. The channel is closed at neutral pHand opens at acidic pH to allow the rapid accessof urea to cytoplasmic urease. Urease producesNH(3) and CO(2), neutralizing entering protonsand thus buffering the periplasm to a pH ofroughly 6.1 even in gastric juice at a pH below2.0. Here we report the structure of HpUreI,revealing six protomers assembled in ahexameric ring surrounding a central bilayer plugof ordered lipids. Each protomer encloses achannel formed by a twisted bundle of sixtransmembrane helices. The bundle defines apreviously unobserved fold comprising atwo-helix hairpin motif repeated three times", "metadata": {}}
+{"_id": "4388082", "title": "", "text": "Drosophila oocyte localization is mediated bydifferential cadherin-based adhesion.In aDrosophila follicle the oocyte always occupies aposterior position among a group of sixteengermline cells. Although the importance of thiscell arrangement for the subsequent formation ofthe anterior-posterior axis of the embryo is welldocumented, the molecular mechanismresponsible for the posterior localization of theoocyte was unknown. Here we show that thehomophilic adhesion molecule DE-cadherinmediates oocyte positioning. During folliclebiogenesis, DE-cadherin is expressed in germline(including oocyte) and surrounding follicle cells,with the highest concentration of DE-cadherinbeing found at the interface between oocyte andposterior follicle cells. Mosaic analysis shows thatDE-cadherin is required in both germline andfollicle cells for correct oocyte localization,indicating that germline-soma interactions maybe involved in this process. By analysing thebehaviour of the oocyte in follicles with a", "metadata": {}}
+{"_id": "4388470", "title": "", "text": "Somatic sex identity is cell-autonomous in thechickenIn the mammalian model of sexdetermination, embryos are considered to besexually indifferent until the transient action of asex-determining gene initiates gonadaldifferentiation. Although this model is thought toapply to all vertebrates, this has yet to beestablished. Here we have examined threelateral gynandromorph chickens (a rare,naturally occurring phenomenon in which oneside of the animal appears male and the otherfemale) to investigate the sex-determiningmechanism in birds. These studies demonstratedthat gynandromorph birds are genuinemale:female chimaeras, and indicated that maleand female avian somatic cells may have aninherent sex identity. To test this hypothesis, wetransplanted presumptive mesoderm betweenembryos of reciprocal sexes to generate embryoscontaining male:female chimaeric gonads. Incontrast to the outcome for mammalianmixed-sex chimaeras, in chicken mixed-sex", "metadata": {}}
+{"_id": "4389252", "title": "", "text": "Centrosome polarization delivers secretorygranules to the immunological synapseCytotoxicT lymphocytes (CTLs) destroy virally infected andtumorigenic cells by releasing the contents ofspecialized secretory lysosomes—termed ‘lyticgranules’—at the immunological synapse formedbetween the CTL and the target. On contact withthe target cell, the microtubule organizing centreof the CTL polarizes towards the target andgranules move along microtubules in aminus-end direction towards the polarizedmicrotubule organizing centre. However, the finalsteps of secretion have remained unclear. Herewe show that CTLs do not require actin orplus-end microtubule motors for secretion, butinstead the centrosome moves to and contactsthe plasma membrane at the centralsupramolecular activation cluster of theimmunological synapse. Actin and IQGAP1 arecleared away from the synapse, and granules aredelivered directly to the plasma membrane.These data show that CTLs use a previously", "metadata": {}}
+{"_id": "4389394", "title": "", "text": "Deubiquitination of p53 by HAUSP is animportant pathway for p53 stabilizationThe p53tumour suppressor is a short-lived protein that ismaintained at low levels in normal cells byMdm2-mediated ubiquitination and subsequentproteolysis. Stabilization of p53 is crucial for itstumour suppressor function. However, theprecise mechanism by which ubiquitinated p53levels are regulated in vivo is not completelyunderstood. By mass spectrometry ofaffinity-purified p53-associated factors, we haveidentified herpesvirus-associatedubiquitin-specific protease (HAUSP) as a novelp53-interacting protein. HAUSP stronglystabilizes p53 even in the presence of excessMdm2, and also induces p53-dependent cellgrowth repression and apoptosis. Significantly,HAUSP has an intrinsic enzymatic activity thatspecifically deubiquitinates p53 both in vitro andin vivo. In contrast, expression of a catalyticallyinactive point mutant of HAUSP in cells increasesthe levels of p53 ubiquitination and destabilizes", "metadata": {}}
+{"_id": "4391121", "title": "", "text": "Defective tryptophan catabolism underliesinflammation in mouse chronic granulomatousdiseaseHalf a century ago, chronicgranulomatous disease (CGD) was first describedas a disease fatally affecting the ability ofchildren to survive infections. Various milestonediscoveries have since been made, from aninsufficient ability of patients’ leucocytes to killmicrobes to the underlying geneticabnormalities. In this inherited disorder,phagocytes lack NADPH oxidase activity and donot generate reactive oxygen species, mostnotably superoxide anion, causing recurrentbacterial and fungal infections. Patients with CGDalso suffer from chronic inflammatory conditions,most prominently granuloma formation in hollowviscera. The precise mechanisms of theincreased microbial pathogenicity have beenunclear, and more so the reasons for theexaggerated inflammatory response. Here weshow that a superoxide-dependent step intryptophan metabolism along the kynurenine", "metadata": {}}
+{"_id": "4391685", "title": "", "text": "Experimental and theoretical study of mitoticspindle orientationThe architecture andadhesiveness of a cell microenvironment is acritical factor for the regulation of spindleorientation in vivo. Using a combination of theoryand experiments, we have investigated spindleorientation in HeLa (human) cells. Here we showthat spindle orientation can be understood as theresult of the action of cortical force generators,which interact with spindle microtubules and areactivated by cortical cues. We develop a simplephysical description of this spindle mechanics,which allows us to calculate angular profiles ofthe torque acting on the spindle, as well as theangular distribution of spindle orientations. Ourmodel accounts for the preferred spindleorientation and the shape of the full angulardistribution of spindle orientations observed in alarge variety of different cellularmicroenvironment geometries. It also correctlydescribes asymmetric spindle orientations, whichare observed for certain distributions of cortical", "metadata": {}}
+{"_id": "4391817", "title": "", "text": "CHROMOTHRIPSIS FROM DNA DAMAGE INMICRONUCLEIGenome sequencing hasuncovered a new mutational phenomenon incancer and congenital disorders calledchromothripsis. Chromothripsis is characterizedby extensive genomic rearrangements and anoscillating pattern of DNA copy number levels, allcuriously restricted to one or a fewchromosomes. The mechanism forchromothripsis is unknown, but we previouslyproposed that it could occur through the physicalisolation of chromosomes in aberrant nuclearstructures called micronuclei. Here, using acombination of live cell imaging and single-cellgenome sequencing, we demonstrate thatmicronucleus formation can indeed generate aspectrum of genomic rearrangements, some ofwhich recapitulate all known features ofchromothripsis. These events are restricted tothe mis-segregated chromosome and occurwithin one cell division. We demonstrate that themechanism for chromothripsis can involve the", "metadata": {}}
+{"_id": "4392608", "title": "", "text": "DNA-binding factors shape the mousemethylome at distal regulatoryregionsMethylation of cytosines is an essentialepigenetic modification in mammalian genomes,yet the rules that govern methylation patternsremain largely elusive. To gain insights into thisprocess, we generated base-pair-resolutionmouse methylomes in stem cells and neuronalprogenitors. Advanced quantitative analysisidentified low-methylated regions (LMRs) with anaverage methylation of 30%. These representCpG-poor distal regulatory regions as evidencedby location, DNase I hypersensitivity, presenceof enhancer chromatin marks and enhanceractivity in reporter assays. LMRs are occupied byDNA-binding factors and their binding isnecessary and sufficient to create LMRs. Acomparison of neuronal and stem-cellmethylomes confirms this dependency, ascell-type-specific LMRs are occupied bycell-type-specific transcription factors. This studyprovides methylome references for the mouse", "metadata": {}}
+{"_id": "4393153", "title": "", "text": "Molecular basis of RNA-dependent RNApolymerase II activityRNA polymerase (Pol) IIcatalyses DNA-dependent RNA synthesis duringgene transcription. There is, however, evidencethat Pol II also possesses RNA-dependent RNApolymerase (RdRP) activity. Pol II can use ahomopolymeric RNA template, can extend RNAby several nucleotides in the absence of DNA,and has been implicated in the replication of theRNA genomes of hepatitis delta virus (HDV) andplant viroids. Here we show the intrinsic RdRPactivity of Pol II with only pure polymerase, anRNA template–product scaffold and nucleosidetriphosphates (NTPs). Crystallography revealsthe template–product duplex in the site occupiedby the DNA–RNA hybrid during transcription.RdRP activity resides at the active site usedduring transcription, but it is slower and lessprocessive than DNA-dependent activity. RdRPactivity is also obtained with part of the HDVantigenome. The complex of transcription factorIIS (TFIIS) with Pol II can cleave one HDV", "metadata": {}}
+{"_id": "4394525", "title": "", "text": "Bacteria activate sensory neurons that modulatepain and inflammationNociceptor sensoryneurons are specialized to detect potentiallydamaging stimuli, protecting the organism byinitiating the sensation of pain and elicitingdefensive behaviours. Bacterial infectionsproduce pain by unknown molecularmechanisms, although they are presumed to besecondary to immune activation. Here wedemonstrate that bacteria directly activatenociceptors, and that the immune responsemediated through TLR2, MyD88, T cells, B cells,and neutrophils and monocytes is not necessaryfor Staphylococcus aureus-induced pain in mice.Mechanical and thermal hyperalgesia in mice iscorrelated with live bacterial load rather thantissue swelling or immune activation. Bacteriainduce calcium flux and action potentials innociceptor neurons, in part via bacterialN-formylated peptides and the pore-formingtoxin α-haemolysin, through distinctmechanisms. Specific ablation of Nav1.8-lineage", "metadata": {}}
+{"_id": "4394817", "title": "", "text": "E2F1-3 Switch from Activators in Progenitor Cellsto Repressors in Differentiating CellsIn theestablished model of mammalian cell cyclecontrol, the retinoblastoma protein (Rb)functions to restrict cells from entering S phaseby binding and sequestering E2f activators (E2f1,E2f2 and E2f3), which are invariably portrayedas the ultimate effectors of a transcriptionalprogram that commit cells to enter and progressthrough S phase. Using a panel of tissue-specificcre-transgenic mice and conditional E2f alleleswe examined the effects of E2f1, E2f2 and E2f3triple deficiency in murine embryonic stem cells,embryos and small intestines. We show that innormal dividing progenitor cells E2f1-3 functionas transcriptional activators, but contrary to thecurrent view, are dispensable for cell division andinstead are necessary for cell survival. Indifferentiating cells E2f1-3 function in a complexwith Rb as repressors to silence E2f targets andfacilitate exit from the cell cycle. The inactivationof Rb in differentiating cells resulted in a switch", "metadata": {}}
+{"_id": "4396105", "title": "", "text": "K-Ras(G12C) inhibitors allosterically control GTPaffinity and effector interactionsSomaticmutations in the small GTPase K-Ras are themost common activating lesions found in humancancer, and are generally associated with poorresponse to standard therapies. Efforts to targetthis oncogene directly have faced difficultiesowing to its picomolar affinity for GTP/GDP andthe absence of known allosteric regulatory sites.Oncogenic mutations result in functionalactivation of Ras family proteins by impairingGTP hydrolysis. With diminished regulation byGTPase activity, the nucleotide state of Rasbecomes more dependent on relative nucleotideaffinity and concentration. This gives GTP anadvantage over GDP and increases theproportion of active GTP-bound Ras. Here wereport the development of small molecules thatirreversibly bind to a common oncogenic mutant,K-Ras(G12C). These compounds rely on themutant cysteine for binding and therefore do notaffect the wild-type protein. Crystallographic", "metadata": {}}
+{"_id": "4398832", "title": "", "text": "Cyclin A Regulates Kinetochore-Microtubules toPromote Faithful Chromosome SegregationThemost conspicuous event in the cell cycle is thealignment of chromosomes in metaphase.Chromosome alignment fosters faithfulsegregation through the formation of bi-orientedattachments of kinetochores to spindlemicrotubules. Notably, numerouskinetochore-microtubule (k-MT) attachmenterrors are present in early mitosis(prometaphase), and the persistence of thoseerrors is the leading cause of chromosomemis-segregation in aneuploid human tumour cellsthat continually mis-segregate wholechromosomes and display chromosomalinstability. How robust error correction isachieved in prometaphase to ensure error-freemitosis remains unknown. Here we show thatk-MT attachments in prometaphase cells areconsiderably less stable than in metaphase cells.The switch to more stable k-MT attachments inmetaphase requires the proteasome-dependent", "metadata": {}}
+{"_id": "4399268", "title": "", "text": "Induced pluripotent stem cells from a spinalmuscular atrophy patientSpinal muscular atrophyis one of the most common inherited forms ofneurological disease leading to infant mortality.Patients have selective loss of lower motorneurons resulting in muscle weakness, paralysisand often death. Although patient fibroblastshave been used extensively to study spinalmuscular atrophy, motor neurons have a uniqueanatomy and physiology which may underlietheir vulnerability to the disease process. Herewe report the generation of induced pluripotentstem cells from skin fibroblast samples takenfrom a child with spinal muscular atrophy. Thesecells expanded robustly in culture, maintainedthe disease genotype and generated motorneurons that showed selective deficits comparedto those derived from the child’s unaffectedmother. This is the first study to show thathuman induced pluripotent stem cells can beused to model the specific pathology seen in agenetically inherited disease. As such, it", "metadata": {}}
+{"_id": "4399311", "title": "", "text": "A role for mitochondria in NLRP3 inflammasomeactivationAn inflammatory response initiated bythe NLRP3 inflammasome is triggered by avariety of situations of host ‘danger’, includinginfection and metabolic dysregulation. Previousstudies suggested that NLRP3 inflammasomeactivity is negatively regulated by autophagy andpositively regulated by reactive oxygen species(ROS) derived from an uncharacterizedorganelle. Here we show thatmitophagy/autophagy blockade leads to theaccumulation of damaged, ROS-generatingmitochondria, and this in turn activates theNLRP3 inflammasome. Resting NLRP3 localizes toendoplasmic reticulum structures, whereas oninflammasome activation both NLRP3 and itsadaptor ASC redistribute to the perinuclear spacewhere they co-localize with endoplasmicreticulum and mitochondria organelle clusters.Notably, both ROS generation andinflammasome activation are suppressed whenmitochondrial activity is dysregulated by", "metadata": {}}
+{"_id": "4401289", "title": "", "text": "Break-induced telomere synthesis underliesalternative telomeremaintenanceHomology-directed DNA repair isessential for genome maintenance throughtemplated DNA synthesis. Alternativelengthening of telomeres (ALT) necessitateshomology-directed DNA repair to maintaintelomeres in about 10–15% of human cancers.How DNA damage induces assembly andexecution of a DNA replication complex(break-induced replisome) at telomeres orelsewhere in the mammalian genome is poorlyunderstood. Here we define break-inducedtelomere synthesis and demonstrate that itutilizes a specialized replisome, which underliesALT telomere maintenance. DNA double-strandbreaks enact nascent telomere synthesis bylong-tract unidirectional replication. Proliferatingcell nuclear antigen (PCNA) loading by replicationfactor C (RFC) acts as the initial sensor oftelomere damage to establish predominance ofDNA polymerase δ (Pol δ) through its POLD3", "metadata": {}}
+{"_id": "4402497", "title": "", "text": "Innate immunity induced bycomposition-dependent RIG-I recognition ofhepatitis C virus RNAInnate immune defencesare essential for the control of virus infection andare triggered through host recognition of viralmacromolecular motifs known aspathogen-associated molecular patterns(PAMPs). Hepatitis C virus (HCV) is an RNA virusthat replicates in the liver, and infects 200million people worldwide. Infection is regulatedby hepatic immune defences triggered by thecellular RIG-I helicase. RIG-I binds PAMP RNAand signals interferon regulatory factor 3activation to induce the expression ofinterferon-α/β and antiviral/interferon-stimulatedgenes (ISGs) that limit infection. Here weidentify the polyuridine motif of the HCV genome3′ non-translated region and its replicationintermediate as the PAMP substrate of RIG-I, andshow that this and similar homopolyuridine orhomopolyriboadenine motifs present in thegenomes of RNA viruses are the chief feature of", "metadata": {}}
+{"_id": "4404433", "title": "", "text": "Generation of transgenic non-human primateswith germline transmissionThe commonmarmoset (Callithrix jacchus) is increasinglyattractive for use as a non-human primateanimal model in biomedical research. It has arelatively high reproduction rate for a primate,making it potentially suitable for transgenicmodification. Although several attempts havebeen made to produce non-human transgenicprimates, transgene expression in the somatictissues of live infants has not been demonstratedby objective analyses such as polymerase chainreaction with reverse transcription or westernblots. Here we show that the injection of aself-inactivating lentiviral vector in sucrosesolution into marmoset embryos results intransgenic common marmosets that expressedthe transgene in several organs. Notably, weachieved germline transmission of the transgene,and the transgenic offspring developed normally.The successful creation of transgenic marmosetsprovides a new animal model for human disease", "metadata": {}}
+{"_id": "4405194", "title": "", "text": "Induction of human neuronal cells by definedtranscription factorsSomatic cell nuclear transfer,cell fusion, or expression of lineage-specificfactors have been shown to induce cell-fatechanges in diverse somatic cell types. Werecently observed that forced expression of acombination of three transcription factors, Brn2(also known as Pou3f2), Ascl1 and Myt1l, canefficiently convert mouse fibroblasts intofunctional induced neuronal (iN) cells. Here weshow that the same three factors can generatefunctional neurons from human pluripotent stemcells as early as 6 days after transgeneactivation. When combined with the basichelix-loop-helix transcription factor NeuroD1,these factors could also convert fetal andpostnatal human fibroblasts into iN cells showingtypical neuronal morphologies and expressingmultiple neuronal markers, even afterdownregulation of the exogenous transcriptionfactors. Importantly, the vast majority of humaniN cells were able to generate action potentials", "metadata": {}}
+{"_id": "4406819", "title": "", "text": "PAAR-repeat proteins sharpen and diversify theType VI secretion system spikeThe bacterial typeVI secretion system (T6SS) is a largemulticomponent, dynamic macromolecularmachine that has an important role in theecology of many Gram-negative bacteria. T6SSis responsible for translocation of a wide range oftoxic effector molecules, allowing predatory cellsto kill both prokaryotic as well as eukaryotic preycells. The T6SS organelle is functionallyanalogous to contractile tails of bacteriophagesand is thought to attack cells by initiallypenetrating them with a trimeric protein complexcalled the VgrG spike. Neither the exact proteincomposition of the T6SS organelle nor themechanisms of effector selection and deliveryare known. Here we report that proteins from thePAAR (proline-alanine-alanine-arginine) repeatsuperfamily form a sharp conical extension onthe VgrG spike, which is further involved inattaching effector domains to the spike. Thecrystal structures of two PAAR-repeat proteins", "metadata": {}}
+{"_id": "4407318", "title": "", "text": "Replication stress activates DNA repair synthesisin mitosisOncogene-induced DNA replicationstress has been implicated as a driver oftumorigenesis. Many chromosomalrearrangements characteristic of human cancersoriginate from specific regions of the genomecalled common fragile sites (CFSs). CFSs aredifficult-to-replicate loci that manifest as gaps orbreaks on metaphase chromosomes (termed CFS‘expression’), particularly when cells have beenexposed to replicative stress. The MUS81–EME1structure-specific endonuclease promotes theappearance of chromosome gaps or breaks atCFSs following replicative stress. Here we showthat entry of cells into mitotic prophase triggersthe recruitment of MUS81 to CFSs. The nucleaseactivity of MUS81 then promotesPOLD3-dependent DNA synthesis at CFSs, whichserves to minimize chromosome mis-segregationand non-disjunction. We propose that theattempted condensation of incompletelyduplicated loci in early mitosis serves as the", "metadata": {}}
+{"_id": "4407385", "title": "", "text": "A specific amyloid-β protein assembly in thebrain impairs memoryMemory function oftendeclines with age, and is believed to deteriorateinitially because of changes in synaptic functionrather than loss of neurons. Some individualsthen go on to develop Alzheimer's disease withneurodegeneration. Here we use Tg2576 mice,which express a human amyloid-β precursorprotein (APP) variant linked to Alzheimer'sdisease, to investigate the cause of memorydecline in the absence of neurodegeneration oramyloid-β protein amyloidosis. Young Tg2576mice (< 6 months old) have normal memory andlack neuropathology, middle-aged mice (6–14months old) develop memory deficits withoutneuronal loss, and old mice (> 14 months old)form abundant neuritic plaques containingamyloid-β (refs 3–6). We found that memorydeficits in middle-aged Tg2576 mice are causedby the extracellular accumulation of a 56-kDasoluble amyloid-β assembly, which we termAβ*56 (Aβ star 56). Aβ*56 purified from the", "metadata": {}}
+{"_id": "4407455", "title": "", "text": "Cleavage of GSDMD by inflammatory caspasesdetermines pyroptotic cell deathInflammatorycaspases (caspase-1, -4, -5 and -11) are criticalfor innate defences. Caspase-1 is activated byligands of various canonical inflammasomes, andcaspase-4, -5 and -11 directly recognizebacterial lipopolysaccharide, both of whichtrigger pyroptosis. Despite the crucial role inimmunity and endotoxic shock, the mechanismfor pyroptosis induction by inflammatorycaspases is unknown. Here we identifygasdermin D (Gsdmd) by genome-wide clusteredregularly interspaced palindromic repeat(CRISPR)-Cas9 nuclease screens of caspase-11-and caspase-1-mediated pyroptosis in mousebone marrow macrophages. GSDMD-deficientcells resisted the induction of pyroptosis bycytosolic lipopolysaccharide and known canonicalinflammasome ligands. Interleukin-1β releasewas also diminished in Gsdmd−/− cells, despiteintact processing by caspase-1. Caspase-1 andcaspase-4/5/11 specifically cleaved the linker", "metadata": {}}
+{"_id": "4409524", "title": "", "text": "Role of corin in trophoblast invasion and uterinespiral artery remodelling in pregnancyInpregnancy, trophoblast invasion and uterinespiral artery remodelling are important forlowering maternal vascular resistance andincreasing uteroplacental blood flow. Impairedspiral artery remodelling has been implicated inpre-eclampsia, a major complication ofpregnancy, for a long time but the underlyingmechanisms remain unclear. Corin (also knownas atrial natriuretic peptide-converting enzyme)is a cardiac protease that activates atrialnatriuretic peptide (ANP), a cardiac hormone thatis important in regulating blood pressure.Unexpectedly, corin expression was detected inthe pregnant uterus. Here we identify a newfunction of corin and ANP in promotingtrophoblast invasion and spiral arteryremodelling. We show that pregnant corin- orANP-deficient mice developed high bloodpressure and proteinuria, characteristics ofpre-eclampsia. In these mice, trophoblast", "metadata": {}}
+{"_id": "4410181", "title": "", "text": "Metabolic rescue in pluripotent cells frompatients with mtDNA diseaseMitochondria have amajor role in energy production via oxidativephosphorylation, which is dependent on theexpression of critical genes encoded bymitochondrial (mt)DNA. Mutations in mtDNA cancause fatal or severely debilitating disorders withlimited treatment options. Clinical manifestationsvary based on mutation type and heteroplasmy(that is, the relative levels of mutant andwild-type mtDNA within each cell). Here wegenerated genetically corrected pluripotent stemcells (PSCs) from patients with mtDNA disease.Multiple induced pluripotent stem (iPS) cell lineswere derived from patients with commonheteroplasmic mutations including 3243A>G,causing mitochondrial encephalomyopathy andstroke-like episodes (MELAS), and 8993T>G and13513G>A, implicated in Leigh syndrome.Isogenic MELAS and Leigh syndrome iPS celllines were generated containing exclusivelywild-type or mutant mtDNA through spontaneous", "metadata": {}}
+{"_id": "4411655", "title": "", "text": "The yeast Pif1p helicase removes telomerasefrom telomeric DNATelomeres are the physicalends of eukaryotic chromosomes. Geneticstudies have established that the baker's yeastPif1p DNA helicase is a negative regulator oftelomerase, the specialized reverse transcriptasethat maintains telomeric DNA, but thebiochemical basis for this inhibition wasunknown. Here we show that in vitro, Pif1preduces the processivity of telomerase andreleases telomerase from telomericoligonucleotides. The released telomerase isenzymatically active because it is able tolengthen a challenger oligonucleotide. In vivo,overexpression of Pif1p reduces telomeraseassociation with telomeres, whereas depletingcells of Pif1p increases the levels oftelomere-bound Est1p, a telomerase subunit thatis present on the telomere when telomerase isactive. We propose that Pif1p helicase activitylimits telomerase action both in vivo and in vitroby displacing active telomerase from DNA ends.", "metadata": {}}
+{"_id": "4411760", "title": "", "text": "Small regulatory RNAs inhibit RNA Polymerase IIduring the elongation phase oftranscriptionEukaryotic cells express a widevariety of endogenous small regulatory RNAsthat regulate heterochromatin formation,developmental timing, defence against parasiticnucleic acids and genome rearrangement. Manysmall regulatory RNAs are thought to function innuclei. For instance, in plants and fungi, shortinterfering RNA (siRNAs) associate with nascenttranscripts and direct chromatin and/or DNAmodifications. To understand further thebiological roles of small regulatory RNAs, weconducted a genetic screen to identify factorsrequired for RNA interference (RNAi) inCaenorhabditis elegans nuclei. Here we showthat the gene nuclear RNAi defective-2 (nrde-2)encodes an evolutionarily conserved protein thatis required for siRNA-mediated silencing innuclei. NRDE-2 associates with the Argonauteprotein NRDE-3 within nuclei and is recruited byNRDE-3/siRNA complexes to nascent transcripts", "metadata": {}}
+{"_id": "4412772", "title": "", "text": "Cdk1 is sufficient to drive the mammalian cellcycleUnicellular organisms such as yeasts requirea single cyclin-dependent kinase, Cdk1, to drivecell division. In contrast, mammalian cells arethought to require the sequential activation of atleast four different cyclin-dependent kinases,Cdk2, Cdk3, Cdk4 and Cdk6, to drive cellsthrough interphase, as well as Cdk1 to proceedthrough mitosis. This model has been challengedby recent genetic evidence that mice survive inthe absence of individual interphase Cdks.Moreover, most mouse cell types proliferate inthe absence of two or even three interphaseCdks. Similar results have been obtained onablation of some of the activating subunits ofCdks, such as the D-type and E-type cyclins.Here we show that mouse embryos lacking allinterphase Cdks (Cdk2, Cdk3, Cdk4 and Cdk6)undergo organogenesis and develop tomidgestation. In these embryos, Cdk1 binds toall cyclins, resulting in the phosphorylation of theretinoblastoma protein pRb and the expression of", "metadata": {}}
+{"_id": "4414481", "title": "", "text": "Calorie restriction extends Saccharomycescerevisiae lifespan by increasingrespirationCalorie restriction (CR) extendslifespan in a wide spectrum of organisms and isthe only regimen known to lengthen the lifespanof mammals. We established a model of CR inbudding yeast Saccharomyces cerevisiae. In thissystem, lifespan can be extended by limitingglucose or by reducing the activity of theglucose-sensing cyclic-AMP-dependent kinase(PKA). Lifespan extension in a mutant withreduced PKA activity requires Sir2 and NAD(nicotinamide adenine dinucleotide). In thisstudy we explore how CR activates Sir2 toextend lifespan. Here we show that the shuntingof carbon metabolism toward the mitochondrialtricarboxylic acid cycle and the concomitantincrease in respiration play a central part in thisprocess. We discuss how this metabolic strategymay apply to CR in animals.", "metadata": {}}
+{"_id": "4414547", "title": "", "text": "Mosaic PPM1D mutations are associated withpredisposition to breast and ovariancancerImproved sequencing technologies offerunprecedented opportunities for investigating therole of rare genetic variation in common disease.However, there are considerable challenges withrespect to study design, data analysis andreplication. Using pooled next-generationsequencing of 507 genes implicated in the repairof DNA in 1,150 samples, an analytical strategyfocused on protein-truncating variants (PTVs)and a large-scale sequencing case–controlreplication experiment in 13,642 individuals,here we show that rare PTVs in the p53-inducibleprotein phosphatase PPM1D are associated withpredisposition to breast cancer and ovariancancer. PPM1D PTV mutations were present in 25out of 7,781 cases versus 1 out of 5,861 controls(P = 1.12 × 10−5), including 18 mutations in6,912 individuals with breast cancer (P = 2.42 ×10−4) and 12 mutations in 1,121 individualswith ovarian cancer (P = 3.10 × 10−9). Notably,", "metadata": {}}
+{"_id": "4416964", "title": "", "text": "Immunogenicity of induced pluripotent stemcellsInduced pluripotent stem cells (iPSCs),reprogrammed from somatic cells with definedfactors, hold great promise for regenerativemedicine as the renewable source of autologouscells. Whereas it has been generally assumedthat these autologous cells should beimmune-tolerated by the recipient from whomthe iPSCs are derived, their immunogenicity hasnot been vigorously examined. We show herethat, whereas embryonic stem cells (ESCs)derived from inbred C57BL/6 (B6) mice canefficiently form teratomas in B6 mice without anyevident immune rejection, the allogeneic ESCsfrom 129/SvJ mice fail to form teratomas in B6mice due to rapid rejection by recipients. B6mouse embryonic fibroblasts (MEFs) werereprogrammed into iPSCs by either retroviralapproach (ViPSCs) or a novel episomal approach(EiPSCs) that causes no genomic integration. Incontrast to B6 ESCs, teratomas formed by B6ViPSCs were mostly immune-rejected by B6", "metadata": {}}
+{"_id": "4417177", "title": "", "text": "Direct conversion of human fibroblasts tomultilineage blood progenitorsAs is the case forembryo-derived stem cells, application ofreprogrammed human induced pluripotent stemcells is limited by our understanding of lineagespecification. Here we demonstrate the ability togenerate progenitors and mature cells of thehaematopoietic fate directly from human dermalfibroblasts without establishing pluripotency.Ectopic expression of OCT4 (also calledPOU5F1)-activated haematopoietic transcriptionfactors, together with specific cytokinetreatment, allowed generation of cells expressingthe pan-leukocyte marker CD45. These uniquefibroblast-derived cells gave rise to granulocytic,monocytic, megakaryocytic and erythroidlineages, and demonstrated in vivo engraftmentcapacity. We note that adult haematopoieticprograms are activated, consistent withbypassing the pluripotent state to generate bloodfate: this is distinct from haematopoiesisinvolving pluripotent stem cells, where", "metadata": {}}
+{"_id": "4417558", "title": "", "text": "Mical links semaphorins to F-actindisassemblyHow instructive cues present on thecell surface have their precise effects on theactin cytoskeleton is poorly understood.Semaphorins are one of the largest families ofthese instructive cues and are widely studied fortheir effects on cell movement, navigation,angiogenesis, immunology and cancer.Semaphorins/collapsins were characterized inpart on the basis of their ability to drasticallyalter actin cytoskeletal dynamics in neuronalprocesses, but despite considerable progress inthe identification of semaphorin receptors andtheir signalling pathways, the molecules linkingthem to the precise control of cytoskeletalelements remain unknown. Recently, highlyunusual proteins of the Mical family of enzymeshave been found to associate with thecytoplasmic portion of plexins, which are largecell-surface semaphorin receptors, and tomediate axon guidance, synaptogenesis,dendritic pruning and other cell morphological", "metadata": {}}
+{"_id": "4418070", "title": "", "text": "Novel Foxo1-dependent transcriptional programscontrol Treg cell functionRegulatory T (Treg)cells, characterized by expression of thetranscription factor forkhead box P3 (Foxp3),maintain immune homeostasis by suppressingself-destructive immune responses. Foxp3operates as a late-acting differentiation factorcontrolling Treg cell homeostasis and function,whereas the early Treg-cell-lineage commitmentis regulated by the Akt kinase and the forkheadbox O (Foxo) family of transcription factors.However, whether Foxo proteins act beyond theTreg-cell-commitment stage to control Treg cellhomeostasis and function remains largelyunexplored. Here we show that Foxo1 is a pivotalregulator of Treg cell function. Treg cells expresshigh amounts of Foxo1 and display reducedT-cell-receptor-induced Akt activation, Foxo1phosphorylation and Foxo1 nuclear exclusion.Mice with Treg-cell-specific deletion of Foxo1develop a fatal inflammatory disorder similar inseverity to that seen in Foxp3-deficient mice, but", "metadata": {}}
+{"_id": "4418112", "title": "", "text": "Functional screening identifies miRNAs inducingcardiac regenerationIn mammals, enlargementof the heart during embryonic development isprimarily dependent on the increase incardiomyocyte numbers. Shortly after birth,however, cardiomyocytes stop proliferating andfurther growth of the myocardium occursthrough hypertrophic enlargement of the existingmyocytes. As a consequence of the minimalrenewal of cardiomyocytes during adult life,repair of cardiac damage through myocardialregeneration is very limited. Here we show thatthe exogenous administration of selectedmicroRNAs (miRNAs) markedly stimulatescardiomyocyte proliferation and promotescardiac repair. We performed a high-contentmicroscopy, high-throughput functionalscreening for human miRNAs that promotedneonatal cardiomyocyte proliferation using awhole-genome miRNA library. Forty miRNAsstrongly increased both DNA synthesis andcytokinesis in neonatal mouse and rat", "metadata": {}}
+{"_id": "4418269", "title": "", "text": "Specificity of sensory–motor connectionsencoded by Sema3e–Plxnd1 recognitionSpinalreflexes are mediated by synaptic connectionsbetween sensory afferents and motor neurons.The organization of these circuits shows severallevels of specificity. Only certain classes ofproprioceptive sensory neurons make direct,monosynaptic connections with motor neurons.Those that do are bound by rules of motor poolspecificity: they form strong connections withmotor neurons supplying the same muscle, butavoid motor pools supplying antagonisticmuscles. This pattern of connectivity is initiallyaccurate and is maintained in the absence ofactivity, implying that wiring specificity relies onthe matching of recognition molecules on thesurface of sensory and motor neurons. However,determinants of fine synaptic specificity here, asin most regions of the central nervous system,have yet to be defined. To address the origins ofsynaptic specificity in these reflex circuits wehave used molecular genetic methods to", "metadata": {}}
+{"_id": "4418582", "title": "", "text": "A chromatin remodelling complex involved intranscription and DNA processing.The packagingof the eukaryotic genome in chromatin presentsbarriers that restrict the access of enzymes thatprocess DNA. To overcome these barriers, cellspossess a number of multi-protein,ATP-dependent chromatin remodellingcomplexes, each containing an ATPase subunitfrom the SNF2/SWI2 superfamily. Chromatinremodelling complexes function by increasingnucleosome mobility and are clearly implicated intranscription. Here we have analysedSNF2/SWI2- and ISWI-related proteins toidentify remodelling complexes that potentiallyassist other DNA transactions. We purified acomplex from Saccharomyces cerevisiae thatcontains the Ino80 ATPase. The INO80 complexcontains about 12 polypeptides including twoproteins related to the bacterial RuvB DNAhelicase, which catalyses branch migration ofHolliday junctions. The purified complexremodels chromatin, facilitates transcription in", "metadata": {}}
+{"_id": "4418878", "title": "", "text": "Oncogenic pathway signatures in human cancersas a guide to targeted therapiesThe developmentof an oncogenic state is a complex processinvolving the accumulation of multipleindependent mutations that lead to deregulationof cell signalling pathways central to the controlof cell growth and cell fate. The ability to definecancer subtypes, recurrence of disease andresponse to specific therapies using DNAmicroarray-based gene expression signatureshas been demonstrated in multiple studies.Various studies have also demonstrated thepotential for using gene expression profiles forthe analysis of oncogenic pathways. Here weshow that gene expression signatures can beidentified that reflect the activation status ofseveral oncogenic pathways. When evaluated inseveral large collections of human cancers, thesegene expression signatures identify patterns ofpathway deregulation in tumours and clinicallyrelevant associations with disease outcomes.Combining signature-based predictions across", "metadata": {}}
+{"_id": "4421547", "title": "", "text": "CTCF mediates methylation-sensitiveenhancer-blocking activity at the H19/Igf2locus.The Insulin-like growth factor 2 (Igf2) andH19 genes are imprinted, resulting in silencing ofthe maternal and paternal alleles, respectively.This event is dependent upon animprinted-control region two kilobases upstreamof H19 (refs 1, 2). On the paternal chromosomethis element is methylated and required for thesilencing of H19 (refs 2-4). On the maternalchromosome the region is unmethylated andrequired for silencing of the Igf2 gene 90kilobases upstream. We have proposed that theunmethylated imprinted-control region acts as achromatin boundary that blocks the interactionof Igf2 with enhancers that lie 3' of H19 (refs 5,6). This enhancer-blocking activity would then belost when the region was methylated, therebyallowing expression of Igf2 paternally. Here weshow, using transgenic mice and tissue culture,that the unmethylated imprinted-control regionsfrom mouse and human H19 exhibit", "metadata": {}}
+{"_id": "4421578", "title": "", "text": "Broad and potent neutralization of HIV-1 by agp41-specific human antibodyCharacterization ofhuman monoclonal antibodies is providingconsiderable insight into mechanisms of broadHIV-1 neutralization. Here we report an HIV-1gp41 membrane-proximal external region(MPER)-specific antibody, named 10E8, whichneutralizes \u000098% of tested viruses. An analysisof sera from 78 healthy HIV-1-infected donorsdemonstrated that 27% contained MPER-specificantibodies and 8% contained 10E8-likespecificities. In contrast to other neutralizingMPER antibodies, 10E8 did not bindphospholipids, was not autoreactive, and boundcell-surface envelope. The structure of 10E8 incomplex with the complete MPER revealed a siteof vulnerability comprising a narrow stretch ofhighly conserved gp41-hydrophobic residues anda critical arginine or lysine just before thetransmembrane region. Analysis of resistantHIV-1 variants confirmed the importance ofthese residues for neutralization. The highly", "metadata": {}}
+{"_id": "4421742", "title": "", "text": "Disruption of the Hepcidin/Ferroportin RegulatorySystem Causes Pulmonary Iron Overload andRestrictive Lung DiseaseEmerging evidencesuggests that pulmonary iron accumulation isimplicated in a spectrum of chronic lungdiseases. However, the mechanism(s) involvedin pulmonary iron deposition and its role in the invivo pathogenesis of lung diseases remainsunknown. Here we show that a point mutation inthe murine ferroportin gene, which causeshereditary hemochromatosis type 4(Slc40a1C326S), increases iron levels in alveolarmacrophages, epithelial cells lining theconducting airways and lung parenchyma, and invascular smooth muscle cells. Pulmonary ironoverload is associated with oxidative stress,restrictive lung disease with decreased total lungcapacity and reduced blood oxygen saturation inhomozygous Slc40a1C326S/C326S micecompared to wild-type controls. These findingsimplicate iron in lung pathology, which is so farnot considered a classical iron-related disorder.", "metadata": {}}
+{"_id": "4421746", "title": "", "text": "Genome-wide genetic analysis of polyploidy inyeastPolyploidy, increased sets of chromosomes,occurs during development, cellular stress,disease and evolution. Despite its prevalence,little is known about the physiological alterationsthat accompany polyploidy. We previouslydescribed ‘ploidy-specific lethality’, where a genedeletion that is not lethal in haploid or diploidbudding yeast causes lethality in triploids ortetraploids. Here we report a genome-widescreen to identify ploidy-specific lethal functions.Only 39 out of 3,740 mutations screenedexhibited ploidy-specific lethality. Almost all ofthese mutations affect genomic stability byimpairing homologous recombination, sisterchromatid cohesion, or mitotic spindle function.We uncovered defects in wild-type tetraploidspredicted by the screen, and identifiedmechanisms by which tetraploidization affectsgenomic stability. We show that tetraploids havea high incidence of syntelic/monopolarkinetochore attachments to the spindle pole. We", "metadata": {}}
+{"_id": "4421787", "title": "", "text": "Diverse and heritable lineage imprinting of earlyhaematopoietic progenitorsHaematopoietic stemcells (HSCs) and their subsequent progenitorsproduce blood cells, but the precise nature andkinetics of this production is a contentious issue.In one model, lymphoid and myeloid productionbranch after the lymphoid-primed multipotentprogenitor (LMPP), with both branchessubsequently producing dendritic cells. However,this model is based mainly on in vitro clonalassays and population-based tracking in vivo,which could miss in vivo single-cell complexity.Here we avoid these issues by using a newquantitative version of ‘cellular barcoding’ totrace the in vivo fate of hundreds of LMPPs andHSCs at the single-cell level. These datademonstrate that LMPPs are highlyheterogeneous in the cell types that theyproduce, separating into combinations oflymphoid-, myeloid- and dendritic-cell-biasedproducers. Conversely, although we observe aknown lineage bias of some HSCs, most cellular", "metadata": {}}
+{"_id": "4422723", "title": "", "text": "Crowding induces live cell extrusion to maintainhomeostatic cell numbers in epitheliaFor anepithelium to provide a protective barrier, itmust maintain homeostatic cell numbers bymatching the number of dividing cells with thenumber of dying cells. Although compensatorycell division can be triggered by dying cells, it isunknown how cell death might relieveovercrowding due to proliferation. When wetrigger apoptosis in epithelia, dying cells areextruded to preserve a functional barrier.Extrusion occurs by cells destined to diesignalling to surrounding epithelial cells tocontract an actomyosin ring that squeezes thedying cell out. However, it is not clear whatdrives cell death during normal homeostasis.Here we show in human, canine and zebrafishcells that overcrowding due to proliferation andmigration induces extrusion of live cells tocontrol epithelial cell numbers. Extrusion of livecells occurs at sites where the highest crowdingoccurs in vivo and can be induced by", "metadata": {}}
+{"_id": "4422734", "title": "", "text": "Direct observation of ligand recognition by TcellsThe activation of T cells through interactionof their T-cell receptors with antigenic peptidebound to major histocompatibility complex(MHC) on the surface of antigen presenting cells(APCs) is a crucial step in adaptive immunity.Here we use three-dimensional fluorescencemicroscopy to visualize individual peptide–I-Ekclass II MHC complexes labelled with thephycobiliprotein phycoerythrin in an effort tocharacterize T-cell sensitivity and therequirements for forming an immunologicalsynapse in single cells. We show that T cellsexpressing the CD4 antigen respond withtransient calcium signalling to even a singleagonist peptide–MHC ligand, and that theorganization of molecules in the contact zone ofthe T cell and APC takes on the characteristics ofan immunological synapse when only about tenagonists are present. This sensitivity is highlydependant on CD4, because blocking thismolecule with antibodies renders T cells unable", "metadata": {}}
+{"_id": "4422868", "title": "", "text": "Crypt stem cells as the cells-of-origin ofintestinal cancerIntestinal cancer is initiated byWnt-pathway-activating mutations in genes suchas adenomatous polyposis coli (APC). As in mostcancers, the cell of origin has remained elusive.In a previously established Lgr5(leucine-rich-repeat containingG-protein-coupled receptor 5) knockin mousemodel, a tamoxifen-inducible Cre recombinase isexpressed in long-lived intestinal stem cells.Here we show that deletion of Apc in these stemcells leads to their transformation within days.Transformed stem cells remain located at cryptbottoms, while fuelling a growing microadenoma.These microadenomas show unimpeded growthand develop into macroscopic adenomas within3-5weeks. The distribution of Lgr5+ cells withinstem-cell-derived adenomas indicates that astem cell/progenitor cell hierarchy is maintainedin early neoplastic lesions. When Apc is deletedin short-lived transit-amplifying cells using adifferent cre mouse, the growth of the induced", "metadata": {}}
+{"_id": "4423203", "title": "", "text": "Microbial engineering for the production ofadvanced biofuelsAdvanced biofuels produced bymicroorganisms have similar properties topetroleum-based fuels, and can 'drop in' to theexisting transportation infrastructure. However,producing these biofuels in yields high enough tobe useful requires the engineering of themicroorganism's metabolism. Such engineeringis not based on just one specific feedstock orhost organism. Data-driven andsynthetic-biology approaches can be used tooptimize both the host and pathways tomaximize fuel production. Despite some success,challenges still need to be met to move advancedbiofuels towards commercialization, and tocompete with more conventional fuels.", "metadata": {}}
+{"_id": "4423220", "title": "", "text": "Sperm chromatin proteomics identifiesevolutionarily conserved fertility factorsMaleinfertility is a long-standing enigma of significantmedical concern. The integrity of spermchromatin is a clinical indicator of male fertilityand in vitro fertilization potential: chromosomeaneuploidy and DNA decondensation or damageare correlated with reproductive failure.Identifying conserved proteins important forsperm chromatin structure and packaging canreveal universal causes of infertility. Here wecombine proteomics, cytology and functionalanalysis in Caenorhabditis elegans to identifyspermatogenic chromatin-associated proteinsthat are important for fertility. Our strategyemployed multiple steps: purification ofchromatin from comparable meiotic cell types,namely those undergoing spermatogenesis oroogenesis; proteomic analysis bymultidimensional protein identificationtechnology (MudPIT) of factors that co-purifywith chromatin; prioritization of sperm proteins", "metadata": {}}
+{"_id": "4423327", "title": "", "text": "Nanog safeguards pluripotency and mediatesgermline developmentNanog is a divergenthomeodomain protein found in mammalianpluripotent cells and developing germ cells.Deletion of Nanog causes early embryoniclethality, whereas constitutive expressionenables autonomous self-renewal of embryonicstem cells. Nanog is accordingly considered acore element of the pluripotent transcriptionalnetwork. However, here we report that Nanogfluctuates in mouse embryonic stem cells.Transient downregulation of Nanog appears topredispose cells towards differentiation but doesnot mark commitment. By genetic deletion weshow that, although they are prone todifferentiate, embryonic stem cells canself-renew indefinitely in the permanent absenceof Nanog. Expanded Nanog null cells colonizeembryonic germ layers and exhibit multilineagedifferentiation both in fetal and adult chimaeras.Although they are also recruited to the germ line,primordial germ cells lacking Nanog fail to", "metadata": {}}
+{"_id": "4423401", "title": "", "text": "Succinate is an inflammatory signal that inducesIL-1β through HIF-1αMacrophages activated bythe Gram-negative bacterial productlipopolysaccharide switch their core metabolismfrom oxidative phosphorylation to glycolysis.Here we show that inhibition of glycolysis with2-deoxyglucose suppresseslipopolysaccharide-induced interleukin-1β but nottumour-necrosis factor-α in mouse macrophages.A comprehensive metabolic map oflipopolysaccharide-activated macrophages showsupregulation of glycolytic and downregulation ofmitochondrial genes, which correlates directlywith the expression profiles of alteredmetabolites. Lipopolysaccharide stronglyincreases the levels of the tricarboxylic-acid cycleintermediate succinate. Glutamine-dependentanerplerosis is the principal source of succinate,although the ‘GABA (γ-aminobutyric acid) shunt’pathway also has a role.Lipopolysaccharide-induced succinate stabilizeshypoxia-inducible factor-1α, an effect that is", "metadata": {}}
+{"_id": "4423559", "title": "", "text": "Planar cell polarity signalling couples cell divisionand morphogenesis duringneurulationEnvironmental and geneticaberrations lead to neural tube closure defects(NTDs) in 1 out of every 1,000 births. Mouse andfrog models for these birth defects haveindicated that Van Gogh-like 2 (Vangl2, alsoknown as Strabismus) and other components ofplanar cell polarity (PCP) signalling might controlneurulation by promoting the convergence ofneural progenitors to the midline. Here we showa novel role for PCP signalling during neurulationin zebrafish. We demonstrate that non-canonicalWnt/PCP signalling polarizes neural progenitorsalong the anteroposterior axis. This polarity istransiently lost during cell division in the neuralkeel but is re-established as daughter cellsreintegrate into the neuroepithelium. Loss ofzebrafish Vangl2 (in trilobite mutants) abolishesthe polarization of neural keel cells, disruptsre-intercalation of daughter cells into theneuroepithelium, and results in ectopic neural", "metadata": {}}
+{"_id": "4424888", "title": "", "text": "The challenge of new drug discovery fortuberculosisTuberculosis (TB) is more prevalentin the world today than at any other time inhuman history. Mycobacterium tuberculosis, thepathogen responsible for TB, uses diversestrategies to survive in a variety of host lesionsand to evade immune surveillance. A keyquestion is how robust are our approaches todiscovering new TB drugs, and what measurescould be taken to reduce the long and protractedclinical development of new drugs. Theemergence of multi-drug-resistant strains of M.tuberculosis makes the discovery of newmolecular scaffolds a priority, and the currentsituation even necessitates the re-engineeringand repositioning of some old drug families toachieve effective control. Whatever the strategyused, success will depend largely on our properunderstanding of the complex interactionsbetween the pathogen and its human host. Inthis review, we discuss innovations in TB drugdiscovery and evolving strategies to bring newer", "metadata": {}}
+{"_id": "4425507", "title": "", "text": "Subunit Arrangement and PhenylethanolamineBinding in GluN1/GluN2B NMDA ReceptorsSinceit was discovered that the anti-hypertensiveagent ifenprodil has neuroprotective activitythrough its effects on NMDA(N-methyl-D-aspartate) receptors, a determinedeffort has been made to understand themechanism of action and to develop improvedtherapeutic compounds on the basis of thisknowledge. Neurotransmission mediated byNMDA receptors is essential for basic braindevelopment and function. These receptors formheteromeric ion channels and become activatedafter concurrent binding of glycine and glutamateto the GluN1 and GluN2 subunits, respectively. Afunctional hallmark of NMDA receptors is thattheir ion-channel activity is allostericallyregulated by binding of small compounds to theamino-terminal domain (ATD) in asubtype-specific manner. Ifenprodil and relatedphenylethanolamine compounds, whichspecifically inhibit GluN1 and GluN2B NMDA", "metadata": {}}
+{"_id": "4427060", "title": "", "text": "Association of NOD2 leucine-rich repeat variantswith susceptibility to Crohn's disease.Crohn'sdisease and ulcerative colitis, the two main typesof chronic inflammatory bowel disease, aremultifactorial conditions of unknown aetiology. Asusceptibility locus for Crohn's disease has beenmapped to chromosome 16. Here we have useda positional-cloning strategy, based on linkageanalysis followed by linkage disequilibriummapping, to identify three independentassociations for Crohn's disease: a frameshiftvariant and two missense variants of NOD2,encoding a member of the Apaf-1/Ced-4superfamily of apoptosis regulators that isexpressed in monocytes. These NOD2 variantsalter the structure of either the leucine-richrepeat domain of the protein or the adjacentregion. NOD2 activates nuclear factor NF-kB; thisactivating function is regulated by thecarboxy-terminal leucine-rich repeat domain,which has an inhibitory role and also acts as anintracellular receptor for components of microbial", "metadata": {}}
+{"_id": "4427392", "title": "", "text": "Human cardiovascular progenitor cells developfrom a KDR+ embryonic-stem-cell-derivedpopulationThe functional heart is comprised ofdistinct mesoderm-derived lineages includingcardiomyocytes, endothelial cells and vascularsmooth muscle cells. Studies in the mouseembryo and the mouse embryonic stem celldifferentiation model have provided evidenceindicating that these three lineages develop froma common Flk-1+ (kinase insert domain proteinreceptor, also known as Kdr) cardiovascularprogenitor that represents one of the earlieststages in mesoderm specification to thecardiovascular lineages. To determine whether acomparable progenitor is present during humancardiogenesis, we analysed the development ofthe cardiovascular lineages in human embryonicstem cell differentiation cultures. Here we showthat after induction with combinations of activinA, bone morphogenetic protein 4 (BMP4), basicfibroblast growth factor (bFGF, also known asFGF2), vascular endothelial growth factor (VEGF,", "metadata": {}}
+{"_id": "4429118", "title": "", "text": "Cancer-related inflammationThe mediators andcellular effectors of inflammation are importantconstituents of the local environment of tumours.In some types of cancer, inflammatory conditionsare present before a malignant change occurs.Conversely, in other types of cancer, anoncogenic change induces an inflammatorymicroenvironment that promotes thedevelopment of tumours. Regardless of its origin,'smouldering' inflammation in the tumourmicroenvironment has many tumour-promotingeffects. It aids in the proliferation and survival ofmalignant cells, promotes angiogenesis andmetastasis, subverts adaptive immuneresponses, and alters responses to hormonesand chemotherapeutic agents. The molecularpathways of this cancer-related inflammation arenow being unravelled, resulting in theidentification of new target molecules that couldlead to improved diagnosis and treatment.", "metadata": {}}
+{"_id": "4429388", "title": "", "text": "ESCRT-III recognition by VPS4 ATPasesTheESCRT (endosomal sorting complex required fortransport) pathway is required for terminalmembrane fission events in several importantbiological processes, including endosomalintraluminal vesicle formation, HIV budding andcytokinesis. VPS4 ATPases perform a keyfunction in this pathway by recognizingmembrane-associated ESCRT-III assemblies andcatalysing their disassembly, possibly inconjunction with membrane fission. Here weshow that the microtubule interacting andtransport (MIT) domains of human VPS4A andVPS4B bind conserved sequence motifs locatedat the carboxy termini of the CHMP1–3 class ofESCRT-III proteins. Structures of VPS4AMIT–CHMP1A and VPS4B MIT–CHMP2Bcomplexes reveal that the C-terminal CHMP motifforms an amphipathic helix that binds in agroove between the last two helices of thetetratricopeptide-like repeat (TPR) of the VPS4MIT domain, but in the opposite orientation to", "metadata": {}}
+{"_id": "4429668", "title": "", "text": "Pif1 family helicases suppress genome instabilityat G-quadruplex motifsThe Saccharomycescerevisiae Pif1 helicase is the prototypicalmember of the Pif1 DNA helicase family, which isconserved from bacteria to humans. Here weshow that exceptionally potent G-quadruplexunwinding is conserved among Pif1 helicases.Moreover, Pif1 helicases from organismsseparated by more than 3 billion years ofevolution suppressed DNA damage atG-quadruplex motifs in yeast. TheG-quadruplex-induced damage generated in theabsence of Pif1 helicases led to new genetic andepigenetic changes. Furthermore, whenexpressed in yeast, human PIF1 suppressed bothG-quadruplex-associated DNA damage andtelomere lengthening.", "metadata": {}}
+{"_id": "4429932", "title": "", "text": "Lysyl oxidase is essential for hypoxia-inducedmetastasisMetastasis is a multistep processresponsible for most cancer deaths, and it can beinfluenced by both the immediatemicroenvironment (cell–cell or cell–matrixinteractions) and the extended tumourmicroenvironment (for example vascularization).Hypoxia (low oxygen) is clinically associated withmetastasis and poor patient outcome, althoughthe underlying processes remain unclear.Microarray studies have shown the expression oflysyl oxidase (LOX) to be elevated in hypoxichuman tumour cells. Paradoxically, LOXexpression is associated with both tumoursuppression and tumour progression, and its rolein tumorigenesis seems dependent on cellularlocation, cell type and transformation status.Here we show that LOX expression is regulatedby hypoxia-inducible factor (HIF) and isassociated with hypoxia in human breast andhead and neck tumours. Patients with highLOX-expressing tumours have poor distant", "metadata": {}}
+{"_id": "4430962", "title": "", "text": "Identification of human brain tumour initiatingcellsThe cancer stem cell (CSC) hypothesissuggests that neoplastic clones are maintainedexclusively by a rare fraction of cells with stemcell properties. Although the existence of CSCs inhuman leukaemia is established, little evidenceexists for CSCs in solid tumours, except forbreast cancer. Recently, we prospectivelyisolated a CD133+ cell subpopulation fromhuman brain tumours that exhibited stem cellproperties in vitro. However, the true measuresof CSCs are their capacity for self renewal andexact recapitulation of the original tumour. Herewe report the development of a xenograft assaythat identified human brain tumour initiatingcells that initiate tumours in vivo. Only theCD133+ brain tumour fraction contains cells thatare capable of tumour initiation in NOD-SCID(non-obese diabetic, severe combinedimmunodeficient) mouse brains. Injection of asfew as 100 CD133+ cells produced a tumour thatcould be serially transplanted and was a", "metadata": {}}
+{"_id": "4432763", "title": "", "text": "Anthropometric reference data for internationaluse: recommendations from a World HealthOrganization Expert Committee.The World HealthOrganization (WHO) convened an ExpertCommittee to reevaluate the use ofanthropometry at different ages for assessinghealth, nutrition, and social wellbeing. TheCommittee's task included identifying referencedata for anthropometric indexes whenappropriate, and providing guidelines on how thedata should be used. For fetal growth, theCommittee recommended an existingsex-specific multiracial reference. In view of thesignificant technical drawbacks of the currentNational Center for Health Statistics(NCHS)/WHO reference and its inadequacy forassessing the growth of breast-fed infants, theCommittee recommended the development of anew reference concerning weight andlength/height for infants and children, which willbe a complex and costly undertaking. Properinterpretation of midupper arm circumference for", "metadata": {}}
+{"_id": "4434951", "title": "", "text": "Diverse interventions that extend mouse lifespansuppress shared age-associated epigeneticchanges at critical gene regulatoryregionsBACKGROUND Age-associated epigeneticchanges are implicated in aging. Notably,age-associated DNA methylation changescomprise a so-called aging \"clock\", a robustbiomarker of aging. However, while genetic,dietary and drug interventions can extendlifespan, their impact on the epigenome isuncharacterised. To fill this knowledge gap, wedefined age-associated DNA methylation changesat the whole-genome, single-nucleotide level inmouse liver and tested the impact oflongevity-promoting interventions, specificallythe Ames dwarf Prop1 df/df mutation, calorierestriction and rapamycin. RESULTS In wild-typemice fed an unsupplemented ad libitum diet,age-associated hypomethylation was enriched atsuper-enhancers in highly expressed genescritical for liver function. Genes harbouringhypomethylated enhancers were enriched for", "metadata": {}}
+{"_id": "4435369", "title": "", "text": "Extracellular vesicles for drugdelivery.Extracellular vesicles (EVs) arecell-derived membrane vesicles, and representan endogenous mechanism for intercellularcommunication. Since the discovery that EVs arecapable of functionally transferring biologicalinformation, the potential use of EVs as drugdelivery vehicles has gained considerablescientific interest. EVs may have multipleadvantages over currently available drug deliveryvehicles, such as their ability to overcomenatural barriers, their intrinsic cell targetingproperties, and stability in the circulation.However, therapeutic applications of EVs as drugdelivery systems have been limited due to a lackof methods for scalable EV isolation and efficientdrug loading. Furthermore, in order to achievetargeted drug delivery, their intrinsic celltargeting properties should be tuned through EVengineering. Here, we review and discuss recentprogress and remaining challenges in thedevelopment of EVs as drug delivery vehicles.", "metadata": {}}
+{"_id": "4442799", "title": "", "text": "Effects of soy isoflavones and phytate onhomocysteine, C-reactive protein, and ironstatus in postmenopausal women.BACKGROUNDSoy protein or its components may protectagainst the atherosclerotic cardiovasculardisease (CVD) risk factors total homocysteine(tHcy), C-reactive protein (CRP), and excessbody iron, which generally increase withmenopause. OBJECTIVE The primary objective ofthis study was to determine the independenteffect of the soy protein components isoflavonesand phytate on CVD risk factors inpostmenopausal women. The secondaryobjective was to identify factors [blood lipids,oxidative stress indexes, serum ferritin, plasmafolate, plasma vitamin B-12, and body massindex (BMI)] contributing to tHcy and CRPconcentrations. DESIGN In a double-blind, 6-wkstudy, 55 postmenopausal women aged 47-72 ywere randomly assigned to 1 of 4 soy protein (40g/d) isolate treatments: native phytate andnative isoflavone (n = 14), native phytate and", "metadata": {}}
+{"_id": "4444861", "title": "", "text": "Replication Fork Stability ConfersChemoresistance in BRCA-deficient CellsCellsdeficient in the Brca1 and Brca2 genes havereduced capacity to repair DNA double-strandbreaks by homologous recombination andconsequently are hypersensitive toDNA-damaging agents, including cisplatin andpoly(ADP-ribose) polymerase (PARP) inhibitors.Here we show that loss of the MLL3/4 complexprotein, PTIP, protects Brca1/2-deficient cellsfrom DNA damage and rescues the lethality ofBrca2-deficient embryonic stem cells. However,PTIP deficiency does not restore homologousrecombination activity at double-strand breaks.Instead, its absence inhibits the recruitment ofthe MRE11 nuclease to stalled replication forks,which in turn protects nascent DNA strands fromextensive degradation. More generally,acquisition of PARP inhibitors and cisplatinresistance is associated with replication forkprotection in Brca2-deficient tumour cells that donot develop Brca2 reversion mutations.", "metadata": {}}
+{"_id": "4445629", "title": "", "text": "Plasma Corin as a Predictor of CardiovascularEvents in Patients With Chronic HeartFailure.OBJECTIVES The aim of this study was todetermine the prognostic value of plasma corinin patients with chronic heart failure (CHF).BACKGROUND In recent years, accumulatingevidence has indicated that corin plays a criticalrole in regulating blood pressure and cardiacfunction. METHODS We enrolled 1,148consecutive CHF patients in a prospective cohortstudy and explored the association betweenplasma corin levels and clinical prognosis usingmultivariate Cox regression analysis. RESULTSPatients with low corin levels (<458 pg/ml) weremore likely to be women and to be hypertensive.Low corin was found to be associated with anincrease in New York Heart Association (NYHA)functional class and N-terminal pro-B-typenatriuretic peptide (NT-proBNP) levels, and adecrease in left ventricular ejection fraction(LVEF) and the estimated glomerular filtrationrate (eGFR). Multivariate Cox regression analysis", "metadata": {}}
+{"_id": "4446814", "title": "", "text": "Cryo-EM structures of Tau filaments fromAlzheimer’s disease brainAlzheimer's disease isthe most common neurodegenerative disease,and there are no mechanism-based therapies.The disease is defined by the presence ofabundant neurofibrillary lesions and neuriticplaques in the cerebral cortex. Neurofibrillarylesions comprise paired helical and straight taufilaments, whereas tau filaments with differentmorphologies characterize otherneurodegenerative diseases. No high-resolutionstructures of tau filaments are available. Here wepresent cryo-electron microscopy (cryo-EM)maps at 3.4-3.5 Å resolution and correspondingatomic models of paired helical and straightfilaments from the brain of an individual withAlzheimer's disease. Filament cores are made oftwo identical protofilaments comprising residues306-378 of tau protein, which adopt a combinedcross-β/β-helix structure and define the seed fortau aggregation. Paired helical and straightfilaments differ in their inter-protofilament", "metadata": {}}
+{"_id": "4447055", "title": "", "text": "Modulation of the proteoglycan receptor PTPσpromotes recovery after spinal cordinjuryContusive spinal cord injury leads to avariety of disabilities owing to limited neuronalregeneration and functional plasticity. It is wellestablished that an upregulation of glial-derivedchondroitin sulphate proteoglycans (CSPGs)within the glial scar and perineuronal net createsa barrier to axonal regrowth and sprouting.Protein tyrosine phosphatase σ (PTPσ), alongwith its sister phosphatase leukocyte commonantigen-related (LAR) and the nogo receptors 1and 3 (NgR), have recently been identified asreceptors for the inhibitory glycosylated sidechains of CSPGs. Here we find in rats that PTPσhas a critical role in converting growth cones intoa dystrophic state by tightly stabilizing themwithin CSPG-rich substrates. We generated amembrane-permeable peptide mimetic of thePTPσ wedge domain that binds to PTPσ andrelieves CSPG-mediated inhibition. Systemicdelivery of this peptide over weeks restored", "metadata": {}}
+{"_id": "4447785", "title": "", "text": "A gp130–Src–YAP module links inflammation toepithelial regenerationInflammation promotesregeneration of injured tissues through poorlyunderstood mechanisms, some of which involveinterleukin (IL)-6 family members, theexpression of which is elevated in many diseasesincluding inflammatory bowel diseases andcolorectal cancer. Here we show in mice andhuman cells that gp130, a co-receptor for IL-6cytokines, triggers activation of YAP and Notch,transcriptional regulators that control tissuegrowth and regeneration, independently of thegp130 effector STAT3. Through YAP and Notch,intestinal gp130 signalling stimulates epithelialcell proliferation, causes aberrant differentiationand confers resistance to mucosal erosion.gp130 associates with the related tyrosinekinases Src and Yes, which are activated onreceptor engagement to phosphorylate YAP andinduce its stabilization and nuclear translocation.This signalling module is strongly activated uponmucosal injury to promote healing and maintain", "metadata": {}}
+{"_id": "4449524", "title": "", "text": "Hemoglobin concentration in white, black, andOriental children: is there a need for separatecriteria in screening for anemia?Theconcentration of hemoglobin in blacks was foundto be 0.5 to 1.0 g/dl lower than that ofincome-matched whites in several large surveys.This difference could be a racial characteristic ofblacks, or it might be due to a higher frequencyof genetic traits such as thalassemia minor andhemoglobinopathies, or to environmental factorssuch as iron deficiency. To help in making thisdistinction, we analyzed the data frommultiphasic examinations (1973 to 1975) on1718 white, 741 black, and 315 Oriental healthy,nonindigent children between 5 and 14 years ofage. In the entire population, the medianhemoglobin concentration averaged 0.5 g/dllower in blacks than in whites of both sexes (ttest, P less than 0.001). The differences stillaveraged 0.5 g/dl (P less than 0.001) afterexclusion of all those with abnormal hemoglobinby electrophoresis (Hgb S and C) and those", "metadata": {}}
+{"_id": "4452318", "title": "", "text": "Divergent reprogramming routes lead toalternative stem-cell statesPluripotency isdefined by the ability of a cell to differentiate tothe derivatives of all the three embryonic germlayers: ectoderm, mesoderm and endoderm.Pluripotent cells can be captured via thearchetypal derivation of embryonic stem cells orvia somatic cell reprogramming. Somatic cellsare induced to acquire a pluripotent stem cell(iPSC) state through the forced expression of keytranscription factors, and in the mouse thesecells can fulfil the strictest of all developmentalassays for pluripotent cells by generatingcompletely iPSC-derived embryos and mice.However, it is not known whether there areadditional classes of pluripotent cells, or what thespectrum of reprogrammed phenotypesencompasses. Here we explore alternativeoutcomes of somatic reprogramming by fullycharacterizing reprogrammed cells independentof preconceived definitions of iPSC states. Wedemonstrate that by maintaining elevated", "metadata": {}}
+{"_id": "4452659", "title": "", "text": "Autophagy mediates degradation of nuclearlaminaMacroautophagy (hereafter referred to asautophagy) is a catabolic membrane traffickingprocess that degrades a variety of cellularconstituents and is associated with humandiseases. Although extensive studies havefocused on autophagic turnover of cytoplasmicmaterials, little is known about the role ofautophagy in degrading nuclear components.Here we report that the autophagy machinerymediates degradation of nuclear laminacomponents in mammals. The autophagy proteinLC3/Atg8, which is involved in autophagymembrane trafficking and substrate delivery, ispresent in the nucleus and directly interacts withthe nuclear lamina protein lamin B1, and binds tolamin-associated domains on chromatin. ThisLC3-lamin B1 interaction does not downregulatelamin B1 during starvation, but mediates itsdegradation upon oncogenic insults, such as byactivated RAS. Lamin B1 degradation is achievedby nucleus-to-cytoplasm transport that delivers", "metadata": {}}
+{"_id": "4454788", "title": "", "text": "Pro-resolving lipid mediators are leads forresolution physiologyAdvances in ourunderstanding of the mechanisms that bringabout the resolution of acute inflammation haveuncovered a new genus of pro-resolving lipidmediators that include the lipoxin, resolvin,protectin and maresin families, collectively calledspecialized pro-resolving mediators. Syntheticversions of these mediators have potentbioactions when administered in vivo. In animalexperiments, the mediators evokeanti-inflammatory and novel pro-resolvingmechanisms, and enhance microbial clearance.Although they have been identified ininflammation resolution, specializedpro-resolving mediators are conserved structuresthat also function in host defence, pain, organprotection and tissue remodelling. This Reviewcovers the mechanisms of specializedpro-resolving mediators and omega-3 essentialfatty acid pathways that could help us tounderstand their physiological functions.", "metadata": {}}
+{"_id": "4455466", "title": "", "text": "ZMYND11 links histone H3.3K36me3 totranscription elongation and tumoursuppressionRecognition of modified histones by‘reader’ proteins plays a critical role in theregulation of chromatin. H3K36 trimethylation(H3K36me3) is deposited onto the nucleosomesin the transcribed regions after RNA polymeraseII elongation. In yeast, this mark in turn recruitsepigenetic regulators to reset the chromatin to arelatively repressive state, thus suppressingcryptic transcription. However, much less isknown about the role of H3K36me3 intranscription regulation in mammals. This isfurther complicated by the transcription-coupledincorporation of the histone variant H3.3 in genebodies. Here we show that the candidate tumoursuppressor ZMYND11 specifically recognizesH3K36me3 on H3.3 (H3.3K36me3) and regulatesRNA polymerase II elongation. Structural studiesshow that in addition to the trimethyl-lysinebinding by an aromatic cage within the PWWPdomain, the H3.3-dependent recognition is", "metadata": {}}
+{"_id": "4456756", "title": "", "text": "Autocrine BDNF–TrkB signalling within a singledendritic spineBrain-derived neurotrophic factor(BDNF) and its receptor TrkB are crucial formany forms of neuronal plasticity, includingstructural long-term potentiation (sLTP), which isa correlate of an animal’s learning. However, it isunknown whether BDNF release and TrkBactivation occur during sLTP, and if so, when andwhere. Here, using a fluorescence resonanceenergy transfer-based sensor for TrkB andtwo-photon fluorescence lifetime imagingmicroscopy, we monitor TrkB activity in singledendritic spines of CA1 pyramidal neurons incultured murine hippocampal slices. In responseto sLTP induction, we find fast (onset < 1 min)and sustained (>20 min) activation of TrkB inthe stimulated spine that depends on NMDAR(N-methyl-d-aspartate receptor) and CaMKIIsignalling and on postsynaptically synthesizedBDNF. We confirm the presence of postsynapticBDNF using electron microscopy to localizeendogenous BDNF to dendrites and spines of", "metadata": {}}
+{"_id": "4457160", "title": "", "text": "Whole genomes redefine the mutationallandscape of pancreatic cancerPancreatic cancerremains one of the most lethal of malignanciesand a major health burden. We performedwhole-genome sequencing and copy numbervariation (CNV) analysis of 100 pancreatic ductaladenocarcinomas (PDACs). Chromosomalrearrangements leading to gene disruption wereprevalent, affecting genes known to be importantin pancreatic cancer (TP53, SMAD4, CDKN2A,ARID1A and ROBO2) and new candidate driversof pancreatic carcinogenesis (KDM6A andPREX2). Patterns of structural variation(variation in chromosomal structure) classifiedPDACs into 4 subtypes with potential clinicalutility: the subtypes were termed stable, locallyrearranged, scattered and unstable. A significantproportion harboured focal amplifications, manyof which contained druggable oncogenes(ERBB2, MET, FGFR1, CDK6, PIK3R3 andPIK3CA), but at low individual patientprevalence. Genomic instability co-segregated", "metadata": {}}
+{"_id": "4457834", "title": "", "text": "Human oocytes reprogram adult somatic nucleiof a type 1 diabetic to diploid pluripotent stemcellsThe transfer of somatic cell nuclei intooocytes can give rise to pluripotent stem cellsthat are consistently equivalent to embryonicstem cells, holding promise for autologous cellreplacement therapy. Although methods toinduce pluripotent stem cells from somatic cellsby transcription factors are widely used in basicresearch, numerous differences between inducedpluripotent stem cells and embryonic stem cellshave been reported, potentially affecting theirclinical use. Because of the therapeutic potentialof diploid embryonic stem-cell lines derived fromadult cells of diseased human subjects, we havesystematically investigated the parametersaffecting efficiency of blastocyst developmentand stem-cell derivation. Here we show thatimprovements to the oocyte activation protocol,including the use of both kinase and translationinhibitors, and cell culture in the presence ofhistone deacetylase inhibitors, promote", "metadata": {}}
+{"_id": "4459491", "title": "", "text": "A three-dimensional human neural cell culturemodel of Alzheimer’s diseaseAlzheimer’s diseaseis the most common form of dementia,characterized by two pathological hallmarks:amyloid-β plaques and neurofibrillary tangles.The amyloid hypothesis of Alzheimer’s diseaseposits that the excessive accumulation ofamyloid-β peptide leads to neurofibrillary tanglescomposed of aggregated hyperphosphorylatedtau. However, to date, no single disease modelhas serially linked these two pathological eventsusing human neuronal cells. Mouse models withfamilial Alzheimer’s disease (FAD) mutationsexhibit amyloid-β-induced synaptic and memorydeficits but they do not fully recapitulate otherkey pathological events of Alzheimer’s disease,including distinct neurofibrillary tanglepathology. Human neurons derived fromAlzheimer’s disease patients have shownelevated levels of toxic amyloid-β species andphosphorylated tau but did not demonstrateamyloid-β plaques or neurofibrillary tangles.", "metadata": {}}
+{"_id": "4460880", "title": "", "text": "Mesenchymal-endothelial-transition contributesto cardiac neovascularizationEndothelial cellscontribute to a subset of cardiac fibroblasts byundergoing endothelial-to-mesenchymaltransition, but whether cardiac fibroblasts canadopt an endothelial cell fate and directlycontribute to neovascularization after cardiacinjury is not known. Here, using genetic fate maptechniques, we demonstrate that cardiacfibroblasts rapidly adopt an endothelial-cell-likephenotype after acute ischaemic cardiac injury.Fibroblast-derived endothelial cells exhibitanatomical and functional characteristics ofnative endothelial cells. We show that thetranscription factor p53 regulates such a switchin cardiac fibroblast fate. Loss of p53 in cardiacfibroblasts severely decreases the formation offibroblast-derived endothelial cells, reducespost-infarct vascular density and worsens cardiacfunction. Conversely, stimulation of the p53pathway in cardiac fibroblasts augmentsmesenchymal-to-endothelial transition, enhances", "metadata": {}}
+{"_id": "4462079", "title": "", "text": "Estimation of optimal serum concentrations of25-hydroxyvitamin D for multiple healthoutcomes.Recent evidence suggests that vitaminD intakes above current recommendations maybe associated with better health outcomes.However, optimal serum concentrations of25-hydroxyvitamin D [25(OH)D] have not beendefined. This review summarizes evidence fromstudies that evaluated thresholds for serum25(OH)D concentrations in relation to bonemineral density (BMD), lower-extremity function,dental health, and risk of falls, fractures, andcolorectal cancer. For all endpoints, the mostadvantageous serum concentrations of 25(OH)Dbegin at 75 nmol/L (30 ng/mL), and the best arebetween 90 and 100 nmol/L (36-40 ng/mL). Inmost persons, these concentrations could not bereached with the currently recommended intakesof 200 and 600 IU vitamin D/d for younger andolder adults, respectively. A comparison ofvitamin D intakes with achieved serumconcentrations of 25(OH)D for the purpose of", "metadata": {}}
+{"_id": "4462139", "title": "", "text": "Cohesin-dependent globules andheterochromatin shape 3D genome architecturein S. pombeEukaryotic genomes are folded intothree-dimensional structures, such asself-associating topological domains, the bordersof which are enriched in cohesin andCCCTC-binding factor (CTCF) required forlong-range interactions. How local chromatininteractions govern higher-order folding ofchromatin fibres and the function of cohesin inthis process remain poorly understood. Here weperform genome-wide chromatin conformationcapture (Hi-C) analysis to explore thehigh-resolution organization of theSchizosaccharomyces pombe genome, whichdespite its small size exhibits fundamentalfeatures found in other eukaryotes. Our analysesof wild-type and mutant strains reveal keyelements of chromosome architecture andgenome organization. On chromosome arms,small regions of chromatin locally interact toform 'globules'. This feature requires a function", "metadata": {}}
+{"_id": "4462155", "title": "", "text": "A temporal shift in the circuits mediatingretrieval of fear memoryFear memories allowanimals to avoid danger, thereby increasing theirchances of survival. Fear memories can beretrieved long after learning, but little is knownabout how retrieval circuits change with time.Here we show that the dorsal midline thalamusof rats is required for the retrieval of auditoryconditioned fear at late (24 hours, 7 days, 28days), but not early (0.5 hours, 6 hours) timepoints after learning. Consistent with this, theparaventricular nucleus of the thalamus (PVT), asubregion of the dorsal midline thalamus,showed increased c-Fos expression only at latetime points, indicating that the PVT is graduallyrecruited for fear retrieval. Accordingly, theconditioned tone responses of PVT neuronsincreased with time after training. The prelimbic(PL) prefrontal cortex, which is necessary for fearretrieval, sends dense projections to the PVT.Retrieval at late time points activated PL neuronsprojecting to the PVT, and optogenetic silencing", "metadata": {}}
+{"_id": "4462419", "title": "", "text": "Derivation of novel human ground state naivepluripotent stem cellsMouse embryonic stem(ES) cells are isolated from the inner cell mass ofblastocysts, and can be preserved in vitro in anaive inner-cell-mass-like configuration byproviding exogenous stimulation with leukaemiainhibitory factor (LIF) and small moleculeinhibition of ERK1/ERK2 and GSK3β signalling(termed 2i/LIF conditions). Hallmarks of naivepluripotency include driving Oct4 (also known asPou5f1) transcription by its distal enhancer,retaining a pre-inactivation X chromosome state,and global reduction in DNA methylation and inH3K27me3 repressive chromatin mark depositionon developmental regulatory gene promoters.Upon withdrawal of 2i/LIF, naive mouse ES cellscan drift towards a primed pluripotent stateresembling that of the post-implantationepiblast. Although human ES cells share severalmolecular features with naive mouse ES cells,they also share a variety of epigenetic propertieswith primed murine epiblast stem cells (EpiSCs).", "metadata": {}}
+{"_id": "4462777", "title": "", "text": "Predicting immunogenic tumour mutations bycombining mass spectrometry and exomesequencingHuman tumours typically harbour aremarkable number of somatic mutations. Ifpresented on major histocompatibility complexclass I molecules (MHCI), peptides containingthese mutations could potentially beimmunogenic as they should be recognized as‘non-self’ neo-antigens by the adaptive immunesystem. Recent work has confirmed that mutantpeptides can serve as T-cell epitopes. However,few mutant epitopes have been describedbecause their discovery required the laboriousscreening of patient tumour-infiltratinglymphocytes for their ability to recognize antigenlibraries constructed following tumour exomesequencing. We sought to simplify the discoveryof immunogenic mutant peptides bycharacterizing their general properties. Wedeveloped an approach that combineswhole-exome and transcriptome sequencinganalysis with mass spectrometry to identify", "metadata": {}}
+{"_id": "4462919", "title": "", "text": "In vivo genome editing using Staphylococcusaureus Cas9The RNA-guided endonuclease Cas9has emerged as a versatile genome-editingplatform. However, the size of the commonlyused Cas9 from Streptococcus pyogenes(SpCas9) limits its utility for basic research andtherapeutic applications that use the highlyversatile adeno-associated virus (AAV) deliveryvehicle. Here, we characterize six smaller Cas9orthologues and show that Cas9 fromStaphylococcus aureus (SaCas9) can edit thegenome with efficiencies similar to those ofSpCas9, while being more than 1 kilobaseshorter. We packaged SaCas9 and its singleguide RNA expression cassette into a single AAVvector and targeted the cholesterol regulatorygene Pcsk9 in the mouse liver. Within one weekof injection, we observed >40% genemodification, accompanied by significantreductions in serum Pcsk9 and total cholesterollevels. We further assess the genome-widetargeting specificity of SaCas9 and SpCas9 using", "metadata": {}}
+{"_id": "4463588", "title": "", "text": "Effects of exercise intensity on cardiovascularfitness, total body composition, and visceraladiposity of obese adolescents.BACKGROUNDLittle is known about how the intensity ofexercise influences cardiovascular fitness andbody composition, especially in obeseadolescents. OBJECTIVE Our goal was todetermine the effects of physical trainingintensity on the cardiovascular fitness,percentage of body fat (%BF), and visceraladipose tissue (VAT) of obese adolescents.DESIGN Obese 13-16-y-olds (n = 80) wereassigned to 1) biweekly lifestyle education (LSE),2) LSE + moderate-intensity physical training, or3) LSE + high-intensity physical training. Theintervention lasted 8 mo. Physical training wasoffered 5 d/wk, and the target energyexpenditure for all subjects in physical traininggroups was 1047 kJ (250 kcal)/session.Cardiovascular fitness was measured with amultistage treadmill test, %BF with dual-energyX-ray absorptiometry, and VAT with magnetic", "metadata": {}}
+{"_id": "4463811", "title": "", "text": "Low methionine ingestion by rats extends lifespan.Dietary energy restriction has been awidely used means of experimentally extendingmammalian life span. We report here thatlifelong reduction in the concentration of a singledietary component, the essential amino acidL-methionine, from 0.86 to 0.17% of the dietresults in a 30% longer life span of male Fischer344 rats. Methionine restriction completelyabolished growth, although food intake wasactually greater on a body weight basis. Studiesof energy consumption in early life indicated thatthe energy intake of 0.17% methionine-fedanimals was near normal for animals of theirsize, although consumption per animal wasbelow that of the much larger 0.86%methionine-fed rats. Increasing the energyintake of rats fed 0.17% methionine failed toincrease their rate of growth, whereas restricting0.85% methionine-fed rats to the food intake of0.17% methionine-fed animals did not materiallyreduce growth, indicating that food restriction", "metadata": {}}
+{"_id": "4464565", "title": "", "text": "Epicatechin and a cocoa polyphenolic extractmodulate gene expression in human Caco-2cells.We performed a functional genomic analysisto study the effect of epicatechin andpolyphenolic cocoa extract in the human colonadenocarcinoma cell line Caco-2. The specificHuman Hematology/Immunology cDNA arrays byClontech, containing 406 genes in duplicate,were used. The differentially expressed geneswere classified according to their level ofexpression, calculated as the ratio of the valueobtained after each treatment relative to controlcells, with a statistical significance of P < 0.05(upregulated: ratio > 1.5; downregulated: ratio< 0.6). Treatment with epicatechin decreasedthe expression of 21 genes and upregulated 24genes. Upon incubation with the cocoapolyphenolic extract, 24 genes wereunderexpressed and 28 were overexpressed. Thechanges in expression for ferritin heavypolypeptide 1 (FTH1), mitogen-activated proteinkinase kinase 1 (MAPKK1), signal transducer and", "metadata": {}}
+{"_id": "4465608", "title": "", "text": "An atlas of active enhancers across human celltypes and tissuesEnhancers control the correcttemporal and cell-type-specific activation of geneexpression in multicellular eukaryotes. Knowingtheir properties, regulatory activity and targets iscrucial to understand the regulation ofdifferentiation and homeostasis. Here we use theFANTOM5 panel of samples, covering themajority of human tissues and cell types, toproduce an atlas of active, in vivo-transcribedenhancers. We show that enhancers shareproperties with CpG-poor messenger RNApromoters but produce bidirectional,exosome-sensitive, relatively short unsplicedRNAs, the generation of which is strongly relatedto enhancer activity. The atlas is used tocompare regulatory programs between differentcells at unprecedented depth, to identifydisease-associated regulatory single nucleotidepolymorphisms, and to classify cell-type-specificand ubiquitous enhancers. We further explorethe utility of enhancer redundancy, which", "metadata": {}}
+{"_id": "4465735", "title": "", "text": "Precision microbiome reconstitution restores bileacid mediated resistance to ClostridiumdifficileThe gastrointestinal tracts of mammalsare colonized by hundreds of microbial speciesthat contribute to health, including colonizationresistance against intestinal pathogens. Manyantibiotics destroy intestinal microbialcommunities and increase susceptibility tointestinal pathogens. Among these, Clostridiumdifficile, a major cause of antibiotic-induceddiarrhoea, greatly increases morbidity andmortality in hospitalized patients. Whichintestinal bacteria provide resistance to C.difficile infection and their in vivo inhibitorymechanisms remain unclear. Here we correlateloss of specific bacterial taxa with developmentof infection, by treating mice with differentantibiotics that result in distinct microbiotachanges and lead to varied susceptibility to C.difficile. Mathematical modelling augmented byanalyses of the microbiota of hospitalizedpatients identifies resistance-associated bacteria", "metadata": {}}
+{"_id": "4465762", "title": "", "text": "Transcription initiation complex structureselucidate DNA openingTranscription of eukaryoticprotein-coding genes begins with assembly ofthe RNA polymerase (Pol) II initiation complexand promoter DNA opening. Here we reportcryo-electron microscopy (cryo-EM) structures ofyeast initiation complexes containing closed andopen DNA at resolutions of 8.8 Å and 3.6 Å,respectively. DNA is positioned and retained overthe Pol II cleft by a network of interactionsbetween the TATA-box-binding protein TBP andtranscription factors TFIIA, TFIIB, TFIIE, andTFIIF. DNA opening occurs around the tip of thePol II clamp and the TFIIE ‘extended wingedhelix’ domain, and can occur in the absence ofTFIIH. Loading of the DNA template strand intothe active centre may be facilitated bymovements of obstructing protein elementstriggered by allosteric binding of the TFIIE‘E-ribbon’ domain. The results suggest a unifiedmodel for transcription initiation with a keyevent, the trapping of open promoter DNA by", "metadata": {}}
+{"_id": "4467129", "title": "", "text": "Multiple mechanisms disrupt the let-7 microRNAfamily in neuroblastomaPoor prognosis inneuroblastoma is associated with geneticamplification of MYCN. MYCN is itself a target oflet-7, a tumour suppressor family of microRNAsimplicated in numerous cancers. LIN28B, aninhibitor of let-7 biogenesis, is overexpressed inneuroblastoma and has been reported toregulate MYCN. Here we show, however, thatLIN28B is dispensable in MYCN-amplifiedneuroblastoma cell lines, despite de-repressionof let-7. We further demonstrate that MYCNmessenger RNA levels in amplified disease areexceptionally high and sufficient to sponge let-7,which reconciles the dispensability of LIN28B. Wefound that genetic loss of let-7 is common inneuroblastoma, inversely associated with MYCNamplification, and independently associated withpoor outcomes, providing a rationale forchromosomal loss patterns in neuroblastoma. Wepropose that let-7 disruption by LIN28B, MYCNsponging, or genetic loss is a unifying", "metadata": {}}
+{"_id": "4468861", "title": "", "text": "Radiation and Dual Checkpoint BlockadeActivates Non-Redundant Immune Mechanismsin CancerImmune checkpoint inhibitors result inimpressive clinical responses, but optimal resultswill require combination with each other andother therapies. This raises fundamentalquestions about mechanisms of non-redundancyand resistance. Here we report major tumourregressions in a subset of patients withmetastatic melanoma treated with an anti-CTLA4antibody (anti-CTLA4) and radiation, andreproduced this effect in mouse models.Although combined treatment improvedresponses in irradiated and unirradiatedtumours, resistance was common. Unbiasedanalyses of mice revealed that resistance wasdue to upregulation of PD-L1 on melanoma cellsand associated with T-cell exhaustion.Accordingly, optimal response in melanoma andother cancer types requires radiation, anti-CTLA4and anti-PD-L1/PD-1. Anti-CTLA4 predominantlyinhibits T-regulatory cells (Treg cells), thereby", "metadata": {}}
+{"_id": "4469125", "title": "", "text": "G-protein-independent coupling of MC4R toKir7.1 in hypothalamic neuronsThe regulatedrelease of anorexigenic α-melanocyte stimulatinghormone (α-MSH) and orexigenic Agouti-relatedprotein (AgRP) from discrete hypothalamicarcuate neurons onto common target sites in thecentral nervous system has a fundamental role inthe regulation of energy homeostasis. Bothpeptides bind with high affinity to themelanocortin-4 receptor (MC4R); existing datashow that α-MSH is an agonist that couples thereceptor to the Gαs signalling pathway, whileAgRP binds competitively to block α-MSH bindingand blocks the constitutive activity mediated bythe ligand-mimetic amino-terminal domain of thereceptor. Here we show that, in mice, regulationof firing activity of neurons from theparaventricular nucleus of the hypothalamus(PVN) by α-MSH and AgRP can be mediatedindependently of Gαs signalling byligand-induced coupling of MC4R to closure ofinwardly rectifying potassium channel, Kir7.1.", "metadata": {}}
+{"_id": "4474874", "title": "", "text": "Role of ghrelin in the relationship betweenhyperphagia and accelerated gastric emptying indiabetic mice.BACKGROUND & AIMS Ghrelin isan orexigenic peptide with gastroprokineticeffects. Mice with streptozotocin (STZ)-induceddiabetes exhibit hyperphagia, altered gastricemptying, and increased plasma ghrelin levels.We investigated the causative role of ghrelinherein by comparing changes in ghrelin receptorknockout (growth hormone secretagoguereceptor [GHS-R](-/-)) and wild-type(GHS-R(+/+)) mice with STZ-induced diabetes.METHODS Gastric emptying was measured withthe [(13)C]octanoic acid breath test. Themessenger RNA (mRNA) expression ofneuropeptide Y (NPY), agouti-related peptide(AgRP), and proopiomelanocortin was quantifiedby real-time reverse-transcription polymerasechain reaction. Neural contractions were elicitedby electrical field stimulation in fundic smoothmuscle strips. RESULTS Diabetes increasedplasma ghrelin levels to a similar extent in both", "metadata": {}}
+{"_id": "4483571", "title": "", "text": "Human serum 25-hydroxycholecalciferolresponse to extended oral dosing withcholecalciferol.BACKGROUND The cholecalciferolinputs required to achieve or maintain any givenserum 25-hydroxycholecalciferol concentrationare not known, particularly within rangescomparable to the probable physiologic supply ofthe vitamin. OBJECTIVES The objectives were toestablish the quantitative relation betweensteady state cholecalciferol input and theresulting serum 25-hydroxycholecalciferolconcentration and to estimate the proportion ofthe daily requirement during winter that is metby cholecalciferol reserves in body tissue stores.DESIGN Cholecalciferol was administered daily incontrolled oral doses labeled at 0, 25, 125, and250 micro g cholecalciferol for approximately 20wk during the winter to 67 men living in Omaha(41.2 degrees N latitude). The time course ofserum 25-hydroxycholecalciferol concentrationwas measured at intervals over the course oftreatment. RESULTS From a mean baseline value", "metadata": {}}
+{"_id": "4489217", "title": "", "text": "Intratumor heterogeneity and branchedevolution revealed by multiregionsequencing.BACKGROUND Intratumorheterogeneity may foster tumor evolution andadaptation and hinder personalized-medicinestrategies that depend on results from singletumor-biopsy samples. METHODS To examineintratumor heterogeneity, we performed exomesequencing, chromosome aberration analysis,and ploidy profiling on multiple spatiallyseparated samples obtained from primary renalcarcinomas and associated metastatic sites. Wecharacterized the consequences of intratumorheterogeneity using immunohistochemicalanalysis, mutation functional analysis, andprofiling of messenger RNA expression. RESULTSPhylogenetic reconstruction revealed branchedevolutionary tumor growth, with 63 to 69% of allsomatic mutations not detectable across everytumor region. Intratumor heterogeneity wasobserved for a mutation within an autoinhibitorydomain of the mammalian target of rapamycin", "metadata": {}}
+{"_id": "4492358", "title": "", "text": "Succession of microbial consortia in thedeveloping infant gut microbiome.Thecolonization process of the infant gut microbiomehas been called chaotic, but this view couldreflect insufficient documentation of the factorsaffecting the microbiome. We performed a 2.5-ycase study of the assembly of the human infantgut microbiome, to relate life events tomicrobiome composition and function. Sixty fecalsamples were collected from a healthy infantalong with a diary of diet and health status.Analysis of >300,000 16S rRNA genes indicatedthat the phylogenetic diversity of the microbiomeincreased gradually over time and that changesin community composition conformed to asmooth temporal gradient. In contrast, majortaxonomic groups showed abrupt shifts inabundance corresponding to changes in diet orhealth. Community assembly was nonrandom:we observed discrete steps of bacterialsuccession punctuated by life events.Furthermore, analysis of ≈ 500,000 DNA", "metadata": {}}
+{"_id": "4500832", "title": "", "text": "gamma-tocopherol, the major form of vitamin Ein the US diet, deserves moreattention.gamma-tocopherol is the major form ofvitamin E in many plant seeds and in the US diet,but has drawn little attention compared withalpha-tocopherol, the predominant form ofvitamin E in tissues and the primary form insupplements. However, recent studies indicatethat gamma-tocopherol may be important tohuman health and that it possesses uniquefeatures that distinguish it fromalpha-tocopherol. gamma-Tocopherol appears tobe a more effective trap for lipophilicelectrophiles than is alpha-tocopherol.gamma-Tocopherol is well absorbed andaccumulates to a significant degree in somehuman tissues; it is metabolized, however,largely to 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman (gamma-CEHC), which ismainly excreted in the urine. gamma-CEHC, butnot the corresponding metabolite derived fromalpha-tocopherol, has natriuretic activity that", "metadata": {}}
+{"_id": "4505748", "title": "", "text": "Disclosure of APOE genotype for risk ofAlzheimer's disease.BACKGROUND Theapolipoprotein E (APOE) genotype providesinformation on the risk of Alzheimer's disease,but the genotyping of patients and their familymembers has been discouraged. We examinedthe effect of genotype disclosure in aprospective, randomized, controlled trial.METHODS We randomly assigned 162asymptomatic adults who had a parent withAlzheimer's disease to receive the results of theirown APOE genotyping (disclosure group) or notto receive such results (nondisclosure group).We measured symptoms of anxiety, depression,and test-related distress 6 weeks, 6 months, and1 year after disclosure or nondisclosure.RESULTS There were no significant differencesbetween the two groups in changes intime-averaged measures of anxiety (4.5 in thedisclosure group and 4.4 in the nondisclosuregroup, P=0.84), depression (8.8 and 8.7,respectively; P=0.98), or test-related distress", "metadata": {}}
+{"_id": "4506414", "title": "", "text": "Blood pressure and incidence of twelvecardiovascular diseases: lifetime risks, healthylife-years lost, and age-specific associations in1·25 million peopleBACKGROUND Theassociations of blood pressure with the differentmanifestations of incident cardiovascular diseasein a contemporary population have not beencompared. In this study, we aimed to analysethe associations of blood pressure with 12different presentations of cardiovascular disease.METHODS We used linked electronic healthrecords from 1997 to 2010 in the CALIBER(CArdiovascular research using LInked Bespokestudies and Electronic health Records)programme to assemble a cohort of 1·25 millionpatients, 30 years of age or older and initiallyfree from cardiovascular disease, a fifth of whomreceived blood pressure-lowering treatments. Westudied the heterogeneity in the age-specificassociations of clinically measured bloodpressure with 12 acute and chroniccardiovascular diseases, and estimated the", "metadata": {}}
+{"_id": "4506702", "title": "", "text": "Can Online Consumers Contribute to DrugKnowledge? A Mixed-Methods Comparison ofConsumer-Generated and ProfessionallyControlled Psychotropic Medication Informationon the InternetBACKGROUND Ongoing initiativesto filter online health searches excludeconsumer-generated content from searchreturns, though its inferiority compared withprofessionally controlled content is notdemonstrated. The antidepressant escitalopramand the antipsychotic quetiapine have rankedover the last 5 years as top-selling agents intheir respective drug classes. Both drugs havevarious off-label mental health and non-mentalhealth uses, ranging from the relief of insomniaand migraines to the treatment of severedevelopmental disorders. OBJECTIVE Ourobjective was to describe the most frequentlyreported effects of escitalopram and quetiapinein online consumer reviews, to compare themwith effects described in professionally controlledcommercial health websites, and to gauge the", "metadata": {}}
+{"_id": "4515975", "title": "", "text": "Effect of supplemental zinc on the growth andserum zinc concentrations of prepubertalchildren: a meta-analysis of randomizedcontrolled trials.BACKGROUND Multiple studieshave been carried out to assess the effect of zincsupplementation on children's growth. Theresults of these studies are inconsistent, and thefactors responsible for these varied outcomes areunknown. OBJECTIVE Meta-analyses ofrandomized controlled intervention trials weretherefore completed to assess the effect of zincsupplementation on the physical growth andserum zinc concentrations of prepubertalchildren. DESIGN A total of 33 acceptable studieswith appropriate data were identified byMEDLINE (National Library of Medicine,Bethesda, MD) searches and other methods.Weighted mean effect sizes (expressed in SDunits) were calculated for changes in height,weight, weight-for-height, and serum zincconcentration by using random-effects models;factors associated with effect sizes were explored", "metadata": {}}
+{"_id": "4530659", "title": "", "text": "Mechanisms of Age-Related MacularDegenerationAge-related macular degeneration(AMD), a progressive condition that isuntreatable in up to 90% of patients, is a leadingcause of blindness in the elderly worldwide. Thetwo forms of AMD, wet and dry, are classifiedbased on the presence or absence of bloodvessels that have disruptively invaded the retina,respectively. A detailed understanding of themolecular mechanisms underlying wet AMD hasled to several robust FDA-approved therapies. Incontrast, there are no approved treatments fordry AMD. In this review, we provide insight intothe critical effector pathways mediating eachform of the disease. A recurring theme thatspans most aspects of AMD pathogenesis isdefective immune modulation in the classicallyimmune-privileged ocular haven. Interestingly,the latest advances in AMD research alsohighlight common molecular disease pathwayswith other neurodegenerative disorders. Finally,the therapeutic potential of intervening at known", "metadata": {}}
+{"_id": "4544916", "title": "", "text": "The N-end rule pathway regulates pathogenresponses in plants.To efficiently counteractpathogens, plants rely on a complex set ofimmune responses that are tightly regulated toallow the timely activation, appropriate durationand adequate amplitude of defense programs.The coordination of the plant immune response isknown to require the activity of theubiquitin/proteasome system, which controls thestability of proteins in eukaryotes. Here, wedemonstrate that the N-end rule pathway, asubset of the ubiquitin/proteasome system,regulates the defense against a wide range ofbacterial and fungal pathogens in the modelplant Arabidopsis thaliana. We show that thispathway positively regulates the biosynthesis ofplant-defense metabolites such asglucosinolates, as well as the biosynthesis andresponse to the phytohormone jasmonic acid,which plays a key role in plant immunity. Ourresults also suggest that the arginylation branchof the N-end rule pathway regulates the timing", "metadata": {}}
+{"_id": "4547102", "title": "", "text": "H3K9 demethylase KDM4E is an epigeneticregulator for bovine embryonic development anda defective factor for nuclearreprogramming.Aberrant epigeneticreprogramming often results in developmentaldefects in somatic cell nuclear transfer (SCNT)embryos during embryonic genome activation(EGA). Bovine eight-cell SCNT embryos exhibitglobal hypermethylation of histone H3 lysine 9tri- and di-methylation (H3K9me3/2), but theintrinsic reason for this remains elusive. Here,we provide evidence that two H3K9 demethylasegenes, lysine-specific demethylase 4D (KDM4D)and 4E (KDM4E), are related to activeH3K9me3/2 demethylation in in vitro fertilized(IVF) embryos and are deficiently expressed incloned embryos at the time of EGA. Moreover,KDM4E plays a more crucial role in IVF and SCNTembryonic development, and overexpression ofKDM4E can restore the global transcriptome,improve blastocyst formation and increase thecloning efficiency of SCNT embryos. Our results", "metadata": {}}
+{"_id": "4550036", "title": "", "text": "Risk of gestational hypertension in relation tofolic acid supplementation during pregnancy.Theauthors investigated the association betweenfolic acid supplementation and gestationalhypertension. The study population includedwomen with nonmalformed infants in the UnitedStates and Canada who were participating in theSlone Epidemiology Center Birth Defects Studybetween 1993 and 2000. Women wereinterviewed within 6 months after delivery aboutsociodemographic and medical factors, theoccurrence of hypertension with or withoutpreeclampsia, and multivitamin use inpregnancy. Relative risks, adjusted for weight,parity, twin pregnancy, diabetes, smoking,education, and family income, were estimatedusing Cox regression models. Of 2,100 women,204 (9.7%) reported gestational hypertension(onset after the 20th week of gestation). Themultivariate-adjusted relative risk of developinggestational hypertension during the month afterfolic acid supplementation, compared with not", "metadata": {}}
+{"_id": "4561402", "title": "", "text": "Aire regulates negative selection oforgan-specific T cellsAutoimmunepolyendocrinopathy syndrome type 1 is arecessive Mendelian disorder resulting frommutations in a novel gene, AIRE, and ischaracterized by a spectrum of organ-specificautoimmune diseases. It is not known whattolerance mechanisms are defective as a resultof AIRE mutation. By tracing the fate ofautoreactive CD4+ T cells with high affinity for apancreatic antigen in transgenic mice with anAire mutation, we show here that Aire deficiencycauses almost complete failure to delete theorgan-specific cells in the thymus. These resultsindicate that autoimmune polyendocrinopathysyndrome 1 is caused by failure of a specializedmechanism for deleting forbidden T cell clones,establishing a central role for this tolerancemechanism.", "metadata": {}}
+{"_id": "4583180", "title": "", "text": "Extracellular Acidic pH Activates the SterolRegulatory Element-Binding Protein 2 to PromoteTumor Progression.Conditions of the tumormicroenvironment, such as hypoxia and nutrientstarvation, play critical roles in cancerprogression. However, the role of acidicextracellular pH in cancer progression is notstudied as extensively as that of hypoxia. Here,we show that extracellular acidic pH (pH 6.8)triggered activation of sterol regulatoryelement-binding protein 2 (SREBP2) bystimulating nuclear translocation and promoterbinding to its targets, along with intracellularacidification. Interestingly, inhibition of SREBP2,but not SREBP1, suppressed the upregulation oflow pH-induced cholesterol biosynthesis-relatedgenes. Moreover, acyl-CoA synthetaseshort-chain family member 2 (ACSS2), a directSREBP2 target, provided a growth advantage tocancer cells under acidic pH. Furthermore, acidicpH-responsive SREBP2 target genes wereassociated with reduced overall survival of", "metadata": {}}
+{"_id": "4587978", "title": "", "text": "Mutation of the Human Circadian Clock GeneCRY1 in Familial Delayed Sleep PhaseDisorderPatterns of daily human activity arecontrolled by an intrinsic circadian clock thatpromotes \u000024 hr rhythms in many behavioraland physiological processes. This system isaltered in delayed sleep phase disorder (DSPD),a common form of insomnia in which sleepepisodes are shifted to later times misalignedwith the societal norm. Here, we report ahereditary form of DSPD associated with adominant coding variation in the core circadianclock gene CRY1, which creates a transcriptionalinhibitor with enhanced affinity for circadianactivator proteins Clock and Bmal1. Thisgain-of-function CRY1 variant causes reducedexpression of key transcriptional targets andlengthens the period of circadian molecularrhythms, providing a mechanistic link to DSPDsymptoms. The allele has a frequency of up to0.6%, and reverse phenotyping of unrelatedfamilies corroborates late and/or fragmented", "metadata": {}}
+{"_id": "4611267", "title": "", "text": "Lateral Hypothalamic Signaling MechanismsUnderlying Feeding Stimulation: DifferentialContributions of Src Family Tyrosine Kinases toFeeding Triggered Either by NMDA Injection orby Food DeprivationIn rats, feeding can betriggered experimentally using manyapproaches. Included among these are (1) fooddeprivation and (2) acute microinjection of theneurotransmitter l-glutamate (Glu) or itsreceptor agonist NMDA into the lateralhypothalamic area (LHA). Under both paradigms,the NMDA receptor (NMDA-R) within the LHAappears critically involved in transferring signalsencoded by Glu to stimulate feeding. However,the intracellular mechanisms underlying thissignal transfer are unknown. Becauseprotein-tyrosine kinases (PTKs) participate inNMDA-R signaling mechanisms, we determinedPTK involvement in LHA mechanisms underlyingboth types of feeding stimulation through foodintake and biochemical measurements. LHAinjections of PTK inhibitors significantly", "metadata": {}}
+{"_id": "4627816", "title": "", "text": "Relationship between advanced glycationend\u0000product accumulation and low skeletalmuscle mass in Japanese men and womenAIMThe present study aimed to investigate therelationship between advanced glycationend-product accumulation and skeletal musclemass among middle-aged and older Japanesemen and women. METHODS A total of 132participants enrolled in this cross-sectionalstudy. Skin autofluorescence was assessed as ameasure of advanced glycation-end products.Appendicular skeletal muscle mass wasmeasured using dual-energy X-rayabsorptiometry, and skeletal muscle index wascalculated by dividing appendicular skeletalmuscle mass by height squared. Participantswere divided into two groups (low skeletalmuscle index and normal skeletal muscle index)using the Asian Working Group for Sarcopenia'sskeletal muscle index criteria for diagnosingsarcopenia. Multivariate logistic regressionanalysis and the area under the receiver", "metadata": {}}
+{"_id": "4632921", "title": "", "text": "Large-Scale Profiling Reveals the Influence ofGenetic Variation on Gene Expression in HumanInduced Pluripotent Stem Cells.In this study, weused whole-genome sequencing and geneexpression profiling of 215 human inducedpluripotent stem cell (iPSC) lines from differentdonors to identify genetic variants associatedwith RNA expression for 5,746 genes. We wereable to predict causal variants for theseexpression quantitative trait loci (eQTLs) thatdisrupt transcription factor binding and validateda subset of them experimentally. We alsoidentified copy-number variant (CNV) eQTLs,including some that appear to affect geneexpression by altering the copy number ofintergenic regulatory regions. In addition, wewere able to identify effects on gene expressionof rare genic CNVs and regulatorysingle-nucleotide variants and found thatreactivation of gene expression on the Xchromosome depends on gene chromosomalposition. Our work highlights the value of iPSCs", "metadata": {}}
+{"_id": "4641348", "title": "", "text": "Ethanol extract of Allium fistulosum inhibitsdevelopment of non-alcoholic fatty liverdiseaseBACKGROUND/OBJECTIVES Non-alcoholicfatty liver disease (NAFLD) is a leading cause ofchronic liver disease and is closely associatedwith metabolic syndrome. In the present study,we observed the effect of ethanol extract ofAllium fistulosum (EAF) on NAFLD and havesuggested the possibility of using EAF as anatural product for application in thedevelopment of a treatment for NAFLD.MATERIALS/METHODS The preventive effect onhepatic lipid accumulation was estimated byusing an oleic acid (OA)-induced NAFLD model invitro and a Western diet (high-fat high-sucrose;WD)-induced obese mouse model. Animals weredivided into three groups (n = 7): normal dietgroup (ND), WD group, and WD plus 1% EAFgroup. RESULTS EAF reduced OA-stimulated lipidaccumulation in HepG2 cells in the absence ofcellular cytotoxicity and significantly blockedtranscriptional activation of sterol regulatory", "metadata": {}}
+{"_id": "4647303", "title": "", "text": "Cardiovascular risk factors in childhood andcarotid artery intima-media thickness inadulthood: the Cardiovascular Risk in YoungFinns Study.CONTEXT Exposure tocardiovascular risk factors during childhood andadolescence may be associated with thedevelopment of atherosclerosis later in life.OBJECTIVE To study the relationship betweencardiovascular risk factors measured in childhoodand adolescence and common carotid arteryintima-media thickness (IMT), a marker ofpreclinical atherosclerosis, measured inadulthood. DESIGN, SETTING, ANDPARTICIPANTS Population-based, prospectivecohort study conducted at 5 centers in Finlandamong 2229 white adults aged 24 to 39 yearswho were examined in childhood andadolescence at ages 3 to 18 years in 1980 andreexamined 21 years later, between September2001 and January 2002. MAIN OUTCOMEMEASURES Association between cardiovascularrisk variables (levels of low-density lipoprotein", "metadata": {}}
+{"_id": "4653837", "title": "", "text": "MicroRNA-29 induces cellular senescence inaging muscle through multiple signalingpathwaysThe mechanisms underlying thedevelopment of aging-induced muscle atrophyare unclear. By microRNA array and individualqPCR analyses, we found significantup-regulation of miR-29 in muscles of agedrodents vs. results in young. With aging, p85α,IGF-1 and B-myb muscle levels were lower whilethe expression of certain cell arrest proteins(p53, p16 and pRB) increased. When miR-29 wasexpressed in muscle progenitor cells (MPC), theirproliferation was impaired while SA-βgalexpression increased signifying the developmentof senescence. Impaired MPC proliferationresulted from interactions between miR-29 andthe 3'-UTR of p85a, IGF-1 and B-myb,suppressing the translation of these mediators ofmyoblast proliferation. In vivo, electroporation ofmiR-29 into muscles of young mice suppressedthe proliferation and increased levels of cellulararrest proteins, recapitulating aging-induced", "metadata": {}}
+{"_id": "4658268", "title": "", "text": "Rictor, a Novel Binding Partner of mTOR, Definesa Rapamycin-Insensitive andRaptor-Independent Pathway that Regulates theCytoskeletonThe mammalian TOR (mTOR)pathway integrates nutrient- and growthfactor-derived signals to regulate growth, theprocess whereby cells accumulate mass andincrease in size. mTOR is a large protein kinaseand the target of rapamycin, animmunosuppressant that also blocks vesselrestenosis and has potential anticancerapplications. mTOR interacts with the raptor andGbetaL proteins to form a complex that is thetarget of rapamycin. Here, we demonstrate thatmTOR is also part of a distinct complex definedby the novel protein rictor (rapamycin-insensitivecompanion of mTOR). Rictor shares homologywith the previously described pianissimo from D.discoidieum, STE20p from S. pombe, and AVO3pfrom S. cerevisiae. Interestingly, AVO3p is partof a rapamycin-insensitive TOR complex thatdoes not contain the yeast homolog of raptor and", "metadata": {}}
+{"_id": "4662264", "title": "", "text": "Activation of the estrogen receptor throughphosphorylation by mitogen-activated proteinkinase.The phosphorylation of the humanestrogen receptor (ER) serine residue at position118 is required for full activity of the ERactivation function 1 (AF-1). This Ser118 isphosphorylated by mitogen-activated proteinkinase (MAPK) in vitro and in cells treated withepidermal growth factor (EGF) and insulin-likegrowth factor (IGF) in vivo. Overexpression ofMAPK kinase (MAPKK) or of the guaninenucleotide binding protein Ras, both of whichactivate MAPK, enhanced estrogen-induced andantiestrogen (tamoxifen)-induced transcriptionalactivity of wild-type ER, but not that of a mutantER with an alanine in place of Ser118. Thus, theactivity of the amino-terminal AF-1 of the ER ismodulated by the phosphorylation of Ser118through the Ras-MAPK cascade of the growthfactor signaling pathways.", "metadata": {}}
+{"_id": "4664540", "title": "", "text": "Regulation of the antimicrobial response by NLRproteins.Nucleotide-binding, oligomerizationdomain (NOD)-like receptor (NLR) proteins are afamily of innate immune receptors that play apivotal role in microbial sensing, leading to theinitiation of antimicrobial immune responses.Dysregulation of the function of multiple NLRfamily members has been linked, both in miceand humans, to a propensity for infection andautoinflammatory disease. Despite our increasedunderstanding of NLR function and interactions,many aspects related to mechanisms of sensing,downstream signaling, and in vivo functionsremain elusive. In this review, we focus on keymembers of the NLR family, describing theiractivation by diverse microbes, downstreameffector functions, and interactions with eachother and with other innate sensor proteinfamilies. Also discussed is the role of microbialsensing by NLR receptors leading to activation ofthe adaptive immune arm that collaborates inthe antimicrobial defense.", "metadata": {}}
+{"_id": "4678846", "title": "", "text": "Acetylcysteine for prevention of acutedeterioration of renal function following electivecoronary angiography and intervention: arandomized controlled trial.CONTEXT Theantioxidant acetylcysteine prevents acutecontrast nephrotoxicity in patients with impairedrenal function who undergo computedtomography scanning. However, its role incoronary angiography is unclear. OBJECTIVE Todetermine whether oral acetylcysteine preventsacute deterioration in renal function in patientswith moderate renal insufficiency who undergoelective coronary angiography. DESIGN ANDSETTING Prospective, randomized, double-blind,placebo-controlled trial conducted from May2000 to December 2001 at the GranthamHospital at the University of Hong Kong.PARTICIPANTS Two hundred Chinese patientsaged mean (SD) 68 (6.5) years with stablemoderate renal insufficiency (creatinineclearance <60 mL/min [1.00 mL/s]) who wereundergoing elective coronary angiography with", "metadata": {}}
+{"_id": "4679264", "title": "", "text": "DNA Methylation in the Human Cerebral CortexIs Dynamically Regulated throughout the LifeSpan and Involves Differentiated NeuronsTherole of DNA cytosine methylation, an epigeneticregulator of chromatin structure and function,during normal and pathological braindevelopment and aging remains unclear. Here,we examined by MethyLight PCR the DNAmethylation status at 50 loci, encompassingprimarily 5′ CpG islands of genes related to CNSgrowth and development, in temporal neocortexof 125 subjects ranging in age from 17 weeks ofgestation to 104 years old. Two psychiatricdisease cohorts—defined by chronicneurodegeneration (Alzheimer's) or lack thereof(schizophrenia)—were included. A robust andprogressive rise in DNA methylation levels acrossthe lifespan was observed for 8/50 loci (GABRA2,GAD1, HOXA1, NEUROD1, NEUROD2, PGR,STK11, SYK) typically in conjunction withdeclining levels of the corresponding mRNAs.Another 16 loci were defined by a sharp rise in", "metadata": {}}
+{"_id": "4680262", "title": "", "text": "Mulberry leaves (Morus alba L.) ameliorateobesity-induced hepatic lipogenesis, fibrosis, andoxidative stress in high-fat diet-fed miceObesityis associated with chronic diseases such as fattyliver, type 2 diabetes, cardiovascular disease,and severe metabolic syndrome. Obesity causesmetabolic impairment including excessive lipidaccumulation and fibrosis in the hepatic tissue aswell as the increase in oxidative stress. In orderto investigate the effect of mulberry leaf (Morusalba L.) extract (MLE) on obesity-inducedoxidative stress, lipogenesis, and fibrosis in liver,MLE has been gavaged for 12 weeks in high-fatdiet (HFD)-induced obese mice. MLE treatmentsignificantly ameliorated LXRα-mediatedlipogenesis and hepatic fibrosis markers such asα-smooth muscle actin, while MLE up-regulatedlipolysis-associated markers such as lipoproteinlipase in the HFD-fed mice. Moreover, MLEnormalized the activities of antioxidant enzymesincluding heme oxygenase-1 and glutathioneperoxidase in accordance with protein levels of", "metadata": {}}
+{"_id": "4687948", "title": "", "text": "HMG-CoA reductase inhibitors and the risk of hipfractures in elderly patients.CONTEXT Recentanimal studies have found that3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) lipid-lowering drugs (statins)substantially increase bone formation, butwhether statin use in humans results in clinicallymeaningful bone formation or a reduction in therisk of osteoporotic fractures is not known.OBJECTIVE To determine whether the use ofstatins is associated with reduced hip fracturerisk. DESIGN Case-control study. SETTING ANDPATIENTS A total of 6110 New Jersey residentsaged 65 years or older and enrolled in Medicareand either Medicaid or the Pharmacy Assistancefor the Aged and Disabled program. Casepatients (n=1222) underwent surgical repair of ahip fracture in 1994. Control patients (n=4888)were identified at a ratio of 4:1 andfrequency-matched to case patients for age andsex. MAIN OUTCOME MEASURE Adjusted oddsratio (OR) of hip fracture by statin use in the 180", "metadata": {}}
+{"_id": "4688277", "title": "", "text": "The quality of modern cross-sectional ecologicstudies: a bibliometric review.The ecologic studydesign is routinely used by epidemiologists inspite of its limitations. It is presently unknownhow well the challenges of the design are dealtwith in epidemiologic research. The purpose ofthis bibliometric review was to critically evaluatethe characteristics, statistical methods, andreporting of results of modern cross-sectionalecologic papers. A search through 6 majorepidemiology journals identified allcross-sectional ecologic studies published sinceJanuary 1, 2000. A total of 125 articles met theinclusion requirements and were assessed viacommon evaluative criteria. It was found that aconsiderable number of cross-sectional ecologicstudies use unreliable methods or containstatistical oversights; most investigators whoadjusted their outcomes for age or sex did soimproperly (64%), statistical validity was apotential issue for 20% of regression models,and simple linear regression was the most", "metadata": {}}
+{"_id": "4688340", "title": "", "text": "Efficacy of Beta1 Integrin and EGFR Targeting inSphere-Forming Human Head and Neck CancerCellsBACKGROUND Resistance to radiotherapycontinues to be a limiting factor in the treatmentof cancer including head and neck squamous cellcarcinoma (HNSCC). Simultaneous targeting ofβ1 integrin and EGFR was shown to have ahigher radiosensitizing potential thanmono-targeting in the majority of tested HNSCCcancer models. As tumor-initiating cells (TIC) arethought to play a key role for therapy resistanceand recurrence and can be enriched in sphereforming conditions, this study investigated theefficacy of β1 integrin/EGFR targeting withoutand in combination with X-ray irradiation on thebehavior of sphere-forming cells (SFC).METHODS HNSCC cell lines (UTSCC15, UTSCC5,Cal33, SAS) were injected subcutaneously intonude mice for tumor up-take and plated forprimary and secondary sphere formation undernon-adhesive conditions which is thought toreflect the enrichment of SFC and their", "metadata": {}}
+{"_id": "4695046", "title": "", "text": "AnxietyOBJECTIVES To examine the effect ofroutinely administered psychiatric questionnaireson the recognition, management, and outcomeof psychiatric disorders in non-psychiatricsettings. DATA SOURCES Embase, Medline,PsycLIT, Cinahl, Cochrane Controlled TrialsRegister, and hand searches of key journals.METHODS A systematic review of randomisedcontrolled trials of the administration and routinefeedback of psychiatric screening and outcomequestionnaires to clinicians in non-psychiatricsettings. Narrative overview of key designfeatures and end points, together with a randomeffects quantitative synthesis of comparablestudies. MAIN OUTCOME MEASURES Recognitionof psychiatric disorders after feedback ofquestionnaire results; interventions forpsychiatric disorders; and outcome of psychiatricdisorders. RESULTS Nine randomised studieswere identified that examined the use ofcommon psychiatric instruments in primary careand general hospital settings. Studies compared", "metadata": {}}
+{"_id": "4695107", "title": "", "text": "The challenges of overcoming antibioticresistance: Plant extracts as potential sources ofantimicrobial and resistance modifyingagentsThe problem of antibiotic resistance, whichhas limited the use of cheap and old antibiotics,has necessitated the need for a continued searchfor new antimicrobial compounds. Understandingthe mechanisms of resistance is important in thedevelopment of strategies to solving theproblem. Active efflux of drugs, alteration oftarget sites and enzymatic degradations are thestrategies by which pathogenic bacteria acquireor develop intrinsic resistance to antibiotics.Multi-drug resistance (MDR) pumps, capable ofrecognizing and expelling a variety of structurallyunrelated compounds from the bacterial cell andconferring resistance to a wide range ofantibiotics have since been characterized inmany gram positive and gram negativepathogens like Staphylococcus aureus,Pseudomonas aeruginosa, Escherichia coli and,more recently, in mycobacteria. The ability of", "metadata": {}}
+{"_id": "4700428", "title": "", "text": "The effect of N-acetylcysteine in the nucleusaccumbens on neurotransmission and relapse tococaine.BACKGROUND Relapse to cocaineseeking has been linked with low glutamate inthe nucleus accumbens core (NAcore) causingpotentiation of synaptic glutamate transmissionfrom prefrontal cortex (PFC) afferents. SystemicN-acetylcysteine (NAC) has been shown torestore glutamate homeostasis, reduce relapseto cocaine seeking, and depotentiate PFC-NAcoresynapses. Here, we examine the effects of NACapplied directly to the NAcore on relapse andneurotransmission in PFC-NAcore synapses, aswell as the involvement of the metabotropicglutamate receptors 2/3 (mGluR2/3) and 5(mGluR5). METHODS Rats were trained toself-administer cocaine for 2 weeks and followingextinction received either intra-accumbens NACor systemic NAC 30 or 120 minutes, respectively,before inducing reinstatement with a conditionedcue or a combined cue and cocaine injection. Wealso recorded postsynaptic currents using in vitro", "metadata": {}}
+{"_id": "4701662", "title": "", "text": "A phospholipid transfer function ofER-mitochondria encounter structure revealed invitroAs phospholipids are synthesized mainly inthe endoplasmic reticulum (ER) andmitochondrial inner membranes, how cellsproperly distribute specific phospholipids todiverse cellular membranes is a crucial problemfor maintenance of organelle-specificphospholipid compositions. Although theER-mitochondria encounter structure (ERMES)was proposed to facilitate phospholipid transferbetween the ER and mitochondria, such a role ofERMES is still controversial and awaitsexperimental demonstration. Here we developeda novel in vitro assay system with isolated yeastmembrane fractions to monitor phospholipidexchange between the ER and mitochondria.With this system, we found that phospholipidtransport between the ER and mitochondriarelies on membrane intactness, but not energysources such as ATP, GTP or the membranepotential across the mitochondrial inner", "metadata": {}}
+{"_id": "4702639", "title": "", "text": "An integrin β3–KRAS–RalB complex drivestumour stemness and resistance to EGFRinhibitionTumour cells, with stem-like properties,are highly aggressive and often show drugresistance. Here, we reveal that integrin αvβ3serves as a marker of breast, lung andpancreatic carcinomas with stem-like propertiesthat are highly resistant to receptor tyrosinekinase inhibitors such as erlotinib. This wasobserved in vitro and in mice bearingpatient-derived tumour xenografts or in clinicalspecimens from lung cancer patients who hadprogressed on erlotinib. Mechanistically, αvβ3, inthe unliganded state, recruits KRAS and RalB tothe tumour cell plasma membrane, leading tothe activation of TBK1 and NF-κB. In fact, αvβ3expression and the resulting KRAS–RalB–NF-κBpathway were both necessary and sufficient fortumour initiation, anchorage independence,self-renewal and erlotinib resistance.Pharmacological targeting of this pathway withbortezomib reversed both tumour stemness and", "metadata": {}}
+{"_id": "4709641", "title": "", "text": "Gain of toxic Apolipoprotein E4 effects in HumaniPSC-Derived Neurons Is Ameliorated by aSmall-Molecule Structure CorrectorEfforts todevelop drugs for Alzheimer's disease (AD) haveshown promise in animal studies, only to fail inhuman trials, suggesting a pressing need tostudy AD in human model systems. Using humanneurons derived from induced pluripotent stemcells that expressed apolipoprotein E4 (ApoE4), avariant of the APOE gene product and the majorgenetic risk factor for AD, we demonstrated thatApoE4-expressing neurons had higher levels oftau phosphorylation, unrelated to their increasedproduction of amyloid-β (Aβ) peptides, and thatthey displayed GABAergic neuron degeneration.ApoE4 increased Aβ production in human, butnot in mouse, neurons. Converting ApoE4 toApoE3 by gene editing rescued thesephenotypes, indicating the specific effects ofApoE4. Neurons that lacked APOE behavedsimilarly to those expressing ApoE3, and theintroduction of ApoE4 expression recapitulated", "metadata": {}}
+{"_id": "4729644", "title": "", "text": "LncRNA NEAT1/let-7a-5p axis regulates thecisplatin resistance in nasopharyngeal carcinomaby targeting Rsf-1 and modulating the Ras-MAPKpathway.The long non-coding RNA nuclearparaspeckle assembly transcript 1 (NEAT1) wasreported to be upregulated and be involved inoncogenic growth and drug resistance innasopharyngeal carcinoma (NPC). However, theexact roles of NEAT1 and its underlyingmechanisms in the drug resistance of NPCremain largely unclear. In this study, theexpressions of NEAT1, let-72-5p and Rsf-1 mRNAwere detected by reversetranscription-quantitative polymerase chainreaction (RT-qPCR). The effects of NEAT1 andlet-72-5p on cell proliferation and cisplatinresistance of NPC cells were investigated by3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and5-ethynyl-20-deoxyuridine (EdU) assay. Westernblot analysis was performed to detect the proteinlevels of Rsf-1, Ras, p-Raf1, Raf1, p-MEK1,", "metadata": {}}
+{"_id": "4740447", "title": "", "text": "Antibacterial peptide microcin J25 inhibitstranscription by binding within and obstructingthe RNA polymerase secondary channel.Theantibacterial peptide microcin J25 (MccJ25)inhibits transcription by bacterial RNApolymerase (RNAP). Biochemical results indicatethat inhibition of transcription occurs at the levelof NTP uptake or NTP binding by RNAP. Geneticresults indicate that inhibition of transcriptionrequires an extensive determinant, comprisingmore than 50 amino acid residues, within theRNAP secondary channel (also known as the\"NTP-uptake channel\" or \"pore\"). Biophysicalresults indicate that inhibition of transcriptioninvolves binding of MccJ25 within the RNAPsecondary channel. Molecular modeling indicatesthat binding of MccJ25 within the RNAPsecondary channel obstructs the RNAP secondarychannel. We conclude that MccJ25 inhibitstranscription by binding within and obstructingthe RNAP secondary channel--acting essentiallyas a \"cork in a bottle. \" Obstruction of the RNAP", "metadata": {}}
+{"_id": "4767806", "title": "", "text": "Exploring and exploiting the systemic effects ofderegulated replication licensing.Maintenanceand accurate propagation of the genetic materialare key features for physiological developmentand wellbeing. The replication licensingmachinery is crucial for replication precision as itensures that replication takes place once per cellcycle. Thus, the expression status of thecomponents comprising the replication licensingapparatus is tightly regulated to avoidre-replication; a form of replication stress thatleads to genomic instability, a hallmark ofcancer. In the present review we discuss themechanistic basis of replication licensingderegulation, which leads to systemic effects,exemplified by its role in carcinogenesis and avariety of genetic syndromes. In addition, newinsights demonstrate that above a particularthreshold, the replication licensing factor Cdc6acts as global transcriptional regulator, outliningnew lines of exploration. The role of the putativereplication licensing factor ChlR1/DDX11,", "metadata": {}}
+{"_id": "4784069", "title": "", "text": "Regulatory principles of pluripotency: from theground state up.Pluripotency is the remarkablecapacity of a single cell to engender all thespecialized cell types of an adult organism. Thisproperty can be captured indefinitely throughderivation of self-renewing embryonic stem cells(ESCs), which represent an invaluable platformto investigate cell fate decisions and disease.Recent advances have revealed thatmanipulation of distinct signaling cues canrender ESCs in a uniform \"ground state\" ofpluripotency, which more closely recapitulatesthe pluripotent naive epiblast. Here we discussthe extrinsic and intrinsic regulatory principlesthat underpin the nature of pluripotency andconsider the emerging spectrum of pluripotentstates.", "metadata": {}}
+{"_id": "4791384", "title": "", "text": "Neonatal Mortality Levels for 193 Countries in2009 with Trends since 1990: A SystematicAnalysis of Progress, Projections, andPrioritiesBACKGROUND Historically, the mainfocus of studies of childhood mortality has beenthe infant and under-five mortality rates.Neonatal mortality (deaths <28 days of age) hasreceived limited attention, although such deathsaccount for about 41% of all child deaths. Tobetter assess progress, we developed annualestimates for neonatal mortality rates (NMRs)and neonatal deaths for 193 countries for theperiod 1990-2009 with forecasts into the future.METHODS AND FINDINGS We compiled adatabase of mortality in neonates and children(<5 years) comprising 3,551 country-years ofinformation. Reliable civil registration data from1990 to 2009 were available for 38 countries. Astatistical model was developed to estimateNMRs for the remaining 155 countries, 17 ofwhich had no national data. Country consultationwas undertaken to identify data inputs and", "metadata": {}}
+{"_id": "4795303", "title": "", "text": "Neuroprotective Effects of Four PhenylethanoidGlycosides on H2O2-Induced Apoptosis on PC12Cells via the Nrf2/ARE PathwayNuclear factorerythroid 2-related factor 2 (Nrf2) is a keytranscription factor against oxidative stress andneurodegenerative disorders. Phenylethanoidglycosides (PhGs; salidroside, acteoside,isoacteoside, and echinacoside) exhibitantioxidant and neuroprotective bioactivities.This study was performed to investigate theneuroprotective effect and molecular mechanismof PhGs. PhGs pretreatment significantlysuppressed H\u0000O\u0000-induced cytotoxicity in PC12cells by triggering the nuclear translocation ofNrf2 and reversing the downregulated proteinexpression of heme oxygenase 1 (HO-1),NAD(P)H quinone oxidoreductase 1 (NQO1),glutamate cysteine ligase-catalytic subunit(GCLC), and glutamate-cysteine ligase modifiersubunit (GCLM). Nrf2 siRNA or HO-1 inhibitorzinc protoporphyrin (ZnPP) reduced theneuroprotective effect. PhGs showed potential", "metadata": {}}
+{"_id": "4810810", "title": "", "text": "Mortality risk attributable to high and lowambient temperature: a multicountryobservational studyBACKGROUND Althoughstudies have provided estimates of prematuredeaths attributable to either heat or cold inselected countries, none has so far offered asystematic assessment across the wholetemperature range in populations exposed todifferent climates. We aimed to quantify the totalmortality burden attributable to non-optimumambient temperature, and the relativecontributions from heat and cold and frommoderate and extreme temperatures. METHODSWe collected data for 384 locations in Australia,Brazil, Canada, China, Italy, Japan, South Korea,Spain, Sweden, Taiwan, Thailand, UK, and USA.We fitted a standard time-series Poisson modelfor each location, controlling for trends and dayof the week. We estimatedtemperature-mortality associations with adistributed lag non-linear model with 21 days oflag, and then pooled them in a multivariate", "metadata": {}}
+{"_id": "4816339", "title": "", "text": "Survivin is not required for the endomitotic cellcycle of megakaryocytes.Survivin is a member ofthe chromosome passenger complex, whichplays an important role in chromosomealignment, separation, and cytokinesis. Althoughsurvivin is required for the proliferation andsurvival of hematopoietic stem and progenitorcells, the extent to which it is necessary forendomitosis of megakaryocytes remainscontroversial. To determine whether survivin isrequired for polyploidization, we analyzed micewith a megakaryocyte-specific deletion.PF4-Cre/survivin(fl/fl) mice harbored normalplatelet counts with megakaryocytes thatreached ploidy states comparable with those ofcontrol littermates. The CD41(+) cells withinthese animals showed little excision butincreased annexin V staining, implying thatsurvivin is required for survival ofmegakaryocyte progenitors in vivo. In contrast,megakaryocytes in which survivin was excised exvivo showed robust excision and an increased", "metadata": {}}
+{"_id": "4820792", "title": "", "text": "β1 integrin mediates an alternative survivalpathway in breast cancer cells resistant tolapatinibINTRODUCTION The overexpression ofhuman epidermal growth factor receptor (HER)-2in 20% of human breast cancers and itsassociation with aggressive growth has led towidespread use of HER2-targeted therapies, suchas trastuzumab (T) and lapatinib (L). Despite thesuccess of these drugs, their efficacy is limited inpatients whose tumors demonstrate de novo oracquired resistance to treatment. The β1 integrinresides on the membrane of the breast cancercell, activating several elements of breast tumorprogression including proliferation and survival.METHODS We developed a panel ofHER2-overexpressing cell lines resistant to L, T,and the potent LT combination throughlong-term exposure and validated these modelsin 3D culture. Parental and L/T/LT-resistant cellswere subject to HER2 and β1 integrin inhibitorsin 3D and monitored for 12 days, followed byquantification of colony number. Parallel", "metadata": {}}
+{"_id": "4824840", "title": "", "text": "Incidence and Trends of Sepsis in US HospitalsUsing Clinical vs Claims Data,2009-2014Importance Estimates fromclaims-based analyses suggest that the incidenceof sepsis is increasing and mortality rates fromsepsis are decreasing. However, estimates fromclaims data may lack clinical fidelity and can beaffected by changing diagnosis and codingpractices over time. Objective To estimate theUS national incidence of sepsis and trends usingdetailed clinical data from the electronic healthrecord (EHR) systems of diverse hospitals.Design, Setting, and Population Retrospectivecohort study of adult patients admitted to 409academic, community, and federal hospitals from2009-2014. Exposures Sepsis was identifiedusing clinical indicators of presumed infectionand concurrent acute organ dysfunction,adapting Third International ConsensusDefinitions for Sepsis and Septic Shock(Sepsis-3) criteria for objective and consistentEHR-based surveillance. Main Outcomes and", "metadata": {}}
+{"_id": "4828631", "title": "", "text": "Body-mass index and risk of 22 specific cancers:a population-based cohort study of 5·24 millionUK adultsBACKGROUND High body-mass index(BMI) predisposes to several site-specificcancers, but a large-scale systematic anddetailed characterisation of patterns of riskacross all common cancers adjusted for potentialconfounders has not previously been undertaken.We aimed to investigate the links between BMIand the most common site-specific cancers.METHODS With primary care data fromindividuals in the Clinical Practice ResearchDatalink with BMI data, we fitted Cox models toinvestigate associations between BMI and 22 ofthe most common cancers, adjusting forpotential confounders. We fitted linear thennon-linear (spline) models; investigated effectmodification by sex, menopausal status,smoking, and age; and calculated populationeffects. FINDINGS 5·24 million individuals wereincluded; 166,955 developed cancers of interest.BMI was associated with 17 of 22 cancers, but", "metadata": {}}
+{"_id": "4828984", "title": "", "text": "Cryo-EM structure of a herpesvirus capsid at 3.1ÅStructurally and genetically, humanherpesviruses are among the largest and mostcomplex of viruses. Using cryo–electronmicroscopy (cryo-EM) with an optimized imagereconstruction strategy, we report the herpessimplex virus type 2 (HSV-2) capsid structure at3.1 angstroms, which is built up of about 3000proteins organized into three types of hexons(central, peripentonal, and edge), pentons, andtriplexes. Both hexons and pentons contain themajor capsid protein, VP5; hexons also contain asmall capsid protein, VP26; and triplexescomprise VP23 and VP19C. Acting as coreorganizers, VP5 proteins form extensiveintermolecular networks, involving multipledisulfide bonds (about 1500 in total) andnoncovalent interactions, with VP26 proteins andtriplexes that underpin capsid stability andassembly. Conformational adaptations of theseproteins induced by their microenvironmentslead to 46 different conformers that assemble", "metadata": {}}
+{"_id": "4833016", "title": "", "text": "Asymptotic and resampling strategies forassessing and comparing indirect effects inmultiple mediator models.Hypotheses involvingmediation are common in the behavioralsciences. Mediation exists when a predictoraffects a dependent variable indirectly through atleast one intervening variable, or mediator.Methods to assess mediation involving multiplesimultaneous mediators have received littleattention in the methodological literature despitea clear need. We provide an overview of simpleand multiple mediation and explore threeapproaches that can be used to investigateindirect processes, as well as methods forcontrasting two or more mediators within asingle model. We present an illustrative example,assessing and contrasting potential mediators ofthe relationship between the helpfulness ofsocialization agents and job satisfaction. We alsoprovide SAS and SPSS macros, as well as Mplusand LISREL syntax, to facilitate the use of thesemethods in applications.", "metadata": {}}
+{"_id": "4841908", "title": "", "text": "Distinct Metabolomic Signatures Are Associatedwith Longevity in HumansAlterations inmetabolism influence lifespan in experimentalmodels, but data in humans are lacking. Here weuse liquid chromatography/mass spectrometry toquantify 217 plasma metabolites and examinetheir relation to longevity in a large cohort ofmen and women followed for up to 20 years. Wefind that, higher concentrations of the citric acidcycle intermediate, isocitrate, and the bile acid,taurocholate, are associated with lower odds oflongevity, defined as attaining 80 years of age.Higher concentrations of isocitrate, but nottaurocholate, are also associated with worsecardiovascular health at baseline, as well as riskof future cardiovascular disease and death. Noneof the metabolites identified are associated withcancer risk. Our findings suggest that some, butnot all, metabolic pathways related to humanlongevity are linked to the risk of commoncauses of death.", "metadata": {}}
+{"_id": "4854076", "title": "", "text": "The expanding problem of adipose depotremodeling and postnatal adipocyte progenitorrecruitment.The rising incidence of obesity andassociated metabolic diseases has increased theurgency in understanding all aspects of adiposetissue biology. This includes the function ofadipocytes, how adipose tissue expands inobesity, and how expanded adipose tissues inadults can impact physiology. Here, we highlightthe growing appreciation for the importance ofde novo adipocyte differentiation to adiposetissue expansion in adult humans and animals.We detail recent efforts to identify adiposeprecursor populations that contribute to thephysiological postnatal recruitment of white,brown, and beige adipocytes in mice, andsummarize new data that reveal the complexityof adipose tissue development in vivo.", "metadata": {}}
+{"_id": "4856149", "title": "", "text": "Clonal competition in BcrAbl-driven leukemia:how transplantations can accelerate clonalconversionBACKGROUND Clonal competition incancer describes the process in which theprogeny of a cell clone supersedes or succumbsto other competing clones due to differences intheir functional characteristics, mostly based onsubsequently acquired mutations. Even thoughthe patterns of those mutations are well exploredin many tumors, the dynamical process of clonalselection is underexposed. METHODS We studiedthe dynamics of clonal competition in aBcrAbl-induced leukemia using a γ-retroviralvector library encoding the oncogene inconjunction with genetic barcodes. To this end,we studied the growth dynamics of transducedcells on the clonal level both in vitro and in vivoin transplanted mice. RESULTS While wedetected moderate changes in clonalabundancies in vitro, we observed monoclonalleukemias in 6/30 mice after transplantation,which intriguingly were caused by only two", "metadata": {}}
+{"_id": "4857085", "title": "", "text": "Open Babel: An open chemicaltoolboxBACKGROUND A frequent problem incomputational modeling is the interconversion ofchemical structures between different formats.While standard interchange formats exist (forexample, Chemical Markup Language) and defacto standards have arisen (for example,SMILES format) , the need to interconvertformats is a continuing problem due to themultitude of different application areas forchemistry data, differences in the data stored bydifferent formats (0D versus 3D, for example),and competition between software along with alack of vendor-neutral formats. RESULTS Wediscuss, for the first time, Open Babel, anopen-source chemical toolbox that speaks themany languages of chemical data. Open Babelversion 2.3 interconverts over 110 formats. Theneed to represent such a wide variety ofchemical and molecular data requires a librarythat implements a wide range ofcheminformatics algorithms, from partial charge", "metadata": {}}
+{"_id": "4857093", "title": "", "text": "Young adolescents' nutrition assessment oncomputer (YANA-C)Objective:To assess therelative validity and acceptability of thecomputerised 24-h recall ‘Young Adolescent'sNutrition Assessment on Computer(YANA-C)’.Design:Food and nutrient intakesassessed with YANA-C were compared with foodrecords (study 1) and 24-h dietary recallinterviews (study 2).Main outcomemeasures:Intakes of food groups (fruit, fruitjuice, vegetables, potatoes, bread, cereals, milk,cheese, other milk products, soft drinks, diet softdrinks, sugar/sweets, pastry/cookies, savourysnacks, butter/sauces, eggs, fish, meat) andnutrients (energy, carbohydrates, protein, fat,fiber, calcium, vitamin C and iron).Subjects andsetting:A total of 237 pupils (11–14 y) from twoprimary and four secondary schools (study 1:n=136; study 2: n=101) in Belgium-Flanders.Results:YANA-C proved to agree well with bothstandard methods in categorizing subjects inconsumers and nonconsumers (κstudy", "metadata": {}}
+{"_id": "4883040", "title": "", "text": "Antiretroviral Therapy for Prevention ofTuberculosis in Adults with HIV: A SystematicReview and Meta-AnalysisBACKGROUND Humanimmunodeficiency virus (HIV) infection is thestrongest risk factor for developing tuberculosisand has fuelled its resurgence, especially insub-Saharan Africa. In 2010, there were anestimated 1.1 million incident cases oftuberculosis among the 34 million people livingwith HIV worldwide. Antiretroviral therapy hassubstantial potential to prevent HIV-associatedtuberculosis. We conducted a systematic reviewof studies that analysed the impact ofantiretroviral therapy on the incidence oftuberculosis in adults with HIV infection.METHODS AND FINDINGS PubMed, Embase,African Index Medicus, LILACS, and clinical trialregistries were systematically searched.Randomised controlled trials, prospective cohortstudies, and retrospective cohort studies wereincluded if they compared tuberculosis incidenceby antiretroviral therapy status in HIV-infected", "metadata": {}}
+{"_id": "4886637", "title": "", "text": "Diabetes, metabolic syndrome, and breastcancer: a review of the currentevidence.Incidences of breast cancer, type 2diabetes, and metabolic syndrome haveincreased over the past decades with the obesityepidemic, especially in industrialized countries.Insulin resistance, hyperinsulinemia, andchanges in the signaling of growth hormones andsteroid hormones associated with diabetes mayaffect the risk of breast cancer. We reviewedepidemiologic studies of the association betweentype 2 diabetes and risk of breast cancer and theavailable evidence on the role of hormonalmediators of an association between diabetesand breast cancer. The combined evidencesupports a modest association between type 2diabetes and the risk of breast cancer, whichappears to be more consistent amongpostmenopausal than among premenopausalwomen. Despite many proposed potentialpathways, the mechanisms underlying anassociation between diabetes and breast cancer", "metadata": {}}
+{"_id": "4889228", "title": "", "text": "Loss of TDP43 inhibits progression oftriple-negative breast cancer in coordination withSRSF3Aberrant alternative splicing has beenhighlighted as a potential hallmark of cancer.Here, we identify TDP43 (TAR DNA-bindingprotein 43) as an important splicing regulatorresponsible for the unique splicing profile intriple-negative breast cancer (TNBC). Clinicaldata demonstrate that TDP43 is highly expressedin TNBC with poor prognosis. Knockdown ofTDP43 inhibits tumor progression, includingproliferation and metastasis, and overexpressionof TDP43 promotes proliferation and malignancyof mammary epithelial cells. Deep sequencinganalysis and functional experiments indicate thatTDP43 alters most splicing events with splicingfactor SRSF3 (serine/arginine-rich splicing factor3), in the regulation of TNBC progression. TheTDP43/SRSF3 complex controls specific splicingevents, including downstream genes PAR3 andNUMB The effect of reduced metastasis andproliferation upon the knockdown of TDP43 or", "metadata": {}}
+{"_id": "4890578", "title": "", "text": "Atherosclerotic plaque rupture--pathologic basisof plaque stability and instability.Time forprimary reveiw 27 days   Atherosclerosiscontinues to be one of the main subjects inpathology research. The intriguing complexity ofits pathogenesis as well as the importance of itsclinical sequelae provide a rationale for this [1].A large number of diseases with totally differentclinical presentations are basicallyatherosclerosis related, and among these,myocardial infarction, stroke, abdominalaneurysms and lower limb ischemia determine toa large extent the morbidity and mortality inWestern style populations. But, despite thisbroad spectrum of clinical disease, most of theacute manifestations of atherosclerosis share acommon pathogenetic feature: rupture of anatherosclerotic plaque [2–4]. Plaque disruptionsmay vary greatly in extent from tiny fissures orerosions of the plaque surface to deep intimaltears which extend into the soft lipid core oflesions; in all these instances, at least some", "metadata": {}}
+{"_id": "4896726", "title": "", "text": "Pioneer factor Pax7 deploys a stable enhancerrepertoire for specification of cell fatePioneertranscription factors establish new cell-fatecompetence by triggering chromatin remodeling.However, many features of pioneer action, suchas their kinetics and stability, remain poorlydefined. Here, we show that Pax7, by opening aunique repertoire of enhancers, is necessary andsufficient for specification of one pituitarylineage. Pax7 binds its targeted enhancersrapidly, but chromatin remodeling and geneactivation are slower. Enhancers opened by Pax7show a loss of DNA methylation and acquirestable epigenetic memory, as evidenced bybinding of nonpioneer factors after Pax7withdrawal. This work shows that transient Pax7expression is sufficient for stable specification ofcell identity. Analysis of Pax7 dynamics duringpituitary lineage specification shows that Pax7binds rapidly at uniquely markedheterochromatin pioneer sites and initiateschromatin opening that remains stable after", "metadata": {}}
+{"_id": "4899981", "title": "", "text": "Human cancer cells utilize mitotic DNA synthesisto resist replication stress at telomeresregardless of their telomere maintenancemechanismTelomeres resemble common fragilesites (CFSs) in that they are difficult-to-replicateand exhibit fragility in mitosis in response to DNAreplication stress. At CFSs, this fragility isassociated with a delay in the completion of DNAreplication until early mitosis, whereupon cellsare proposed to switch to a RAD52-dependentform of break-induced replication. Here, we showthat this mitotic DNA synthesis (MiDAS) is also afeature of human telomeres. Telomeric MiDAS isnot restricted to those telomeres displaying overtfragility, and is a feature of a wide range of celllines irrespective of whether their telomeres aremaintained by telomerase or by the alternativelengthening of telomeres (ALT) mechanism.MiDAS at telomeres requires RAD52, and ismechanistically similar to CFS-associated MiDAS,with the notable exception that telomeric MiDASdoes not require the MUS81-EME1 endonuclease.", "metadata": {}}
+{"_id": "4910408", "title": "", "text": "Low drug levels and thrombotic complications inhigh\u0000risk atrial fibrillation patients treated withdirect oral anticoagulantsEssentials Direct oralanticoagulants (DOACs) do not requirelaboratory monitoring currently. DOAC specificmeasurements were performed at trough inpatients with atrial fibrillation. Patients whodeveloped thromboembolic events showed lowerDOAC plasma levels. This study supports theconcept of measuring DOAC levels at steadystate. SUMMARY Background Direct oralanticoagulants (DOACs) are administered atfixed doses without the need for doseadjustment according to laboratory testing. Highinterindividual variability in drug blood levels hasbeen shown with all DOACs. To evaluate apossible relationship between DOAC C-troughanticoagulant levels and thromboembolic events,565 consecutive naive patients with atrialfibrillation (AF) were enrolled in this studyperformed within the START Laboratory Registry.Methods DOAC-specific measurements (diluted", "metadata": {}}
+{"_id": "4911006", "title": "", "text": "Consensus guidelines for the detection ofimmunogenic cell death.Apoptotic cells have longbeen considered as intrinsically tolerogenic orunable to elicit immune responses specific fordead cell-associated antigens. However, multiplestimuli can trigger a functionally peculiar type ofapoptotic demise that does not go unnoticed bythe adaptive arm of the immune system, whichwe named \"immunogenic cell death\" (ICD). ICDis preceded or accompanied by the emission of aseries of immunostimulatory damage-associatedmolecular patterns (DAMPs) in a precisespatiotemporal configuration. Several anticanceragents that have been successfully employed inthe clinic for decades, including variouschemotherapeutics and radiotherapy, can elicitICD. Moreover, defects in the components thatunderlie the capacity of the immune system toperceive cell death as immunogenic negativelyinfluence disease outcome among cancerpatients treated with ICD inducers. Thus, ICDhas profound clinical and therapeutic", "metadata": {}}
+{"_id": "4920376", "title": "", "text": "Long-Term ERK Inhibition in KRAS-MutantPancreatic Cancer Is Associated with MYCDegradation and Senescence-like GrowthSuppression.Induction of compensatorymechanisms and ERK reactivation has limited theeffectiveness of Raf and MEK inhibitors inRAS-mutant cancers. We determined that directpharmacologic inhibition of ERK suppressed thegrowth of a subset of KRAS-mutant pancreaticcancer cell lines and that concurrentphosphatidylinositol 3-kinase (PI3K) inhibitioncaused synergistic cell death. Additionalcombinations that enhanced ERK inhibitor actionwere also identified. Unexpectedly, long-termtreatment of sensitive cell lines causedsenescence, mediated in part by MYCdegradation and p16 reactivation. Enhancedbasal PI3K-AKT-mTOR signaling was associatedwith de novo resistance to ERK inhibitor, as wereother protein kinases identified by kinome-widesiRNA screening and a genetic gain-of-functionscreen. Our findings reveal distinct consequences", "metadata": {}}
+{"_id": "4926049", "title": "", "text": "TRF2 Recruits RTEL1 to Telomeres in S Phase toPromote T-Loop UnwindingThe helicase RTEL1promotes t-loop unwinding and suppressestelomere fragility to maintain the integrity ofvertebrate telomeres. An interaction betweenRTEL1 and PCNA is important to preventtelomere fragility, but how RTEL1 engages withthe telomere to promote t-loop unwinding isunclear. Here, we establish that the shelterinprotein TRF2 recruits RTEL1 to telomeres in Sphase, which is required to prevent catastrophict-loop processing by structure-specific nucleases.We show that the TRF2-RTEL1 interaction ismediated by a metal-coordinating C4C4 motif inRTEL1, which is compromised by theHoyeraal-Hreidarsson syndrome (HHS) mutation,RTEL1(R1264H). Conversely, we define aTRF2(I124D) substitution mutation within theTRFH domain of TRF2, which eliminates RTEL1binding and phenocopies the RTEL1(R1264H)mutation, giving rise to aberrant t-loop excision,telomere length heterogeneity, and loss of the", "metadata": {}}
+{"_id": "4928057", "title": "", "text": "Macrophages Facilitate Electrical Conduction inthe HeartOrgan-specific functions oftissue-resident macrophages in the steady-stateheart are unknown. Here, we show that cardiacmacrophages facilitate electrical conductionthrough the distal atrioventricular node, whereconducting cells densely intersperse withelongated macrophages expressing connexin 43.When coupled to spontaneously beatingcardiomyocytes via connexin-43-containing gapjunctions, cardiac macrophages have a negativeresting membrane potential and depolarize insynchrony with cardiomyocytes. Conversely,macrophages render the resting membranepotential of cardiomyocytes more positive and,according to computational modeling, acceleratetheir repolarization. Photostimulation ofchannelrhodopsin-2-expressing macrophagesimproves atrioventricular conduction, whereasconditional deletion of connexin 43 inmacrophages and congenital lack ofmacrophages delay atrioventricular conduction.", "metadata": {}}
+{"_id": "4928282", "title": "", "text": "A Tunable Diffusion\u0000Consumption Mechanism ofCytokine Propagation Enables Plasticity inCell\u0000to\u0000Cell Communication in the ImmuneSystem&NA; Immune cells communicate byexchanging cytokines to achieve acontext\u0000appropriate response, but the distancesover which such communication happens are notknown. Here, we used theoretical considerationsand experimental models of immune responsesin vitro and in vivo to quantify the spatial extentof cytokine communications in dense tissues. Weestablished that competition between cytokinediffusion and consumption generated spatialniches of high cytokine concentrations with sharpboundaries. The size of these self\u0000assembledniches scaled with the density ofcytokine\u0000consuming cells, a parameter that getstuned during immune responses. In vivo, wemeasured interactions on length scales of80–120 &mgr;m, which resulted in a high degreeof cell\u0000to\u0000cell variance in cytokine exposure.Such heterogeneous distributions of cytokines", "metadata": {}}
+{"_id": "4932668", "title": "", "text": "Cardiac neural crest contributes tocardiomyogenesis in zebrafish.In birds andmammals, cardiac neural crest is essential forheart development and contributes toconotruncal cushion formation and outflow tractseptation. The zebrafish prototypical heart lacksoutflow tract septation, raising the question ofwhether cardiac neural crest exists in zebrafish.Here, results from three distinct lineage-labelingapproaches identify zebrafish cardiac neuralcrest cells and indicate that these cells have theability to generate MF20-positive muscle cells inthe myocardium of the major chambers duringdevelopment. Fate-mapping demonstrates thatcardiac neural crest cells originate both fromneural tube regions analogous to those found inbirds, as well as from a novel region rostral tothe otic vesicle. In contrast to other vertebrates,cardiac neural crest invades the myocardium inall segments of the heart, including outflow tract,atrium, atrioventricular junction, and ventricle inzebrafish. Three distinct groups of premigratory", "metadata": {}}
+{"_id": "4939312", "title": "", "text": "Sodium Hydroxide Production from SeawaterDesalination Brine: Process Design and EnergyEfficiency.The ability to increase pH is a crucialneed for desalination pretreatment (especially inreverse osmosis) and for other industries, butprocesses used to raise pH often incur significantemissions and nonrenewable resource use.Alternatively, waste brine from desalination canbe used to create sodium hydroxide, viaappropriate concentration and purificationpretreatment steps, for input into the chlor-alkaliprocess. In this work, an efficient process train(with variations) is developed and modeled forsodium hydroxide production from seawaterdesalination brine using membrane chlor-alkalielectrolysis. The integrated system includesnanofiltration, concentration via evaporation ormechanical vapor compression, chemicalsoftening, further ion-exchange softening,dechlorination, and membrane electrolysis.System productivity, component performance,and energy consumption of the NaOH production", "metadata": {}}
+{"_id": "4942718", "title": "", "text": "High-Throughput Genetic Screens Identify aLarge and Diverse Collection of New SporulationGenes in Bacillus subtilisThe differentiation of thebacterium Bacillus subtilis into a dormant sporeis among the most well-characterizeddevelopmental pathways in biology. Classicalgenetic screens performed over the past halfcentury identified scores of factors involved inevery step of this morphological process. Morerecently, transcriptional profiling uncoveredadditional sporulation-induced genes required forsuccessful spore development. Here, we usedtransposon-sequencing (Tn-seq) to assesswhether there were any sporulation genes left tobe discovered. Our screen identified 133 out ofthe 148 genes with known sporulation defects.Surprisingly, we discovered 24 additional genesthat had not been previously implicated in sporeformation. To investigate their functions, weused fluorescence microscopy to survey early,middle, and late stages of differentiation of nullmutants from the B. subtilis ordered knockout", "metadata": {}}
+{"_id": "4951831", "title": "", "text": "Psychobiological mechanisms underlying thesocial buffering of thehypothalamic-pituitary-adrenocortical axis: areview of animal models and human studiesacross development.Discovering thestress-buffering effects of social relationships hasbeen one of the major findings in psychobiologyin the last century. However, an understandingof the underlying neurobiological andpsychological mechanisms of this buffering isonly beginning to emerge. An important avenueof this research concerns the neurocircuitry thatcan regulate the activity of thehypothalamic-pituitary-adrenocortical (HPA)axis. The present review is a translational effortaimed at integrating animal models and humanstudies of the social regulation of the HPA axisfrom infancy to adulthood, specifically focusingon the process that has been named socialbuffering. This process has been noted acrossspecies and consists of a dampened HPA axisstress response to threat or challenge that", "metadata": {}}
+{"_id": "4959368", "title": "", "text": "Elevation of circulating branched-chain aminoacids is an early event in human pancreaticadenocarcinoma developmentMost patients withpancreatic ductal adenocarcinoma (PDAC) arediagnosed with advanced disease and surviveless than 12 months. PDAC has been linked withobesity and glucose intolerance, but whetherchanges in circulating metabolites are associatedwith early cancer progression is unknown. Tobetter understand metabolic derangementsassociated with early disease, we profiledmetabolites in prediagnostic plasma fromindividuals with pancreatic cancer (cases) andmatched controls from four prospective cohortstudies. We find that elevated plasma levels ofbranched-chain amino acids (BCAAs) areassociated with a greater than twofold increasedrisk of future pancreatic cancer diagnosis. Thiselevated risk was independent of knownpredisposing factors, with the strongestassociation observed among subjects withsamples collected 2 to 5 years before diagnosis,", "metadata": {}}
+{"_id": "4961038", "title": "", "text": "Effective Use of PI3K and MEK Inhibitors to TreatMutant K-Ras G12D and PIK3CA H1047R MurineLung CancersSomatic mutations that activatephosphoinositide 3-kinase (PI3K) have beenidentified in the p110-alpha catalytic subunit(encoded by PIK3CA). They are most frequentlyobserved in two hotspots: the helical domain(E545K and E542K) and the kinase domain(H1047R). Although the p110-alpha mutants aretransforming in vitro, their oncogenic potentialhas not been assessed in genetically engineeredmouse models. Furthermore, clinical trials withPI3K inhibitors have recently been initiated, andit is unknown if their efficacy will be restricted tospecific, genetically defined malignancies. In thisstudy, we engineered a mouse model of lungadenocarcinomas initiated and maintained byexpression of p110-alpha H1047R. Treatment ofthese tumors with NVP-BEZ235, a dual pan-PI3Kand mammalian target of rapamycin (mTOR)inhibitor in clinical development, led to markedtumor regression as shown by positron emission", "metadata": {}}
+{"_id": "4979184", "title": "", "text": "Transdifferentiation of glioblastoma cells intovascular endothelial cells.Glioblastoma (GBM) isthe most malignant brain tumor and is highlyresistant to intensive combination therapies andanti-VEGF therapies. To assess the resistancemechanism to anti-VEGF therapy, we examinedthe vessels of GBMs in tumors that were inducedby the transduction of p53(+/-) heterozygousmice with lentiviral vectors containing oncogenesand the marker GFP in the hippocampus ofGFAP-Cre recombinase (Cre) mice. We weresurprised to observe GFP(+) vascular endothelialcells (ECs). Transplantation of mouse GBM cellsrevealed that the tumor-derived endothelial cells(TDECs) originated from tumor-initiating cellsand did not result from cell fusion of ECs andtumor cells. An in vitro differentiation assaysuggested that hypoxia is an important factor inthe differentiation of tumor cells to ECs and isindependent of VEGF. TDEC formation was notonly resistant to an anti-VEGF receptor inhibitorin mouse GBMs but it led to an increase in their", "metadata": {}}
+{"_id": "4993011", "title": "", "text": "Ribosomal DNA copy loss and repeat instability inATRX-mutated cancersATRX (alphathalassemia/mental retardation X-linked)complexes with DAXX to deposit histone variantH3.3 into repetitive heterochromatin. Recentgenome sequencing studies in cancers haverevealed mutations in ATRX and their associationwith ALT (alternative lengthening of telomeres)activation. Here we report depletion of ATRX inmouse ES cells leads to selective loss inribosomal RNA gene (rDNA) copy number.Supporting this, ATRX-mutated humanALT-positive tumors also show a substantiallylower rDNA copy than ALT-negative tumors.Further investigation shows that the rDNA copyloss and repeat instability are caused by adisruption in H3.3 deposition and thus a failure inheterochromatin formation at rDNA repeats inthe absence of ATRX. We also find thatATRX-depleted cells are reduced in ribosomalRNA transcription output and show increasedsensitivity to RNA polymerase I (Pol I)", "metadata": {}}
+{"_id": "4999387", "title": "", "text": "Combining indoor residual spraying andinsecticide-treated nets for malaria control inAfrica: a review of possible outcomes and anoutline of suggestions for thefutureInsecticide-treated nets (ITNs) and indoorresidual spraying (IRS) are currently thepreferred methods of malaria vector control. Inmany cases, these methods are used together inthe same households, especially to suppresstransmission in holoendemic and hyperendemicscenarios. Though widespread, there has beenlimited evidence suggesting that suchco-application confers greater protective benefitsthan either ITNs or IRS when used alone. Sinceboth methods are insecticide-based andintradomicilliary, this article hypothesises thatoutcomes of their combination would depend oneffects of the candidate active ingredients onmosquitoes that enter or those that attempt toenter houses. It is suggested here that enhancedhousehold level protection can be achieved if theITNs and IRS have divergent yet complementary", "metadata": {}}
+{"_id": "4999633", "title": "", "text": "Membrane estrogen receptor-α levels in MCF-7breast cancer cells predict cAMP and proliferationresponses17β-estradiol (E2) can rapidly inducecAMP production, but the conditions under whichthese cAMP levels are best measured and thesignaling pathways responsible for theconsequent proliferative effects on breast cancercells are not fully understood. To help resolvethese issues, we compared cAMP mechanisticresponses in MCF-7 cell lines selected for low(mERlow) and high (mERhigh) expression of themembrane form of estrogen receptor (mER)-α,and thus addressed the receptor subforminvolved in cAMP signaling. MCF-7 cells wereimmunopanned and subsequently separated byfluorescence activated cell sorting into mERhigh(mER-α-enriched) and mERlow(mER-α-depleted) populations. Unique(compared with previously reported) incubationconditions at 4°C were found to be optimal fordemonstrating E2-induced cAMP production.Time-dependent and dose-dependent effects of", "metadata": {}}
+{"_id": "5002665", "title": "", "text": "The embryonic cell lineage of the nematodeCaenorhabditis elegans.The embryonic celllineage of Caenorhabditis elegans has beentraced from zygote to newly hatched larva, withthe result that the entire cell lineage of thisorganism is now known. During embryogenesis671 cells are generated; in the hermaphrodite113 of these (in the male 111) undergoprogrammed death and the remainder eitherdifferentiate terminally or become postembryonicblast cells. The embryonic lineage is highlyinvariant, as are the fates of the cells to which itgives rise. In spite of the fixed relationshipbetween cell ancestry and cell fate, thecorrelation between them lacks much obviouspattern. Thus, although most neurons arise fromthe embryonic ectoderm, some are produced bythe mesoderm and a few are sisters to muscles;again, lineal boundaries do not necessarilycoincide with functional boundaries.Nevertheless, cell ablation experiments (as wellas previous cell isolation experiments)", "metadata": {}}
+{"_id": "5003144", "title": "", "text": "Self-Reactive B Cells in the Germinal CenterReaction.Maintenance of immunologicalself-tolerance requires lymphocytes carryingself-reactive antigen receptors to be selectivelyprevented from mounting destructive orinflammatory effector responses. Classically,self-tolerance is viewed in terms of the removal,editing, or silencing of B and T cells that haveformed self-reactive antigen receptors duringtheir early development. However, B cellsactivated by foreign antigen can enter germinalcenters (GCs), where they further modify theirantigen receptor by somatic hypermutation(SHM) of their immunoglobulin genes. Theinevitable emergence of activated, self-reactiveGC B cells presents a unique challenge to themaintenance of self-tolerance that must berapidly countered to avoid autoantibodyproduction. Here we discuss current knowledgeof the mechanisms that enforce B cellself-tolerance, with particular focus on thecontrol of self-reactive GC B cells. We also", "metadata": {}}
+{"_id": "5035827", "title": "", "text": "Chronic inflammation (inflammaging) and itspotential contribution to age-associateddiseases.Human aging is characterized by achronic, low-grade inflammation, and thisphenomenon has been termed as \"inflammaging.\" Inflammaging is a highly significant risk factorfor both morbidity and mortality in the elderlypeople, as most if not all age-related diseasesshare an inflammatory pathogenesis.Nevertheless, the precise etiology ofinflammaging and its potential causal role incontributing to adverse health outcomes remainlargely unknown. The identification of pathwaysthat control age-related inflammation acrossmultiple systems is therefore important in orderto understand whether treatments that modulateinflammaging may be beneficial in old people.The session on inflammation of the Advances inGerosciences meeting held at the NationalInstitutes of Health/National Institute on Aging inBethesda on October 30 and 31, 2013 was aimedat defining these important unanswered", "metadata": {}}
+{"_id": "5035851", "title": "", "text": "Cryptochromes Enabling Plants and Animals toDetermine Circadian TimeCryptochromes areflavin-containing blue light photoreceptorsrelated to photolyases-they are found in bothplants and animals and have recently beendescribed for bacteria. In plants, cryptochromesperform a variety of functions including theentrainment of circadian rhythms. They serve asimilar role in Drosophila and mammals, wherethe cryptochromes also perform an additionalfunction as an essential component of thecircadian clock.", "metadata": {}}
+{"_id": "5085118", "title": "", "text": "Neural crest-derived stem cells migrate anddifferentiate into cardiomyocytes aftermyocardial infarction.OBJECTIVE We recentlydemonstrated that primitive neural crest-derived(NC) cells migrate from the cardiac neural crestduring embryonic development and remain in theheart as dormant stem cells, with the capacity todifferentiate into various cell types, includingcardiomyocytes. Here, we examined themigration and differentiation potential of thesecells on myocardial infarction (MI). METHODSAND RESULTS We obtained double-transgenicmice by crossing protein-0 promoter-Cre micewith Floxed-enhanced green fluorescent proteinmice, in which the NC cells express enhancedgreen fluorescent protein. In the neonatal heart,NC stem cells (NCSCs) were localizedpredominantly in the outflow tract, but they werealso distributed in a gradient from base to apexthroughout the ventricular myocardium.Time-lapse video analysis revealed that theNCSCs were migratory. Some NCSCs persisted in", "metadata": {}}
+{"_id": "5094468", "title": "", "text": "Mitochondria as sensors and regulators ofcalcium signallingDuring the past two decadescalcium (Ca2+) accumulation in energizedmitochondria has emerged as a biologicalprocess of utmost physiological relevance.Mitochondrial Ca2+ uptake was shown to controlintracellular Ca2+ signalling, cell metabolism,cell survival and other cell-type specific functionsby buffering cytosolic Ca2+ levels and regulatingmitochondrial effectors. Recently, the identity ofmitochondrial Ca2+ transporters has beenrevealed, opening new perspectives forinvestigation and molecular intervention.", "metadata": {}}
+{"_id": "5099266", "title": "", "text": "Caspase-11 promotes the fusion of phagosomesharboring pathogenic bacteria with lysosomes bymodulating actin polymerization.Inflammasomesare multiprotein complexes that includemembers of the NLR (nucleotide-binding domainleucine-rich repeat containing) family andcaspase-1. Once bacterial molecules are sensedwithin the macrophage, the inflammasome isassembled, mediating the activation ofcaspase-1. Caspase-11 mediates caspase-1activation in response to lipopolysaccharide andbacterial toxins, and yet its role during bacterialinfection is unknown. Here, we demonstratedthat caspase-11 was dispensable for caspase-1activation in response to Legionella, Salmonella,Francisella, and Listeria. We also determined thatactive mouse caspase-11 was required forrestriction of L. pneumophila infection. Similarly,human caspase-4 and caspase-5, homologs ofmouse caspase-11, cooperated to restrict L.pneumophila infection in human macrophages.Caspase-11 promoted the fusion of the L.", "metadata": {}}
+{"_id": "5106691", "title": "", "text": "Adipocyte inflammation is essential for healthyadipose tissue expansion and remodeling.Chronicinflammation constitutes an important linkbetween obesity and its pathophysiologicalsequelae. In contrast to the belief thatinflammatory signals exert a fundamentallynegative impact on metabolism, we show thatproinflammatory signaling in the adipocyte is infact required for proper adipose tissueremodeling and expansion. Three mouse modelswith an adipose tissue-specific reduction inproinflammatory potential were generated thatdisplay a reduced capacity for adipogenesis invivo, while the differentiation potential isunaltered in vitro. Upon high-fat-diet exposure,the expansion of visceral adipose tissue isprominently affected. This is associated withdecreased intestinal barrier function, increasedhepatic steatosis, and metabolic dysfunction. Animpaired local proinflammatory response in theadipocyte leads to increased ectopic lipidaccumulation, glucose intolerance, and systemic", "metadata": {}}
+{"_id": "5107861", "title": "", "text": "Chronic variable stress activates hematopoieticstem cellsExposure to psychosocial stress is arisk factor for many diseases, includingatherosclerosis. Although incompletelyunderstood, interaction between the psyche andthe immune system provides one potentialmechanism linking stress and disease inceptionand progression. Known cross-talk between thebrain and immune system includes thehypothalamic-pituitary-adrenal axis, whichcentrally drives glucocorticoid production in theadrenal cortex, and thesympathetic-adrenal-medullary axis, whichcontrols stress-induced catecholamine release insupport of the fight-or-flight reflex. It remainsunknown, however, whether chronic stresschanges hematopoietic stem cell activity. Herewe show that stress increases proliferation ofthese most primitive hematopoietic progenitors,giving rise to higher levels of disease-promotinginflammatory leukocytes. We found that chronicstress induced monocytosis and neutrophilia in", "metadata": {}}
+{"_id": "5108807", "title": "", "text": "CNTF reverses obesity-induced insulin resistanceby activating skeletal muscle AMPKCiliaryneurotrophic factor (CNTF) induces weight lossand improves glucose tolerance in humans androdents. CNTF is thought to act centrally byinducing hypothalamic neurogenesis to modulatefood intake and peripherally by altering hepaticgene expression, in a manner similar to that ofleptin. Here, we show that CNTF signals throughthe CNTFRα–IL-6R–gp130β receptor complex toincrease fatty-acid oxidation and reduce insulinresistance in skeletal muscle by activatingAMP-activated protein kinase (AMPK),independent of signaling through the brain.Thus, our findings further show that theantiobesogenic effects of CNTF in the peripheryresult from direct effects on skeletal muscle, andthat these peripheral effects are not suppressedby diet-induced or genetic models of obesity, anessential requirement for the therapeutictreatment of obesity-related diseases.", "metadata": {}}
+{"_id": "5114282", "title": "", "text": "The Global Spread of Hepatitis C Virus 1a and1b: A Phylodynamic and PhylogeographicAnalysisBACKGROUND Hepatitis C virus (HCV) isestimated to affect 130-180 million peopleworldwide. Although its origin is unknown,patterns of viral diversity suggest that HCVgenotype 1 probably originated from West Africa.Previous attempts to estimate thespatiotemporal parameters of the virus, bothglobally and regionally, have suggested thatepidemic HCV transmission began in 1900 andgrew steadily until the late 1980s. However,epidemiological data suggest that the expansionof HCV may have occurred after the SecondWorld War. The aim of our study was to elucidatethe timescale and route of the global spread ofHCV. METHODS AND FINDINGS We show thatthe rarely sequenced HCV region (E2P7NS2) ismore informative for molecular epidemiologystudies than the more commonly used NS5Bregion. We applied phylodynamic methods to asubstantial set of new E2P7NS2 and NS5B", "metadata": {}}
+{"_id": "5114940", "title": "", "text": "Pharmacological interventions for smokingcessation: an overview and networkmeta-analysis.BACKGROUND Smoking is theleading preventable cause of illness andpremature death worldwide. Some medicationshave been proven to help people to quit, withthree licensed for this purpose in Europe and theUSA: nicotine replacement therapy (NRT),bupropion, and varenicline. Cytisine (a treatmentpharmacologically similar to varenicline) is alsolicensed for use in Russia and some of the formersocialist economy countries. Other therapies,including nortriptyline, have also been tested foreffectiveness. OBJECTIVES How do NRT,bupropion and varenicline compare with placeboand with each other in achieving long-termabstinence (six months or longer)? How do theremaining treatments compare with placebo inachieving long-term abstinence? How do therisks of adverse and serious adverse events(SAEs) compare between the treatments, andare there instances where the harms may", "metadata": {}}
+{"_id": "5116145", "title": "", "text": "A library of yeast transcription factor motifsreveals a widespread function for Rsc3 intargeting nucleosome exclusion at promoters.Thesequence specificity of DNA-binding proteins isthe primary mechanism by which the cellrecognizes genomic features. Here, we describesystematic determination of yeast transcriptionfactor DNA-binding specificities. We obtainedbinding specificities for 112 DNA-binding proteinsrepresenting 19 distinct structural classes.One-third of the binding specificities have notbeen previously reported. Several bindingsequences have striking genomic distributionsrelative to transcription start sites, supportingtheir biological relevance and suggesting a role inpromoter architecture. Among these are Rsc3binding sequences, containing the core CGCG,which are found preferentially approximately 100bp upstream of transcription start sites. Mutationof RSC3 results in a dramatic increase innucleosome occupancy in hundreds of proximalpromoters containing a Rsc3 binding element,", "metadata": {}}
+{"_id": "5123516", "title": "", "text": "EphA3 maintains tumorigenicity and is atherapeutic target in glioblastomamultiforme.Significant endeavor has beenapplied to identify functional therapeutic targetsin glioblastoma (GBM) to halt the growth of thisaggressive cancer. We show that the receptortyrosine kinase EphA3 is frequentlyoverexpressed in GBM and, in particular, in themost aggressive mesenchymal subtype.Importantly, EphA3 is highly expressed on thetumor-initiating cell population in glioma andappears critically involved in maintaining tumorcells in a less differentiated state by modulatingmitogen-activated protein kinase signaling.EphA3 knockdown or depletion of EphA3-positivetumor cells reduced tumorigenic potential to adegree comparable to treatment with atherapeutic radiolabelled EphA3-specificmonoclonal antibody. These results identifyEphA3 as a functional, targetable receptor inGBM.", "metadata": {}}
+{"_id": "5132358", "title": "", "text": "Chimeric antigen receptor-modified T cells foracute lymphoid leukemia.Chimeric antigenreceptor-modified T cells with specificity forCD19 have shown promise in the treatment ofchronic lymphocytic leukemia (CLL). It remainsto be established whether chimeric antigenreceptor T cells have clinical activity in acutelymphoblastic leukemia (ALL). Two children withrelapsed and refractory pre-B-cell ALL receivedinfusions of T cells transduced with anti-CD19antibody and a T-cell signaling molecule (CTL019chimeric antigen receptor T cells), at a dose of1.4×10(6) to 1.2×10(7) CTL019 cells perkilogram of body weight. In both patients,CTL019 T cells expanded to a level that wasmore than 1000 times as high as the initialengraftment level, and the cells were identifiedin bone marrow. In addition, the chimericantigen receptor T cells were observed in thecerebrospinal fluid (CSF), where they persistedat high levels for at least 6 months. Eight grade3 or 4 adverse events were noted. The", "metadata": {}}
+{"_id": "5132461", "title": "", "text": "Extended-connectivityfingerprints.Extended-connectivity fingerprints(ECFPs) are a novel class of topologicalfingerprints for molecular characterization.Historically, topological fingerprints weredeveloped for substructure and similaritysearching. ECFPs were developed specifically forstructure-activity modeling. ECFPs are circularfingerprints with a number of useful qualities:they can be very rapidly calculated; they are notpredefined and can represent an essentiallyinfinite number of different molecular features(including stereochemical information); theirfeatures represent the presence of particularsubstructures, allowing easier interpretation ofanalysis results; and the ECFP algorithm can betailored to generate different types of circularfingerprints, optimized for different uses. Whilethe use of ECFPs has been widely adopted andvalidated, a description of their implementationhas not previously been presented in theliterature.", "metadata": {}}
+{"_id": "5137019", "title": "", "text": "Suppressor of cytokine signaling 3 inhibitsantiviral IFN-beta signaling to enhance HIV-1replication in macrophages.HIV-1 replicationwithin macrophages of the CNS often results incognitive and motor impairment, which is knownas HIV-associated dementia (HAD) in its mostsevere form. IFN-beta suppresses viralreplication within these cells during early CNSinfection, but the effect is transient. HIV-1eventually overcomes this protective innateimmune response to resume replication throughan unknown mechanism, initiating theprogression toward HAD. In this article, we showthat Suppressor of Cytokine Signaling (SOCS)3,a molecular inhibitor of IFN signaling, may allowHIV-1 to evade innate immunity within the CNS.We found that SOCS3 is elevated in an in vivoSIV/macaque model of HAD and that the patternof expression correlates with recurrence of viralreplication and onset of CNS disease. In vitro,the HIV-1 regulatory protein transactivator oftranscription induces SOCS3 in human and", "metadata": {}}
+{"_id": "5144381", "title": "", "text": "Molecular model of the human 26Sproteasome.The 26S proteasome plays afundamental role in eukaryotic homeostasis byundertaking the highly controlled degradation ofa wide range of proteins, including key cellularregulators such as those controlling cell-cycleprogression and apoptosis. Here we report thestructure of the human 26S proteasomedetermined by cryo-electron microscopy andsingle-particle analysis, with secondary structureelements identified both in the 20S proteolyticcore region and in the 19S regulatory particle.We have used this information together withcrystal structures, homology models, and otherbiochemical information to construct a molecularmodel of the complete 26S proteasome. Thismodel allows for a detailed description of the 20Score within the 26S proteasome and redefinesthe overall assignment of subunits within the19S regulatory particle. The informationpresented here provides a strong basis for amechanistic understanding of the 26S", "metadata": {}}
+{"_id": "5145974", "title": "", "text": "Urinary bisphenol A concentrations and earlyreproductive health outcomes among womenundergoing IVF.STUDY QUESTION In womenundergoing IVF, are urinary bisphenol A (BPA)concentrations associated with ovarian responseand early reproductive outcomes, includingoocyte maturation and fertilization, Day 3embryo quality and blastocyst formation?SUMMARY ANSWER Higher urinary BPAconcentrations were found to be associated withdecreased ovarian response, number of fertilizedoocytes and decreased blastocyst formation.WHAT IS KNOWN ALREADY Experimental animaland in vitro studies have reported associationsbetween BPA exposure and adverse reproductiveoutcomes. We previously reported an associationbetween urinary BPA and decreased ovarianresponse [peak serum estradiol (E(2)) andoocyte count at the time of retrieval] in womenundergoing IVF; however, there are limitedhuman data on reproductive health outcomes,such as fertilization and embryo development.", "metadata": {}}
+{"_id": "5151024", "title": "", "text": "Cost-effectiveness of options for the diagnosis ofhigh blood pressure in primary care: a modellingstudy.BACKGROUND The diagnosis ofhypertension has traditionally been based onblood-pressure measurements in the clinic, buthome and ambulatory measurements bettercorrelate with cardiovascular outcome, andambulatory monitoring is more accurate thanboth clinic and home monitoring in diagnosinghypertension. We aimed to compare thecost-effectiveness of different diagnosticstrategies for hypertension. METHODS We did aMarkov model-based probabilisticcost-effectiveness analysis. We used ahypothetical primary-care population aged 40years or older with a screening blood-pressuremeasurement greater than 140/90 mm Hg andrisk-factor prevalence equivalent to the generalpopulation. We compared three diagnosticstrategies-further blood pressure measurementin the clinic, at home, and with an ambulatorymonitor-in terms of lifetime costs,", "metadata": {}}
+{"_id": "5152028", "title": "", "text": "Folic acid improves endothelial function incoronary artery disease via mechanisms largelyindependent of homocysteinelowering.BACKGROUND Homocysteine is a riskfactor for coronary artery disease (CAD),although a causal relation remains to be proven.The importance of determining direct causalityrests in the fact that plasma homocysteine canbe safely and inexpensively reduced by 25% withfolic acid. This reduction is maximally achievedby doses of 0.4 mg/d. High-dose folic acid (5mg/d) improves endothelial function in CAD,although the mechanism is controversial. It hasbeen proposed that improvement occurs throughreduction in total (tHcy) or free (non-proteinbound) homocysteine (fHcy). We investigatedthe effects of folic acid on endothelial functionbefore a change in homocysteine in patients withCAD. METHODS AND RESULTS A randomized,placebo-controlled study of folic acid (5 mg/d)for 6 weeks was undertaken in 33 patients.Endothelial function, assessed by flow-mediated", "metadata": {}}
+{"_id": "5172048", "title": "", "text": "Focal adhesion kinase links mechanical force toskin fibrosis via inflammatory signalingExuberantfibroproliferation is a common complication afterinjury for reasons that are not well understood.One key component of wound repair that is oftenoverlooked is mechanical force, which regulatescell-matrix interactions through intracellular focaladhesion components, including focal adhesionkinase (FAK). Here we report that FAK isactivated after cutaneous injury and that thisprocess is potentiated by mechanical loading.Fibroblast-specific FAK knockout mice havesubstantially less inflammation and fibrosis thancontrol mice in a model of hypertrophic scarformation. We show that FAK acts throughextracellular-related kinase (ERK) tomechanically trigger the secretion of monocytechemoattractant protein-1 (MCP-1, also knownas CCL2), a potent chemokine that is linked tohuman fibrotic disorders. Similarly, MCP-1knockout mice form minimal scars, indicatingthat inflammatory chemokine pathways are a", "metadata": {}}
+{"_id": "5185871", "title": "", "text": "Prognostic Accuracy of the SOFA Score, SIRSCriteria, and qSOFA Score for In-HospitalMortality Among Adults With Suspected InfectionAdmitted to the Intensive Care UnitImportanceThe Sepsis-3 Criteria emphasized the value of achange of 2 or more points in the Sequential[Sepsis-related] Organ Failure Assessment(SOFA) score, introduced quick SOFA (qSOFA),and removed the systemic inflammatoryresponse syndrome (SIRS) criteria from thesepsis definition. Objective Externally validateand assess the discriminatory capacities of anincrease in SOFA score by 2 or more points, 2 ormore SIRS criteria, or a qSOFA score of 2 ormore points for outcomes among patients whoare critically ill with suspected infection. Design,Setting, and Participants Retrospective cohortanalysis of 184 875 patients with aninfection-related primary admission diagnosis in182 Australian and New Zealand intensive careunits (ICUs) from 2000 through 2015. ExposuresSOFA, qSOFA, and SIRS criteria applied to data", "metadata": {}}
+{"_id": "5222182", "title": "", "text": "Predictors of mammographic density: insightsgained from a novel regression analysis of a twinstudy.Understanding which factors influencemammographically dense and nondense areas isimportant because percent mammographicdensity adjusted for age is a strong, continuouslydistributed risk factor for breast cancer,especially when adjusted for weight or bodymass index. Using computer-assisted methods,we measured mammographically dense areas for571 monozygotic and 380 dizygotic Australianand North American twin pairs ages 40 to 70years. We used a novel regression modelingapproach in which each twin's measure of denseand nondense area was regressed against one orboth of the twin's and co-twin's covariates. Thenature of changes to regression estimates withthe inclusion of the twin and/or co-twin'scovariates can be evaluated for consistency withcausal and/or other models. By causal, we meanthat if it were possible to vary a covariateexperimentally then the expected value of the", "metadata": {}}
+{"_id": "5223817", "title": "", "text": "Shaping the landscape of the Escherichia colichromosome: replication-transcriptionencounters in cells with an ectopic replicationoriginEach cell division requires the unwinding ofmillions of DNA base pairs to allow chromosomeduplication and gene transcription. As DNAreplication and transcription share the sametemplate, conflicts between both processes areunavoidable and head-on collisions are thoughtto be particularly problematic. Surprisingly, arecent study reported unperturbed cell cycleprogression in Escherichia coli cells with anectopic replication origin in which highlytranscribed rrn operons were forced to bereplicated opposite to normal. In this study wehave re-generated a similar strain and found thedoubling time to be twice that of normal cells.Replication profiles of this background revealedsignificant deviations in comparison to wild-typeprofiles, particularly in highly transcribed regionsand the termination area. These deviations werealleviated by mutations that either inactivate the", "metadata": {}}
+{"_id": "5236443", "title": "", "text": "Epithelial–mesenchymal transitions in tumourprogressionWithout epithelial–mesenchymaltransitions, in which polarized epithelial cells areconverted into motile cells, multicellularorganisms would be incapable of getting past theblastula stage of embryonic development.However, this important developmentalprogramme has a more sinister role in tumourprogression. Epithelial–mesenchymal transitionprovides a new basis for understanding theprogression of carcinoma towardsdedifferentiated and more malignant states.", "metadata": {}}
+{"_id": "5238341", "title": "", "text": "Platelets at the interface of thrombosis,inflammation, and cancer.Although onceprimarily recognized for its roles in hemostasisand thrombosis, the platelet has beenincreasingly recognized as a multipurpose cell.Indeed, circulating platelets have the ability toinfluence a wide range of seemingly unrelatedpathophysiologic events. Here, we highlightsome of the notable observations that linkplatelets to inflammation, reinforcing theplatelet's origin from a lower vertebrate cell typewith both hemostatic and immunologic roles. Inaddition, we consider the relevance of plateletsin cancer biology by focusing on the hallmarks ofcancer and the ways platelets can influencemultistep development of tumors. Beyond itstraditional role in hemostasis and thrombosis,the platelet's involvement in the interplaybetween hemostasis, thrombosis, inflammation,and cancer is likely complex, yet extremelyimportant in each disease process. The existenceof animal models of platelet dysfunction and", "metadata": {}}
+{"_id": "5252837", "title": "", "text": "Cellular roles of DNA topoisomerases: amolecular perspectiveDNA topoisomerases arethe magicians of the DNA world — by allowingDNA strands or double helices to pass througheach other, they can solve all of the topologicalproblems of DNA in replication, transcription andother cellular transactions. Extensive biochemicaland structural studies over the past threedecades have provided molecular models of howthe various subfamilies of DNA topoisomerasemanipulate DNA. In this review, the cellular rolesof these enzymes are examined from a molecularpoint of view.", "metadata": {}}
+{"_id": "5253987", "title": "", "text": "MicroRNA sponges: progress andpossibilities.The microRNA (miRNA) \"sponge\"method was introduced three years ago as ameans to create continuous miRNA loss offunction in cell lines and transgenic organisms.Sponge RNAs contain complementary bindingsites to a miRNA of interest, and are producedfrom transgenes within cells. As with mostmiRNA target genes, a sponge's binding sites arespecific to the miRNA seed region, which allowsthem to block a whole family of related miRNAs.This transgenic approach has proven to be auseful tool to probe miRNA functions in a varietyof experimental systems. Here we will discussthe ways sponge and related constructs can beoptimized and review recent applications of thismethod with particular emphasis on stableexpression in cancer studies and in transgenicanimals.", "metadata": {}}
+{"_id": "5254463", "title": "", "text": "Wip1 phosphatase regulates p53-dependentapoptosis of stem cells and tumorigenesis in themouse intestine.Colorectal cancer is one of themajor causes of cancer-related deaths. To gainfurther insights into the mechanisms underlyingits development, we investigated the role ofWip1 phosphatase, which is highly expressed inintestinal stem cells, in the mouse model ofAPC(Min)-driven polyposis. We found that Wip1removal increased the life span of APC(Min) micethrough a significant suppression of polypformation. This protection was dependent on thep53 tumor suppressor, which plays a putativerole in the regulation of apoptosis of intestinalstem cells. Activation of apoptosis in stem cellsof Wip1-deficient mice, but not wild-typeAPC(Min) mice, increased when the Wnt pathwaywas constitutively activated. We propose,therefore, that the Wip1 phosphatase regulateshomeostasis of intestinal stem cells. In turn,Wip1 loss suppresses APC(Min)-driven polyposisby lowering the threshold for p53-dependent", "metadata": {}}
+{"_id": "5254741", "title": "", "text": "The shunt problem: control of functionalshunting in normal and tumourvasculatureNetworks of blood vessels in normaland tumour tissues have heterogeneousstructures, with widely varying blood flowpathway lengths. To achieve efficient blood flowdistribution, mechanisms for the structuraladaptation of vessel diameters must be able toinhibit the formation of functional shunts(whereby short pathways become enlarged andflow bypasses long pathways). Such adaptationrequires information about tissue metabolicstatus to be communicated upstream to feedingvessels, through conducted responses. Wepropose that impaired vascular communication intumour microvascular networks, leading tofunctional shunting, is a primary cause ofdysfunctional microcirculation and local hypoxiain cancer. We suggest that anti-angiogenictreatment of tumours may restore vascularcommunication and thereby improve ornormalize flow distribution in tumour", "metadata": {}}
+{"_id": "5256564", "title": "", "text": "Pharmacological Blockade of ASCT2-dependentGlutamine Transport Leads To Anti-tumorEfficacy in Preclinical ModelsThe uniquemetabolic demands of cancer cells underscorepotentially fruitful opportunities for drugdiscovery in the era of precision medicine.However, therapeutic targeting of cancermetabolism has led to surprisingly few new drugsto date. The neutral amino acid glutamine servesas a key intermediate in numerous metabolicprocesses leveraged by cancer cells, includingbiosynthesis, cell signaling, and oxidativeprotection. Herein we report the preclinicaldevelopment of V-9302, a competitive smallmolecule antagonist of transmembraneglutamine flux that selectively and potentlytargets the amino acid transporter ASCT2.Pharmacological blockade of ASCT2 with V-9302resulted in attenuated cancer cell growth andproliferation, increased cell death, and increasedoxidative stress, which collectively contributed toantitumor responses in vitro and in vivo. This is", "metadata": {}}
+{"_id": "5260382", "title": "", "text": "An Antidepressant Decreases CSF Aβ Productionin Healthy Individuals and in Transgenic ADMiceSerotonin signaling suppresses generation ofamyloid-β (Aβ) in vitro and in animal models ofAlzheimer’s disease (AD). We show that in anaged transgenic AD mouse model (APP/PS1plaque-bearing mice), the antidepressantcitalopram, a selective serotonin reuptakeinhibitor, decreased Aβ in brain interstitial fluid ina dose-dependent manner. Growth of individualamyloid plaques was assessed in plaque-bearingmice that were chronically administeredcitalopram. Citalopram arrested the growth ofpreexisting plaques and reduced the appearanceof new plaques by 78%. In healthy humanvolunteers, citalopram’s effects on Aβ productionand Aβ concentrations in cerebrospinal fluid(CSF) were measured prospectively using stableisotope labeling kinetics, with CSF samplingduring acute dosing of citalopram. Aβ productionin CSF was slowed by 37% in the citalopramgroup compared to placebo. This change was", "metadata": {}}
+{"_id": "5262240", "title": "", "text": "Variations in the quality and sustainability oflong-term glycaemic control with continuoussubcutaneous insulin infusion.AIMS Toinvestigate the pattern of changes in HbA1c inpeople with Type 1 diabetes managed bylong-term Continuous subcutaneous insulininfusion. METHODS We studied HbA1c changesusing computerized clinic records in 35 adultpeople with Type 1 diabetes and an elevatedHbA1c (≥ 64 mmol/mol, 8.0%) on multiple dailyinsulin injections, who were then switched tocontinuous subcutaneous insulin infusion for atleast 5 years. RESULTS We identified threesubgroups with similar baseline HbA1c butdifferent long-term responses to pump therapy:group A--those with improvement followed bydeterioration (57%); group B--those withimprovement that was sustained throughout the5 years (31%); and group C-those where HbA1cdid not change significantly from baseline (12%).The patients in group C had a higher BMI: 31.0 ±5.2 vs. 25.9 ± 3.3 vs. 25.2 ± 3.1 kg/m² (group", "metadata": {}}
+{"_id": "5266423", "title": "", "text": "Historical review: megakaryopoiesis andthrombopoiesis.The study of thrombopoiesis hasevolved greatly since an era when platelets weretermed \"the dust of the blood,\" only about 100years ago. During this time megakaryocyteswere identified as the origin of blood platelets;marrow-derived megakaryocytic progenitor cellswere functionally defined and then purified; andthe primary regulator of the process,thrombopoietin, was cloned and characterizedand therapeutic thrombopoietic agentsdeveloped. During this journey we continue tolearn that the physiologic mechanisms that driveproplatelet formation can be recapitulated incell-free systems and their biochemistryevaluated; the molecular underpinnings ofendomitosis are being increasingly understood;the intracellular signals sent by engagement of alarge number of megakaryocyte surfacereceptors have been defined; and many of thetranscription factors that drive megakaryocyticfate determination have been identified and", "metadata": {}}
+{"_id": "5268462", "title": "", "text": "Obesity and Its Metabolic Complications: TheRole of Adipokines and the Relationship betweenObesity, Inflammation, Insulin Resistance,Dyslipidemia and Nonalcoholic Fatty LiverDiseaseAccumulating evidence indicates thatobesity is closely associated with an increasedrisk of metabolic diseases such as insulinresistance, type 2 diabetes, dyslipidemia andnonalcoholic fatty liver disease. Obesity resultsfrom an imbalance between food intake andenergy expenditure, which leads to an excessiveaccumulation of adipose tissue. Adipose tissue isnow recognized not only as a main site ofstorage of excess energy derived from foodintake but also as an endocrine organ. Theexpansion of adipose tissue produces a numberof bioactive substances, known asadipocytokines or adipokines, which triggerchronic low-grade inflammation and interact witha range of processes in many different organs.Although the precise mechanisms are stillunclear, dysregulated production or secretion of", "metadata": {}}
+{"_id": "5270265", "title": "", "text": "Combating trastuzumab resistance by targetingSRC, a common node downstream of multipleresistance pathwaysTrastuzumab is a successfulrationally designed ERBB2-targeted therapy.However, about half of individuals withERBB2-overexpressing breast cancer do notrespond to trastuzumab-based therapies, owingto various resistance mechanisms. Clinicallyapplicable regimens for overcoming trastuzumabresistance of different mechanisms are not yetavailable. We show that the nonreceptor tyrosinekinase c-SRC (SRC) is a key modulator oftrastuzumab response and a common nodedownstream of multiple trastuzumab resistancepathways. We find that SRC is activated in bothacquired and de novo trastuzumab-resistant cellsand uncover a novel mechanism of SRCregulation involving dephosphorylation by PTEN.Increased SRC activation conferred considerabletrastuzumab resistance in breast cancer cells andcorrelated with trastuzumab resistance inpatients. Targeting SRC in combination with", "metadata": {}}
+{"_id": "5271210", "title": "", "text": "MicroRNAs: new tools for diagnosis, prognosis,and therapy in hepatocellularcarcinoma?MicroRNAs (miRNAs) areevolutionarily conserved small noncoding RNAsinvolved in the regulation of gene expression andprotein translation. Many studies have shownthat they play a crucial role in driving organ andtissue differentiation during embryogenesis andin the fine-tuning of fundamental biologicalprocesses, such as proliferation and apoptosis.Growing evidence indicates that theirderegulation plays an important role in canceronset and progression as well, where they act asoncogenes or oncosuppressors. In this review,we highlight the most recent findings regardingthe role of miRNAs in hepatocellular carcinoma(HCC) by analyzing the possible mechanisms bywhich they contribute to this neoplasm.Moreover, we discuss the possible role ofcirculating miRNAs as biomarkers, a field thatneeds urgent improvement in the clinicalsurveillance of HCC, and the fascinating", "metadata": {}}
+{"_id": "5273056", "title": "", "text": "A vertebrate gene, ticrr, is an essentialcheckpoint and replication regulator.Eukaryoteshave numerous checkpoint pathways to protectgenome fidelity during normal cell division and inresponse to DNA damage. Through a screen forG2/M checkpoint regulators in zebrafish, weidentified ticrr (for TopBP1-interacting,checkpoint, and replication regulator), apreviously uncharacterized gene that is requiredto prevent mitotic entry after treatment withionizing radiation. Ticrr deficiency isembryonic-lethal in the absence of exogenousDNA damage because it is essential for normalcell cycle progression. Specifically, the loss ofticrr impairs DNA replication and disrupts theS/M checkpoint, leading to premature mitoticentry and mitotic catastrophe. We show that thehuman TICRR ortholog associates with TopBP1, aknown checkpoint protein and a core componentof the DNA replication preinitiation complex(pre-IC), and that the TICRR-TopBP1 interactionis stable without chromatin and requires BRCT", "metadata": {}}
+{"_id": "5278233", "title": "", "text": "A maternally methylated CpG island in KvLQT1 isassociated with an antisense paternal transcriptand loss of imprinting in Beckwith-Wiedemannsyndrome.Loss of imprinting at IGF2, generallythrough an H19-independent mechanism, isassociated with a large percentage of patientswith the overgrowth and cancer predispositioncondition Beckwith-Wiedemann syndrome(BWS). Imprinting control elements are proposedto exist within the KvLQT1 locus, becausemultiple BWS-associated chromosomerearrangements disrupt this gene. We haveidentified an evolutionarily conserved, maternallymethylated CpG island (KvDMR1) in an intron ofthe KvLQT1 gene. Among 12 cases of BWS withnormal H19 methylation, 5 showeddemethylation of KvDMR1 in fibroblast orlymphocyte DNA; whereas, in 4 cases of BWSwith H19 hypermethylation, methylation atKvDMRl was normal. Thus, inactivation of H19and hypomethylation at KvDMR1 (or anassociated phenomenon) represent distinct", "metadata": {}}
+{"_id": "5284188", "title": "", "text": "Alarming levels of drug-resistant tuberculosis inBelarus: results of a survey in MinskResistanceto anti-tuberculosis (TB) medicines is a majorpublic health threat in most countries of theformer Soviet Union. As no representative andquality-assured information on the magnitude ofthis problem existed in Belarus, a survey wasconducted in the capital city of Minsk. BetweenNovember 2009 and December 2010, 156consecutively diagnosed new and 68 previouslytreated culture-positive TB patients residing inMinsk were enrolled in the survey.Mycobacterium tuberculosis isolates wereobtained from each patient and tested forsusceptibility to first- and second-line anti-TBdrugs. Multidrug-resistant (MDR)-TB was foundin 35.3% (95% CI 27.7-42.8) of new patientsand 76.5% (95% CI 66.1-86.8) of thosepreviously treated. Overall, nearly one in twopatients enrolled had MDR-TB. Extensivelydrug-resistant TB was reported in 15 of the 107MDR-TB patients (14.0%, 95% CI 7.3-20.7).", "metadata": {}}
+{"_id": "5289038", "title": "", "text": "Partitioning regulatory mechanisms ofwithin-host malaria dynamics using the effectivepropagation number.Immune clearance andresource limitation (via red blood cell depletion)shape the peaks and troughs of malariaparasitemia, which in turn affect disease severityand transmission. Quantitatively partitioning therelative roles of these effects through time ischallenging. Using data from rodent malaria, weestimated the effective propagation number,which reflects the relative importance ofcontrasting within-host control mechanismsthrough time and is sensitive to the inoculatingparasite dose. Our analysis showed that thecapacity of innate responses to restrict initialparasite growth saturates with parasite dose andthat experimentally enhanced innate immunitycan affect parasite density indirectly via resourcedepletion. Such a statistical approach offers atool to improve targeting of drugs or vaccines forhuman therapy by revealing the dynamics andinteractions of within-host regulatory", "metadata": {}}
+{"_id": "5293024", "title": "", "text": "Life is sweet: candy consumption andlongevity.Our attitude towards candy—“if ittastes that good, it can't be healthy”—betrayssociety's puritanical stance towards pleasure.Candy has been blamed for various ills, includinghyperactivity in children; however, clinical trialshave not supported this.1  Candy—sugarconfectionery and chocolate—is not a recentinvention: the ancient Arabs, Chinese, andEgyptians candied fruits and nuts in honey, andthe Aztecs made a chocolate drink from the beanof the cacao tree. Today, Americans gratifythemselves with, on average, 5.4 kg of sugarcandy and 6.5 kg of chocolate per personannually.2  Since candy has existed forcenturies, we surmised that it cannot be totallyunhealthy. We decided to investigate whethercandy consumption was associated withlongevity. Subjects were from the Harvardalumni health study, an ongoing study of menentering Harvard University as undergraduatesbetween 1916 and 1950. We included 7841 men,", "metadata": {}}
+{"_id": "5304891", "title": "", "text": "Inter-individual variability and genetic influenceson cytokine responses to bacteria and fungiLittleis known about the inter-individual variation ofcytokine responses to different pathogens inhealthy individuals. To systematically describecytokine responses elicited by distinct pathogensand to determine the effect of genetic variationon cytokine production, we profiled cytokinesproduced by peripheral blood mononuclear cellsfrom 197 individuals of European origin from the200 Functional Genomics (200FG) cohort in theHuman Functional Genomics Project(http://www.humanfunctionalgenomics.org),obtained over three different years. Wecompared bacteria- and fungi-induced cytokineprofiles and found that most cytokine responseswere organized around a physiological responseto specific pathogens, rather than around aparticular immune pathway or cytokine. We thencorrelated genome-wide single-nucleotidepolymorphism (SNP) genotypes with cytokineabundance and identified six cytokine", "metadata": {}}
+{"_id": "5321708", "title": "", "text": "Integrins promote cytokinesis through the RSKsignaling axis.Cytokinesis is the final stage in celldivision. Although integrins can regulatecytokinesis, the mechanisms involved are notfully understood. In this study, we demonstratethat integrin-regulated ERK (extracellularsignal-related kinase) and RSK (p90 ribosomalS6 kinase) signaling promotes successfulcytokinesis. Inhibiting the activation of ERK andRSK in CHO cells by a mutation in the integrin β1cytoplasmic tail or with pharmacologicalinhibitors results in the accumulation of cells withmidbodies and the formation of binucleated cells.Activation of ERK and RSK signaling by theexpression of constitutively active RAF1suppresses the mutant phenotype in aRSK-dependent manner. Constitutively activeRSK2 also restores cytokinesis inhibited by themutant integrin. Importantly, the regulatory roleof the RSK pathway is not specific to CHO cells.MCF-10A human mammary epithelial cells andHPNE human pancreatic ductal epithelial cells", "metadata": {}}
+{"_id": "5323845", "title": "", "text": "Sympathetic neural mechanisms in normal andhypertensive pregnancy inhumans.BACKGROUND Direct recordings fromperipheral sympathetic nerves have shown anincreased sympathetic drive inpregnancy-induced hypertension (PIH) andpreeclampsia (PE). It is unknown whethersympathetic drive is altered in normalpregnancy, when arterial blood pressure can benormal or relatively low. The aim of this studywas to measure and compare peripheralsympathetic discharge, its vasoconstrictor effectand its baroreceptor control, during pregnancyand postpartum in women with normalpregnancy (NP) and PIH and in normotensivenonpregnant (NN) women. METHODS ANDRESULTS Twenty-one women with NP, 18women with PIH, and 21 NN women had musclesympathetic nerve activity assessed frommultiunit discharges (MSNA) and from singleunits with defined vasoconstrictor properties(s-MSNA). The s-MSNA in NP (38+/-6.6", "metadata": {}}
+{"_id": "5339554", "title": "", "text": "Barriers to recruiting urban African Americanwomen into research studies in communitysettings.This qualitative study identified barriersto African American women's participation in acommunity-based behavioral intervention trial toincrease mammography screening. Four themesemerged from focus group discussions withcommunity agency providers and research teammembers. These themes were (1) going to thegatekeepers; (2) knowing the culture; (3)location is everything; and (4) protocols,policies, and possibilities. A checklist of actionsthat nurse researchers could consider to increaseAfrican American women's participation incommunity trials is provided.", "metadata": {}}
+{"_id": "5372432", "title": "", "text": "Geographical access to healthcare in NorthernEngland and post-mortem diagnosis ofcancer.BACKGROUND There is some previousevidence that diagnosis of cancer at death,recorded as registry death certificate onlyrecords, is associated with problems of access tocare. METHODS Records from the Northern andYorkshire Cancer Registry for patients registeredwith breast, colorectal, lung, ovarian or prostatecancer between 1994 and 2002 weresupplemented with measures of travel time togeneral practitioner and hospital services, andsocial deprivation. Logistic regression was usedto identify predictors of records where diagnosiswas at death. RESULTS There was no associationbetween the odds diagnosis at death and accessto primary care. For all sites except breast, thehighest odds of being a cancer diagnosed atdeath fell among those living in the highestquartile of hospital travel time, although it wasonly statistically significant for colorectal andovary tumours. Those in the most deprived and", "metadata": {}}
+{"_id": "5372773", "title": "", "text": "Enhanced monocyte Fc phagocytosis by ahomologue of interleukin-10 encoded by humancytomegalovirus.Human cytomegalovirus(HCMV) expresses several homologues of humaninterleukin 10 (hIL-10) possessingimmunomodulatory properties which maypromote viral infection by modulating thefunction of myeloid cells. We examined thephenotype and phagocytic capability of humanmonocytes exposed to hIL-10, an HCMV-encodedhIL-10 homologue expressed during theproductive phase of infection (cmvIL-10), and adifferentially spliced form of cmvIL-10 expressedduring latent and productive phases of infection,(LAcmvIL-10). hIL-10 and cmvIL-10 upregulatedexpression of Fcgamma receptors, stimulatedphagocytosis of IgG-opsonised erythrocytes anddecreased MHC class II (HLA-DR) expression onpurified monocytes within 24 h. In contrast,LAcmvIL-10 decreased HLA-DR expression atlater times (48 h and 72 h) but did not increaseFcgamma receptor expression. We conclude that", "metadata": {}}
+{"_id": "5373138", "title": "", "text": "3D Chromosome Regulatory Landscape ofHuman Pluripotent Cells.In this study, wedescribe the 3D chromosome regulatorylandscape of human naive and primed embryonicstem cells. To devise this map, we identifiedtranscriptional enhancers and insulators in thesecells and placed them within the context ofcohesin-associated CTCF-CTCF loops usingcohesin ChIA-PET data. The CTCF-CTCF loops weidentified form a chromosomal framework ofinsulated neighborhoods, which in turn formtopologically associating domains (TADs) that arelargely preserved during the transition betweenthe naive and primed states. Regulatory changesin enhancer-promoter interactions occur withininsulated neighborhoods during cell statetransition. The CTCF anchor regions we identifiedare conserved across species, influence geneexpression, and are a frequent site of mutationsin cancer cells, underscoring their functionalimportance in cellular regulation. These 3Dregulatory maps of human pluripotent cells", "metadata": {}}
+{"_id": "5377059", "title": "", "text": "Functional analysis via standardized whole-bloodstimulation systems defines the boundaries of ahealthy immune response to complexstimuli.Standardization of immunophenotypingprocedures has become a high priority. We havedeveloped a suite of whole-blood, syringe-basedassay systems that can be used to reproduciblyassess induced innate or adaptive immuneresponses. By eliminating preanalytical errorsassociated with immune monitoring, we havedefined the protein signatures induced by (1)medically relevant bacteria, fungi, and viruses;(2) agonists specific for defined host sensors; (3)clinically employed cytokines; and (4) activatorsof T cell immunity. Our results provide an initialassessment of healthy donor reference values forinduced cytokines and chemokines and we reportthe failure to release interleukin-1α as a commonimmunological phenotype. The observednaturally occurring variation of the immuneresponse may help to explain differentialsusceptibility to disease or response to", "metadata": {}}
+{"_id": "5377642", "title": "", "text": "SATB1 Expression Governs Epigenetic Repressionof PD\u00001 in Tumor\u0000Reactive T Cells&NA; Despitethe importance of programmed cell death\u00001(PD\u00001) in inhibiting T cell effector activity, themechanisms regulating its expression remainpoorly defined. We found that the chromatinorganizer special AT\u0000rich sequence\u0000bindingprotein\u00001 (Satb1) restrains PD\u00001 expressioninduced upon T cell activation by recruiting anucleosome remodeling deacetylase (NuRD)complex to Pdcd1 regulatory regions. Satb1deficienct T cells exhibited a 40\u0000fold increase inPD\u00001 expression. Tumor\u0000derived transforminggrowth factor &bgr; (Tgf\u0000&bgr;) decreasedSatb1 expression through binding of Smadproteins to the Satb1 promoter. Smad proteinsalso competed with the Satb1\u0000NuRD complexfor binding to Pdcd1 enhancers, releasing Pdcd1expression from Satb1\u0000mediated repression,Satb1\u0000deficient tumor\u0000reactive T cells losteffector activity more rapidly than wild\u0000typelymphocytes at tumor beds expressing PD\u00001", "metadata": {}}
+{"_id": "5386514", "title": "", "text": "Activation of the NLRP3 inflammasome indendritic cells induces IL-1β–dependent adaptiveimmunity against tumorsThe therapeutic efficacyof anticancer chemotherapies may depend ondendritic cells (DCs), which present antigensfrom dying cancer cells to prime tumor-specificinterferon-γ (IFN-γ)–producing T lymphocytes.Here we show that dying tumor cells releaseATP, which then acts on P2X7 purinergicreceptors from DCs and triggers the NOD-likereceptor family, pyrin domain containing-3protein (NLRP3)-dependent caspase-1 activationcomplex ('inflammasome'), allowing for thesecretion of interleukin-1β (IL-1β). The primingof IFN-γ–producing CD8+ T cells by dying tumorcells fails in the absence of a functional IL-1receptor 1 and in Nlpr3-deficient (Nlrp3−/−) orcaspase-1–deficient (Casp-1−/−) mice unlessexogenous IL-1β is provided. Accordingly,anticancer chemotherapy turned out to beinefficient against tumors established inpurinergic receptor P2rx7−/− or Nlrp3−/− or", "metadata": {}}
+{"_id": "5389095", "title": "", "text": "Mfge8 promotes obesity by mediating the uptakeof dietary fats and serum fatty acidsFatty acidsare integral mediators of energy storage,membrane formation and cell signaling. Thepathways that orchestrate uptake of fatty acidsremain incompletely understood. Expression ofthe integrin ligand Mfge8 is increased in humanobesity and in mice on a high-fat diet, but its rolein obesity is unknown. We show here that Mfge8promotes the absorption of dietary triglyceridesand the cellular uptake of fatty acid and thatMfge8-deficient (Mfge8−/−) mice are protectedfrom diet-induced obesity, steatohepatitis andinsulin resistance. Mechanistically, we found thatMfge8 coordinates fatty acid uptake throughαvβ3 integrin– and αvβ5 integrin–dependentphosphorylation of Akt byphosphatidylinositide-3 kinase and mTORcomplex 2, leading to translocation of Cd36 andFatp1 from cytoplasmic vesicles to the cellsurface. Collectively, our results imply a role forMfge8 in regulating the absorption and storage of", "metadata": {}}
+{"_id": "5389523", "title": "", "text": "RAD52 Facilitates Mitotic DNA SynthesisFollowing Replication Stress.Homologousrecombination (HR) is necessary to counteractDNA replication stress. Common fragile site(CFS) loci are particularly sensitive to replicationstress and undergo pathological rearrangementsin tumors. At these loci, replication stressfrequently activates DNA repair synthesis inmitosis. This mitotic DNA synthesis, termedMiDAS, requires the MUS81-EME1 endonucleaseand a non-catalytic subunit of the Pol-deltacomplex, POLD3. Here, we examine thecontribution of HR factors in promoting MiDAS inhuman cells. We report that RAD51 and BRCA2are dispensable for MiDAS but are required tocounteract replication stress at CFS loci duringS-phase. In contrast, MiDAS is RAD52dependent, and RAD52 is required for the timelyrecruitment of MUS81 and POLD3 to CFSs inearly mitosis. Our results provide furthermechanistic insight into MiDAS and define aspecific function for human RAD52. Furthermore,", "metadata": {}}
+{"_id": "5395426", "title": "", "text": "Excitotoxic brain injury in adult zebrafishstimulates neurogenesis and long-distanceneuronal integration.Zebrafish maintain agreater capacity than mammals for centralnervous system repair after injury.Understanding differences in regenerativeresponses between different vertebrate speciesmay shed light on mechanisms to improve repairin humans. Quinolinic acid is an excitotoxin thathas been used to induce brain injury in rodentsfor modeling Huntington's disease and stroke.When injected into the adult rodent striatum,this toxin stimulates subventricular zoneneurogenesis and neuroblast migration to injury.However, most new neurons fail to survive andlesion repair is minimal. We used quinolinic acidto lesion the adult zebrafish telencephalon tostudy reparative processes. We also usedconditional transgenic lineage mapping of adultradial glial stem cells to explore survival andintegration of neurons generated after injury.Telencephalic lesioning with quinolinic acid, and", "metadata": {}}
+{"_id": "5398179", "title": "", "text": "Germinal Center T Follicular Helper Cells AreHighly Permissive to HIV-1 and Alter TheirPhenotype during Virus Replication.HIV-1replication is concentrated within CD4(+) T cellsin B cell follicles of secondary lymphoid tissuesduring asymptomatic disease. Limited datasuggest that a subset of T follicular helper cells(TFH) within germinal centers (GC) is highlypermissive to HIV-1. Whether GC TFH are themajor HIV-1 virus-producing cells in vivo has notbeen established. In this study, we investigatedTFH permissivity to HIV-1 ex vivo byspinoculating and culturing tonsil cells with HIV-1GFP reporter viruses. Using flow cytometry,higher percentages of GC TFH(CXCR5(high)PD-1(high)) andCXCR5(+)programmed cell death-1 (PD-1)(low)cells were GFP(+) than non-GC TFH(CXCR5(+)PD-1(intermediate)) or extrafollicular(EF) (CXCR5(-)) cells. When sorted prior tospinoculation, however, GC TFH weresubstantially more permissive than", "metadata": {}}
+{"_id": "5402581", "title": "", "text": "Risk of death with atypical antipsychotic drugtreatment for dementia: meta-analysis ofrandomized placebo-controlled trials.CONTEXTAtypical antipsychotic medications are widelyused to treat delusions, aggression, and agitationin people with Alzheimer disease and otherdementia; however, concerns have arisen aboutthe increased risk for cerebrovascular adverseevents, rapid cognitive decline, and mortalitywith their use. OBJECTIVE To assess theevidence for increased mortality from atypicalantipsychotic drug treatment for people withdementia. DATA SOURCES MEDLINE (1966 toApril 2005), the Cochrane Controlled TrialsRegister (2005, Issue 1), meetings presentations(1997-2004), and information from the sponsorswere searched using the terms for atypicalantipsychotic drugs (aripiprazole, clozapine,olanzapine, quetiapine, risperidone, andziprasidone), dementia, Alzheimer disease, andclinical trial. STUDY SELECTION Published andunpublished randomized placebo-controlled,", "metadata": {}}
+{"_id": "5403286", "title": "", "text": "PI3K in cancer: divergent roles of isoforms,modes of activation and therapeutictargetingPhosphatidylinositol 3-kinases (PI3Ks)are crucial coordinators of intracellular signallingin response to extracellular stimuli.Hyperactivation of PI3K signalling cascades isone of the most common events in humancancers. In this Review, we discuss recentadvances in our knowledge of the roles ofspecific PI3K isoforms in normal and oncogenicsignalling, the different ways in which PI3K canbe upregulated, and the current state and futurepotential of targeting this pathway in the clinic.", "metadata": {}}
+{"_id": "5406411", "title": "", "text": "Amphiregulin enhances regulatory Tcell-suppressive function via the epidermalgrowth factor receptor.Epidermal growth factorreceptor (EGFR) is known to be critically involvedin tissue development and homeostasis as wellas in the pathogenesis of cancer. Here weshowed that Foxp3(+) regulatory T (Treg) cellsexpress EGFR under inflammatory conditions.Stimulation with the EGF-like growth factorAmphiregulin (AREG) markedly enhanced Tregcell function in vitro, and in a colitis and tumorvaccination model we showed that AREG wascritical for efficient Treg cell function in vivo. Inaddition, mast cell-derived AREG fully restoredoptimal Treg cell function. These findings revealEGFR as a component in the regulation of localimmune responses and establish a link betweenmast cells and Treg cells. Targeting of thisimmune regulatory mechanism may contributeto the therapeutic successes of EGFR-targetingtreatments in cancer patients.", "metadata": {}}
+{"_id": "5409325", "title": "", "text": "Gonadotrope-specific deletion of Dicer results inseverely suppressed gonadotropins and fertilitydefects.Pituitary gonadotropinsfollicle-stimulating hormone and luteinizinghormone are heterodimeric glycoproteinsexpressed in gonadotropes. They act on gonadsand promote their development and functionsincluding steroidogenesis and gametogenesis.Although transcriptional regulation ofgonadotropin subunits has been well studied, thepost-transcriptional regulation of gonadotropinsubunits is not well understood. To test ifmicroRNAs regulate the hormone-specificgonadotropin β subunits in vivo, we deleted Dicerin gonadotropes by a Cre-lox genetic approach.We found that many of the DICER-dependentmicroRNAs, predicted in silico to bindgonadotropin β subunit mRNAs, were suppressedin purified gonadotropes of mutant mice. Loss ofDICER-dependent microRNAs in gonadotropesresulted in profound suppression ofgonadotropin-β subunit proteins and,", "metadata": {}}
+{"_id": "5409905", "title": "", "text": "Sequential histone-modifying activitiesdetermine the robustness oftransdifferentiationNatural interconversionsbetween distinct somatic cell types have beenreported in species as diverse as jellyfish andmice. The efficiency and reproducibility of somereprogramming events represent unexploitedavenues in which to probe mechanisms thatensure robust cell conversion. We report that aconserved H3K27me3/me2 demethylase,JMJD-3.1, and the H3K4 methyltransferase Set1complex cooperate to ensure invarianttransdifferentiation (Td) of postmitoticCaenorhabditis elegans hindgut cells into motorneurons. At single-cell resolution, robustconversion requires stepwise histone-modifyingactivities, functionally partitioned into discretephases of Td through nuclear degradation ofJMJD-3.1 and phase-specific interactions withtranscription factors that have conserved roles incell plasticity and terminal fate selection. Ourresults draw parallels between epigenetic", "metadata": {}}
+{"_id": "5415832", "title": "", "text": "Normal and leukemic stem cell niches: insightsand therapeutic opportunities.Hematopoieticstem cells (HSCs) rely on instructive cues fromthe bone marrow (BM) niche to maintain theirquiescence and adapt blood production to theorganism's needs. Alterations in the BM niche arecommonly observed in blood malignancies anddirectly contribute to the aberrant function ofdisease-initiating leukemic stem cells (LSCs).Here, we review recent insights into the cellularand molecular determinants of the normal HSCniche and describe how genetic changes instromal cells and leukemia-induced BM nicheremodeling contribute to blood malignancies.Moreover, we discuss how these findings can beapplied to non-cell-autonomous therapiestargeting the LSC niche.", "metadata": {}}
+{"_id": "5431268", "title": "", "text": "Role of common hypnotics on the phenotypiccauses of obstructive sleep apnoea: paradoxicaleffects of zolpidem.Hypnotics are contraindicatedin obstructive sleep apnoea (OSA) because ofconcerns of pharyngeal muscle relaxation anddelayed arousal worsening hypoxaemia.However, human data are lacking. This studyaimed to determine the effects of three commonhypnotics on the respiratory arousal threshold,genioglossus muscle responsiveness and upperairway collapsibility during sleep.21 individualswith and without OSA (18-65 years) completed84 detailed sleep studies after receivingtemazepam (10 mg), zolpidem (10 mg),zopiclone (7.5 mg) and placebo on fouroccasions in a randomised, double-blind,placebo-controlled, crossover trial(ACTRN12612001004853).The arousal thresholdincreased with zolpidem and zopiclone versusplacebo (mean±sd -18.3±10 and -19.1±9 versus-14.6±7 cmH2O; p=0.02 and p<0.001) but notwith temazepam (-16.8±9 cmH2O; p=0.17).", "metadata": {}}
+{"_id": "5433667", "title": "", "text": "Clinical human papillomavirus detection forecastscervical cancer risk in women over 18 years offollow-up.PURPOSE To describe the long-term (≥10 years) benefits of clinical humanpapillomavirus (HPV) DNA testing for cervicalprecancer and cancer risk prediction. METHODSCervicovaginal lavages collected from 19,512women attending a health maintenance programwere retrospectively tested for HPV using aclinical test. HPV positives were tested for HPV16and HPV18 individually using a research test. APapanicolaou (Pap) result classified as atypicalsquamous cells of undetermined significance(ASC-US) or more severe was consideredabnormal. Women underwent follow-upprospectively with routine annual Pap testing upto 18 years. Cumulative incidence rates (CIRs) of≥ grade 3 cervical intraepithelial neoplasia(CIN3+) or cancer for enrollment test resultswere calculated. RESULTS A baseline negativeHPV test provided greater reassurance againstCIN3+ over the 18-year follow-up than a normal", "metadata": {}}
+{"_id": "5436081", "title": "", "text": "MG53 nucleates assembly of cell membranerepair machineryDynamic membrane repair andremodelling is an elemental process thatmaintains cell integrity and mediates efficientcellular function. Here we report that MG53, amuscle-specific tripartite motif family protein(TRIM72), is a component of the sarcolemmalmembrane-repair machinery. MG53 interactswith phosphatidylserine to associate withintracellular vesicles that traffic to and fuse withsarcolemmal membranes. Mice null for MG53show progressive myopathy and reducedexercise capability, associated with defectivemembrane-repair capacity. Injury of thesarcolemmal membrane leads to entry of theextracellular oxidative environment and MG53oligomerization, resulting in recruitment ofMG53-containing vesicles to the injury site. Aftervesicle translocation, entry of extracellular Ca2+facilitates vesicle fusion to reseal the membrane.Our data indicate that intracellular vesicletranslocation and Ca2+-dependent membrane", "metadata": {}}
+{"_id": "5448119", "title": "", "text": "A large-scale replication study identifies TNIP1,PRDM1, JAZF1, UHRF1BP1 and IL10 as risk locifor systemic lupus erythematosusGenome-wideassociation studies have recently identified atleast 15 susceptibility loci for systemic lupuserythematosus (SLE). To confirm additional riskloci, we selected SNPs from 2,466 regions thatshowed nominal evidence of association to SLE(P < 0.05) in a genome-wide study andgenotyped them in an independent sample of1,963 cases and 4,329 controls. This replicationeffort identified five new SLE susceptibility loci (P< 5 × 10−8): TNIP1 (odds ratio (OR) = 1.27),PRDM1 (OR = 1.20), JAZF1 (OR = 1.20),UHRF1BP1 (OR = 1.17) and IL10 (OR = 1.19).We identified 21 additional candidate loci with P≤1 × 10−5. A candidate screen of allelespreviously associated with other autoimmunediseases suggested five loci (P < 1 × 10−3) thatmay contribute to SLE: IFIH1, CFB, CLEC16A,IL12B and SH2B3. These results expand thenumber of confirmed and candidate SLE", "metadata": {}}
+{"_id": "5468807", "title": "", "text": "ARID1A-mutated ovarian cancers depend onHDAC6 activityARID1A, encoding a subunit of theSWI/SNF chromatin-remodelling complex, is themost frequently mutated epigenetic regulatoracross all human cancers. ARID1A and TP53mutations are typically mutually exclusive.Therapeutic approaches that correlate with thisgenetic characteristic remain to be explored.Here, we show that HDAC6 activity is essential inARID1A-mutated ovarian cancers. Inhibition ofHDAC6 activity using a clinically applicablesmall-molecule inhibitor significantly improvedthe survival of mice bearing ARID1A-mutatedtumours. This correlated with the suppression ofgrowth and dissemination of ARID1A-mutated,but not wild-type, tumours. The dependence onHDAC6 activity in ARID1A-mutated cellscorrelated with a direct transcriptional repressionof HDAC6 by ARID1A. HDAC6 inhibitionselectively promoted apoptosis ofARID1A-mutated cells. HDAC6 directlydeacetylates Lys120 of p53, a pro-apoptotic", "metadata": {}}
+{"_id": "5473074", "title": "", "text": "Solution NMR structure of the TatA component ofthe twin-arginine protein transport system fromgram-positive bacterium Bacillus subtilis.Thetwin-arginine transport (Tat) system translocatesfolded proteins across the bacterial cytoplasmicor chloroplast thylakoid membrane of plants. TheTat system in most Gram-positive bacteriaconsists of two essential components, the TatAand TatC proteins. TatA is considered to be abifunctional subunit, which can form aprotein-conducting channel byself-oligomerization and can also participate insubstrate recognition. However, the molecularmechanism underlying protein translocationremains elusive. Herein, we report the solutionstructure of the TatA(d) protein from Bacillussubtilis by NMR spectroscopy, the first structureof the Tat system at atomic resolution. TatA(d)shows an L-shaped structure formed by atransmembrane helix and an amphipathic helix,while the C-terminal tail is largely unstructured.Our results strongly support the postulated", "metadata": {}}
+{"_id": "5476778", "title": "", "text": "Autoimmunity due to molecular mimicry as acause of neurological diseaseOne hypothesis thatcouples infection with autoimmune disease ismolecular mimicry. Molecular mimicry ischaracterized by an immune response to anenvironmental agent that cross-reacts with ahost antigen, resulting in disease. Thishypothesis has been implicated in thepathogenesis of diabetes, lupus and multiplesclerosis (MS). There is limited direct evidencelinking causative agents with pathogenic immunereactions in these diseases. Our studyestablishes a clear link between viral infection,autoimmunity and neurological disease inhumans. As a model for molecular mimicry, westudied patients with human T-lymphotropicvirus type 1 (HTLV-1)-associatedmyelopathy/tropical spastic paraparesis(HAM/TSP), a disease that can beindistinguishable from MS (refs. 5,6,7). HAM/TSPpatients develop antibodies to neurons. Wehypothesized these antibodies would identify a", "metadata": {}}
+{"_id": "5483793", "title": "", "text": "Altered recognition of antigen is a mechanism ofCD8+ T cell tolerance in cancerAntigen-specificCD8+ T-cell tolerance, induced bymyeloid-derived suppressor cells (MDSCs), isone of the main mechanisms of tumor escape.Using in vivo models, we show here that MDSCsdirectly disrupt the binding of specificpeptide–major histocompatibility complex(pMHC) dimers to CD8-expressing T cellsthrough nitration of tyrosines in a T-cell receptor(TCR)-CD8 complex. This process makesCD8-expressing T cells unable to bind pMHC andto respond to the specific peptide, although theyretain their ability to respond to nonspecificstimulation. Nitration of TCR-CD8 is induced byMDSCs through hyperproduction of reactiveoxygen species and peroxynitrite during directcell-cell contact. Molecular modeling suggestsspecific sites of nitration that might affect theconformational flexibility of TCR-CD8 and itsinteraction with pMHC. These data identify apreviously unknown mechanism of T-cell", "metadata": {}}
+{"_id": "5484763", "title": "", "text": "A new genetic subgroup of chronicgranulomatous disease with autosomal recessivemutations in p40 phox and selective defects inneutrophil NADPH oxidase activity.Chronicgranulomatous disease (CGD), animmunodeficiency with recurrent pyogenicinfections and granulomatous inflammation,results from loss of phagocyte superoxideproduction by recessive mutations in any 1 of 4genes encoding subunits of the phagocyteNADPH oxidase. These include gp91(phox) andp22(phox), which form the membrane-integratedflavocytochrome b, and cytosolic subunitsp47(phox) and p67(phox). A fifth subunit,p40(phox), plays an important role inphagocytosis-induced superoxide production viaa phox homology (PX) domain that binds tophosphatidylinositol 3-phosphate (PtdIns(3)P).We report the first case of autosomal recessivemutations in NCF4, the gene encodingp40(phox), in a boy who presented withgranulomatous colitis. His neutrophils showed a", "metadata": {}}
+{"_id": "5487448", "title": "", "text": "Birth weight and mammographic density amongpostmenopausal women in Sweden.Birth weightis a significant predictor of breast cancer risk inadult life and mammary gland mass could be anintermediate stage in this long process. We havestudied the association of birth sizemeasurements with mammographic density, amarker of mammary gland mass. For apopulation-based sample of 893 postmenopausalwomen without previous cancer in Sweden, weretrieved information on birth size from birthrecords and their most recent mammography.Film mammograms of the medio-lateral obliqueview were digitized and the Cumulus softwarewas used for computer-assisted semi-automatedthresholding of mammographic density. Resultswere analyzed using generalized linear modelscontrolling for possible confounders. Meanpercent mammographic density increased whencomparing the extreme categories of birth weight(from 15.6% to 18.6%) and head circumference(from 15.5% to 20.4%), and the corresponding", "metadata": {}}
+{"_id": "5492542", "title": "", "text": "Oral ciclopirox olamine displays biological activityin a phase I study in patients with advancedhematologic malignancies.The antimycoticciclopirox olamine is an intracellular iron chelatorthat has anticancer activity in vitro and in vivo.We developed an oral formulation of ciclopiroxolamine and conducted the first-in-human phaseI study of this drug in patients with relapsed orrefractory hematologic malignancies (Trialregistration ID: NCT00990587). Patients weretreated with 5-80 mg/m² oral ciclopirox olamineonce daily for five days in 21-day treatmentcycles. Pharmacokinetic and pharmacodynamiccompanion studies were performed in a subset ofpatients. Following definition of the half-life ofciclopirox olamine, an additional cohort wasenrolled and treated with 80 mg/m² ciclopiroxolamine four times daily. Adverse events andclinical response were monitored throughout thetrial. Twenty-three patients received studytreatment. Ciclopirox was rapidly absorbed andcleared with a short half-life. Plasma", "metadata": {}}
+{"_id": "5500086", "title": "", "text": "Cancer cell–autonomous contribution of type Iinterferon signaling to the efficacy ofchemotherapySome of the anti-neoplastic effectsof anthracyclines in mice originate from theinduction of innate and T cell–mediatedanticancer immune responses. Here wedemonstrate that anthracyclines stimulate therapid production of type I interferons (IFNs) bymalignant cells after activation of the endosomalpattern recognition receptor Toll-like receptor 3(TLR3). By binding to IFN-α and IFN-β receptors(IFNARs) on neoplastic cells, type I IFNs triggerautocrine and paracrine circuitries that result inthe release of chemokine (C-X-C motif) ligand 10(CXCL10). Tumors lacking Tlr3 or Ifnar failed torespond to chemotherapy unless type I IFN orCxcl10, respectively, was artificially supplied.Moreover, a type I IFN–related signaturepredicted clinical responses toanthracycline-based chemotherapy in severalindependent cohorts of patients with breastcarcinoma characterized by poor prognosis. Our", "metadata": {}}
+{"_id": "5503194", "title": "", "text": "alphaE-catenin controls cerebral cortical size byregulating the hedgehog signalingpathway.During development, cells monitor andadjust their rates of accumulation to produceorgans of predetermined size. We show here thatcentral nervous system-specific deletion of theessential adherens junction gene,alphaE-catenin, causes abnormal activation ofthe hedgehog pathway, resulting in shortening ofthe cell cycle, decreased apoptosis, and corticalhyperplasia. We propose that alphaE-cateninconnects cell-density-dependent adherensjunctions with the developmental hedgehogpathway and that this connection may provide anegative feedback loop controlling the size ofdeveloping cerebral cortex.", "metadata": {}}
+{"_id": "5508750", "title": "", "text": "Molecular regulation of effector and memory Tcell differentiationImmunological memory is acardinal feature of adaptive immunity and animportant goal of vaccination strategies. Here wehighlight advances in the understanding of thediverse T lymphocyte subsets that provide acuteand long-term protection from infection. Theseinclude new insights into the transcriptionfactors, and the upstream 'pioneering' factorsthat regulate their accessibility to key sites ofgene regulation, as well as metabolic regulatorsthat contribute to the differentiation of effectorand memory subsets; ontogeny and definingcharacteristics of tissue-resident memorylymphocytes; and origins of the remarkableheterogeneity exhibited by activated T cells.Collectively, these findings underscore progressin delineating the underlying pathways thatcontrol diversification in T cell responses but alsoreveal gaps in the knowledge, as well as thechallenges that arise in the application of thisknowledge to rationally elicit desired T cell", "metadata": {}}
+{"_id": "5511240", "title": "", "text": "Liver-resident macrophage necroptosisorchestrates type 1 microbicidal inflammationand type-2-mediated tissue repair duringbacterial infection.Kupffer cells, the phagocytesof fetal origin that line the liver sinusoids, arekey contributors of host defense againstenteroinvasive bacteria. Here, we found thatinfection by Listeria monocytogenes induced theearly necroptotic death of Kupffer cells, whichwas followed by monocyte recruitment and ananti-bacterial type 1 inflammatory response.Kupffer cell death also triggered a type 2response that involved the hepatocyte-derivedalarmin interleukin-33 (IL-33) andbasophil-derived interleukin-4 (IL-4). This led tothe alternative activation of themonocyte-derived macrophages recruited to theliver, which thereby replaced ablated Kupffercells and restored liver homeostasis. Kupffer celldeath is therefore a key signal orchestrating type1 microbicidal inflammation and type-2-mediatedliver repair upon infection. This indicates that", "metadata": {}}
+{"_id": "5519177", "title": "", "text": "Gene regulation in the immune system by longnoncoding RNAsLong noncoding RNAs (lncRNAs)are emerging as critical regulators of geneexpression in the immune system. Studies haveshown that lncRNAs are expressed in a highlylineage-specific manner and control thedifferentiation and function of innate andadaptive cell types. In this Review, we focus onmechanisms used by lncRNAs to regulate genesencoding products involved in the immuneresponse, including direct interactions withchromatin, RNA and proteins. In addition, weaddress new areas of lncRNA biology, such asthe functions of enhancer RNAs, circular RNAsand chemical modifications to RNA in cellularprocesses. We emphasize critical gaps inknowledge and future prospects for the roles oflncRNAs in the immune system and autoimmunedisease.", "metadata": {}}
+{"_id": "5531479", "title": "", "text": "The Ly49Q receptor plays a crucial role inneutrophil polarization and migration byregulating raft trafficking.Neutrophils rapidlyundergo polarization and directional movementto infiltrate the sites of infection andinflammation. Here, we show that an inhibitoryMHC I receptor, Ly49Q, was crucial for the swiftpolarization of and tissue infiltration byneutrophils. During the steady state, Ly49Qinhibited neutrophil adhesion by preventingfocal-complex formation, likely by inhibiting Srcand PI3 kinases. However, in the presence ofinflammatory stimuli, Ly49Q mediated rapidneutrophil polarization and tissue infiltration inan ITIM-domain-dependent manner. Theseopposite functions appeared to be mediated bydistinct use of effector phosphatase SHP-1 andSHP-2. Ly49Q-dependent polarization andmigration were affected by Ly49Q regulation ofmembrane raft functions. We propose thatLy49Q is pivotal in switching neutrophils to theirpolarized morphology and rapid migration upon", "metadata": {}}
+{"_id": "5548081", "title": "", "text": "Prevalence of Kaposi sarcoma-associatedherpesvirus infection in homosexual men atbeginning of and during the HIVepidemic.CONTEXT Some studies have inferredthat an epidemic of Kaposi sarcoma-associatedherpesvirus (KSHV) infection in homosexual menin the United States occurred concurrently withthat of human immunodeficiency virus (HIV), butthere have been no direct measurements ofKSHV prevalence at the beginning of the HIVepidemic. OBJECTIVES To determine theprevalence of KSHV infection in homosexual menin San Francisco, Calif, at the beginning of theHIV epidemic in 1978 and 1979 and to examinechanges in prevalence of KSHV at time pointsfrom 1978 through 1996 in light of changes insexual behavior. DESIGN, SETTING, ANDPARTICIPANTS Analysis of a clinic-based sample(n = 398) derived from the San Francisco CityClinic Cohort (ages 18-66 years) (n = 2666 foranalyses herein) and from population-basedsamples from the San Francisco Men's Health", "metadata": {}}
+{"_id": "5551138", "title": "", "text": "Nortriptyline for smoking cessation: areview.This article reviews the efficacy ofnortriptyline for smoking cessation based on ameta-analysis of the Cochrane Library. Sixplacebo-controlled trials have shown nortriptyline(75-100 mg) doubles quit rates (OR = 2.1).Between 4% and 12% of smokers dropped outbecause of adverse events, but no seriousadverse events occurred. The efficacy ofnortriptyline did not appear to be related to itsantidepressant actions. Nortriptyline is anefficacious aid to smoking cessation with amagnitude of effect similar to that for bupropionand nicotine replacement therapies. Whethernortriptyline produces serious side effects atthese doses in healthy, nondepressed smokersremains unclear because it has been tested inonly 500 smokers. The finding that nortriptylineand bupropion are effective for smokingcessation but that selective serotonin-reuptakeinhibitors are not suggests that dopaminergic oradrenergic, but not serotonergic, activity is", "metadata": {}}
+{"_id": "5556809", "title": "", "text": "Emotion dysregulation in attention deficithyperactivity disorder.Although it has long beenrecognized that many individuals with attentiondeficit hyperactivity disorder (ADHD) also havedifficulties with emotion regulation, no consensushas been reached on how to conceptualize thisclinically challenging domain. The authorsexamine the current literature using bothquantitative and qualitative methods. Three keyfindings emerge. First, emotion dysregulation isprevalent in ADHD throughout the lifespan and isa major contributor to impairment. Second,emotion dysregulation in ADHD may arise fromdeficits in orienting toward, recognizing, and/orallocating attention to emotional stimuli; thesedeficits implicate dysfunction within astriato-amygdalo-medial prefrontal corticalnetwork. Third, while current treatments forADHD often also ameliorate emotiondysregulation, a focus on this combination ofsymptoms reframes clinical questions and couldstimulate novel therapeutic approaches. The", "metadata": {}}
+{"_id": "5558754", "title": "", "text": "Use of serum C reactive protein and procalcitoninconcentrations in addition to symptoms andsigns to predict pneumonia in patients presentingto primary care with acute cough: diagnosticstudyOBJECTIVES To quantify the diagnosticaccuracy of selected inflammatory markers inaddition to symptoms and signs for predictingpneumonia and to derive a diagnostic tool.DESIGN Diagnostic study performed between2007 and 2010. Participants had their historytaken, underwent physical examination andmeasurement of C reactive protein (CRP) andprocalcitonin in venous blood on the day theyfirst consulted, and underwent chest radiographywithin seven days. SETTING Primary care centresin 12 European countries. PARTICIPANTS Adultspresenting with acute cough. MAIN OUTCOMEMEASURES Pneumonia as determined byradiologists, who were blind to all otherinformation when they judged chest radiographs.RESULTS Of 3106 eligible patients, 286 wereexcluded because of missing or inadequate chest", "metadata": {}}
+{"_id": "5560962", "title": "", "text": "Somatic Mutations of the ImmunoglobulinFramework Are Generally Required for Broad andPotent HIV-1 NeutralizationBroadly neutralizingantibodies (bNAbs) to HIV-1 can preventinfection and are therefore of great importancefor HIV-1 vaccine design. Notably, bNAbs arehighly somatically mutated and generated by afraction of HIV-1-infected individuals severalyears after infection. Antibodies typicallyaccumulate mutations in the complementaritydetermining region (CDR) loops, which usuallycontact the antigen. The CDR loops arescaffolded by canonical framework regions(FWRs) that are both resistant to and lesstolerant of mutations. Here, we report that incontrast to most antibodies, including those withlimited HIV-1 neutralizing activity, most bNAbsrequire somatic mutations in their FWRs.Structural and functional analyses reveal thatsomatic mutations in FWR residues enhancebreadth and potency by providing increasedflexibility and/or direct antigen contact. Thus, in", "metadata": {}}
+{"_id": "5567005", "title": "", "text": "Etiology of type 1 diabetes.Recent geneticmapping and gene-phenotype studies haverevealed the genetic architecture of type 1diabetes. At least ten genes so far can be singledout as strong causal candidates. The knownfunctions of these genes indicate the primaryetiological pathways of this disease, includingHLA class II and I molecules binding topreproinsulin peptides and T cell receptors, T andB cell activation, innate pathogen-viralresponses, chemokine and cytokine signaling,and T regulatory and antigen-presenting cellfunctions. This review considers research in thefield of type 1 diabetes toward identifyingdisease mechanisms using genetic approaches.The expression and functions of these pathways,and, therefore, disease susceptibility, will beinfluenced by epigenetic and environmentalfactors. Certain inherited immune phenotypeswill be early precursors of type 1 diabetes andcould be useful in future clinical trials.", "metadata": {}}
+{"_id": "5567223", "title": "", "text": "Plasticity of epithelial stem cells in tissueregenerationTissues rely upon stem cells forhomeostasis and repair. Recent studies showthat the fate and multilineage potential ofepithelial stem cells can change depending onwhether a stem cell exists within its residentniche and responds to normal tissuehomeostasis, whether it is mobilized to repair awound, or whether it is taken from its niche andchallenged to de novo tissue morphogenesisafter transplantation. In this Review, we discusshow different populations of naturallylineage-restricted stem cells and committedprogenitors can display remarkable plasticity andreversibility and reacquire long-termself-renewing capacities and multilineagedifferentiation potential during physiological andregenerative conditions. We also discuss theimplications of cellular plasticity for regenerativemedicine and for cancer.", "metadata": {}}
+{"_id": "5572127", "title": "", "text": "Atm-deficient mice exhibit increased sensitivityto dextran sulfate sodium-induced colitischaracterized by elevated DNA damage andpersistent immune activation.The role of ataxiatelangiectasia mutated (ATM), a DNAdouble-strand break recognition and responseprotein, in inflammation and inflammatorydiseases is unclear. We have previously shownthat high levels of systemic DNA damage areinduced by intestinal inflammation in wild-typemice. To determine the effect of Atm deficiencyin inflammation, we induced experimental colitisin Atm(-/-), Atm(+/-), and wild-type mice viadextran sulfate sodium (DSS) administration.Atm(-/-) mice had higher disease activity indicesand rates of mortality compared withheterozygous and wild-type mice. Systemic DNAdamage and immune response werecharacterized in peripheral blood throughout andafter three cycles of treatment. Atm(-/-) miceshowed increased sensitivity to levels of DNAstrand breaks in peripheral leukocytes, as well as", "metadata": {}}
+{"_id": "5573975", "title": "", "text": "Activin–like kinase–3 activity is important forkidney regeneration and reversal offibrosisMolecules associated with thetransforming growth factor β (TGF-β)superfamily, such as bone morphogenic proteins(BMPs) and TGF-β, are key regulators ofinflammation, apoptosis and cellular transitions.Here we show that the BMP receptor activin-likekinase 3 (Alk3) is elevated early in diseasedkidneys after injury. We also found that itsdeletion in the tubular epithelium leads toenhanced TGF-β1-Smad family member 3(Smad3) signaling, epithelial damage andfibrosis, suggesting a protective role forAlk3-mediated signaling in the kidney. Astructure-function analysis of the BMP-Alk3-BMPreceptor, type 2 (BMPR2) ligand-receptorcomplex, along with synthetic organic chemistry,led us to construct a library of small peptideagonists of BMP signaling that function throughthe Alk3 receptor. One such peptide agonist,THR-123, suppressed inflammation, apoptosis", "metadata": {}}
+{"_id": "5579368", "title": "", "text": "COHCAP: an integrative genomic pipeline forsingle-nucleotide resolution DNA methylationanalysisCOHCAP (City of Hope CpG IslandAnalysis Pipeline) is an algorithm to analyzesingle-nucleotide resolution DNA methylationdata produced by either an Illumina methylationarray or targeted bisulfite sequencing. The goalof the COHCAP algorithm is to identify CpGislands that show a consistent pattern ofmethylation among CpG sites. COHCAP iscurrently the only DNA methylation package thatprovides integration with gene expression datato identify a subset of CpG islands that are mostlikely to regulate downstream gene expression,and it can generate lists of differentiallymethylated CpG islands with \u000050% concordancewith gene expression from both cell line data andheterogeneous patient data. For example, thisarticle describes known breast cancer biomarkers(such as estrogen receptor) with a negativecorrelation between DNA methylation and geneexpression. COHCAP also provides visualization", "metadata": {}}
+{"_id": "5586392", "title": "", "text": "Subgrouping of patients with neuropathic painaccording to pain-related sensory abnormalities:a first step to a stratified treatmentapproach.BACKGROUND Patients withneuropathic pain present with variouspain-related sensory abnormalities. Thesesensory features form different patterns ormosaics-the sensory profile-in individualpatients. One hypothesis for the development ofsensory profiles is that distinctpathophysiological mechanisms of paingeneration produce specific sensoryabnormalities. Several controlled trials ofpromising new drugs have produced negativeresults, but these findings could have been aresult of heterogeneity in the patient population.Subgrouping patients on the basis of individualsensory profiles could reduce this heterogeneityand improve trial design. RECENTDEVELOPMENTS A statistical categorisation ofpatients with neuropathic pain showed thatsubgroups of patients with distinct sensory", "metadata": {}}
+{"_id": "5596332", "title": "", "text": "The Third International Consensus Definitions forSepsis and Septic Shock (Sepsis-3).IMPORTANCEDefinitions of sepsis and septic shock were lastrevised in 2001. Considerable advances havesince been made into the pathobiology (changesin organ function, morphology, cell biology,biochemistry, immunology, and circulation),management, and epidemiology of sepsis,suggesting the need for reexamination.OBJECTIVE To evaluate and, as needed, updatedefinitions for sepsis and septic shock. PROCESSA task force (n = 19) with expertise in sepsispathobiology, clinical trials, and epidemiologywas convened by the Society of Critical CareMedicine and the European Society of IntensiveCare Medicine. Definitions and clinical criteriawere generated through meetings, Delphiprocesses, analysis of electronic health recorddatabases, and voting, followed by circulation tointernational professional societies, requestingpeer review and endorsement (by 31 societieslisted in the Acknowledgment). KEY FINDINGS", "metadata": {}}
+{"_id": "5597586", "title": "", "text": "Stem cell transplantation in patients withautonomic neuropathy due to primary (AL)amyloidosis.OBJECTIVES Patients with ALamyloidosis can benefit from high-dosechemotherapy and autologous stem celltransplantation (ASCT). Transplantation can bechallenging due to fluid shifts, sepsis, andcardiac dysrhythmias. Amyloidosis may presentwith autonomic neuropathy (AN) that rendersperitransplant care problematic. The purpose ofthis study was to determine the outcome ofpatients with AN during and after ASCT.METHODS We performed a case-control study ofpatients with AL amyloidosis with associated ANand compared them to a large matched cohortwithout AN who also underwent ASCT. RESULTSWe identified 13 patients with AN who underwentASCT and a matched control group of 95 patientswithout AN. Patients with AN had more organsinvolved (median 2.5 vs 1, p < 0.001) and theconditioning dose of melphalan was oftenreduced by 30% compared to controls without", "metadata": {}}
+{"_id": "5612738", "title": "", "text": "MicroRNA-148a regulates LDL receptor andABCA1 expression to control circulatinglipoprotein levelsThe hepatic low-densitylipoprotein receptor (LDLR) pathway is essentialfor clearing circulating LDL cholesterol (LDL-C).Whereas the transcriptional regulation of LDLR iswell characterized, the post-transcriptionalmechanisms that govern LDLR expression arejust beginning to emerge. Here we develop ahigh-throughput genome-wide screening assayto systematically identify microRNAs (miRNAs)that regulate LDLR activity in human hepaticcells. From this screen we identified andcharacterized miR-148a as a negative regulatorof LDLR expression and activity and defined asterol regulatory element–binding protein 1(SREBP1)-mediated pathway through whichmiR-148a regulates LDL-C uptake. In mice,inhibition of miR-148a increased hepatic LDLRexpression and decreased plasma LDL-C.Moreover, we found that miR-148a regulateshepatic expression of ATP-binding cassette,", "metadata": {}}
+{"_id": "5633876", "title": "", "text": "BRACHYURY and CDX2 Mediate BMP-InducedDifferentiation of Human and Mouse PluripotentStem Cells into Embryonic and ExtraembryonicLineagesBMP is thought to induce hESCdifferentiation toward multiple lineages includingmesoderm and trophoblast. The BMP-inducedtrophoblast phenotype is a long-standingparadox in stem cell biology. Here wereaddressed BMP function in hESCs and mouseepiblast-derived cells. We found that BMP4cooperates with FGF2 (via ERK) to inducemesoderm and to inhibit endodermdifferentiation. These conditions induced cellswith high levels of BRACHYURY (BRA) thatcoexpressed CDX2. BRA was necessary for andpreceded CDX2 expression; both genes wereessential for expression not only of mesodermalgenes but also of trophoblast-associated genes.Maximal expression of the latter was seen in theabsence of FGF but these cells coexpressedmesodermal genes and moreover they differed incell surface and epigenetic properties from", "metadata": {}}
+{"_id": "5633957", "title": "", "text": "Degradation of Cellular miR-27 by a Novel,Highly Abundant Viral Transcript Is Important forEfficient Virus Replication InVivoCytomegaloviruses express large amounts ofviral miRNAs during lytic infection, yet, they onlymodestly alter the cellular miRNA profile. Themost prominent alteration upon lytic murinecytomegalovirus (MCMV) infection is the rapiddegradation of the cellular miR-27a andmiR-27b. Here, we report that this regulation ismediated by the \u00001.7 kb spliced and highlyabundant MCMV m169 transcript. Specificity tomiR-27a/b is mediated by a single, apparentlyoptimized, miRNA binding site located in its3'-UTR. This site is easily and efficientlyretargeted to other cellular and viral miRNAs bytarget site replacement. Expression of the 3'-UTRof m169 by an adenoviral vector was sufficient tomediate its function, indicating that no otherviral factors are essential in this process.Degradation of miR-27a/b was found to beaccompanied by 3'-tailing and -trimming.", "metadata": {}}
+{"_id": "5641851", "title": "", "text": "Social and geographical factors affecting accessto treatment of colorectal cancer: a cancerregistry studyOBJECTIVE Cancer outcomes varybetween and within countries with patients fromdeprived backgrounds known to have inferiorsurvival. The authors set out to explore theeffect of deprivation in relation to theaccessibility of hospitals offering diagnostic andtherapeutic services on stage at presentation andreceipt of treatment. DESIGN Analysis of aCancer Registry Database. Data included stageand treatment details from the first 6 months.The socioeconomic status of the immediate areaof residence and the travel time from home tohospital was derived from the postcode.SETTING Population-based study of patientsresident in a large area in the north of England.PARTICIPANTS 39 619 patients with colorectalcancer diagnosed between 1994 and 2002.OUTCOMES MEASURED Stage of diagnosis andreceipt of treatment in relation to deprivationand distance from hospital. RESULTS Patients in", "metadata": {}}
+{"_id": "5649538", "title": "", "text": "Development of candidate genomic markers toselect breast cancer patients for dasatinibtherapy.Patient selection is important fortargeted therapies, yet phase I/II trials are oftenunderpowered for developing predictors of drugresponse. The goal of this research was to definegenomic predictors for dasatinib that could beprospectively tested in early-phase clinical trials.Gene expression profiles of dasatinib-sensitiveand dasatinib-resistant cell lines (n = 23) werecompared to develop a dasatinib-sensitivityindex (modified DS index). A Src pathwayactivity index (revised Src index) was definedusing genes induced by the Src transfection ofmammary epithelial cells and was optimized tobe reproducible across cell lines and humanspecimens. A dasatinib target index was devisedusing the weighted sum of 19 kinases that bindto dasatinib with variable affinity. Theperformance of these prediction models wasassessed in independent cell lines with knowndasatinib sensitivity. The feasibility of applying", "metadata": {}}
+{"_id": "5650232", "title": "", "text": "BEDTools: a flexible suite of utilities forcomparing genomic featuresMOTIVATIONTesting for correlations between different sets ofgenomic features is a fundamental task ingenomics research. However, searching foroverlaps between features with existingweb-based methods is complicated by themassive datasets that are routinely producedwith current sequencing technologies. Fast andflexible tools are therefore required to askcomplex questions of these data in an efficientmanner. RESULTS This article introduces a newsoftware suite for the comparison, manipulationand annotation of genomic features in BrowserExtensible Data (BED) and General FeatureFormat (GFF) format. BEDTools also supports thecomparison of sequence alignments in BAMformat to both BED and GFF features. The toolsare extremely efficient and allow the user tocompare large datasets (e.g. next-generationsequencing data) with both public and customgenome annotation tracks. BEDTools can be", "metadata": {}}
+{"_id": "5687200", "title": "", "text": "Vegetarian diet improves insulin resistance andoxidative stress markers more than conventionaldiet in subjects with Type 2 diabetesAIMS Theaim of this study was to compare the effects ofcalorie-restricted vegetarian and conventionaldiabetic diets alone and in combination withexercise on insulin resistance, visceral fat andoxidative stress markers in subjects with Type 2diabetes. METHODS A 24-week, randomized,open, parallel design was used. Seventy-fourpatients with Type 2 diabetes were randomlyassigned to either the experimental group (n =37), which received a vegetarian diet, or thecontrol group (n = 37), which received aconventional diabetic diet. Both diets wereisocaloric, calorie restricted (-500 kcal/day). Allmeals during the study were provided. Thesecond 12 weeks of the diet were combined withaerobic exercise. Participants were examined atbaseline, 12 weeks and 24 weeks. Primaryoutcomes were: insulin sensitivity measured byhyperinsulinaemic isoglycaemic clamp; volume of", "metadata": {}}
+{"_id": "5691302", "title": "", "text": "Antidepressant use and risk of adverse outcomesin older people: population based cohortstudyOBJECTIVES To investigate the associationbetween antidepressant treatment and risk ofseveral potential adverse outcomes in olderpeople with depression and to examine risks byclass of antidepressant, duration of use, anddose. DESIGN Cohort study of people aged 65and over diagnosed as having depression.SETTING 570 general practices in the UnitedKingdom supplying data to the QResearchprimary care database. PARTICIPANTS 60,746patients diagnosed as having a new episode ofdepression between the ages of 65 and 100years from 1 January 1996 to 31 December 2007and followed up until 31 December 2008. MAINOUTCOME MEASURES Hazard ratios associatedwith antidepressant use for all cause mortality,attempted suicide/self harm, myocardialinfarction, stroke/transient ischaemic attack,falls, fractures, upper gastrointestinal bleeding,epilepsy/seizures, road traffic accidents, adverse", "metadata": {}}
+{"_id": "5698494", "title": "", "text": "The benefits of statins in people withoutestablished cardiovascular disease but withcardiovascular risk factors: meta-analysis ofrandomised controlled trialsOBJECTIVES Toinvestigate whether statins reduce all causemortality and major coronary andcerebrovascular events in people withoutestablished cardiovascular disease but withcardiovascular risk factors, and whether theseeffects are similar in men and women, in youngand older (>65 years) people, and in people withdiabetes mellitus. DESIGN Meta-analysis ofrandomised trials. DATA SOURCES Cochranecontrolled trials register, Embase, and Medline.Data abstraction Two independent investigatorsidentified studies on the clinical effects of statinscompared with a placebo or control group andwith follow-up of at least one year, at least 80%or more participants without establishedcardiovascular disease, and outcome data onmortality and major cardiovascular diseaseevents. Heterogeneity was assessed using the Q", "metadata": {}}
+{"_id": "5700349", "title": "", "text": "Mechanical coupling between transsynapticN-cadherin adhesions and actin flow stabilizesdendritic spinesThe morphology of neuronaldendritic spines is a critical indicator of synapticfunction. It is regulated by several factors,including the intracellular actin/myosincytoskeleton and transcellular N-cadherinadhesions. To examine the mechanicalrelationship between these molecularcomponents, we performed quantitativelive-imaging experiments in primaryhippocampal neurons. We found that actinturnover and structural motility were lower indendritic spines than in immature filopodia andincreased upon expression of a nonadhesiveN-cadherin mutant, resulting in an inverserelationship between spine motility and actinenrichment. Furthermore, the pharmacologicalstimulation of myosin II induced the rearwardmotion of actin structures in spines, showing thatmyosin II exerts tension on the actin network.Strikingly, the formation of stable, spine-like", "metadata": {}}
+{"_id": "5702790", "title": "", "text": "Phosphate and R2D2 restrict the substratespecificity of Dicer-2, an ATP-drivenribonuclease.Drosophila Dicer-2 generates smallinterfering RNAs (siRNAs) from longdouble-stranded RNA (dsRNA), whereas Dicer-1produces microRNAs (miRNAs) from pre-miRNA.What makes the two Dicers specific for theirbiological substrates? We find that purifiedDicer-2 can efficiently cleave pre-miRNA, butthat inorganic phosphate and the Dicer-2 partnerprotein R2D2 inhibit pre-miRNA cleavage.Dicer-2 contains C-terminal RNase III domainsthat mediate RNA cleavage and an N-terminalhelicase motif, whose function is unclear. Weshow that Dicer-2 is a dsRNA-stimulated ATPasethat hydrolyzes ATP to ADP; ATP hydrolysis isrequired for Dicer-2 to process long dsRNA, butnot pre-miRNA. Wild-type Dicer-2, but not amutant defective in ATP hydrolysis, can generatesiRNAs faster than it can dissociate from a longdsRNA substrate. We propose that the Dicer-2helicase domain uses ATP to generate many", "metadata": {}}
+{"_id": "5704562", "title": "", "text": "Therapeutic potential of mood stabilizers lithiumand valproic acid: beyond bipolar disorder.Themood stabilizers lithium and valproic acid (VPA)are traditionally used to treat bipolar disorder(BD), a severe mental illness arising fromcomplex interactions between genes andenvironment that drive deficits in cellularplasticity and resiliency. The therapeuticpotential of these drugs in other central nervoussystem diseases is also gaining support. Thisarticle reviews the various mechanisms of actionof lithium and VPA gleaned from cellular andanimal models of neurologic, neurodegenerative,and neuropsychiatric disorders. Clinical evidenceis included when available to provide acomprehensive perspective of the field and toacknowledge some of the limitations of thesetreatments. First, the review describes howaction at these drugs' primary targets--glycogensynthase kinase-3 for lithium and histonedeacetylases for VPA--induces the transcriptionand expression of neurotrophic, angiogenic, and", "metadata": {}}
+{"_id": "5710820", "title": "", "text": "The feasibility of malaria elimination in SouthAfricaBACKGROUND Following the last majormalaria epidemic in 2000, malaria incidence inSouth Africa has declined markedly. Thedecrease has been so emphatic that South Africanow meets the World Health Organization (WHO)threshold for malaria elimination. Given theMillennium Development Goal of reversing thespread of malaria by 2015, South Africa is beingurged to adopt an elimination agenda. This studyaimed to determine the appropriateness ofimplementing a malaria elimination programmein present day South Africa. METHODS Anassessment of the progress made by SouthAfrica in terms of implementing an integratedmalaria control programme across the threemalaria-endemic provinces was undertaken.Vector control and case management data wereanalysed from the period of 2000 until 2011.RESULTS Both malaria-related morbidity andmortality have decreased significantly across allthree malaria-endemic provinces since 2000. The", "metadata": {}}
+{"_id": "5735492", "title": "", "text": "The epidemiology of sexually transmittedco-infections in HIV-positive and HIV-negativeAfrican-Caribbean women inTorontoBACKGROUND HIV disproportionatelyaffects African-Caribbean women in Canada butthe frequency and distribution of sexuallytransmitted infections in this community havenot been previously studied. METHODS Werecruited women based on HIV status through aToronto community health centre. Participantscompleted a socio-behavioural questionnaireusing Audio Computer Assisted Self-Interview(ACASI) and provided blood for syphilis, HIV,hepatitis B and C, herpes simplex virus type 1(HSV-1), herpes simplex virus type 2 (HSV-2),and human cytomegalovirus (CMV) serology,urine for chlamydia and gonorrhea moleculartesting and vaginal secretions for bacterialvaginosis (BV) and human papillomavirus (HPV).Differences in prevalence were assessed forstatistical significance using chi-square. RESULTSWe recruited 126 HIV-positive and 291", "metadata": {}}
+{"_id": "5752492", "title": "", "text": "Characterization of Programmed Death-1Homologue-1 (PD-1H) Expression and Functionin Normal and HIV Infected IndividualsChronicimmune activation that persists despiteanti-retroviral therapy (ART) is the strongestpredictor of disease progression in HIV infection.Monocyte/macrophages in HIV-infectedindividuals are known to spontaneously secretecytokines, although neither the mechanism northe molecules involved are known. Here we showthat overexpression of the newly describedco-stimulatory molecule, PD1 homologue(PD-1H) in human monocyte/macrophages issufficient to induce spontaneous secretion ofmultiple cytokines. The process requiressignaling via PD-1H as cytokine secretion couldbe abrogated by deletion of the cytoplasmicdomain. Such overexpression of PD-1H,associated with spontaneous cytokine expressionis seen in monocytes from chronicallyHIV-infected individuals and this correlates withimmune activation and CD4 depletion, but not", "metadata": {}}
+{"_id": "5760247", "title": "", "text": "A conserved mechanism for centromericnucleosome recognition by centromere proteinCENP-C.Chromosome segregation during mitosisrequires assembly of the kinetochore complex atthe centromere. Kinetochore assembly dependson specific recognition of the histone variantCENP-A in the centromeric nucleosome bycentromere protein C (CENP-C). We have definedthe determinants of this recognition mechanismand discovered that CENP-C binds a hydrophobicregion in the CENP-A tail and docks onto theacidic patch of histone H2A and H2B. We furtherfound that the more broadly conserved CENP-Cmotif uses the same mechanism for CENP-Anucleosome recognition. Our findings reveal aconserved mechanism for protein recruitment tocentromeres and a histone recognition modewhereby a disordered peptide binds the histonetail through hydrophobic interactions facilitatedby nucleosome docking.", "metadata": {}}
+{"_id": "5764562", "title": "", "text": "Chemical tools for biomolecular imaging.Thevisualization of biologically relevant moleculesand activities inside living cells continues totransform cell biology into a truly quantitativescience. However, despite the spectacularachievements in some areas of cell biology, themajority of cellular processes still operateinvisibly, not illuminated by even our brightestlaser beams. Further progress therefore willdepend not only on improvements ininstrumentation but also increasingly on thedevelopment of new fluorophores andfluorescent sensors to target these activities. Inthe following, we review some of the recentapproaches to generating such sensors, themethods to attach them to selectedbiomolecules, and their applications to variousbiological problems.", "metadata": {}}
+{"_id": "5765455", "title": "", "text": "Reactive oxygen species, DNA damage, anderror-prone repair: a model for genomicinstability with progression in myeloidleukemia?Myelodysplastic syndromes (MDS)comprise a heterogeneous group of disorderscharacterized by ineffective hematopoiesis, withan increased propensity to develop acutemyelogenous leukemia (AML). The molecularbasis for MDS progression is unknown, but a keyelement in MDS disease progression is loss ofchromosomal material (genomic instability).Using our two-step mouse model for myeloidleukemic disease progression involvingoverexpression of human mutant NRAS andBCL2 genes, we show that there is a stepwiseincrease in the frequency of DNA damage leadingto an increased frequency of error-prone repairof double-strand breaks (DSB) bynonhomologous end-joining. There is aconcomitant increase in reactive oxygen species(ROS) in these transgenic mice with diseaseprogression. Importantly, RAC1, an essential", "metadata": {}}
+{"_id": "5774746", "title": "", "text": "A link between inflammation and metastasis:serum amyloid A1 and A3 induce metastasis, andare targets of metastasis-inducingS100A4S100A4 is implicated in metastasis andchronic inflammation, but its function remainsuncertain. Here we establish anS100A4-dependent link between inflammationand metastatic tumor progression. We found thatthe acute-phase response proteins serumamyloid A (SAA) 1 and SAA3 are transcriptionaltargets of S100A4 via Toll-like receptor 4(TLR4)/nuclear factor-κB signaling. SAA proteinsstimulated the transcription of RANTES(regulated upon activation normal T-cellexpressed and presumably secreted), G-CSF(granulocyte-colony-stimulating factor) andMMP2 (matrix metalloproteinase 2), MMP3,MMP9 and MMP13. We have also shown for thefirst time that SAA stimulate their owntranscription as well as that of proinflammatoryS100A8 and S100A9 proteins. Moreover, theystrongly enhanced tumor cell adhesion to", "metadata": {}}
+{"_id": "5775033", "title": "", "text": "Pyruvate dehydrogenase activity and acetylgroup accumulation during exercise afterdifferent diets.Pyruvate dehydrogenase activity(PDHa) and acetyl group accumulation wereexamined in human skeletal muscle at rest andduring exercise after different diets. Five malescycled at 75% of maximal O2 uptake (VO2 max)to exhaustion after consuming alow-carbohydrate diet (LCD) for 3 days andagain 1-2 wk later for the same duration afterconsuming a high-carbohydrate diet (HCD) for 3days. Resting PDHa was lower after a LCD (0.20+/- 0.04 vs. 0.69 +/- 0.05 mmol.min-1.kg wetwt-1; P < 0.05) and coincided with a greaterintramuscular acetyl-CoA-to-CoASH ratio,acetyl-CoA content, and acetylcarnitine content.PDHa increased during exercise in bothconditions but at a lower rate in the LCDcondition compared with the HCD condition (1.46+/- 0.25 vs. 2.65 +/- 0.23 mmol.min-1.kg wetwt-1 at 16 min and 1.88 +/- 0.20 vs. 3.11 +/-0.14 at the end of exercise; P < 0.05). During", "metadata": {}}
+{"_id": "5782614", "title": "", "text": "Clonal hematopoiesis of indeterminate potentialand its distinction from myelodysplasticsyndromes.Recent genetic analyses of largepopulations have revealed that somaticmutations in hematopoietic cells leading to clonalexpansion are commonly acquired during humanaging. Clonally restricted hematopoiesis isassociated with an increased risk of subsequentdiagnosis of myeloid or lymphoid neoplasia andincreased all-cause mortality. Althoughmyelodysplastic syndromes (MDS) are defined bycytopenias, dysplastic morphology of blood andmarrow cells, and clonal hematopoiesis, mostindividuals who acquire clonal hematopoiesisduring aging will never develop MDS. Therefore,acquisition of somatic mutations that drive clonalexpansion in the absence of cytopenias anddysplastic hematopoiesis can be consideredclonal hematopoiesis of indeterminate potential(CHIP), analogous to monoclonal gammopathy ofundetermined significance and monoclonal B-celllymphocytosis, which are precursor states for", "metadata": {}}
+{"_id": "5783785", "title": "", "text": "DNA Methylation mediated down-regulating ofMicroRNA-33b and its role in gastric cancerThediscovery of microRNAs (miRNAs) provides a newand powerful tool for studying the mechanism,diagnosis and treatment of human cancers.Currently, down-regulation of tumor suppressivemiRNAs by CpG island hypermethylation isemerging as a common hallmark of cancer. Here,we reported that the down-regulation of miR-33bwas associated with pM stage of gastric cancer(GC) patients. Ectopic expression of miR-33b inHGC-27 and MGC-803 cells inhibited cellproliferation, migration and invasion, whichmight be due to miR-33b targeting oncogenec-Myc. Moreover, enhanced methylation level ofthe CpG island upstream of miR-33b in GCpatients with down-regulated miR-33b wasconfirmed by methylation-specific PCR (MSP)amplification. Furthermore, re-introduction ofmiR-33b significantly suppressed tumorigenesisof GC cells in the nude mice. In conclusion,miR-33b acts as a tumor suppressor and", "metadata": {}}
+{"_id": "5785219", "title": "", "text": "Modulation of glucose metabolism inmacrophages by products of nitric oxidesynthase.Nitric oxide (NO) is a product ofL-arginine metabolism that suppresses cellularoxidative metabolism through the inhibition oftricarboxylic acid cycle and electron transportchain enzymes. The impact of NO synthase(NOS) activity on specific pathways of glucosemetabolism in freshly harvested andovernight-cultured rat resident peritonealmacrophages, at rest and after stimulation withzymosan, was investigated using radiolabeledglucose. NOS activity was modulated through theL-arginine concentration in culture media and theuse of its specific inhibitor,NG-monomethyl-L-arginine, and quantitatedusing radiolabeled L-arginine. Resultsdemonstrated that NOS activity was associatedwith increased glucose disappearance, glycolysis,and hexose monophosphate shunt activity and,in line with the known inhibition of oxidativemetabolism associated with the production of", "metadata": {}}
+{"_id": "5798227", "title": "", "text": "SOCS1/JAB is a negative regulator ofLPS-induced macrophage activation.Bacteriallipopolysaccharide (LPS) triggers innate immuneresponses through Toll-like receptor (TLR) 4. Weshow here that the suppressor ofcytokine-signaling-1 (SOCS1/JAB) is rapidlyinduced by LPS and negatively regulates LPSsignaling. SOCS1(+/-) mice or SOCS1(-/-) micewith interferon-gamma (IFNgamma)-deficientbackground were more sensitive to LPS-inducedlethal effects than were wild-type littermates.LPS-induced NO(2)(-) synthesis and TNFalphaproduction were augmented in SOCS1(-/-)macrophages. Furthermore, LPS tolerance, aprotection mechanism against endotoxin shock,was also strikingly reduced in SOCS1(-/-) cells.LPS-induced I-kappaB and p38 phosphorylationwas upregulated in SOCS1(-/-) macrophages,and forced expression of SOCS1 suppressedLPS-induced NF-kappaB activation. Thus, SOCS1directly suppresses TLR4 signaling andmodulates innate immunity.", "metadata": {}}
+{"_id": "5800138", "title": "", "text": "Bacteria-triggered CD4+ T Regulatory CellsSuppress Helicobacter hepaticus–inducedColitisWe have previously demonstrated thatinterleukin (IL)-10–deficient (IL-10 knockout[KO]) but not wild-type (WT) mice develop colitisafter infection with Helicobacter hepaticus . Here,we show that infected recombination activatinggene (RAG) KO mice develop intestinalinflammation after reconstitution with CD4+ Tcells from IL-10 KO animals and that thecotransfer of CD4+ T cells from H. hepaticus–infected but not uninfected WT mice preventsthis colitis. The disease-protective WT CD4+ cellsare contained within the CD45RBlow fraction andunexpectedly were found in both the CD25+ andthe CD25− subpopulations of these cells, theirfrequency being higher in the latter. Themechanism by which CD25+ and CD25−CD45RBlow CD4+ cells block colitis involvesIL-10 and not transforming growth factor(TGF)-β, as treatment with anti–IL-10R but notanti–TGF-β monoclonal antibody abrogated their", "metadata": {}}
+{"_id": "5811042", "title": "", "text": "The NLRP12 Sensor Negatively RegulatesAutoinflammatory Disease by ModulatingInterleukin-4 Production in T Cells.Missensemutations in the nucleotide-bindingoligomerization domain (NOD)-like receptor pyrindomain containing family of gene 12 (Nlrp12) areassociated with periodic fever syndromes andatopic dermatitis in humans. Here, we havedemonstrated a crucial role for NLRP12 innegatively regulating pathogenic T cellresponses. Nlrp12(-/-) mice responded toantigen immunization with hyperinflammatory Tcell responses. Furthermore, transfer ofCD4(+)CD45RB(hi)Nlrp12(-/-) T cells intoimmunodeficient mice led to more severe colitisand atopic dermatitis. NLRP12 deficiency did not,however, cause exacerbated ascending paralysisduring experimental autoimmuneencephalomyelitis (EAE); instead, Nlrp12(-/-)mice developed atypical neuroinflammatorysymptoms that were characterized by ataxia andloss of balance. Enhanced T-cell-mediated", "metadata": {}}
+{"_id": "5821617", "title": "", "text": "Shc coordinates signals from intercellularjunctions and integrins to regulate flow-inducedinflammationAtherosclerotic plaques develop inregions of the vasculature associated withchronic inflammation due to disturbed flowpatterns. Endothelial phenotype modulation byflow requires the integration of numerousmechanotransduction pathways, but how this isachieved is not well understood. We show herethat, in response to flow, the adaptor protein Shcis activated and associates with cell-cell andcell-matrix adhesions. Shc activation requires thetyrosine kinases vascular endothelial growthfactor receptor 2 and Src. Shc activation and itsvascular endothelial cadherin (VE-cadherin)association are matrix independent. In contrast,Shc binding to integrins requires VE-cadherin butoccurs only on specific matrices. Silencing Shcresults in reduction in both matrix-independentand matrix-dependent signals. Furthermore, Shcregulates flow-induced inflammatory signaling byactivating nuclear factor kappaB-dependent", "metadata": {}}
+{"_id": "5824955", "title": "", "text": "SIRT1 Redistribution on Chromatin PromotesGenomic Stability but Alters Gene Expressionduring AgingGenomic instability and alterationsin gene expression are hallmarks of eukaryoticaging. The yeast histone deacetylase Sir2silences transcription and stabilizes repetitiveDNA, but during aging or in response to a DNAbreak, the Sir complex relocalizes to sites ofgenomic instability, resulting in the desilencing ofgenes that cause sterility, a characteristic ofyeast aging. Using embryonic stem cells, weshow that mammalian Sir2, SIRT1, repressesrepetitive DNA and a functionally diverse set ofgenes across the mouse genome. In response toDNA damage, SIRT1 dissociates from these lociand relocalizes to DNA breaks to promote repair,resulting in transcriptional changes that parallelthose in the aging mouse brain. Increased SIRT1expression promotes survival in a mouse modelof genomic instability and suppressesage-dependent transcriptional changes. Thus,DNA damage-induced redistribution of SIRT1 and", "metadata": {}}
+{"_id": "5824985", "title": "", "text": "Bariatric Surgery in the United Kingdom: ACohort Study of Weight Loss and ClinicalOutcomes in Routine Clinical Care.BACKGROUNDBariatric surgery is becoming a more widespreadtreatment for obesity. Comprehensive evidenceof the long-term effects of contemporary surgeryon a broad range of clinical outcomes in largepopulations treated in routine clinical practice islacking. The objective of this study was tomeasure the association between bariatricsurgery, weight, body mass index, andobesity-related co-morbidities. METHODS ANDFINDINGS This was an observationalretrospective cohort study using data from theUnited Kingdom Clinical Practice ResearchDatalink. All 3,882 patients registered in thedatabase and with bariatric surgery on or before31 December 2014 were included and matchedby propensity score to 3,882 obese patientswithout surgery. The main outcome measureswere change in weight and body mass index over4 y; incident diagnoses of type 2 diabetes", "metadata": {}}
+{"_id": "5828251", "title": "", "text": "Notch signalling acts in postmitotic avianmyogenic cells to control MyoD activation.DuringDrosophila myogenesis, Notch signalling acts atmultiple steps of the muscle differentiationprocess. In vertebrates, Notch activation hasbeen shown to block MyoD activation and muscledifferentiation in vitro, suggesting that thispathway may act to maintain the cells in anundifferentiated proliferative state. In this paper,we address the role of Notch signalling in vivoduring chick myogenesis. We first demonstratethat the Notch1 receptor is expressed inpostmitotic cells of the myotome and that theNotch ligands Delta1 and Serrate2 are detectedin subsets of differentiating myogenic cells andare thus in position to signal to Notch1 duringmyogenic differentiation. We also reinvestigatethe expression of MyoD and Myf5 during avianmyogenesis, and observe that Myf5 is expressedearlier than MyoD, consistent with previousresults in the mouse. We then show that forcedexpression of the Notch ligand, Delta1, during", "metadata": {}}
+{"_id": "5835149", "title": "", "text": "Hepatitis C virus infection in a large cohort ofhomosexually active men: independentassociations with HIV-1 infection and injectingdrug use but not sexual behaviour.OBJECTIVE Todetermine the prevalence and risk factors forhepatitis C virus (HCV) infection in a cohort ofhomosexually active men, with particularreference to assessing sexual transmission.DESIGN Prevalence based on cross-sectionaltesting for HCV (c100 protein) antibody in acohort using sera stored between 1984 and1989, and assessment of risk factors using acase-control analysis based on questionnairedata from HCV positive and negative subjects.SUBJECTS/SETTING 1038 homosexually activemen who were participating in a prospectivestudy established to identify risk factors forAIDS. They had been recruited through privateand public primary care and sexuallytransmissible disease (STD) services in centralSydney. MAIN OUTCOME MEASURES Prevalenceof HCV antibody and its association with human", "metadata": {}}
+{"_id": "5838067", "title": "", "text": "Analysis of human cytomegalovirus-encodedmicroRNA activity during infection.MicroRNAs(miRNAs) are expressed in a wide variety oforganisms, ranging from plants to animals, andare key posttranscriptional regulators of geneexpression. Virally encoded miRNAs are uniquein that they could potentially target both viraland host genes. Indeed, we have previouslydemonstrated that a human cytomegalovirus(HCMV)-encoded miRNA, miR-UL112,downregulates the expression of a host immunegene, MICB. Remarkably, it was shown that thesame miRNA also downregulatesimmediate-early viral genes and that its ectopicexpression resulted in reduced viral replicationand viral titers. The targets for most of the viralmiRNAs, and hence their functions, are stillunknown. Here we demonstrate that miR-UL112also targets the UL114 gene, and we presentevidence that the reduction of UL114 bymiR-UL112 reduces its activity as uracil DNAglycosylase but only minimally affects virus", "metadata": {}}
+{"_id": "5839365", "title": "", "text": "Anti-obesity drugs: past, present and futureTheideal anti-obesity drug would produce sustainedweight loss with minimal side effects. Themechanisms that regulate energy balance havesubstantial built-in redundancy, overlapconsiderably with other physiological functions,and are influenced by social, hedonic andpsychological factors that limit the effectivenessof pharmacological interventions. It is thereforeunsurprising that anti-obesity drug discoveryprogrammes have been littered with false starts,failures in clinical development, and withdrawalsdue to adverse effects that were not fullyappreciated at the time of launch. Drugs thattarget pathways in metabolic tissues, such asadipocytes, liver and skeletal muscle, haveshown potential in preclinical studies but nonehas yet reached clinical development. Recentimprovements in the understanding ofpeptidergic signalling of hunger and satiety fromthe gastrointestinal tract mediated by ghrelin,cholecystokinin (CCK), peptide YY (PYY) and", "metadata": {}}
+{"_id": "5849439", "title": "", "text": "Cytochemical Analysis of Pollen Development inWild-Type Arabidopsis and a Male-SterileMutant.Microsporogenesis has been examined inwild-type Arabidopsis thaliana and the nuclearmale-sterile mutant BM3 by cytochemicalstaining. The mutant lacks adeninephosphoribosyltransferase, an enzyme of thepurine salvage pathway that converts adenine toAMP. Pollen development in the mutant began todiverge from wild type just after meiosis, as thetetrads of microspores were released from theircallose walls. The first indication of abnormalpollen development in the mutant was a darkerstaining of the microspore wall due to anincomplete synthesis of the intine. Vacuoleformation was delayed and irregular in themutant, and the majority of the mutantmicrospores failed to undergo mitotic divisions.Enzyme activities of alcohol dehydrogenase andesterases decreased in the mutant soon aftermeiosis and were undetectable in mature pollengrains of the mutant. RNA accumulation was also", "metadata": {}}
+{"_id": "5850219", "title": "", "text": "Prevalence, risk factors, and uptake ofinterventions for sexually transmitted infectionsin Britain: findings from the National Surveys ofSexual Attitudes and Lifestyles(Natsal)BACKGROUND Population-basedestimates of prevalence, risk distribution, andintervention uptake inform delivery of controlprogrammes for sexually transmitted infections(STIs). We undertook the third National Surveyof Sexual Attitudes and Lifestyles (Natsal-3)after implementation of national sexual healthstrategies, and describe the epidemiology of fourSTIs in Britain (England, Scotland, and Wales)and the uptake of interventions. METHODSBetween Sept 6, 2010 and Aug 31, 2012 , we dida probability sample survey of 15,162 womenand men aged 16-74 years in Britain.Participants were interviewed withcomputer-assisted face-to-face andself-completion questionnaires. Urine from asample of participants aged 16-44 years whoreported at least one sexual partner over the", "metadata": {}}
+{"_id": "5855168", "title": "", "text": "Cancer Pharmacogenomics andPharmacoepidemiology: Setting a ResearchAgenda to Accelerate TranslationRecentadvances in genomic research havedemonstrated a substantial role for genomicfactors in predicting response to cancertherapies. Researchers in the fields of cancerpharmacogenomics and pharmacoepidemiologyseek to understand why individuals responddifferently to drug therapy, in terms of bothadverse effects and treatment efficacy. Toidentify research priorities as well as theresources and infrastructure needed to advancethese fields, the National Cancer Institute (NCI)sponsored a workshop titled \"CancerPharmacogenomics: Setting a Research Agendato Accelerate Translation\" on July 21, 2009, inBethesda, MD. In this commentary, wesummarize and discuss five science-basedrecommendations and four infrastructure-basedrecommendations that were identified as a resultof discussions held during this workshop. Key", "metadata": {}}
+{"_id": "5860364", "title": "", "text": "Differential transcription of the orphan receptorRORbeta in nuclear extracts derived fromNeuro2A and HeLa cells.An important modelsystem for studying the process leading toproductive transcription is provided by thesuperfamily of nuclear receptors, which are forthe most part ligand-controlled transcriptionfactors. Over the past years several 'orphan'nuclear receptors have been isolated for whichno ligand has yet been identified. Very little isknown about how these 'orphan' receptorsregulate transcription. In this study we haveanalysed the biochemical and transcriptionalproperties of the neuronally expressed orphannuclear receptor RORbeta (NR1F2) andcompared them with the retinoic acid receptorheterodimer RXRalpha-RARalpha(NR2B1-NR1B1) and Gal-VP16 in vitro. AlthoughRORbeta binds to its DNA-binding sites withcomparatively low affinity, it efficiently directstranscription in nuclear extracts derived from aneuronal cell line, Neuro2A, but not in nuclear", "metadata": {}}
+{"_id": "5864770", "title": "", "text": "Estrogens, progestogens, normal breast cellproliferation, and breast cancerrisk.Epidemiologic studies suggest that ovarianhormones contribute to the development ofbreast cancer at all stages. Early menopause andpremenopausal obesity reduces the risk whilepostmenopausal obesity and menopausalestrogen replacement therapy increases the risk.Combined oral contraceptives and Depo-Proverado not reduce the risk. It appears that estrogensand progestogens act through and withproto-oncogenes and growth factors to affectbreast cell proliferation and breast canceretiology. Animal studies suggest that estrogencauses interlobular ductal cell division andprogesterone causes increased terminal ductlobular unit cell division in the luteal phase. Mostbreast carcinomas originate from terminal ductlobular unit cells. During pregnancy, these cellsfully multiply. Their reproduction is alsoincreased during the luteal phase. Yet, there isconsiderable interpersonal variation. No studies", "metadata": {}}
+{"_id": "5867846", "title": "", "text": "Analysis of the interaction of primateretroviruses with the human RNA interferencemachinery.The question of whether retroviruses,including human immunodeficiency virus type 1(HIV-1), interact with the cellular RNAinterference machinery has been controversial.Here, we present data showing that neitherHIV-1 nor human T-cell leukemia virus type 1(HTLV-1) expresses significant levels of eithersmall interfering RNAs or microRNAs inpersistently infected T cells. We alsodemonstrate that the retroviral nucleartranscription factors HIV-1 Tat and HTLV-1 Tax,as well as the Tas transactivator encoded byprimate foamy virus, fail to inhibit RNAinterference in human cells. Moreover, the stableexpression of physiological levels of HIV-1 Tatdid not globally inhibit microRNA production orexpression in infected human cells. Together,these data argue that HIV-1 and HTLV-1 neitherinduce the production of viral small interferingRNAs or microRNAs nor repress the cellular RNA", "metadata": {}}
+{"_id": "5884524", "title": "", "text": "Impact of diabetes on long-term prognosis inpatients with unstable angina and non-Q-wavemyocardial infarction: results of the OASIS(Organization to Assess Strategies for IschemicSyndromes) Registry.BACKGROUND Althoughunstable coronary artery disease is the mostcommon reason for admission to a coronary careunit, the long-term prognosis of patients withthis diagnosis is unknown. This is particularlytrue for patients with diabetes mellitus, who areknown to have a high morbidity and mortalityafter an acute myocardial infarction. METHODSAND RESULTS Prospectively collected data from6 different countries in the Organization toAssess Strategies for Ischemic Syndromes(OASIS) registry were analyzed to determine the2-year prognosis of diabetic and nondiabeticpatients who were hospitalized with unstableangina or non-Q-wave myocardial infarction.Overall, 1718 of 8013 registry patients (21%)had diabetes. Diabetic patients had a higher rateof coronary bypass surgery than nondiabetic", "metadata": {}}
+{"_id": "5885376", "title": "", "text": "Strain improvement by metabolic engineering:lysine production as a case study for systemsbiology.A central goal of systems biology is theelucidation of cell function and physiologythrough the integrated use of broad basedgenomic and physiological data. Such systemicapproaches have been employed extensively inthe past, as they are a central element ofmetabolic flux analysis, the distribution of kineticcontrol in pathways, and the key differentiatingcharacteristic of metabolic engineering. In onecase study, these tools have been applied to theimprovement of lysine-producing strains ofCorynebacterium glutamicum. The systematicstudy of the physiology of this organism allowedthe identification of specific metabolic targetsand subsequently led to significantimprovements in product yield and productivity.This case study can serve as a guide for thedevelopment of systems biology tools for theutilization of large volumes of cell- andgenome-wide transcriptional and physiological", "metadata": {}}
+{"_id": "5912283", "title": "", "text": "Cognitive behavioral therapy vs zopiclone fortreatment of chronic primary insomnia in olderadults: a randomized controlled trial.CONTEXTInsomnia is a common condition in older adultsand is associated with a number of adversemedical, social, and psychological consequences.Previous research has suggested beneficialoutcomes of both psychological andpharmacological treatments, but blindedplacebo-controlled trials comparing the effects ofthese treatments are lacking. OBJECTIVE Toexamine short- and long-term clinical efficacy ofcognitive behavioral therapy (CBT) andpharmacological treatment in older adultsexperiencing chronic primary insomnia. DESIGN,SETTING, AND PARTICIPANTS A randomized,double-blinded, placebo-controlled trial of 46adults (mean age, 60.8 y; 22 women) withchronic primary insomnia conducted betweenJanuary 2004 and December 2005 in a singleNorwegian university-based outpatient clinic foradults and elderly patients. INTERVENTION CBT", "metadata": {}}
+{"_id": "5914739", "title": "", "text": "Local changes in lipid environment of TCRmicroclusters regulate membrane binding by theCD3ε cytoplasmic domainThe CD3ε and ζcytoplasmic domains of the T cell receptor bindto the inner leaflet of the plasma membrane(PM), and a previous nuclear magnetic resonancestructure showed that both tyrosines of the CD3εimmunoreceptor tyrosine-based activation motifpartition into the bilayer. Electrostaticinteractions between acidic phospholipids andclusters of basic CD3ε residues were previouslyshown to be essential for CD3ε and ζ membranebinding. Phosphatidylserine (PS) is the mostabundant negatively charged lipid on the innerleaflet of the PM and makes a major contributionto membrane binding by the CD3ε cytoplasmicdomain. Here, we show that TCR triggering bypeptide--MHC complexes induces dissociation ofthe CD3ε cytoplasmic domain from the plasmamembrane. Release of the CD3ε cytoplasmicdomain from the membrane is accompanied by asubstantial focal reduction in negative charge", "metadata": {}}
+{"_id": "5921065", "title": "", "text": "Humans and great apes share a large frontalcortexSome of the outstanding cognitivecapabilities of humans are commonly attributedto a disproportionate enlargement of the humanfrontal lobe during evolution. This claim is basedprimarily on comparisons between the brains ofhumans and of other primates, to the exclusionof most great apes. We compared the relativesize of the frontal cortices in living specimens ofseveral primate species, including all extanthominoids, using magnetic resonance imaging.Human frontal cortices were notdisproportionately large in comparison to thoseof the great apes. We suggest that the specialcognitive abilities attributed to a frontaladvantage may be due to differences inindividual cortical areas and to a richerinterconnectivity, none of which required anincrease in the overall relative size of the frontallobe during hominid evolution.", "metadata": {}}
+{"_id": "5922085", "title": "", "text": "Virus-Plus-Susceptibility Gene InteractionDetermines Crohn's Disease Gene Atg16L1Phenotypes in IntestineIt is unclear why diseaseoccurs in only a small proportion of personscarrying common risk alleles of diseasesusceptibility genes. Here we demonstrate thatan interaction between a specific virus infectionand a mutation in the Crohn's diseasesusceptibility gene Atg16L1 induces intestinalpathologies in mice. This virus-plus-susceptibilitygene interaction generated abnormalities ingranule packaging and unique patterns of geneexpression in Paneth cells. Further, the responseto injury induced by the toxic substance dextransodium sulfate was fundamentally altered toinclude pathologies resembling aspects ofCrohn's disease. These pathologies triggered byvirus-plus-susceptibility gene interaction weredependent on TNFalpha and IFNgamma andwere prevented by treatment with broadspectrum antibiotics. Thus, we provide a specificexample of how a virus-plus-susceptibility gene", "metadata": {}}
+{"_id": "5927534", "title": "", "text": "CaMKII Triggers the Diffusional Trapping ofSurface AMPARs through Phosphorylation ofStargazinThe Ca(2+)/calmodulin-dependentprotein kinase II (CaMKII) is critically requiredfor the synaptic recruitment of AMPA-typeglutamate receptors (AMPARs) during bothdevelopment and plasticity. However, theunderlying mechanism is unknown. Usingsingle-particle tracking of AMPARs, we show thatCaMKII activation and postsynaptic translocationinduce the synaptic trapping of AMPARs diffusingin the membrane. AMPAR immobilizationrequires both phosphorylation of the auxiliarysubunit Stargazin and its binding to PDZ domainscaffolds. It does not depend on the PDZ bindingdomain of GluA1 AMPAR subunit nor itsphosphorylation at Ser831. Finally,CaMKII-dependent AMPAR immobilizationregulates short-term plasticity. Thus,NMDA-dependent Ca(2+) influx in thepost-synapse triggers a CaMKII- andStargazin-dependent decrease in AMPAR", "metadata": {}}
+{"_id": "5935987", "title": "", "text": "Epigenetics in diabetic nephropathy, immunityand metabolismWhen it comes to theepigenome, there is a fine line between clarityand confusion-walk that line and you willdiscover another fascinating level of transcriptioncontrol. With the genetic code representing thecornerstone of rules for information that isencoded to proteins somewhere above thegenome level there is a set of rules by whichchemical information is also read. Theseepigenetic modifications show a different side ofthe genetic code that is diverse and regulated,hence modifying genetic transcriptiontransiently, ranging from short- to long-termalterations. While this complexity bringsexquisite control it also poses a formidablechallenge to efforts to decode mechanismsunderlying complex disease. Recenttechnological and computational advances haveimproved unbiased acquisition of epigenomicpatterns to improve our understanding of thecomplex chromatin landscape. Key to resolving", "metadata": {}}
+{"_id": "5939172", "title": "", "text": "Drinking pattern and mortality: the Italian RiskFactor and Life Expectancy poolingproject.PURPOSE To analyze the relationshipbetween an aspect of drinking pattern (i.e.,drinking with or without meals) and risk ofall-cause and specific-cause mortality. METHODSThe Risk Factors and Life Expectancy Study, is apooling of a series of epidemiological studiesconducted in Italy. Eight-thousand six-hundredand forty-seven men and 6521 women, age30-59 at baseline, and free of cardiovasculardisease, were followed for mortality from allcauses, cardiovascular and noncardiovascular,during an average follow-up of 7 years. RESULTSDrinkers of wine outside meals exhibited higherdeath rates from all causes, noncardiovasculardiseases, and cancer, as compared to drinkers ofwine with meals. This association wasindependent from the cardiovascular disease(CVD) risk factors measured at baseline and theamount of alcohol consumed and seemed to bestronger in women as compared to men.", "metadata": {}}
+{"_id": "5944514", "title": "", "text": "Pointing in the right direction: new developmentsin the field of planar cell polarityPlanar cellpolarity (PCP) is observed in an array ofdevelopmental processes that involve collectivecell movement and tissue organization, and itsdisruption can lead to severe developmentaldefects. Recent studies in flies and vertebrateshave identified new functions for PCP as well asnew signalling components, and have proposednew mechanistic models. However, despite thisprogress, the search to simplify principles ofunderstanding continues and importantmechanistic uncertainties still pose formidablechallenges.", "metadata": {}}
+{"_id": "5953485", "title": "", "text": "ADAR1 Forms a Complex with Dicer to PromoteMicroRNA Processing and RNA-Induced GeneSilencingAdenosine deaminases acting on RNA(ADARs) are involved in RNA editing thatconverts adenosine residues to inosinespecifically in double-stranded RNAs. In thisstudy, we investigated the interaction of the RNAediting mechanism with the RNA interference(RNAi) machinery and found that ADAR1 forms acomplex with Dicer through directprotein-protein interaction. Most importantly,ADAR1 increases the maximum rate (Vmax) ofpre-microRNA (miRNA) cleavage by Dicer andfacilitates loading of miRNA onto RNA-inducedsilencing complexes, identifying a new role ofADAR1 in miRNA processing and RNAimechanisms. ADAR1 differentiates its functionsin RNA editing and RNAi by the formation ofeither ADAR1/ADAR1 homodimer orDicer/ADAR1 heterodimer complexes,respectively. As expected, the expression ofmiRNAs is globally inhibited in ADAR1(-/-) mouse", "metadata": {}}
+{"_id": "5956016", "title": "", "text": "Interchangeability of Biosimilars: A EuropeanPerspectiveMany of the best-selling ‘blockbuster’biological medicinal products are, or will soon be,facing competition from similar biologicalmedicinal products (biosimilars) in the EU.Biosimilarity is based on the comparabilityconcept, which has been used successfully forseveral decades to ensure close similarity of abiological product before and after amanufacturing change. Over the last 10 years,experience with biosimilars has shown that evencomplex biotechnology-derived proteins can becopied successfully. Most best-selling biologicalsare used for chronic treatment. This hastriggered intensive discussion on theinterchangeability of a biosimilar with itsreference product, with the main concern beingimmunogenicity. We explore the theoretical basisof the presumed risks of switching between abiosimilar and its reference product and theavailable data on switches. Our conclusion is thata switch between comparable versions of the", "metadata": {}}
+{"_id": "5956380", "title": "", "text": "Exome sequencing identifies somaticgain-of-function PPM1D mutations in brainstemgliomasGliomas arising in the brainstem andthalamus are devastating tumors that aredifficult to surgically resect. To determine thegenetic and epigenetic landscape of thesetumors, we performed exomic sequencing of 14brainstem gliomas (BSGs) and 12 thalamicgliomas. We also performed targeted mutationalanalysis of an additional 24 such tumors andgenome-wide methylation profiling of 45gliomas. This study led to the discovery oftumor-specific mutations in PPM1D, encodingwild-type p53-induced protein phosphatase 1D(WIP1), in 37.5% of the BSGs that harboredhallmark H3F3A mutations encoding p. Lys27Metsubstitutions. PPM1D mutations were mutuallyexclusive with TP53 mutations in BSG andattenuated p53 activation in vitro. PPM1Dmutations were truncating alterations in exon 6that enhanced the ability of PPM1D to suppressthe activation of the DNA damage response", "metadata": {}}
+{"_id": "5966635", "title": "", "text": "Crystal structure of a nucleosome core particlecontaining the variant histone H2A.ZActivation oftranscription within chromatin has beencorrelated with the incorporation of the essentialhistone variant H2A.Z into nucleosomes. H2A.Zand other histone variants may establishstructurally distinct chromosomal domains;however, the molecular mechanism by whichthey function is largely unknown. Here we reportthe 2.6 Å crystal structure of a nucleosome coreparticle containing the histone variant H2A.Z.The overall structure is similar to that of thepreviously reported 2.8 Å nucleosome structurecontaining major histone proteins. However,distinct localized changes result in the subtledestabilization of the interaction between the(H2A.Z–H2B) dimer and the (H3–H4)2 tetramer.Moreover, H2A.Z nucleosomes have an alteredsurface that includes a metal ion. This alteredsurface may lead to changes in higher orderstructure, and/or could result in the associationof specific nuclear proteins with H2A.Z. Finally,", "metadata": {}}
+{"_id": "5979056", "title": "", "text": "Dendritic Cell KLF2 Expression Regulates T CellActivation and Proatherogenic ImmuneResponses.Dendritic cells (DCs) have beenimplicated as important regulators of innate andadaptive inflammation in many diseases,including atherosclerosis. However, themolecular mechanisms by which DCs mitigate orpromote inflammatory pathogenesis are onlypartially understood. Previous studies haveshown an important anti-inflammatory role forthe transcription factor Krüppel-like factor 2(KLF2) in regulating activation of various celltypes that participate in atherosclerotic lesiondevelopment, including endothelial cells,macrophages, and T cells. We used a pan-DC,CD11c-specific cre-lox gene knockout mousemodel to assess the role of KLF2 in DCactivation, function, and control of inflammationin the context of hypercholesterolemia andatherosclerosis. We found that KLF2 deficiencyenhanced surface expression of costimulatorymolecules CD40 and CD86 in DCs and promoted", "metadata": {}}
+{"_id": "5991309", "title": "", "text": "Targeting tumor-necrosis factor receptorpathways for tumor immunotherapyWith thesuccess of ipilimumab and promise ofprogrammed death-1 pathway-targeted agents,the field of tumor immunotherapy is expandingrapidly. Newer targets for clinical developmentinclude select members of the tumor necrosisfactor receptor (TNFR) family. Agonist antibodiesto these co-stimulatory molecules target both Tand B cells, modulating T-cell activation andenhancing immune responses. In vitro and invivo preclinical data have provided the basis forcontinued development of 4-1BB, OX40,glucocorticoid-induced TNFR-related gene,herpes virus entry mediator, and CD27 aspotential therapies for patients with cancer. Inthis review, we summarize the immune responseto tumors, consider preclinical and early clinicaldata on select TNFR family members, discusspotential translational challenges and suggestpossible combination therapies with the aim ofinducing durable antitumor responses.", "metadata": {}}
+{"_id": "5993745", "title": "", "text": "Plasma soluble corin in patients with heartfailure.BACKGROUND Corin is a transmembraneprotease that processes natriuretic peptides inthe heart. Like many membrane proteins, corinis shed from the cell surface. METHODS ANDRESULTS In this study, we obtained plasmasamples from healthy controls and patients withheart failure (HF) and acute myocardialinfarction. Soluble corin levels in plasma weremeasured by an ELISA method. In healthy adults(n=198), plasma corin levels were 690 pg/mL(SD, 260 pg/mL). The corin levels did not differsignificantly among different age groups. Inpatients with HF (n=291), plasma corin levelswere significantly lower compared with that ofhealthy controls (365 pg/mL [SD, 259];P<0.001). The reduction in plasma corin levelsseemed to correlate with the severity of HF. Inpatients of New York Heart Association classesII, III, and IV, plasma corin levels were 450pg/mL (SD, 281 pg/mL; n=69), 377 pg/mL (SD,270 pg/mL; n=132), and 282 pg/mL (SD, 194", "metadata": {}}
+{"_id": "6000423", "title": "", "text": "The NLRP3 inflammasome functions as a driverof the myelodysplastic syndromephenotype.Despite genetic heterogeneity,myelodysplastic syndromes (MDSs) sharefeatures of cytological dysplasia and ineffectivehematopoiesis. We report that a hallmark ofMDSs is activation of the NLRP3 inflammasome,which drives clonal expansion and pyroptotic celldeath. Independent of genotype, MDShematopoietic stem and progenitor cells (HSPCs)overexpress inflammasome proteins andmanifest activated NLRP3 complexes that directactivation of caspase-1, generation ofinterleukin-1β (IL-1β) and IL-18, and pyroptoticcell death. Mechanistically, pyroptosis istriggered by the alarmin S100A9 that is found inexcess in MDS HSPCs and bone marrow plasma.Further, like somatic gene mutations,S100A9-induced signaling activates NADPHoxidase (NOX), increasing levels of reactiveoxygen species (ROS) that initiate cation influx,cell swelling, and β-catenin activation. Notably,", "metadata": {}}
+{"_id": "6036535", "title": "", "text": "Structural Brain Correlates Associated withProfessional Handball PlayingBACKGROUNDThere is no doubt that good bimanualperformance is very important for skilledhandball playing. The control of thenon-dominant hand is especially demandingsince efficient catching and throwing needs bothhands. METHODOLOGY/HYPOTHESES Weinvestigated training-induced structuralneuroplasticity in professional handball playersusing several structural neuroimaging techniquesand analytic approaches and also provide areview of the literature about sport-inducedstructural neuroplastic alterations. Structuralbrain adaptations were expected in regionsrelevant for motor and somatosensoryprocessing such as the grey matter (GM) of theprimary/secondary motor (MI/supplementarymotor area, SMA) and somatosensory cortex(SI/SII), basal ganglia, thalamus, andcerebellum and in the white matter (WM) of thecorticospinal tract (CST) and corpus callosum,", "metadata": {}}
+{"_id": "6040392", "title": "", "text": "The role of epigenetics in aging and age-relateddiseasesThe role of epigenetics in aging andage-related diseases is a key issue in molecularphysiology and medicine because certainepigenetic factors are thought to mediate, atleast in part, the relationship between thegenome and the environment. An active role forepigenetics in aging must meet two priorconditions: there must be specific epigeneticchanges during aging and they must befunctionally associated with the aged phenotype.Assuming that specific epigenetic modificationscan have a direct functional outcome in aging, itis also essential to establish whether theydepend on genetic, environmental or stochasticfactors, and if they can be transmitted from onegeneration to the next. Here we discuss currentknowledge about these matters and futuredirections in the field.", "metadata": {}}
+{"_id": "6042706", "title": "", "text": "Effects of a high-fat diet exposure in utero on themetabolic syndrome-like phenomenon in mouseoffspring through epigenetic changes inadipocytokine gene expression.The links betweenobesity in parents and their offspring and therole of genes and a shared environment are notcompletely understood. Adipocytokines such asleptin and adiponectin play important roles inglucose and lipid metabolism. Therefore, weexamined whether the offspring from damsexposed to a high-fat diet during pregnancy (OHmice) exhibited hypertension, insulin resistance,and hyperlipidemia along with epigeneticchanges in the expression of adipocytokinegenes. OH mice were significantly heavier thanthe offspring of dams exposed to a control dietduring pregnancy (OC mice) from 14 wk of ageafter an increased caloric intake from 8 wk. OHmice exhibited higher blood pressure and worseglucose tolerance than the OC mice at 24 wk.Total triglyceride and leptin levels weresignificantly higher and the adiponectin level was", "metadata": {}}
+{"_id": "6054657", "title": "", "text": "Highly efficient miRNA-mediated reprogrammingof mouse and human somatic cells topluripotency.Transcription factor-based cellularreprogramming has opened the way toconverting somatic cells to a pluripotent state,but has faced limitations resulting from therequirement for transcription factors and therelative inefficiency of the process. We show herethat expression of the miR302/367 clusterrapidly and efficiently reprograms mouse andhuman somatic cells to an iPSC state without arequirement for exogenous transcription factors.This miRNA-based reprogramming approach istwo orders of magnitude more efficient thanstandard Oct4/Sox2/Klf4/Myc-mediatedmethods. Mouse and human miR302/367 iPSCsdisplay similar characteristics toOct4/Sox2/Klf4/Myc-iPSCs, includingpluripotency marker expression, teratomaformation, and, for mouse cells, chimeracontribution and germline contribution. We foundthat miR367 expression is required for", "metadata": {}}
+{"_id": "6057195", "title": "", "text": "Unmet needs and depression among carers ofpeople newly diagnosed with cancer.AIMS Theaims of this analysis were to examine levels ofunmet needs and depression among carers ofpeople newly diagnosed with cancer and toidentify groups who may be at higher risk, byexamining relationships with demographiccharacteristics. METHODS One hundred and fiftydyads of people newly diagnosed with cancer andtheir carers, aged 18 years and older, wererecruited from four Australian hospitals. Peoplewith cancer receiving adjuvant cancer treatmentwith curative intent, were eligible to participate.Carers completed the Supportive Care NeedsSurvey-Partners & Caregivers (SCNS-P&C45),and both carers and patients completed theCentre of Epidemiologic-Depression Scale(CES-D). RESULTS Overall, 57% of carersreported at least one, 37% at least three, 31%at least five, and 15% at least 10 unmet needs;the most commonly endorsed unmet needs werein the domains of information and health care", "metadata": {}}
+{"_id": "6061927", "title": "", "text": "Glucose Sensing in L Cells: A Primary CellStudyGlucagon-like peptide-1 (GLP-1) is anenteric hormone that stimulates insulin secretionand improves glycaemia in type 2 diabetes.Although GLP-1-based treatments are clinicallyavailable, alternative strategies to increaseendogenous GLP-1 release from L cells arehampered by our limited physiologicalunderstanding of this cell type. By generatingtransgenic mice with L cell-specific expression ofa fluorescent protein, we studied thecharacteristics of primary L cells byelectrophysiology, fluorescence calcium imaging,and expression analysis and show that single Lcells are electrically excitable and glucoseresponsive. Sensitivity to tolbutamide andlow-millimolar concentrations of glucose andalpha-methylglucopyranoside, assessed in singleL cells and by hormone secretion from primarycultures, suggested that GLP-1 release isregulated by the activity of sodium glucosecotransporter 1 and ATP-sensitive K(+)", "metadata": {}}
+{"_id": "6070278", "title": "", "text": "Total atherosclerotic burden by whole bodymagnetic resonance angiography predicts majoradverse cardiovascular events.OBJECTIVE Thepurpose of the present study was to investigatethe relationship between the TotalAtherosclerotic Score (TAS), a measurement ofthe overall atherosclerotic burden of the arterialtree by whole body magnetic resonanceangiography (WBMRA), and the risk of majoradverse cardiovascular events (MACE), definedas cardiac death, myocardial infarction, strokeand/or coronary revascularization, assuming thatTAS predicts MACE. METHODS AND RESULTS305 randomly selected 70 year-old subjects(47% women) underwent WBMRA. Theiratherosclerotic burden was evaluated and TAS >0, that is atherosclerotic changes, were found in68% of subjects. During follow-up (mean 4.8years), MACE occurred in 25 subjects (8.2%).Adjusting for multiple risk factors, TAS wasassociated with MACE (OR 8.86 for any degree ofvessel lumen abnormality, 95%CI 1.14-69.11, p", "metadata": {}}
+{"_id": "6076903", "title": "", "text": "Regulation of ADMP and BMP2/4/7 at OppositeEmbryonic Poles Generates a Self-RegulatingMorphogenetic FieldEmbryos have the ability toself-regulate and regenerate normal structuresafter being sectioned in half. How is such amorphogenetic field established? We discoveredthat quadruple knockdown of ADMP andBMP2/4/7 in Xenopus embryos eliminatesself-regulation, causing ubiquitous neuralinduction throughout the ectoderm. ADMPtranscription in the Spemann organizer isactivated at low BMP levels. When ventralBMP2/4/7 signals are depleted, Admp expressionincreases, allowing for self-regulation. ADMP hasBMP-like activity and signals via the ALK-2receptor. It is unable to signal dorsally becauseof inhibition by Chordin. The ventral BMPantagonists Sizzled and Bambi further refine thepattern. By transplanting dorsal or ventralwild-type grafts into ADMP/BMP2/4/7-depletedhosts, we demonstrate that both poles serve assignaling centers that can induce histotypic", "metadata": {}}
+{"_id": "6077214", "title": "", "text": "Genetic control of mosquitoes.Genetics canpotentially provide new, species-specific,environmentally friendly methods for mosquitocontrol. Genetic control strategies aim either tosuppress target populations or to introduce aharm-reducing novel trait. Different approachesdiffer considerably in their properties, especiallybetween self-limiting strategies, where themodification has limited persistence, andself-sustaining strategies, which are intended topersist indefinitely in the target population andmay invade other populations. Several methodswith different molecular biology are underdevelopment and the first field trials have beencompleted successfully.", "metadata": {}}
+{"_id": "6078882", "title": "", "text": "Colorectal Cancers from Distinct AncestralPopulations Show Variations in BRAF MutationFrequencyIt has been demonstrated for somecancers that the frequency of somatic oncogenicmutations may vary in ancestral populations. Todetermine whether key driver alterations mightoccur at different frequencies in colorectalcancer, we applied a high-throughput genotypingplatform (OncoMap) to query 385 mutationsacross 33 known cancer genes in colorectalcancer DNA from 83 Asian, 149 Black and 195White patients. We found that Asian patients hadfewer canonical oncogenic mutations in thegenes tested (60% vs Black 79% (P = 0.011)and White 77% (P = 0.015)), and that BRAFmutations occurred at a higher frequency inWhite patients (17% vs Asian 4% (P = 0.004)and Black 7% (P = 0.014)). These resultssuggest that the use of genomic approaches toelucidate the different ancestral determinantsharbored by patient populations may help tomore precisely and effectively treat colorectal", "metadata": {}}
+{"_id": "6079486", "title": "", "text": "Direct neuronal reprogramming: learning fromand for development.The key signallingpathways and transcriptional programmes thatinstruct neuronal diversity during developmenthave largely been identified. In this Review, wediscuss how this knowledge has been used tosuccessfully reprogramme various cell types intoan amazing array of distinct types of functionalneurons. We further discuss the extent to whichdirect neuronal reprogramming recapitulatesembryonic development, and examine theparticular barriers to reprogramming that mayexist given a cell's unique developmental history.We conclude with a recently proposed model forcell specification called the 'Cook Islands' model,and consider whether it is a fitting model for cellspecification based on recent results from thedirect reprogramming field.", "metadata": {}}
+{"_id": "6082738", "title": "", "text": "Cell fusion hypothesis of the cancer stem cell.Amajor advance in recent cancer research is theidentification of tumor cells with stem cell-likeproperties. Cancer stem cells (CSCs) oftenrepresent a rare population in the tumor massand possess the exclusive ability to initiate thegrowth of a heterogeneous tumor. The origin ofCSCs remains elusive and is likely to be cancertype specific. One possible but under-appreciatedpotential mechanism for the generation of CSCsis through fusion between stem cells anddifferentiated cells. The cell fusion hypothesis ofCSCs adds an important functional underpinningto the potential multifaceted roles of cell fusionin the initiation and progression of cancer.", "metadata": {}}
+{"_id": "6083952", "title": "", "text": "Antidepressant fluoxetine enhancesglucocorticoid receptor function in vitro bymodulating membrane steroid transporters.1.Incubation of LMCAT fibroblast cells withantidepressants potentiates glucocorticoidreceptor (GR)-mediated gene transcription in thepresence of dexamethasone and cortisol, but notof corticosterone. We have shown thatantidepressants do so by inhibiting the LMCATcell membrane steroid transporter (which isvirtually identical to the multidrug resistanceP-glycoprotein) and thus by increasingdexamethasone or cortisol intracellularconcentrations. However, previous experimentswith the antidepressant fluoxetine in thepresence of dexamethasone have producednegative results (Pariante et al. (2001). Br. J.Pharmacol., 134, 1335-1343). 2. We have sincere-examined the effects of fluoxetine onGR-mediated gene transcription in the presenceof dexamethasone. Moreover, we have examinedthe effects of fluoxetine on GR-mediated gene", "metadata": {}}
+{"_id": "6085365", "title": "", "text": "Physician knowledge levels and barriers tocoronary risk prevention in women: surveyresults from the Women and Heart DiseasePhysician Education Initiative.BACKGROUND Fewstudies have examined whether physicianknowledge, attitudes, or practice patterns mightcontribute to gender disparities in the primaryprevention of coronary heart disease (CHD),including among physicians caring for the largestnumber of reproductive-age women,obstetricians and gynecologists (OB/GYNs). Wesought to identify barriers affecting the provisionof recommended coronary risk factor therapies inwomen. METHODS We surveyed internists andOB/GYNs who attended Grand Roundspresentations developed for the New York StateWomen and Heart Disease Physician EducationInitiative. This program was designed to improvescreening and management of coronary riskfactors in women. Attendees were asked tocomplete a 7-minute questionnaire. RESULTSThe mean age of the 529 respondents was 40.3", "metadata": {}}
+{"_id": "6106004", "title": "", "text": "Separation of mother and daughtercells.Publisher Summary The budding yeastSaccharomyces cerevisiae ( S. cerevisiae )divides asymmetrically. In vegetative growth,yeast cells reproduce by budding, and theposition where the bud forms ultimatelydetermines the plane of cell division. Thischapter describes the detailed procedures for theseparation and isolation of mothers anddaughters. These protocols have been used byinvestigators studying aging, bud site selection,and other aspects of asymmetric cell division.The chapter describes the procedures forperforming life span analysis bymicromanipulation and the steps for thelarge-scale collection of old cells. At thebeginning and the end of a life span, it can bedifficult to distinguish mothers from daughters.At most points in the life span, daughter cells aresmaller than the mothers that produced them. Inaddition, mother cells will generally bud a secondtime before their daughter cells form their first", "metadata": {}}
+{"_id": "6108481", "title": "", "text": "Postnatal development of adipocyte cellularity inthe normal rat.It has been shown by severalinvestigators that adipocyte number is stable inmature human beings and several species ofrodents. Although the number of new cellsappearing in the adipose depot can be measuredhistometrically and by Coulter counting ofosmium-fixed cells, such methods do notdistinguish between \"lipid filling\" of preexistentadipocytes and synthesis of new adipocytes. Theexperiments reported here using in vivo injectionof [(3)H]thymidine show that synthesis of newadipocytes in the Sprague-Dawley rat continuesafter birth and ceases before sexual maturity.Furthermore, during the second and thirdpostnatal weeks, a \"bed\" of preadipocytes issynthesized. Preadipocytes may take as long as30 days to appear as mature adipocytes.", "metadata": {}}
+{"_id": "6112053", "title": "", "text": "Withdrawal Symptoms after Selective SerotoninReuptake Inhibitor Discontinuation: A SystematicReviewBackground: Selective serotonin reuptakeinhibitors (SSRI) are widely used in medicalpractice. They have been associated with a broadrange of symptoms, whose clinical meaning hasnot been fully appreciated. Methods: ThePRISMA guidelines were followed to conduct asystematic review of the literature. Titles,abstracts, and topics were searched using thefollowing terms: ‘withdrawal symptoms' OR‘withdrawal syndrome' OR ‘discontinuationsyndrome' OR ‘discontinuation symptoms', AND‘SSRI' OR ‘serotonin' OR ‘antidepressant' OR‘paroxetine' OR ‘fluoxetine' OR ‘sertraline' OR‘fluvoxamine' OR ‘citalopram' OR ‘escitalopram'.The electronic research literature databasesincluded CINAHL, the Cochrane Library, PubMedand Web-of-Science from inception of eachdatabase to July 2014. Results: There were 15randomized controlled studies, 4 open trials, 4retrospective investigations, and 38 case reports.", "metadata": {}}
+{"_id": "6121555", "title": "", "text": "Sphingosine Kinase 1 Regulates theAkt/FOXO3a/Bim Pathway and Contributes toApoptosis Resistance in Glioma CellsThe aim ofthis study was to investigate the mechanismthrough which Sphingosine kinase-1 (SPHK1)exerts its anti-apoptosis activity in glioma cancercells. We here report that dysregulation ofSPHK1 alters the sensitivity of glioma toapoptosis both in vitro and in vivo. Furthermechanistic study examined the expression ofBcl-2 family members, including Bcl-2, Mcl-1,Bax and Bim, in SPHK1-overexpressing gliomacells and revealed that only pro-apoptotic Bimwas downregulated by SPHK1. Moreover, thetranscriptional level of Bim was also altered bySPHK1 in glioma cells. We next confirmed thecorrelation between SPHK1 and Bim expressionin primary glioma specimens. Importantly,increasing SPHK1 expression in glioma cellsmarkedly elevated Akt activity andphosphorylated inactivation of FOXO3a, whichled to downregulation of Bim. A pharmacological", "metadata": {}}
+{"_id": "6121668", "title": "", "text": "COX-2 and survivin are overexpressed andpositively correlated in endometrialcarcinoma.OBJECTIVES To investigate theexpressions of survivin and Cyclooxygenase-2(COX-2), and their possible correlations in thedevelopment of endometrial adenocarcinoma(EC). We also looked at their association withclassical prognostic factors in EC. To ourknowledge, this is the first time survivinexpression is investigated in terms of its relationto COX-2 in the developmental pathway of EC.METHODS Archived tissue samples of 50 EC, 30endometrial hyperplasia and 20 proliferativeendometrium were selected andimmunohistochemically analyzed for survivin andCOX-2 expression. RESULTS Both survivin andCOX-2 were overexpressed in hyperplasia andendometrial adenocarcinoma cases compared toproliferative endometrium, which wasstatistically significant (p=0.01, p=0.02,respectively). Among EC cases, survivin andCOX-2 were strongly positive in 38 (76%) and 30", "metadata": {}}
+{"_id": "6123521", "title": "", "text": "Structural plasticity of the adult brain: howanimal models help us understand brain changesin depression and systemic disorders related todepressionThe brain interprets experiences andtranslates them into behavioral and physiologicalresponses. Stressful events are those which arethreatening or, at the very least, unexpected andsurprising, and the physiological and behavioralresponses are intended to promote adaptationvia a process called \"allostasis. \" Chemicalmediators of allostasis include cortisol andadrenalin from the adrenal glands, otherhormones, and neurotransmitters, theparasympathetic and sympathetic nervoussystems, and cytokines and chemokines from theimmune system. Two brain structures, theamygdala and hippocampus, play key roles ininterpreting what is stressful and determiningappropriate responses. The hippocampus, a keystructure for memories of events and contexts,expresses receptors that enable it to respond toglucocorticoid hormones in the blood, it", "metadata": {}}
+{"_id": "6123924", "title": "", "text": "CCR7 provides localized access to IL-2 anddefines homeostatically distinct regulatory T cellsubsetsImmune tolerance and activation dependon precise control over the number and functionof immunosuppressive Foxp3(+) regulatory T (Treg) cells, and the importance of IL-2 inmaintaining tolerance and preventingautoimmunity is clear. However, the homeostaticrequirement for IL-2 among specific populationsof peripheral T reg cells remains poorlyunderstood. We show that IL-2 selectivelymaintains a population of quiescentCD44(lo)CD62L(hi) T reg cells that gain access toparacrine IL-2 produced in the T cell zones ofsecondary lymphoid tissues due to theirexpression of the chemokine receptor CCR7. Incontrast, CD44(hi)CD62L(lo)CCR7(lo) T reg cellsthat populate nonlymphoid tissues do not accessIL-2-prevalent regions in vivo and are insensitiveto IL-2 blockade; instead, their maintenancedepends on continued signaling through theco-stimulatory receptor ICOS (inducible", "metadata": {}}
+{"_id": "6128334", "title": "", "text": "Assessing sequence comparison methods withreliable structurally identified distantevolutionary relationships.Pairwise sequencecomparison methods have been assessed usingproteins whose relationships are known reliablyfrom their structures and functions, as describedin the SCOP database [Murzin, A. G., Brenner, S.E., Hubbard, T. & Chothia C. (1995) J. Mol. Biol.247, 536-540]. The evaluation tested theprograms BLAST [Altschul, S. F., Gish, W., Miller,W., Myers, E. W. & Lipman, D. J. (1990). J. Mol.Biol. 215, 403-410], WU-BLAST2 [Altschul, S. F.& Gish, W. (1996) Methods Enzymol. 266,460-480], FASTA [Pearson, W. R. & Lipman, D.J. (1988) Proc. Natl. Acad. Sci. USA 85,2444-2448], and SSEARCH [Smith, T. F. &Waterman, M. S. (1981) J. Mol. Biol. 147,195-197] and their scoring schemes. The errorrate of all algorithms is greatly reduced by usingstatistical scores to evaluate matches rather thanpercentage identity or raw scores. The E-valuestatistical scores of SSEARCH and FASTA are", "metadata": {}}
+{"_id": "6129301", "title": "", "text": "Evaluation of a mental health outreach servicefor homeless families.AIMS To describe thecharacteristics of homeless children and familiesseen by the mental health outreach service(MHOS), to evaluate the impact of this service onthe short term psychosocial functioning ofchildren and parents, and to establishperceptions of, and satisfaction with, the service.METHODS Twenty seven children from 23families who were in receipt of the MHOS and 27children from 23 families residing in otherhostels where no such service was available werestudied. The MHOS was delivered by a clinicalnurse specialist with expertise in child mentalhealth, who offered the following interventions:assessment and brief treatment of mental healthdisorders in children; liaison with agencies; andtraining of homeless centre staff. RESULTSChildren in the experimental group had asignificantly higher decrease in Strengths andDifficulties Questionnaire (SDQ) total scores.Having received the intervention was the", "metadata": {}}
+{"_id": "6137330", "title": "", "text": "Evaluation of individuals with pulmonarynodules: when is it lung cancer? Diagnosis andmanagement of lung cancer, 3rd ed: AmericanCollege of Chest Physicians evidence-basedclinical practice guidelines.OBJECTIVES Theobjective of this article is to update previousevidence-based recommendations for evaluationand management of individuals with solidpulmonary nodules and to generate newrecommendations for those with nonsolidnodules. METHODS We updated prior literaturereviews, synthesized evidence, and formulatedrecommendations by using the methodsdescribed in the \"Methodology for Developmentof Guidelines for Lung Cancer\" in the AmericanCollege of Chest Physicians Lung CancerGuidelines, 3rd ed. RESULTS We formulatedrecommendations for evaluating solid pulmonarynodules that measure > 8 mm in diameter, solidnodules that measure ≤ 8 mm in diameter, andsubsolid nodules. The recommendations stressthe value of assessing the probability of", "metadata": {}}
+{"_id": "6144337", "title": "", "text": "AgDscam, a Hypervariable ImmunoglobulinDomain-Containing Receptor ofthe       Anopheles gambiae Innate ImmuneSystemActivation of the insect innate immunesystem is dependent on a limited number ofpattern recognition receptors (PRRs) capable ofinteracting with pathogen-associated molecularpattern. Here we report a novel role of analternatively spliced hypervariableimmunoglobulin domain-encoding gene, Dscam,in generating a broad range of PRRs implicated inimmune defense in the malaria vector Anophelesgambiae. The mosquito Down syndrome celladhesion molecule gene, AgDscam, has acomplex genome organization with 101 exonsthat can produce over 31,000 potentialalternative splice forms with differentcombinations of adhesive domains andinteraction specificities. AgDscam responds toinfection by producing pathogenchallenge-specific splice form repertoires.Transient silencing of AgDscam compromises the", "metadata": {}}
+{"_id": "6144969", "title": "", "text": "Enterovirus-induced gene expression profile iscritical for human pancreatic isletdestructionVirally induced inflammatoryresponses, beta cell destruction and release ofbeta cell autoantigens may lead to autoimmunereactions culminating in type 1 diabetes.Therefore, viral capability to induce beta celldeath and the nature of virus-induced immuneresponses are among key determinants ofdiabetogenic viruses. We hypothesised thatenterovirus infection induces a specific geneexpression pattern that results in isletdestruction and that such a host responsepattern is not shared among all enterovirusinfections but varies between virus strains. Thechanges in global gene expression and secretedcytokine profiles induced by lytic or benignenterovirus infections were studied in primaryhuman pancreatic islet using DNA microarraysand viral strains either isolated at the clinicalonset of type 1 diabetes or capable of causing adiabetes-like condition in mice. The expression of", "metadata": {}}
+{"_id": "6148876", "title": "", "text": "Islet1 derivatives in the heart are of both neuralcrest and second heart field origin.RATIONALEIslet1 (Isl1) has been proposed as a marker ofcardiac progenitor cells derived from the secondheart field and is utilized to identify and purifycardiac progenitors from murine and humanspecimens for ex vivo expansion. The use of Isl1as a specific second heart field marker isdependent on its exclusion from other cardiaclineages such as neural crest. OBJECTIVEDetermine whether Isl1 is expressed by cardiacneural crest. METHODS AND RESULTS We usedan intersectional fate-mapping system using theRC::FrePe allele, which reports dual Flpe and Crerecombination. Combining Isl1(Cre/+), a SHFdriver, and Wnt1::Flpe, a neural crest driver,with Rc::FrePe reveals that some Isl1 derivativesin the cardiac outflow tract derive fromWnt1-expressing neural crest progenitors. Incontrast, no overlap was observed betweenWnt1-derived neural crest and an alternativesecond heart field driver, Mef2c-AHF-Cre.", "metadata": {}}
+{"_id": "6153754", "title": "", "text": "Review of the secondary injury theory of acutespinal cord trauma with emphasis on vascularmechanisms.In patients with spinal cord injury,the primary or mechanical trauma seldom causestotal transection, even though the functional lossmay be complete. In addition, biochemical andpathological changes in the cord may worsenafter injury. To explain these phenomena, theconcept of the secondary injury has evolved forwhich numerous pathophysiological mechanismshave been postulated. This paper reviews theconcept of secondary injury with specialemphasis on vascular mechanisms. Evidence ispresented to support the theory of secondaryinjury and the hypothesis that a key mechanismis posttraumatic ischemia with resultantinfarction of the spinal cord. Evidence for the roleof vascular mechanisms has been obtained froma variety of models of acute spinal cord injury inseveral species. Many different angiographicmethods have been used for assessingmicrocirculation of the cord and for measuring", "metadata": {}}
+{"_id": "6157371", "title": "", "text": "Chronophin mediates an ATP-sensing mechanismfor cofilin dephosphorylation and neuronalcofilin-actin rod formation.Actin and its keyregulatory component, cofilin, are found togetherin large rod-shaped assemblies in neuronssubjected to energy stress. Such inclusions arealso enriched in Alzheimer's disease brain, andappear in transgenic models ofneurodegeneration. Neuronal insults, such asenergy loss and/or oxidative stress, result inrapid dephosphorylation of the cellular cofilinpool prior to its assembly into rod-shapedinclusions. Although these events implicate a rolefor phosphatases in cofilin rod formation, amechanism linking energy stress, phosphocofilinturnover, and subsequent rod assembly has beenelusive. We demonstrate the ATP-sensitiveinteraction of the cofilin phosphatase chronophin(CIN) with the chaperone hsp90 to form abiosensor that mediates cofilin/actin rodformation. Our results suggest a model wherebyattenuated interactions between CIN and hsp90", "metadata": {}}
+{"_id": "6157837", "title": "", "text": "Renal considerations in angiotensin convertingenzyme inhibitor therapy: a statement forhealthcare professionals from the Council on theKidney in Cardiovascular Disease and the Councilfor High Blood Pressure Research of theAmerican Heart Association.Angiotensinconverting enzyme (ACE) inhibitors are now oneof the most frequently used classes ofantihypertensive drugs. Beyond their utility inthe management of hypertension, their use hasbeen extended to the long-term management ofpatients with congestive heart failure (CHF), aswell as diabetic and nondiabetic nephropathies.Although ACE inhibitor therapy usually improvesrenal blood flow (RBF) and sodium excretionrates in CHF and reduces the rate of progressiverenal injury in chronic renal disease, its use canalso be associated with a syndrome of “functionalrenal insufficiency” and/or hyperkalemia. Thisform of acute renal failure (ARF) most commonlydevelops shortly after initiation of ACE inhibitortherapy but can be observed after months or", "metadata": {}}
+{"_id": "6158879", "title": "", "text": "Greater clinical benefit of more intensive oralantiplatelet therapy with prasugrel in patientswith diabetes mellitus in the trial to assessimprovement in therapeutic outcomes byoptimizing platelet inhibition withprasugrel-Thrombolysis in Myocardial Infarction38.BACKGROUND Patients with diabetes mellitus(DM) are at high risk for recurrent cardiovascularevents after acute coronary syndromes, in partbecause of increased platelet reactivity. The Trialto Assess Improvement in Therapeutic Outcomesby Optimizing Platelet Inhibition WithPrasugrel-Thrombolysis in Myocardial Infarction38 (TRITON-TIMI 38) showed an overallreduction in ischemic events with more intensiveantiplatelet therapy with prasugrel than withclopidogrel but with more bleeding. Wecompared prasugrel with clopidogrel amongsubjects with DM in TRITON-TIMI 38. METHODSAND RESULTS We classified 13 608 subjects onthe basis of preexisting history of DM and furtheraccording to insulin use. Prespecified analyses of", "metadata": {}}
+{"_id": "6163801", "title": "", "text": "Kinetics of early T cell receptor signaling regulatethe pathway of lytic granule delivery to thesecretory domain.Cytolytic granules mediatekilling of virus-infected cells by cytotoxic Tlymphocytes. We show here that the granulescan take long or short paths to the secretorydomain. Both paths utilized the sameintracellular molecular events, which havedifferent spatial and temporal arrangements andare regulated by the kinetics of Ca(2+)-mediatedsignaling. Rapid signaling caused swift granuleconcentration near the microtubule-organizingcenter (MTOC) and subsequent delivery by thepolarized MTOC directly to the secretorydomain-the shortest path. Indolent signaling ledto late recruitment of granules that moved alongmicrotubules to the periphery of the synapse andthen moved tangentially to fuse at the outeredge of the secretory domain-a longer path. Theshort pathway is associated with faster granulerelease and more efficient killing than the longpathway. Thus, the kinetics of early signaling", "metadata": {}}
+{"_id": "6171953", "title": "", "text": "Sirtuin-1 is a nutrient-dependent modulator ofinflammationInflammation accompanies obesityand its comorbidities-type 2 diabetes,non-alcoholic fatty liver disease andatherosclerosis, among others-and maycontribute to their pathogenesis. Yet the cellularmachinery that links nutrient sensing toinflammation remains incompletelycharacterized. The protein deacetylase sirtuin-1(SirT1) is activated by energy depletion andplays a critical role in the mammalian responseto fasting. More recently it has been implicated inthe repression of inflammation. SirT1 mRNA andprotein expression are suppressed in obeserodent and human white adipose tissue, whileexperimental reduction of SirT1 in adipocytesand macrophages causes low-gradeinflammation that mimics that observed inobesity. Thus suppression of SirT1 duringovernutrition may be critical to the developmentof obesity-associated inflammation. This effect isattributable to multiple actions of SirT1, including", "metadata": {}}
+{"_id": "6173523", "title": "", "text": "A culture-independent sequence-basedmetagenomics approach to the investigation ofan outbreak of Shiga-toxigenic Escherichia coliO104:H4.IMPORTANCE Identification of thebacterium responsible for an outbreak can aid indisease management. However, traditionalculture-based diagnosis can be difficult,particularly if no specific diagnostic test isavailable for an outbreak strain. OBJECTIVE Toexplore the potential of metagenomics, which isthe direct sequencing of DNA extracted frommicrobiologically complex samples, as anopen-ended clinical discovery platform capable ofidentifying and characterizing bacterial strainsfrom an outbreak without laboratory culture.DESIGN, SETTING, AND PATIENTS In aretrospective investigation, 45 samples wereselected from fecal specimens obtained frompatients with diarrhea during the 2011 outbreakof Shiga-toxigenic Escherichia coli (STEC)O104:H4 in Germany. Samples were subjectedto high-throughput sequencing", "metadata": {}}
+{"_id": "6176498", "title": "", "text": "Biomarkers of endothelial dysfunction and risk oftype 2 diabetes mellitus.CONTEXT Endothelialdysfunction occurs in diagnosed type 2 diabetesmellitus but may also precede development ofdiabetes. OBJECTIVE To determine whetherelevated plasma levels of biomarkers reflectingendothelial dysfunction (E-selectin; intercellularadhesion molecule 1 [ICAM-1]; and vascular celladhesion molecule 1 [VCAM-1]) predictdevelopment of type 2 diabetes in initiallynondiabetic women. DESIGN AND SETTINGProspective, nested case-control study within theNurses' Health Study, an ongoing US studyinitiated in 1976. PARTICIPANTS Of 121 700women initially enrolled, 32 826 provided bloodsamples in 1989-1990; of those free of diabetes,cardiovascular disease, or cancer at baseline,737 developed incident diabetes by 2000.Controls (n = 785) were selected according tomatched age, fasting status, and race. MAINOUTCOME MEASURE Risk of confirmed clinicallydiagnosed type 2 diabetes by baseline levels of", "metadata": {}}
+{"_id": "6182947", "title": "", "text": "Nrf2 protects human alveolar epithelial cellsagainst injury induced by influenza AvirusBACKGROUND Influenza A virus (IAV)infection primarily targets respiratory epithelialcells and produces clinical outcomes rangingfrom mild upper respiratory infection to severepneumonia. Recent studies have shown theimportance of lung antioxidant defense systemsagainst injury by IAV. Nuclear factor-erythroid 2related factor 2 (Nrf2) activates the majority ofantioxidant genes. METHODS Alveolar type II(ATII) cells and alveolar macrophages (AM) wereisolated from human lungs not suitable fortransplantation and donated for medicalresearch. In some studies ATII cells weretransdifferentiated to alveolar type I-like(ATI-like) cells. Alveolar epithelial cells wereinfected with A/PR/8/34 (PR8) virus. Weanalyzed PR8 virus production, influenza Anucleoprotein levels, ROS generation andexpression of antiviral genes.Immunocytofluorescence was used to determine", "metadata": {}}
+{"_id": "6190603", "title": "", "text": "Dynamics in the plasma membrane: how tocombine fluidity and order.Cell membranes arefascinating supramolecular aggregates that notonly form a barrier between compartments butalso harbor many chemical reactions essential tothe existence and functioning of a cell. Here, it isproposed to review the molecular dynamics andmosaic organization of the plasma membrane,which are thought to have important functionalimplications. We will first summarize the basicconcepts of Brownian diffusion and lipid domainformation in model membranes and then trackthe development of ideas and tools in this field,outlining key results obtained on the dynamicprocesses at work in membrane structure andassembly. We will focus in particular on findingsmade using fluorescent labeling and imagingprocedures to record these dynamic processes.We will also discuss a few examples showing theimpact of lateral diffusion on cell signaltransduction, and outline some futuremethodological challenges which must be met", "metadata": {}}
+{"_id": "6191684", "title": "", "text": "Management of chronic tension-type headachewith tricyclic antidepressant medication, stressmanagement therapy, and their combination: arandomized controlled trial.CONTEXT Chronictension-type headaches are characterized bynear-daily headaches and often are difficult tomanage in primary practice. Behavioral andpharmacological therapies each appear modestlyeffective, but data are lacking on their separateand combined effects. OBJECTIVE To evaluatethe clinical efficacy of behavioral andpharmacological therapies, singly and combined,for chronic tension-type headaches. DESIGNAND SETTING Randomized placebo-controlledtrial conducted from August 1995 to January1998 at 2 outpatient sites in Ohio.PARTICIPANTS Two hundred three adults (meanage, 37 years; 76% women) with diagnosis ofchronic tension-type headaches (mean, 26headache d/mo). INTERVENTIONS Participantswere randomly assigned to receive tricyclicantidepressant (amitriptyline hydrochloride, up", "metadata": {}}
+{"_id": "6202834", "title": "", "text": "Maximum likelihood estimates of species trees:how accuracy of phylogenetic inference dependsupon the divergence history and samplingdesign.The understanding that gene trees areoften in discord with each other and with thespecies trees that contain them has ledresearchers to methods that incorporate theinherent stochasticity of genetic processes in thephylogenetic estimation procedure. Recentlydeveloped methods for species-tree estimationthat not only consider the retention and sortingof ancestral polymorphism but also quantify theactual probabilities of incomplete lineage sortingare expected to provide an improvement overearlier summary-statistic based approaches thatdiscard much of the information content of genetrees. However, these new methods have yet tobe tested on truly challenging evolutionaryhistories such as those marked by recent rapidspeciation where high levels of incompletelineage sorting and discord among gene treespredominate. Here, we test a new", "metadata": {}}
+{"_id": "6207111", "title": "", "text": "Relationship of soft drink consumption to globaloverweight, obesity, and diabetes: across-national analysis of 75countries.OBJECTIVES We estimated therelationship between soft drink consumption andobesity and diabetes worldwide. METHODS Weused multivariate linear regression to estimatethe association between soft drink consumptionand overweight, obesity, and diabetesprevalence in 75 countries, controlling for otherfoods (cereals, meats, fruits and vegetables, oils,and total calories), income, urbanization, andaging. Data were obtained from the EuromonitorGlobal Market Information Database, the WorldHealth Organization, and the InternationalDiabetes Federation. Bottled water consumption,which increased with per-capita income inparallel to soft drink consumption, served as anatural control group. RESULTS Soft drinkconsumption increased globally from 9.5 gallonsper person per year in 1997 to 11.4 gallons in2010. A 1% rise in soft drink consumption was", "metadata": {}}
+{"_id": "6209599", "title": "", "text": "Extensive translation of circular RNAs driven byN6-methyladenosineExtensive pre-mRNAback-splicing generates numerous circular RNAs(circRNAs) in human transcriptome. However,the biological functions of these circRNAs remainlargely unclear. Here we report thatN6-methyladenosine (m6A), the most abundantbase modification of RNA, promotes efficientinitiation of protein translation from circRNAs inhuman cells. We discover that consensus m6Amotifs are enriched in circRNAs and a single m6Asite is sufficient to drive translation initiation.This m6A-driven translation requires initiationfactor eIF4G2 and m6A reader YTHDF3, and isenhanced by methyltransferase METTL3/14,inhibited by demethylase FTO, and upregulatedupon heat shock. Further analyses throughpolysome profiling, computational prediction andmass spectrometry reveal that m6A-driventranslation of circRNAs is widespread, withhundreds of endogenous circRNAs havingtranslation potential. Our study expands the", "metadata": {}}
+{"_id": "6212802", "title": "", "text": "Simvastatin reduces CD40 expression in anexperimental model of early arterialization ofsaphenous vein graft.BACKGROUND Saphenousvein graft (VG) failure occurs more frequentlycompared with arterial grafts, and graftthrombosis represents the main cause of earlyocclusion. Because CD40-CD40L pathway CD40represents a culprit link between localinflammation and coagulation cascade, weinvestigate the role of CD40 and its solubleligand (sCD40L) in the immediate in vitroresponse of VG to arterial pressures, and thepotential effects of Simvastatin (MerckSharp&Dohme, White-house Station, NJ)supplementation. METHODS Samples ofsaphenous vein and of internal mammary artery(IMA) were obtained from sixteen patientswithout history of statin therapy. Segmentsunderwent pulsatile pressure distension andculture with or without supplementation ofSimvastatin. CD40 and sCD40L were assessed intissue lysate and in culture supernatant,", "metadata": {}}
+{"_id": "6219790", "title": "", "text": "Cancer Cell Membrane-Coated Nanoparticles forAnticancer Vaccination and DrugDeliveryCell-derived nanoparticles have beengarnering increased attention due to their abilityto mimic many of the natural propertiesdisplayed by their source cells. This top-downengineering approach can be applied toward thedevelopment of novel therapeutic strategiesowing to the unique interactions enabled throughthe retention of complex antigenic information.Herein, we report on the biologicalfunctionalization of polymeric nanoparticles witha layer of membrane coating derived from cancercells. The resulting core-shell nanostructures,which carry the full array of cancer cellmembrane antigens, offer a robust platform withapplicability toward multiple modes of anticancertherapy. We demonstrate that by coupling theparticles with an immunological adjuvant, theresulting formulation can be used to promote atumor-specific immune response for use invaccine applications. Moreover, we show that by", "metadata": {}}
+{"_id": "6227220", "title": "", "text": "Autophagy deficiency leads to protection fromobesity and insulin resistance by inducing Fgf21as a mitokineDespite growing interest and arecent surge in papers, the role of autophagy inglucose and lipid metabolism is unclear. Weproduced mice with skeletal muscle–specificdeletion of Atg7 (encoding autophagy-related 7).Unexpectedly, these mice showed decreased fatmass and were protected from diet-inducedobesity and insulin resistance; this phenotypewas accompanied by increased fatty acidoxidation and browning of white adipose tissue(WAT) owing to induction of fibroblast growthfactor 21 (Fgf21). Mitochondrial dysfunctioninduced by autophagy deficiency increased Fgf21expression through induction of Atf4, a masterregulator of the integrated stress response.Mitochondrial respiratory chain inhibitors alsoinduced Fgf21 in an Atf4-dependent manner. Wealso observed induction of Fgf21, resistance todiet-induced obesity and amelioration of insulinresistance in mice with autophagy deficiency in", "metadata": {}}
+{"_id": "6250701", "title": "", "text": "Laboratory prediction of the requirement forrenal replacement in acute falciparummalariaBACKGROUND Acute renal failure is acommon complication of severe malaria inadults, and without renal replacement therapy(RRT), it carries a poor prognosis. Even whenRRT is available, delaying its initiation mayincrease mortality. Earlier identification ofpatients who will need RRT may improveoutcomes. METHOD Prospectively collected datafrom two intervention studies in adults withsevere malaria were analysed focusing onlaboratory features on presentation and theirassociation with a later requirement for RRT. Inparticular, laboratory indices of acute tubularnecrosis (ATN) and acute kidney injury (AKI)that are used in other settings were examined.RESULTS Data from 163 patients were availablefor analysis. Whether or not the patients shouldhave received RRT (a retrospective assessmentdetermined by three independent reviewers) wasused as the reference. Forty-three (26.4%)", "metadata": {}}
+{"_id": "6251620", "title": "", "text": "Antineutrophil cytoplasmic antibodies(ANCA).Antineutrophil cytoplasmic antibodies(ANCA) are a sensitive and specific marker forANCA-associated systemic vasculitis. Usingindirect immunofluorescence on ethanol-fixedneutrophils, two major fluoroscopic patterns canbe recognised: a diffuse cytoplasmic staining(C-ANCA), and a perinuclear/nuclear staining(P-ANCA). In patients with vasculitis, more of90% of C-ANCA are directed against proteinase 3(PR3-ANCA) whereas approximately 80-90% ofP-ANCA recognise myelperoxidase (MPO-ANCA).Although C-ANCA (PR3-ANCA) is preferentiallyassociated with Wegener's granulomatosis (WG),and P-ANCA (MPO-ANCA) with microscopicpolyangiitis (MPA), idiopathic necrotisingcrescentic glomerulonephritis (iNCGN) andChurg-Strauss syndrome (CSS), there is notabsolute specificity. Between 10-20% of patientswith classical WG show P-ANCA (MPO-ANCA),and even a larger percentage of patients withMPA or CSS have C-ANCA (PR3-ANCA).", "metadata": {}}
+{"_id": "6259170", "title": "", "text": "Emerging functional cross-talk between theKeap1-Nrf2 system and mitochondriaNuclearfactor erythroid-derived 2-related factor 2 (Nrf2)was originally identified as a positive regulator ofdrug detoxifying enzyme gene expression duringexposure to environmental electrophiles.Currently, Nrf2 is known to regulate theexpression of hundreds of cytoprotective genesto counteract endogenously or exogenouslygenerated oxidative stress. Furthermore, whenactivated in human tumors by somaticmutations, Nrf2 confers growth advantages andchemoresistance by regulating genes involved invarious processes such as the pentose phosphatepathway and nucleotide synthesis in addition toantioxidant proteins. Interestingly, increasingevidence shows that Nrf2 is associated withmitochondrial biogenesis during environmentalstresses in certain tissues such as the heart.Furthermore, SKN-1, a functional homolog ofNrf2 in C. elegans, is activated by mitochondrialreactive oxygen species and extends life span by", "metadata": {}}
+{"_id": "6264468", "title": "", "text": "Regulation of pluripotency by RNA bindingproteins.Establishment, maintenance, and exitfrom pluripotency require precise coordination ofa cell's molecular machinery. Substantialheadway has been made in deciphering manyaspects of this elaborate system, particularlywith respect to epigenetics, transcription, andnoncoding RNAs. Less attention has been paid toposttranscriptional regulatory processes such asalternative splicing, RNA processing andmodification, nuclear export, regulation oftranscript stability, and translation. Here, weintroduce the RNA binding proteins that enablethe posttranscriptional regulation of geneexpression, summarizing current and ongoingresearch on their roles at different regulatorypoints and discussing how they help script thefate of pluripotent stem cells.", "metadata": {}}
+{"_id": "6268106", "title": "", "text": "The ubiquitin ligase Drosophila Mind bombpromotes Notch signaling by regulating thelocalization and activity of Serrate and Delta.Thereceptor Notch and its ligands of theDelta/Serrate/LAG2 (DSL) family are the centralcomponents in the Notch pathway, afundamental cell signaling system that regulatespattern formation during animal development.Delta is directly ubiquitinated by Drosophila andXenopus Neuralized, and by zebrafish Mindbomb, two unrelated RING-type E3 ubiquitinligases with common abilities to promote Deltaendocytosis and signaling activity. Althoughorthologs of both Neuralized and Mind bomb arefound in most metazoan organisms, their relativecontributions to Notch signaling in any singleorganism have not yet been assessed. We showhere that a Drosophila ortholog of Mind bomb(D-mib) is a positive component of Notchsignaling that is required for multipleNeuralized-independent, Notch-dependentdevelopmental processes. Furthermore, we show", "metadata": {}}
+{"_id": "6270720", "title": "", "text": "Myeloid differentiation factor-88/interleukin-1signaling controls cardiac fibrosis and heartfailure progression in inflammatory dilatedcardiomyopathy.RATIONALE The myeloiddifferentiation factor (MyD)88/interleukin (IL)-1axis activates self-antigen-presenting cells andpromotes autoreactive CD4(+) T-cell expansionin experimental autoimmune myocarditis, amouse model of inflammatory heart disease.OBJECTIVE The aim of this study was todetermine the role of MyD88 and IL-1 in theprogression of acute myocarditis to an end-stageheart failure. METHODS AND RESULTS Usingalpha-myosin heavy chain peptide(MyHC-alpha)-loaded, activated dendritic cells,we induced myocarditis in wild-type andMyD88(-/-) mice with similar distributions ofheart-infiltrating cell subsets and comparableCD4(+) T-cell responses. Injection of completeFreund's adjuvant (CFA) or MyHC-alpha/CFA intodiseased mice promoted cardiac fibrosis, inducedventricular dilation, and impaired heart function", "metadata": {}}
+{"_id": "6277638", "title": "", "text": "Mechanisms of Life Span Extension byRapamycin in the Fruit Fly DrosophilamelanogasterThe target of rapamycin (TOR)pathway is a major nutrient-sensing pathwaythat, when genetically downregulated, increaseslife span in evolutionarily diverse organismsincluding mammals. The central component ofthis pathway, TOR kinase, is the target of theinhibitory drug rapamycin, a highly specific andwell-described drug approved for human use. Weshow here that feeding rapamycin to adultDrosophila produces the life span extension seenin some TOR mutants. Increase in life span byrapamycin was associated with increasedresistance to both starvation and paraquat.Analysis of the underlying mechanisms revealedthat rapamycin increased longevity specificallythrough the TORC1 branch of the TOR pathway,through alterations to both autophagy andtranslation. Rapamycin could increase life spanof weak insulin/Igf signaling (IIS) pathwaymutants and of flies with life span maximized by", "metadata": {}}
+{"_id": "6280907", "title": "", "text": "Conversion of vascular endothelial cells intomultipotent stem-like cellsMesenchymal stemcells can give rise to several cell types, butvarying results depending on isolation methodsand tissue source have led to controversiesabout their usefulness in clinical medicine. Herewe show that vascular endothelial cells cantransform into multipotent stem-like cells by anactivin-like kinase-2 (ALK2) receptor–dependentmechanism. In lesions from individuals withfibrodysplasia ossificans progressiva (FOP), adisease in which heterotopic ossification occursas a result of activating ALK2 mutations, or fromtransgenic mice expressing constitutively activeALK2, chondrocytes and osteoblasts expressedendothelial markers. Lineage tracing ofheterotopic ossification in mice using a Tie2-Creconstruct also suggested an endothelial origin ofthese cell types. Expression of constitutivelyactive ALK2 in endothelial cells causedendothelial-to-mesenchymal transition andacquisition of a stem cell–like phenotype. Similar", "metadata": {}}
+{"_id": "6285534", "title": "", "text": "miR-302 Is Required for Timing of NeuralDifferentiation, Neural Tube Closure, andEmbryonic ViabilityThe evolutionarily conservedmiR-302 family of microRNAs is expressed duringearly mammalian embryonic development. Here,we report that deletion of miR-302a-d in miceresults in a fully penetrant late embryonic lethalphenotype. Knockout embryos have an anteriorneural tube closure defect associated with athickened neuroepithelium. The neuroepitheliumshows increased progenitor proliferation,decreased cell death, and precocious neuronaldifferentiation. mRNA profiling at multiple timepoints during neurulation uncovers a complexpattern of changing targets over time.Overexpression of one of these targets, Fgf15, inthe neuroepithelium of the chick embryo inducesprecocious neuronal differentiation. Compoundmutants between mir-302 and the relatedmir-290 locus have a synthetic lethal phenotypeprior to neurulation. Our results show thatmir-302 helps regulate neurulation by", "metadata": {}}
+{"_id": "6290112", "title": "", "text": "Low copy number of the salivary amylase genepredisposes to obesityCommon multi-allelic copynumber variants (CNVs) appear enriched forphenotypic associations compared to theirbiallelic counterparts. Here we investigated theinfluence of gene dosage effects on adipositythrough a CNV association study of geneexpression levels in adipose tissue. We identifiedsignificant association of a multi-allelic CNVencompassing the salivary amylase gene (AMY1)with body mass index (BMI) and obesity, and wereplicated this finding in 6,200 subjects.Increased AMY1 copy number was positivelyassociated with both amylase gene expression (P= 2.31 × 10(-14)) and serum enzyme levels (P< 2.20 × 10(-16)), whereas reduced AMY1 copynumber was associated with increased BMI(change in BMI per estimated copy = -0.15(0.02) kg/m(2); P = 6.93 × 10(-10)) and obesityrisk (odds ratio (OR) per estimated copy = 1.19,95% confidence interval (CI) = 1.13-1.26; P =1.46 × 10(-10)). The OR value of 1.19 per copy", "metadata": {}}
+{"_id": "6296189", "title": "", "text": "Loss, trauma, and human resilience: have weunderestimated the human capacity to thriveafter extremely aversive events?Many people areexposed to loss or potentially traumatic events atsome point in their lives, and yet they continueto have positive emotional experiences and showonly minor and transient disruptions in theirability to function. Unfortunately, because muchof psychology's knowledge about how adultscope with loss or trauma has come fromindividuals who sought treatment or exhibitedgreat distress, loss and trauma theorists haveoften viewed this type of resilience as either rareor pathological. The author challenges theseassumptions by reviewing evidence thatresilience represents a distinct trajectory fromthe process of recovery, that resilience in theface of loss or potential trauma is more commonthan is often believed, and that there aremultiple and sometimes unexpected pathways toresilience.", "metadata": {}}
+{"_id": "6308416", "title": "", "text": "Role of boundary conditions in an experimentalmodel of epithelial wound healing.Coordinatedcell movements in epithelial layers are essentialfor proper tissue morphogenesis andhomeostasis, but our understanding of themechanisms that coordinate the behavior ofmultiple cells in these processes is far fromcomplete. Recent experiments with Madin-Darbycanine kidney epithelial monolayers revealed awave-like pattern of injury-induced MAPKactivation and showed that it is essential forcollective cell migration after wounding. Toinvestigate the effects of the different aspects ofwounding on cell sheet migration, we engineereda system that allowed us to dissect the classicwound healing assay. We studied Madin-Darbycanine kidney sheet migration under threedifferent conditions: 1) the classic wound healingassay, 2) empty space induction, where aconfluent monolayer is grown adjacent to a slabof polydimethylsiloxane and the monolayer is notinjured but allowed to migrate upon removal of", "metadata": {}}
+{"_id": "6309659", "title": "", "text": "Reproductive period and risk of dementia inpostmenopausal women.CONTEXT Exogenousestrogen use may lower risk of dementia inpostmenopausal women. A relationship betweenlong-term exposure to endogenous estrogensand incident dementia has been hypothesizedbut not studied. OBJECTIVE To determinewhether a longer reproductive period, as anindicator of longer exposure to endogenousestrogens, is associated with lower risk ofdementia and Alzheimer disease (AD) in womenwho have natural menopause. DESIGN ANDSETTING The Rotterdam Study, apopulation-based prospective cohort studyconducted in the Netherlands. PARTICIPANTS Atotal of 3601 women aged 55 years or older whodid not have dementia at baseline (1990-1993)and had information on age at menarche, age atmenopause, and type of menopause. Participantswere reexamined in 1993-1994 and 1997-1999and were continuously monitored fordevelopment of dementia. MAIN OUTCOME", "metadata": {}}
+{"_id": "6313547", "title": "", "text": "Effects of growth hormone and insulin-likegrowth factor 1 deficiency on ageing andlongevity.Present knowledge on the effects ofgrowth hormone (GH)/insulin-like growthhormone (IGF)1 deficiency on ageing andlifespan are reviewed. Evidence is presented thatisolated GH deficiency (IGHD), multiple pituitaryhormone deficiencies (MPHD) including GH, aswell as primary IGE1 deficiency (GH resistance,Laron syndrome) present signs of early ageingsuch as thin and wrinkled skin, obesity,hyperglycemia and osteoporosis. These changesdo not seem to affect the lifespan, as patientsreach old age. Animal models of genetic MPHD(Ames and Snell mice) and GH receptor knockoutmice (primary IGF1 deficiency) also have astatistically significant higher longevity comparedto normal controls. On the contrary, micetransgenic for GH and acromegalic patientssecreting large amounts of GH have prematuredeath. In conclusion longstanding GH/IGF1deficiency affects several parameters of the", "metadata": {}}
+{"_id": "6315132", "title": "", "text": "KLF1-null neonates display hydrops fetalis and aderanged erythroid transcriptome.We describe acase of severe neonatal anemia with kernicteruscaused by compound heterozygosity for nullmutations in KLF1, each inherited fromasymptomatic parents. One of the mutations isnovel. This is the first described case of aKLF1-null human. The phenotype of severenonspherocytic hemolytic anemia, jaundice,hepatosplenomegaly, and markederythroblastosis is more severe than that presentin congenital dyserythropoietic anemia type IV asa result of dominant mutations in the secondzinc-finger of KLF1. There was a very high levelof HbF expression into childhood (>70%),consistent with a key role for KLF1 in humanhemoglobin switching. We performed RNA-seqon circulating erythroblasts and found thathuman KLF1 acts like mouse Klf1 to coordinateexpression of many genes required to build a redcell including those encoding globins,cytoskeletal components, AHSP, heme synthesis", "metadata": {}}
+{"_id": "6319826", "title": "", "text": "Quantifying heterogeneity in a meta-analysis.Theextent of heterogeneity in a meta-analysis partlydetermines the difficulty in drawing overallconclusions. This extent may be measured byestimating a between-study variance, butinterpretation is then specific to a particulartreatment effect metric. A test for the existenceof heterogeneity exists, but depends on thenumber of studies in the meta-analysis. Wedevelop measures of the impact of heterogeneityon a meta-analysis, from mathematical criteria,that are independent of the number of studiesand the treatment effect metric. We derive andpropose three suitable statistics: H is the squareroot of the chi2 heterogeneity statistic divided byits degrees of freedom; R is the ratio of thestandard error of the underlying mean from arandom effects meta-analysis to the standarderror of a fixed effect meta-analytic estimate,and I2 is a transformation of (H) that describesthe proportion of total variation in studyestimates that is due to heterogeneity. We", "metadata": {}}
+{"_id": "6323196", "title": "", "text": "Neurocognitive Development in ChildrenExperiencing Intrauterine Growth Retardationand Born Small for Gestational Age: Pathological,Constitutional and Therapeutic PathwaysInterestin the neurocognitive and psychosocial outcomesin children who are born small for gestationalage (SGA) has increased since the recentapproval of growth hormone (GH) therapy in thisindication. The objective of GH treatment in SGAchildren is to provide a symptomatic treatmentfor growth retardation. From a patientperspective, the ultimate goals of GH therapy arethe reduction in the present or future risk ofneurocognitive, psychological, social oroccupational impairment, not the accompanyingimprovements in growth velocity and final heightper se. Therefore, from a scientific perspective,neurocognitive and psychosocial endpointsbecome relevant domains of assessment todetermine the final treatment benefitexperienced by the patient born SGA. This articlereviews recent available studies on", "metadata": {}}
+{"_id": "6325527", "title": "", "text": "Gpr124 is essential for blood–brain barrierintegrity in central nervous systemdiseaseAlthough blood–brain barrier (BBB)compromise is central to the etiology of diversecentral nervous system (CNS) disorders,endothelial receptor proteins that control BBBfunction are poorly defined. The endothelialG-protein-coupled receptor (GPCR) Gpr124 hasbeen reported to be required for normalforebrain angiogenesis and BBB function inmouse embryos, but the role of this receptor inadult animals is unknown. Here Gpr124conditional knockout (CKO) in the endothelia ofadult mice did not affect homeostatic BBBintegrity, but resulted in BBB disruption andmicrovascular hemorrhage in mouse models ofboth ischemic stroke and glioblastoma,accompanied by reduced cerebrovascularcanonical Wnt–β-catenin signaling. Constitutiveactivation of Wnt–β-catenin signaling fullycorrected the BBB disruption and hemorrhagedefects of Gpr124-CKO mice, with rescue of the", "metadata": {}}
+{"_id": "6327940", "title": "", "text": "Vegan proteins may reduce risk of cancer,obesity, and cardiovascular disease by promotingincreased glucagon activity.Amino acidsmodulate the secretion of both insulin andglucagon; the composition of dietary proteintherefore has the potential to influence thebalance of glucagon and insulin activity. Soyprotein, as well as many other vegan proteins,are higher in non-essential amino acids thanmost animal-derived food proteins, and as aresult should preferentially favor glucagonproduction. Acting on hepatocytes, glucagonpromotes (and insulin inhibits) cAMP-dependentmechanisms that down-regulate lipogenicenzymes and cholesterol synthesis, whileup-regulating hepatic LDL receptors andproduction of the IGF-I antagonist IGFBP-1. Theinsulin-sensitizing properties of many vegandiets--high in fiber, low in saturated fat--shouldamplify these effects by down-regulating insulinsecretion. Additionally, the relatively lowessential amino acid content of some vegan diets", "metadata": {}}
+{"_id": "6333347", "title": "", "text": "AIR-2: An Aurora/Ipl1-related Protein KinaseAssociated with Chromosomes and MidbodyMicrotubules Is  Required for Polar BodyExtrusion and Cytokinesis  in Caenorhabditiselegans EmbryosAn emerging family of kinasesrelated to the Drosophila Aurora and buddingyeast Ipl1 proteins has been implicated inchromosome segregation and mitotic spindleformation in a number of organisms. Unlike otherAurora/Ipl1-related kinases, the Caenorhabditiselegans orthologue, AIR-2, is associated withmeiotic and mitotic chromosomes. AIR-2 isinitially localized to the chromosomes of themost mature prophase I–arrested oocyteresiding next to the spermatheca. Thislocalization is dependent on the presence ofsperm in the spermatheca. After fertilization,AIR-2 remains associated with chromosomesduring each meiotic division. However, duringboth meiotic anaphases, AIR-2 is presentbetween the separating chromosomes. AIR-2also remains associated with both extruded polar", "metadata": {}}
+{"_id": "6334188", "title": "", "text": "History of chronic comorbidity and risk ofchemotherapy-induced febrile neutropenia incancer patients not receiving G-CSFprophylaxis.BACKGROUNDChemotherapy-induced febrile neutropenia (FN)is a clinically important complication that affectspatient outcome by delaying chemotherapydoses or reducing dose intensity. Risk of FNdepends on chemotherapy- and patient-levelfactors. We sought to determine the effects ofchronic comorbidities on risk of FN. DESIGN Weconducted a cohort study to examine theassociation between a variety of chroniccomorbidities and risk of FN in patientsdiagnosed with six types of cancer (non-Hodgkinlymphoma and breast, colorectal, lung, ovary,and gastric cancer) from 2000 to 2009 who weretreated with chemotherapy at Kaiser PermanenteSouthern California, a large managed careorganization. We excluded those patients whoreceived primary prophylactic granulocytecolony-stimulating factor. History of", "metadata": {}}
+{"_id": "6363093", "title": "", "text": "Glioblastoma Subclasses Can Be Defined byActivity among Signal Transduction Pathwaysand Associated GenomicAlterationsBACKGROUND Glioblastomamultiforme (GBM) is an umbrella designationthat includes a heterogeneous group of primarybrain tumors. Several classification strategies ofGBM have been reported, some by clinical courseand others by resemblance to cell types either inthe adult or during development. From apractical and therapeutic standpoint, classifyingGBMs by signal transduction pathway activationand by mutation in pathway member genes maybe particularly valuable for the development oftargeted therapies. METHODOLOGY/PRINCIPALFINDINGS We performed targeted proteomicanalysis of 27 surgical glioma samples to identifypatterns of coordinate activation amongglioma-relevant signal transduction pathways,then compared these results with integratedanalysis of genomic and expression data of 243GBM samples from The Cancer Genome Atlas", "metadata": {}}
+{"_id": "6368017", "title": "", "text": "Loss of sex discrimination and male-maleaggression in mice deficient for TRP2.The mousevomeronasal organ (VNO) is thought to mediatesocial behaviors and neuroendocrine changeselicited by pheromonal cues. The molecularmechanisms underlying the sensory response topheromones and the behavioral repertoireinduced through the VNO are not fullycharacterized. Using the tools of mouse geneticsand multielectrode recording, we demonstratethat the sensory activation of VNO neuronsrequires TRP2, a putative ion channel of thetransient receptor potential family that isexpressed exclusively in these neurons.Moreover, we show that male mice deficient inTRP2 expression fail to display male-maleaggression, and they initiate sexual andcourtship behaviors toward both males andfemales. Our study suggests that, in the mouse,sensory activation of the VNO is essential for sexdiscrimination of conspecifics and thus ensuresgender-specific behavior.", "metadata": {}}
+{"_id": "6372244", "title": "", "text": "Antibiotic-induced shifts in the mouse gutmicrobiome and metabolome increasesusceptibility to Clostridium difficileinfectionAntibiotics can have significant andlong-lasting effects on the gastrointestinal tractmicrobiota, reducing colonization resistanceagainst pathogens including Clostridium difficile.Here we show that antibiotic treatment inducessubstantial changes in the gut microbialcommunity and in the metabolome of micesusceptible to C. difficile infection. Levels ofsecondary bile acids, glucose, free fatty acidsand dipeptides decrease, whereas those ofprimary bile acids and sugar alcohols increase,reflecting the modified metabolic activity of thealtered gut microbiome. In vitro and ex vivoanalyses demonstrate that C. difficile can exploitspecific metabolites that become more abundantin the mouse gut after antibiotics, including theprimary bile acid taurocholate for germination,and carbon sources such as mannitol, fructose,sorbitol, raffinose and stachyose for growth. Our", "metadata": {}}
+{"_id": "6374918", "title": "", "text": "Chemosensitization of acute myeloid leukemia(AML) following mobilization by the CXCR4antagonist AMD3100.The CXCR4-SDF-1 axisplays a central role in the trafficking andretention of normal and malignant stem cells inthe bone marrow (BM) microenvironment. Here,we used a mouse model of acute promyelocyticleukemia (APL) and a small molecule competitiveantagonist of CXCR4, AMD3100, to examine theinteraction of mouse APL cells with the BMmicroenvironment. APL cells from a murinecathepsin G-PML-RARalpha knockin mouse weregenetically modified with firefly luciferase(APL(luc)) to allow tracking by bioluminescenceimaging. Coculture of APL(luc) cells withM2-10B4 stromal cells protected the leukemiacells from chemotherapy-induced apoptosis invitro. Upon injection into syngeneic recipients,APL(luc) cells rapidly migrated to the BMfollowed by egress to the spleen then to theperipheral blood with death due to leukostasis byday 15. Administration of AMD3100 to leukemic", "metadata": {}}
+{"_id": "6386930", "title": "", "text": "Insights into G-quadruplex specific recognitionby the DEAH-box helicase RHAU: Solutionstructure of a peptide-quadruplexcomplex.Four-stranded nucleic acid structurescalled G-quadruplexes have been associated withimportant cellular processes, which shouldrequire G-quadruplex-protein interaction.However, the structural basis for specificG-quadruplex recognition by proteins has notbeen understood. The DEAH (Asp-Glu-Ala-His)box RNA helicase associated with AU-richelement (RHAU) (also named DHX36 or G4R1)specifically binds to and resolvesparallel-stranded G-quadruplexes. Here weidentified an 18-amino acidG-quadruplex-binding domain of RHAU anddetermined the structure of this peptide bound toa parallel DNA G-quadruplex. Our structureexplains how RHAU specifically recognizesparallel G-quadruplexes. The peptide covers aterminal guanine base tetrad (G-tetrad), andclamps the G-quadruplex using", "metadata": {}}
+{"_id": "6387956", "title": "", "text": "IQ and non-clinical psychotic symptoms in12-year-olds: results  from the ALSPAC birthcohortBACKGROUND Non-clinical psychoticsymptoms appear common in children, but it ispossible that a proportion of reported symptomsresult from misinterpretation. There is awell-established association between pre-morbidlow IQ score and schizophrenia. Psychosis-likesymptoms in children may also be a risk factorfor psychotic disorder but their relationship withIQ is unclear. AIMS To investigate theprevalence, nature and frequency ofpsychosis-like symptoms in 12-year-old childrenand study their relationship with IQ. METHODLongitudinal study using the Avon LongitudinalStudy of Parents and Children (ALSPAC) birthcohort. A total of 6455 children completedscreening questions for 12 psychotic symptomsfollowed by a semi-structured clinicalassessment. IQ was assessed at 8 years of ageusing the Wechsler Intelligence Scale forChildren (3rd UK edition). RESULTS The 6-month", "metadata": {}}
+{"_id": "6397191", "title": "", "text": "Endothelin-1 is induced by cytokines in humanvascular smooth muscle cells: evidence forintracellular endothelin-convertingenzyme.Endothelin-1 (ET-1) is the predominantendothelin isopeptide generated by the vascularwall and therefore appears to be the mostimportant peptide involved in regulation ofcardiovascular events. Many pathologicconditions are associated with elevations of ET-1in the blood vessel wall. Because theseconditions are often cytokine driven, weexamined the effects of a mixture of cytokines onET-1 production in human vascular smoothmuscle cells (VSMCs) derived from internalmammary artery and saphenous vein (SV).Incubation of IMA and SV VSMCs with tumornecrosis factor-alpha (10 ng/ml) andinterferon-gamma (1000 U/ml) in combinationfor up to 48 h markedly elevated the expressionof mRNA for prepro-ET-1 and the release of ET-1into the culture medium. Thiscytokine-stimulated release of ET-1 was inhibited", "metadata": {}}
+{"_id": "6401675", "title": "", "text": "Transposable elements have rewired the coreregulatory network of human embryonic stemcellsDetection of new genomic control elementsis critical in understanding transcriptionalregulatory networks in their entirety. We studiedthe genome-wide binding locations of three keyregulatory proteins (POU5F1, also known asOCT4; NANOG; and CTCF) in human and mouseembryonic stem cells. In contrast to CTCF, wefound that the binding profiles of OCT4 andNANOG are markedly different, with only \u00005% ofthe regions being homologously occupied. Weshow that transposable elements contributed upto 25% of the bound sites in humans and miceand have wired new genes into the coreregulatory network of embryonic stem cells.These data indicate that species-specifictransposable elements have substantially alteredthe transcriptional circuitry of pluripotent stemcells.", "metadata": {}}
+{"_id": "6404801", "title": "", "text": "Cytomegalovirus microRNAs Facilitate PersistentVirus Infection in Salivary GlandsMicro (mi)RNAsare small non-coding RNAs that regulate theexpression of their targets' messenger RNAsthrough both translational inhibition andregulation of target RNA stability. Recently, anumber of viruses, particularly of the herpesvirusfamily, have been shown to express their ownmiRNAs to control both viral and cellulartranscripts. Although some targets of viralmiRNAs are known, their function in aphysiologically relevant infection remains to beelucidated. As such, no in vivo phenotype of aviral miRNA knock-out mutant has beendescribed so far. Here, we report on the firstfunctional phenotype of a miRNA knock-out virusin vivo. During subacute infection of a mutantmouse cytomegalovirus lacking two viralmiRNAs, virus production is selectively reducedin salivary glands, an organ essential for viruspersistence and horizontal transmission. Thisphenotype depends on several parameters", "metadata": {}}
+{"_id": "6407356", "title": "", "text": "Coxibs and other nonsteroidal anti-inflammatorydrugs in animal models of cancerchemoprevention.Coxibs, including celecoxib,and other nonsteroidal anti-inflammatory drugs(NSAID), including aspirin, are among the mostpromising cancer chemopreventive agents indevelopment today. This article examines thedata on the efficacy of these agents in animalmodel studies of cancer prevention carried outby the authors. The studies evaluated here arerestricted to our rodent models ofcolon/intestinal, bladder, and nonmelanoma skincancer, in which celecoxib and other NSAIDswere administered as either cancer preventive ortherapeutic agents. These studies may shed lighton several questions. Is celecoxib uniquecompared with other NSAIDs, and if so, whatimplications would this have for human use? Arestandard NSAIDs (which inhibit both COX-1 andCOX-2) as effective as celecoxib in animalstudies? Is the efficacy of celecoxib in particularor NSAIDs in general due to their off-target", "metadata": {}}
+{"_id": "6415816", "title": "", "text": "The porphyrias: advances in diagnosis andtreatment.The inborn errors of hemebiosynthesis, the porphyrias, are 8 geneticallydistinct metabolic disorders that can be classifiedas \"acute hepatic,\" \"hepatic cutaneous,\" and\"erythropoietic cutaneous\" diseases. Recentadvances in understanding their pathogenesisand molecular genetic heterogeneity have led toimproved diagnosis and treatment. Theseadvances include DNA-based diagnoses for allthe porphyrias, new understanding of thepathogenesis of the acute hepatic porphyrias,identification of the iron overload-inducedinhibitor of hepatic uroporphyrin decarboxylaseactivity that causes the most common porphyria,porphyria cutanea tarda, the identification of anX-linked form of erythropoietic protoporphyriadue to gain-of-function mutations inerythroid-specific 5-aminolevulinate synthase(ALAS2), and new and experimental treatmentsfor the erythropoietic porphyrias. Knowledge ofthese advances is relevant for hematologists", "metadata": {}}
+{"_id": "6417632", "title": "", "text": "Neutrophilic infiltration within the airway smoothmuscle in patients with COPD.BACKGROUNDCOPD is an inflammatory disorder characterisedby chronic airflow limitation, but the extent towhich airway inflammation is related tofunctional abnormalities is still uncertain. Theinteraction between inflammatory cells andairway smooth muscle may have a crucial role.METHODS To investigate the microlocalisation ofinflammatory cells within the airway smoothmuscle in COPD, surgical specimens obtainedfrom 26 subjects undergoing thoracotomy (eightsmokers with COPD, 10 smokers with normallung function, and eight non-smoking controls)were examined. Immunohistochemical analysiswas used to quantify the number of neutrophils,macrophages, mast cells, CD4+ and CD8+ cellslocalised within the smooth muscle of peripheralairways. RESULTS Smokers with COPD had anincreased number of neutrophils and CD8+ cellsin the airway smooth muscle compared withnon-smokers. Smokers with normal lung function", "metadata": {}}
+{"_id": "6421734", "title": "", "text": "Characteristics of service users and providerorganisations associated with experience of outof hours general practitioner care in England:population based cross sectional postalquestionnaire survey.OBJECTIVE To investigatethe experience of users of out of hours generalpractitioner services in England, UK. DESIGNPopulation based cross sectional postalquestionnaire survey. SETTING General PracticePatient Survey 2012-13. MAIN OUTCOMEMEASURES Potential associations betweensociodemographic factors (including ethnicityand ability to take time away from work duringworking hours to attend a healthcareconsultation) and provider organisation type (notfor profit, NHS, or commercial) and serviceusers' experience of out of hours care(timeliness, confidence and trust in the out ofhours clinician, and overall experience of theservice), rated on a scale of 0-100. Whichsociodemographic/provider characteristics wereassociated with service users' experience, the", "metadata": {}}
+{"_id": "6421792", "title": "", "text": "Activating mutations in the NT5C2 nucleotidasegene drive chemotherapy resistance in relapsedALLAcute lymphoblastic leukemia (ALL) is anaggressive hematological tumor resulting fromthe malignant transformation of lymphoidprogenitors. Despite intensive chemotherapy,20% of pediatric patients and over 50% of adultpatients with ALL do not achieve a completeremission or relapse after intensifiedchemotherapy, making disease relapse andresistance to therapy the most substantialchallenge in the treatment of this disease. Usingwhole-exome sequencing, we identify mutationsin the cytosolic 5'-nucleotidase II gene (NT5C2),which encodes a 5'-nucleotidase enzyme that isresponsible for the inactivation ofnucleoside-analog chemotherapy drugs, in20/103 (19%) relapse T cell ALLs and 1/35 (3%)relapse B-precursor ALLs. NT5C2 mutantproteins show increased nucleotidase activity invitro and conferred resistance to chemotherapywith 6-mercaptopurine and 6-thioguanine when", "metadata": {}}
+{"_id": "6422576", "title": "", "text": "Ubiquitin-dependent protein degradation.Agrowing number of cellular regulatorymechanisms are being linked to proteinmodification by the polypeptide ubiquitin. Theseinclude key transitions in the cell cycle, class Iantigen processing, signal transductionpathways, and receptor-mediated endocytosis.In most, but not all, of these examples,ubiquitination of a protein leads to itsdegradation by the 26S proteasome. Followingattachment of ubiquitin to a substrate andbinding of the ubiquitinated protein to theproteasome, the bound substrate must beunfolded (and eventually deubiquitinated) andtranslocated through a narrow set of channelsthat leads to the proteasome interior, where thepolypeptide is cleaved into short peptides.Protein ubiquitination and deubiquitination areboth mediated by large enzyme families, and theproteasome itself comprises a family of relatedbut functionally distinct particles. This diversityunderlies both the high substrate specificity of", "metadata": {}}
+{"_id": "6426919", "title": "", "text": "A novel molecular mechanism of dual resistanceto nucleoside and nonnucleoside reversetranscriptase inhibitors.Recently, mutations inthe connection subdomain (CN) and RNase Hdomain of HIV-1 reverse transcriptase (RT) wereobserved to exhibit dual resistance to nucleosideand nonnucleoside reverse transcriptaseinhibitors (NRTIs and NNRTIs). To elucidate themechanism by which CN and RH mutationsconfer resistance to NNRTIs, we hypothesizedthat these mutations reduce RNase H cleavageand provide more time for the NNRTI todissociate from the RT, resulting in theresumption of DNA synthesis and enhancedNNRTI resistance. We observed that the effect ofthe reduction in RNase H cleavage on NNRTIresistance is dependent upon the affinity of eachNNRTI to the RT and further influenced by thepresence of NNRTI-binding pocket (BP) mutants.D549N, Q475A, and Y501A mutants, whichreduce RNase H cleavage, enhance resistance tonevirapine (NVP) and delavirdine (DLV), but not", "metadata": {}}
+{"_id": "6431384", "title": "", "text": "Location Coding by Opponent Neural Populationsin the Auditory CortexAlthough the auditorycortex plays a necessary role in soundlocalization, physiological investigations in thecortex reveal inhomogeneous sampling ofauditory space that is difficult to reconcile withlocalization behavior under the assumption oflocal spatial coding. Most neurons respondmaximally to sounds located far to the left orright side, with few neurons tuned to the frontalmidline. Paradoxically, psychophysical studiesshow optimal spatial acuity across the frontalmidline. In this paper, we revisit the problem ofinhomogeneous spatial sampling in three fieldsof cat auditory cortex. In each field, we confirmthat neural responses tend to be greatest forlateral positions, but show the greatestmodulation for near-midline source locations.Moreover, identification of source locations basedon cortical responses shows sharp discriminationof left from right but relatively inaccuratediscrimination of locations within each half of", "metadata": {}}
+{"_id": "6441369", "title": "", "text": "MLL1 Inhibition Reprograms Epiblast Stem Cellsto Naive Pluripotency.The interconversionbetween naive and primed pluripotent states isaccompanied by drastic epigeneticrearrangements. However, it is unclear whetherintrinsic epigenetic events can drivereprogramming to naive pluripotency or ifdistinct chromatin states are instead simply areflection of discrete pluripotent states. Here, weshow that blocking histone H3K4methyltransferase MLL1 activity with thesmall-molecule inhibitor MM-401 reprogramsmouse epiblast stem cells (EpiSCs) to naivepluripotency. This reversion is highly efficientand synchronized, with more than 50% oftreated EpiSCs exhibiting features of naiveembryonic stem cells (ESCs) within 3 days.Reverted ESCs reactivate the silenced Xchromosome and contribute to embryosfollowing blastocyst injection, generatinggermline-competent chimeras. Importantly,blocking MLL1 leads to global redistribution of", "metadata": {}}
+{"_id": "6446747", "title": "", "text": "MafB/c-Maf deficiency enables self-renewal ofdifferentiated functional macrophages.Inmetazoan organisms, terminal differentiation isgenerally tightly linked to cell cycle exit, whereasthe undifferentiated state of pluripotent stemcells is associated with unlimited self-renewal.Here, we report that combined deficiency for thetranscription factors MafB and c-Maf enablesextended expansion of mature monocytes andmacrophages in culture without loss ofdifferentiated phenotype and function. Upontransplantation, the expanded cells arenontumorigenic and contribute to functionalmacrophage populations in vivo. Small hairpinRNA inactivation shows that continuousproliferation of MafB/c-Maf deficientmacrophages requires concomitant up-regulationof two pluripotent stem cell-inducing factors,KLF4 and c-Myc. Our results indicate thatMafB/c-MafB deficiency renders self-renewalcompatible with terminal differentiation. It thusappears possible to amplify functional", "metadata": {}}
+{"_id": "6454371", "title": "", "text": "Macropinocytosis: an endocytic pathway forinternalising large gulps.Macropinocytosis is aregulated form of endocytosis that mediates thenon-selective uptake of solute molecules,nutrients and antigens. It is an actin-dependentprocess initiated from surface membrane rufflesthat give rise to large endocytic vacuoles calledmacropinosomes. Macropinocytosis is importantin a range of physiological processes; it is highlyactive in macrophages and dendritic cells whereit is a major pathway for the capture of antigens,it is relevant to cell migration and tumourmetastasis and it represents a portal of cell entryexploited by a range of pathogens. Themolecular basis for the formation and maturationof macropinosomes has only recently begun tobe defined. Here, we review the generalcharacteristics of macropinocytosis, describesome of the regulators of this pathway, whichhave been identified to date and highlightstrategies to explore the relevance of thisendocytosis pathway in vivo.", "metadata": {}}
+{"_id": "6455142", "title": "", "text": "KDM5B regulates embryonic stem cellself-renewal and represses cryptic intragenictranscription.Although regulation of histonemethylation is believed to contribute toembryonic stem cell (ESC) self-renewal, themechanisms remain obscure. We show here thatthe histone H3 trimethyl lysine 4 (H3K4me3)demethylase, KDM5B, is a downstream Nanogtarget and critical for ESC self-renewal. AlthoughKDM5B is believed to function as apromoter-bound repressor, we find that itparadoxically functions as an activator of a genenetwork associated with self-renewal. ChIP-Seqreveals that KDM5B is predominantly targeted tointragenic regions and that it is recruited toH3K36me3 via an interaction with thechromodomain protein MRG15. Depletion ofKDM5B or MRG15 increases intragenic H3K4me3,increases cryptic intragenic transcription, andinhibits transcriptional elongation of KDM5Btarget genes. We propose that KDM5B activatesself-renewal-associated gene expression by", "metadata": {}}
+{"_id": "6472746", "title": "", "text": "Increased CDK1 activity determines the timing ofkinetochore-microtubule attachments in meiosisIChromosome segregation during cell divisiondepends on stable attachment of kinetochores tospindle microtubules. Mitotic spindle formationand kinetochore-microtubule (K-MT) capturetypically occur within minutes of nuclearenvelope breakdown. In contrast, during meiosisI in mouse oocytes, formation of theacentrosomal bipolar spindle takes 3-4 h, andstabilization of K-MT attachments is delayed anadditional 3-4 h. The mechanism responsible forthis delay, which likely prevents stabilization oferroneous attachments during spindle formation,is unknown. Here we show that during meiosis I,attachments are regulated by CDK1 activity,which gradually increases through prometaphaseand metaphase I. Partial reduction of CDK1activity delayed formation of stable attachments,whereas a premature increase in CDK1 activityled to precocious formation of stableattachments and eventually lagging", "metadata": {}}
+{"_id": "6477536", "title": "", "text": "Discontinuation and non-publication of surgicalrandomised controlled trials: observationalstudyOBJECTIVE To determine the rate of earlydiscontinuation and non-publication ofrandomised controlled trials involving patientsundergoing surgery. DESIGN Cross sectionalobservational study of registered and publishedtrials. SETTING Randomised controlled trials ofinterventions in patients undergoing a surgicalprocedure. DATA SOURCES The ClinicalTrials.govdatabase was searched for interventional trialsregistered between January 2008 and December2009 using the keyword \"surgery\". Recruitmentstatus was extracted from the ClinicalTrials.govdatabase. A systematic search for studiespublished in peer reviewed journals wasperformed; if they were not found, results postedon the ClinicalTrials.gov results database weresought. Email queries were sent to trialinvestigators of discontinued and unpublishedcompleted trials if no reason for the respectivestatus was disclosed. MAIN OUTCOME", "metadata": {}}
+{"_id": "6477740", "title": "", "text": "Efficient Generation of Fully ReprogrammedHuman iPS Cells via Polycistronic RetroviralVector and a New Cocktail of ChemicalCompoundsDirect reprogramming of humansomatic cells into induced pluripotent stem (iPS)cells by defined transcription factors (TFs)provides great potential for regenerativemedicine and biomedical research. Thisprocedure has many challenges, including lowreprogramming efficiency, many partiallyreprogrammed colonies, somatic codingmutations in the genome, etc. Here, we describea simple approach for generating fullyreprogrammed human iPS cells by using a singlepolycistronic retroviral vector expressing fourhuman TFs in a single open reading frame (ORF),combined with a cocktail containing three smallmolecules (Sodium butyrate, SB431542, andPD0325901). Our results demonstrate thathuman iPS cells generated by this approachexpress human ES cells markers and exhibitpluripotency demonstrated by their abilities to", "metadata": {}}
+{"_id": "6490571", "title": "", "text": "Prevalence, severity, and unmet need fortreatment of mental disorders in the WorldHealth Organization World Mental HealthSurveys.CONTEXT Little is known about theextent or severity of untreated mental disorders,especially in less-developed countries.OBJECTIVE To estimate prevalence, severity, andtreatment of Diagnostic and Statistical Manual ofMental Disorders, Fourth Edition (DSM-IV)mental disorders in 14 countries (6 lessdeveloped, 8 developed) in the World HealthOrganization (WHO) World Mental Health (WMH)Survey Initiative. DESIGN, SETTING, ANDPARTICIPANTS Face-to-face household surveysof 60 463 community adults conducted from2001-2003 in 14 countries in the Americas,Europe, the Middle East, Africa, and Asia. MAINOUTCOME MEASURES The DSM-IV disorders,severity, and treatment were assessed with theWMH version of the WHO CompositeInternational Diagnostic Interview (WMH-CIDI),a fully structured, lay-administered psychiatric", "metadata": {}}
+{"_id": "6491532", "title": "", "text": "Successful '9-month Bangladesh regimen' formultidrug-resistant tuberculosis among over 500consecutive patients.SETTING Tuberculosis (TB)program, Damien Foundation Projects,Bangladesh. OBJECTIVE To summarize theoutcome and its determinants of the firsttreatment for multidrug-resistant TB using astandardized regimen consisting of a minimum 9months. DESIGN This was a prospective,observational study of a gatifloxacin (GFX) baseddirectly observed regimen, mainly with initialhospitalization. The 4-month intensive phase wasextended until sputum smear conversion.Patients were monitored using culture for up to 2years after treatment completion. RESULTS Ofthe 515 patients who met the study inclusioncriteria and were successively enrolled from2005 to 2011, 84.4% had a bacteriologicallyfavorable outcome. Due to extensive diseasewith delayed sputum conversion, only half of thepatients completed treatment within 9 months;however, 95% were able to complete treatment", "metadata": {}}
+{"_id": "6492658", "title": "", "text": "A Null Mutation in Inositol Polyphosphate4-Phosphatase Type I Causes Selective NeuronalLoss in Weeble Mutant MiceWeeble mutant micehave severe locomotor instability and significantneuronal loss in the cerebellum and in thehippocampal CA1 field. Genetic mapping wasused to localize the mutation to the geneencoding inositol polyphosphate 4-phosphatasetype I (Inpp4a), where a single nucleotidedeletion results in a likely null allele. Thesubstrates of INPP4A are intermediates in apathway affecting intracellular Ca(2+) releasebut are also involved in cell cycle regulationthrough binding the Akt protooncogene;dysfunction in either may account for theneuronal loss of weeble mice. Although othermutations in phosphoinositide enzymes areassociated with synaptic defects withoutneuronal loss, weeble shows that Inpp4a iscritical for the survival of a subset of neuronsduring postnatal development in mice.", "metadata": {}}
+{"_id": "6493422", "title": "", "text": "The myeloid transcription factor KLF2 regulatesthe host response to polymicrobial infection andendotoxic shock.Precise control of myeloid cellactivation is required for optimal host defense.However, this activation process must be underexquisite control to prevent uncontrolledinflammation. Herein, we identify theKruppel-like transcription factor 2 (KLF2) as apotent regulator of myeloid cell activation invivo. Exposure of myeloid cells to hypoxia and/orbacterial products reduced KLF2 expression whileinducing hypoxia inducible factor-1α (HIF-1α),findings that were recapitulated in human septicpatients. Myeloid KLF2 was found to be a potentinhibitor of nuclear factor-kappaB(NF-κB)-dependent HIF-1α transcription and,consequently, a critical determinant of outcomein models of polymicrobial infection andendotoxemia. Collectively, these observationsidentify KLF2 as a tonic repressor of myeloid cellactivation in vivo and an essential regulator ofthe innate immune system.", "metadata": {}}
+{"_id": "6501747", "title": "", "text": "PQBP1 Is a Proximal Sensor of thecGAS-Dependent Innate Response toHIV-1Dendritic cells (DCs) play a critical role inthe immune response to viral infection throughthe facilitation of cell-intrinsic antiviral activityand the activation of adaptive immunity. HIV-1infection of DCs triggers an IRF3-dependentinnate immune response, which requires theactivity of cyclic GAMP synthase (cGAS). Wereport the results of a targeted RNAi screenutilizing primary human monocyte-derived DCs(MDDCs) to identify immune regulators thatdirectly interface with HIV-1-encoded features toinitiate this innate response. Polyglutaminebinding protein 1 (PQBP1) emerged as a strongcandidate through this analysis. We found thatPQBP1 directly binds to reverse-transcribedHIV-1 DNA and interacts with cGAS to initiate anIRF3-dependent innate response. MDDCs derivedfrom Renpenning syndrome patients, who harbormutations in the PQBP1 locus, possess a severelyattenuated innate immune response to HIV-1", "metadata": {}}
+{"_id": "6503185", "title": "", "text": "Malaria biology and disease pathogenesis:insights for new treatmentsPlasmodiumfalciparum malaria, an infectious disease causedby a parasitic protozoan, claims the lives ofnearly a million children each year in Africa aloneand is a top public health concern. Evidence isaccumulating that resistance to artemisininderivatives, the frontline therapy for the asexualblood stage of the infection, is developing insoutheast Asia. Renewed initiatives to eliminatemalaria will benefit from an expanded repertoireof antimalarials, including new drugs that killcirculating P. falciparum gametocytes, therebypreventing transmission. Our currentunderstanding of the biology of asexualblood-stage parasites and gametocytes and theability to culture them in vitro lends optimismthat high-throughput screenings of largechemical libraries will produce a new generationof antimalarial drugs. There is also a need fornew therapies to reduce the high mortality ofsevere malaria. An understanding of the", "metadata": {}}
+{"_id": "6503534", "title": "", "text": "Mutations among Italian mucopolysaccharidosistype I patientsA group of 27 Italian patients wasscreened for α-L-iduronidasemucopolysaccharidosis type I mutations.Mutations were found in 18 patients, with 28alleles identified. The two most commonmutations in northern Europeans (W402X andQ70X) accounted for 11% and 13% of thealleles, respectively. The R89Q mutation,uncommon in Europeans, was found only in onepatient, accounting for 1 of 54 alleles (1.9%).The other mutations, P533R, A327P and G51D,accounted for 11%, 5.6% and 9.3% of the totalalleles, respectively. Interestingly, the highfrequency of the P533R mutation seems to beconfined to Sicily and is higher than the 3%reported in a British/Australian study.", "metadata": {}}
+{"_id": "6504953", "title": "", "text": "Radiation-Related Cancer Risks at Low Dosesamong Atomic Bomb SurvivorsAbstract Pierce, D.A. and Preston, D. L. Radiation-Related CancerRisks at Low Doses among Atomic BombSurvivors. To clarify the information in theRadiation Effects Research Foundation dataregarding cancer risks of low radiation doses, wefocus on survivors with doses less than 0.5 Sv.For reasons indicated, we also restrict attentionmainly to survivors within 3,000 m of thehypocenter of the bombs. Analysis is of solidcancer incidence from 1958–1994, involving7,000 cancer cases among 50,000 survivors inthat dose and distance range. The resultsprovide useful risk estimates for doses as low as0.05–0.1 Sv, which are not overestimated bylinear risk estimates computed from the widerdose ranges 0–2 Sv or 0–4 Sv. There is astatistically significant risk in the range 0–0.1 Sv,and an upper confidence limit on any possiblethreshold is computed as 0.06 Sv. It is indicatedthat modification of the neutron dose estimates", "metadata": {}}
+{"_id": "6517267", "title": "", "text": "Barriers and facilitators to implement shareddecision making in multidisciplinary sciatica care:a qualitative studyBACKGROUND The Dutchmultidisciplinary sciatica guideline recommendsthat the team of professionals involved in sciaticacare and the patient together decide on surgicalor prolonged conservative treatment (shareddecision making [SDM]). Despite thisrecommendation, SDM is not yet integrated insciatica care. Existing literature concerningbarriers and facilitators to SDM implementationmainly focuses on one discipline only, whereasmultidisciplinary care may involve other barriersand facilitators, or make these more complex forboth professionals and patients. Therefore, thisqualitative study aims to identify barriers andfacilitators perceived by patients andprofessionals for SDM implementation inmultidisciplinary sciatica care. METHODS Weconducted 40 semi-structured interviews withprofessionals involved in sciatica care (generalpractitioners, physical therapists, neurologists,", "metadata": {}}
+{"_id": "6517763", "title": "", "text": "Molecular characterization of long-term survivorsof glioblastoma using genome- andtranscriptome-wide profiling.The prognosis ofglioblastoma, the most malignant type of glioma,is still poor, with only a minority of patientsshowing long-term survival of more than threeyears after diagnosis. To elucidate the molecularaberrations in glioblastomas of long-termsurvivors, we performed genome- and/ortranscriptome-wide molecular profiling ofglioblastoma samples from 94 patients, including28 long-term survivors with >36 months overallsurvival (OS), 20 short-term survivors with <12months OS and 46 patients with intermediateOS. Integrative bioinformatic analyses were usedto characterize molecular aberrations in thedistinct survival groups considering establishedmolecular markers such as isocitratedehydrogenase 1 or 2 (IDH1/2) mutations, andO(6) -methylguanine DNA methyltransferase(MGMT) promoter methylation. Patients withlong-term survival were younger and more often", "metadata": {}}
+{"_id": "6525844", "title": "", "text": "Impact of aortic stiffness on survival inend-stage renal disease.BACKGROUND Damageto large arteries is a major factor in the highcardiovascular morbidity and mortality ofpatients with end-stage renal disease (ESRD).Increased arterial stiffness and intima-mediathickness, together with increased pulsepressure, are the principal arterial alterations.Whether increased aortic pulse-wave velocity(PWV), a classic marker of increased arterialstiffness, may predict all-cause and/orcardiovascular mortality has never beeninvestigated. METHODS AND RESULTS A cohortof 241 patients with ESRD undergoinghemodialysis was studied between April 1987and April 1998. The mean duration of follow-upwas 72+/-41 months (mean+/-SD). Mean age atentry was 51.5+/-16.3 years. Seventy-threedeaths occurred, including 48 cardiovascular and25 noncardiovascular fatal events. At entry,together with standard clinical and biochemicalanalyses, patients underwent echocardiography", "metadata": {}}
+{"_id": "6532806", "title": "", "text": "An integrated database of genes responsive tothe Myc oncogenic transcription factor:identification of direct genomic targetsWe reporta database of genes responsive to the Myconcogenic transcription factor. The database MycTarget Gene prioritizes candidate target genesaccording to experimental evidence and clustersresponsive genes into functional groups. Wecoupled the prioritization of target genes withphylogenetic sequence comparisons to predictc-Myc target binding sites, which are in turnvalidated by chromatin immunoprecipitationassays. This database is essential for theunderstanding of the genetic regulatory networksunderlying the genesis of cancers.", "metadata": {}}
+{"_id": "6535392", "title": "", "text": "siRNA specificity searching incorporatingmismatch tolerance data.UNLABELLED Artificiallysynthesized short interfering RNAs (siRNAs) arewidely used in functional genomics to knockdown specific target genes. One ongoingchallenge is to guarantee that the siRNA does notelicit off-target effects. Initial reports suggestedthat siRNAs were highly sequence-specific;however, subsequent data indicates that this isnot necessarily the case. It is still uncertain whatlevel of similarity and other rules are required foran off-target effect to be observed, and scoringschemes have not been developed to lookbeyond simple measures such as the number ofmismatches or the number of consecutivematching bases present. We created design rulesfor predicting the likelihood of a non-specificeffect and present a web server that allows theuser to check the specificity of a given siRNA in aflexible manner using a combination of methods.The server finds potential off-target matches inthe corresponding RefSeq database and ranks", "metadata": {}}
+{"_id": "6536598", "title": "", "text": "The Ino80 chromatin-remodeling complexrestores chromatin structure during UV DNAdamage repairChromatin structure is modulatedduring deoxyribonucleic acid excision repair, buthow this is achieved is unclear. Loss of the yeastIno80 chromatin-remodeling complex (Ino80-C)moderately sensitizes cells to ultraviolet (UV)light. In this paper, we show that INO80 acts inthe same genetic pathway as nucleotide excisionrepair (NER) and that the Ino80-C contributes toefficient UV photoproduct removal in a region ofhigh nucleosome occupancy. Moreover, Ino80interacts with the early NER damage recognitioncomplex Rad4-Rad23 and is recruited tochromatin by Rad4 in a UV damage-dependentmanner. Using a modified chromatinimmunoprecipitation assay, we find thatchromatin disruption during UV lesion repair isnormal, whereas the restoration of nucleosomestructure is defective in ino80 mutant cells.Collectively, our work suggests that Ino80 isrecruited to sites of UV lesion repair through", "metadata": {}}
+{"_id": "6540064", "title": "", "text": "Effects of PCSK9 Inhibition With Alirocumab onLipoprotein Metabolism in HealthyHumansBACKGROUND Alirocumab, a monoclonalantibody to proprotein convertasesubtilisin/kexin type 9 (PCSK9), lowers plasmalow-density lipoprotein (LDL) cholesterol andapolipoprotein B100 (apoB). Although studies inmice and cells have identified increased hepaticLDL receptors as the basis for LDL lowering byPCSK9 inhibitors, there have been no humanstudies characterizing the effects of PCSK9inhibitors on lipoprotein metabolism. Inparticular, it is not known whether inhibition ofPCSK9 has any effects on very low-densitylipoprotein or intermediate-density lipoprotein(IDL) metabolism. Inhibition of PCSK9 alsoresults in reductions of plasma lipoprotein (a)levels. The regulation of plasma Lp(a) levels,including the role of LDL receptors in theclearance of Lp(a), is poorly defined, and nomechanistic studies of the Lp(a) lowering byalirocumab in humans have been published to", "metadata": {}}
+{"_id": "6544701", "title": "", "text": "A more efficient method to generateintegration-free human iPS cellsWe report asimple method, using p53 suppression andnontransforming L-Myc, to generate humaninduced pluripotent stem cells (iPSCs) withepisomal plasmid vectors. We generated humaniPSCs from multiple donors, including twoputative human leukocyte antigen(HLA)-homozygous donors who match \u000020% ofthe Japanese population at major HLA loci; mostiPSCs are integrated transgene-free. Thismethod may provide iPSCs suitable forautologous and allologous stem-cell therapy inthe future.", "metadata": {}}
+{"_id": "6549091", "title": "", "text": "Permanent cardiac pacing versus medicaltreatment for the prevention of recurrentvasovagal syncope: a multicenter, randomized,controlled trial.BACKGROUND This clinicalinvestigation was performed to compare theeffects of permanent dual-chamber cardiacpacing with pharmacological therapy in patientswith recurrent vasovagal syncope. METHODSAND RESULTS Patients from 14 centers wererandomized to receive either a DDD pacemakerprovided with rate-drop response function or thebeta-blocker atenolol at the dosage of 100 mgonce a day. Inclusion criteria were age >35years, >/=3 syncopal spells in the preceding 2years, and positive response to tilt table testingwith syncope occurring in association withrelative bradycardia. The primary outcome wasthe first recurrence of syncope afterrandomization. Enrollment was started inDecember 1997, and the first formal interimanalysis was performed on July 30, 2000. By thattime, 93 patients (38 men and 55 women; mean", "metadata": {}}
+{"_id": "6550579", "title": "", "text": "A central role for HER3 in HER2-amplified breastcancer: implications for targetedtherapy.Epidermal growth factor receptor (EGFR)and HER3 each form heterodimers with HER2and have independently been implicated as keycoreceptors that drive HER2-amplified breastcancer. Some studies suggest a dominant rolefor EGFR, a notion of renewed interest given thedevelopment of dual HER2/EGFR small-moleculeinhibitors. Other studies point to HER3 as theprimary coreceptor. To clarify the relativecontributions of EGFR and HER3 to HER2signaling, we studied receptor knockdown viasmall interfering RNA technology across a panelof six HER2-overexpressing cell lines.Interestingly, HER3 was as critical as HER2 formaintaining cell proliferation in most cell lines,whereas EGFR was dispensable. Induction ofHER3 knockdown in the HER2-overexpressingBT474M1 cell line was found to inhibit growth inthree-dimensional culture and induce rapidtumor regression of in vivo xenografts.", "metadata": {}}
+{"_id": "6559201", "title": "", "text": "Mechanisms of astrocytogenesis in themammalian brain.In the mammalian centralnervous system, astrocytes are the mostabundant cell type and play crucial roles in braindevelopment and function. Astrocytes are knownto be produced from multipotent neural stemcells (NSCs) at the late gestational stage duringbrain development, and accumulating evidenceindicates that this stage-dependent generation ofastrocytes from NSCs is achieved by systematiccooperation between environmental cues andcell-intrinsic programs. Exemplifying the formeris cytokine signaling through the gp130-Januskinase/signal transducer and activator oftranscription 3 pathway, and exemplifying thelatter is epigenetic modification ofastrocyte-specific genes. Here, we introducerecent advances in our understanding of themechanisms that coordinate astrocytogenesisfrom NSCs by modulating signaling pathwaysand epigenetic programs, with a particular focuson the developing mammalian forebrain.", "metadata": {}}
+{"_id": "6559701", "title": "", "text": "Regulation of the latent-lytic switch inEpstein-Barr virus.Epstein-Barr virus (EBV)infection contributes to the development ofseveral different types of human malignancy,including Burkitt lymphoma, Hodgkin lymphoma,and nasopharyngeal carcinoma. As aherpesvirus, EBV can establish latent or lyticinfection in cells. EBV-positive tumors arecomposed almost exclusively of cells with latentEBV infection. Strategies for inducing the lyticform of EBV infection in tumor cells are beinginvestigated as a potential therapy forEBV-positive tumors. In this article, we reviewhow cellular and viral proteins regulate thelatent-lytic EBV switch in infected B cells andepithelial cells, and discuss how harnessing lyticviral reactivation might be used therapeutically.", "metadata": {}}
+{"_id": "6561200", "title": "", "text": "Efficacy of HPV DNA testing with cytology triageand/or repeat HPV DNA testing in primarycervical cancer screening.BACKGROUND Primarycervical screening with both humanpapillomavirus (HPV) DNA testing and cytologicalexamination of cervical cells with a Pap test(cytology) has been evaluated in randomizedclinical trials. Because the vast majority ofwomen with positive cytology are also HPV DNApositive, screening strategies that use HPV DNAtesting as the primary screening test may bemore effective. METHODS We used the databasefrom the intervention arm (n = 6,257 women) ofa population-based randomized trial of doublescreening with cytology and HPV DNA testing toevaluate the efficacy of 11 possible cervicalscreening strategies that are based on HPV DNAtesting alone, cytology alone, and HPV DNAtesting combined with cytology among womenaged 32-38 years. The main outcome measureswere sensitivity for detection of cervicalintraepithelial neoplasia grade 3 or worse", "metadata": {}}
+{"_id": "6565037", "title": "", "text": "Extrasynaptic Glutamate Spillover in theHippocampus: Dependence on Temperature andthe Role of Active Glutamate UptakeAt excitatorysynapses on CA1 pyramidal cells of thehippocampus, a larger quantal content is sensedby N-methyl-D-aspartic acid receptors (NMDARs)than by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). A novelexplanation for this discrepancy is that glutamatereleased from terminals presynaptic to one cellcan diffuse to and activate NMDARs, but notAMPARs, on a neighboring cell. If this occurs inthe living brain, it could invalidate the view thatglutamatergic synapses function as privatecommunication channels between neurons. Here,we show that the discrepancy in quantal contentmediated by the two receptors is greatlydecreased at physiological temperature,compared with conventional recordingconditions. This effect of temperature is not dueto changes in release probability or uncovering oflatent AMPARs. It is, however, partially reversed", "metadata": {}}
+{"_id": "6580081", "title": "", "text": "Molecular mechanisms of hepaticischemia-reperfusion injury andpreconditioning.Ischemia-reperfusion injury is, atleast in part, responsible for the morbidityassociated with liver surgery under total vascularexclusion or after liver transplantation. Thepathophysiology of hepatic ischemia-reperfusionincludes a number of mechanisms thatcontribute to various degrees in the overallinjury. Some of the topics discussed in thisreview include cellular mechanisms of injury,formation of pro- and anti-inflammatorymediators, expression of adhesion molecules,and the role of oxidant stress during theinflammatory response. Furthermore, the rolesof nitric oxide in preventing microcirculatorydisturbances and as a substrate for peroxynitriteformation are reviewed. In addition, emergingmechanisms of protection by ischemicpreconditioning are discussed. On the basis ofcurrent knowledge, preconditioning orpharmacological interventions that mimic these", "metadata": {}}
+{"_id": "6588614", "title": "", "text": "Characterization of a FGF19 Variant with AlteredReceptor Specificity Revealed a Central Role forFGFR1c in the Regulation of GlucoseMetabolismDiabetes and associated metabolicconditions have reached pandemic proportionsworldwide, and there is a clear unmet medicalneed for new therapies that are both effectiveand safe. FGF19 and FGF21 are distinctivemembers of the FGF family that function asendocrine hormones. Both have potent effects onnormalizing glucose, lipid, and energyhomeostasis, and therefore, represent attractivepotential next generation therapies forcombating the growing epidemics of type 2diabetes and obesity. The mechanismresponsible for these impressive metaboliceffects remains unknown. While both FGF19 andFGF21 can activate FGFRs 1c, 2c, and 3c in thepresence of co-receptor βKlotho in vitro, whichreceptor is responsible for the metabolicactivities observed in vivo remains unknown.Here we have generated a variant of FGF19,", "metadata": {}}
+{"_id": "6599693", "title": "", "text": "Empirical verification of evolutionary theories ofagingWe recently selected 3 long-lived mutantstrains of Saccharomyces cerevisiae by a lastingexposure to exogenous lithocholic acid. Eachmutant strain can maintain the extendedchronological lifespan after numerous passagesin medium without lithocholic acid. In this study,we used these long-lived yeast mutants forempirical verification of evolutionary theories ofaging. We provide evidence that the dominantpolygenic trait extending longevity of each ofthese mutants 1) does not affect such keyfeatures of early-life fitness as the exponentialgrowth rate, efficacy of post-exponential growthand fecundity; and 2) enhances such features ofearly-life fitness as susceptibility to chronicexogenous stresses, and the resistance toapoptotic and liponecrotic forms of programmedcell death. These findings validate evolutionarytheories of programmed aging. We alsodemonstrate that under laboratory conditionsthat imitate the process of natural selection", "metadata": {}}
+{"_id": "6609935", "title": "", "text": "Differential regulation of actin microfilaments byhuman MICAL proteins.The Drosophilamelanogaster MICAL protein is essential for theneuronal growth cone machinery that functionsthrough plexin- and semaphorin-mediatedaxonal signaling. Drosophila MICAL is alsoinvolved in regulating myofilament organizationand synaptic structures, and serves as an actindisassembly factor downstream ofplexin-mediated axonal repulsion. In mammaliancells there are three known isoforms, MICAL1,MICAL2 and MICAL3, as well as the MICAL-likeproteins MICAL-L1 and MICAL-L2, but little isknown of their function, and information comesalmost exclusively from neural cells. In this studywe show that in non-neural cells human MICALsare required for normal actin organization, andall three MICALs regulate actin stress fibers.Moreover, we provide evidence that thegeneration of reactive oxygen species by MICALproteins is crucial for their actin-regulatoryfunction. However, although MICAL1 is", "metadata": {}}
+{"_id": "6625693", "title": "", "text": "Suppression of inflammatory and neuropathicpain by uncoupling CRMP-2 from the presynapticCa2+ channel complexThe use of N-typevoltage-gated calcium channel (CaV2.2) blockersto treat pain is limited by many physiological sideeffects. Here we report that inflammatory andneuropathic hypersensitivity can be suppressedby inhibiting the binding of collapsin responsemediator protein 2 (CRMP-2) to CaV2.2 andthereby reducing channel function. A peptide ofCRMP-2 fused to the HIV transactivator oftranscription (TAT) protein (TAT-CBD3)decreased neuropeptide release from sensoryneurons and excitatory synaptic transmission indorsal horn neurons, reduced meningeal bloodflow, reduced nocifensive behavior induced byformalin injection or corneal capsaicin applicationand reversed neuropathic hypersensitivityproduced by an antiretroviral drug. TAT-CBD3was mildly anxiolytic without affecting memoryretrieval, sensorimotor function or depression. Atdoses tenfold higher than that required to reduce", "metadata": {}}
+{"_id": "6636088", "title": "", "text": "Identification and characterization of a commonset of complex I assembly intermediates inmitochondria from patients with complex Ideficiency.Deficiencies in the activity of complexI (NADH: ubiquinone oxidoreductase) are animportant cause of human mitochondrial disease.Complex I is composed of at least 46 structuralsubunits that are encoded in both nuclear andmitochondrial DNA. Enzyme deficiency can resultfrom either impaired catalytic efficiency or aninability to assemble the holoenzyme complex;however, the assembly process remains poorlyunderstood. We have used two-dimensionalBlue-Native/SDS gel electrophoresis and a panelof 11 antibodies directed against structuralsubunits of the enzyme to investigate complex Iassembly in the muscle mitochondria from fourpatients with complex I deficiency caused byeither mitochondrial or nuclear gene defects.Immunoblot analyses of second dimensiondenaturing gels identified seven distinct complexI subcomplexes in the patients studied, five of", "metadata": {}}
+{"_id": "6647414", "title": "", "text": "Leisure time physical activity and mortality: adetailed pooled analysis of the dose-responserelationship.IMPORTANCE The 2008 PhysicalActivity Guidelines for Americans recommendeda minimum of 75 vigorous-intensity or 150moderate-intensity minutes per week (7.5metabolic-equivalent hours per week) of aerobicactivity for substantial health benefit andsuggested additional benefits by doing more thandouble this amount. However, the upper limit oflongevity benefit or possible harm with morephysical activity is unclear. OBJECTIVE Toquantify the dose-response association betweenleisure time physical activity and mortality anddefine the upper limit of benefit or harmassociated with increased levels of physicalactivity. DESIGN, SETTING, AND PARTICIPANTSWe pooled data from 6 studies in the NationalCancer Institute Cohort Consortium (baseline1992-2003). Population-based prospectivecohorts in the United States and Europe withself-reported physical activity were analyzed in", "metadata": {}}
+{"_id": "6650933", "title": "", "text": "Green tea polyphenol causes differentialoxidative environments in tumor versus normalepithelial cells.Green tea polyphenols (GTPPs)are considered beneficial to human health,especially as chemopreventive agents. Recently,cytotoxic reactive oxygen species (ROS) wereidentified in tumor and certain normal cellcultures incubated with high concentrations ofthe most abundant GTPP,(-)-epigallocatechin-3-gallate (EGCG). If EGCGalso provokes the production of ROS in normalepithelial cells, it may preclude the topical use ofEGCG at higher doses. The current studyexamined the oxidative status of normalepithelial, normal salivary gland, and oralcarcinoma cells treated with EGCG, using ROSmeasurement and catalase and superoxidedismutase activity assays. The resultsdemonstrated that high concentrations of EGCGinduced oxidative stress only in tumor cells. Incontrast, EGCG reduced ROS in normal cells tobackground levels. 3-(4,5-dimethylthiazol-2-yl)-", "metadata": {}}
+{"_id": "6669242", "title": "", "text": "Protein acetylation affects acetate metabolism,motility and acid stress response in EscherichiacoliAlthough protein acetylation is widelyobserved, it has been associated with fewspecific regulatory functions making it poorlyunderstood. To interrogate its functionality, weanalyzed the acetylome in Escherichia coliknockout mutants of cobB, the only knownsirtuin-like deacetylase, and patZ, thebest-known protein acetyltransferase. For fourgrowth conditions, more than 2,000 uniqueacetylated peptides, belonging to 809 proteins,were identified and differentially quantified.Nearly 65% of these proteins are related tometabolism. The global activity of CobBcontributes to the deacetylation of a largenumber of substrates and has a major impact onphysiology. Apart from the regulation ofacetyl-CoA synthetase, we found thatCobB-controlled acetylation of isocitrate lyasecontributes to the fine-tuning of the glyoxylateshunt. Acetylation of the transcription factor", "metadata": {}}
+{"_id": "6670101", "title": "", "text": "Ribosome biogenesis: Achilles heel of cancer?Itis long been known that cancer and non-cancercells can be distinguished on the basis of theirnucleolar morphologies. As early as the 19thcentury, it was reported that cancer cells havelarger and more irregularly shaped nucleoli.Since then, pathologists have used nucleolarmorphology to predict the clinical outcome [1].Nucleolar morphology is altered due to theup-regulation of ribosomal gene transcription.Within nucleoli, ribosomal genes (rDNA) aretranscribed by RNA polymerase I (pol I). Thepre-ribosomal RNA (pre-rRNA) transcripts aresubsequently modified and processed into themature 18S, 5.8S and 28S rRNAs. 5S rRNA istranscribed by RNA polymerase III in thenucleoplasm. Together with the ribosomalproteins, the 5S rRNA is imported into thenucleolus where 40S and 60S ribosomal subunitsare assembled prior to export to the cytoplasm[1, 2]. Oncogenes such as c-Myc can bothdirectly and indirectly upregulate rDNA", "metadata": {}}
+{"_id": "6673421", "title": "", "text": "Cell and molecular mechanisms ofinsulin-induced angiogenesisAngiogenesis, thedevelopment of new blood vessel frompre-existing vessels, is a key process in theformation of the granulation tissue during woundhealing. The appropriate development of newblood vessels, along with their subsequentmaturation and differentiation, establishes thefoundation for functional wound neovasculature.We performed studies in vivo and used a varietyof cellular and molecular approaches in vitro toshow that insulin stimulates angiogenesis and toelucidate the signalling mechanisms by whichthis protein stimulates microvessel development.Mice skin injected with insulin shows longervessels with more branches, along withincreased numbers of associated alpha-smoothmuscle actin-expressing cells, suggesting theappropriate differentiation and maturation of thenew vessels. We also found that insulinstimulates human microvascular endothelial cellmigration and tube formation, and that these", "metadata": {}}
+{"_id": "6690087", "title": "", "text": "Inhibition of mammalian target of rapamycinpotentiates thrombin-induced intercellularadhesion molecule-1 expression by acceleratingand stabilizing NF-kappa B activation inendothelial cells.We addressed the regulatoryfunction of mammalian target of rapamycin(mTOR) in the mechanism of thrombin-inducedICAM-1 gene expression in endothelial cells.Pretreatment of HUVECs with rapamycin, aninhibitor of mTOR, augmented thrombin-inducedICAM-1 expression. Inhibition of mTOR by thisapproach promoted whereas over-expression ofmTOR inhibited thrombin-induced transcriptionalactivity of NF-kappaB, an essential regulator ofICAM-1 transcription. Analysis of the NF-kappaBsignaling pathway revealed that inhibition ofmTOR potentiated IkappaB kinase activationresulting in a rapid and persistentphosphorylation of IkappaBalpha on Ser32 andSer36, a requirement for IkappaBalphadegradation. Consistent with these data, weobserved a more efficient and stable nuclear", "metadata": {}}
+{"_id": "6710699", "title": "", "text": "Homologous recombination resolution defect inwerner syndrome.Werner syndrome (WRN) is anuncommon autosomal recessive disease whosephenotype includes features of premature aging,genetic instability, and an elevated risk ofcancer. We used three different experimentalstrategies to show that WRN cellular phenotypesof limited cell division potential, DNA damagehypersensitivity, and defective homologousrecombination (HR) are interrelated. WRN cellsurvival and the generation of viable mitoticrecombinant progeny could be rescued byexpressing wild-type WRN protein or byexpressing the bacterial resolvase protein RusA.The dependence of WRN cellular phenotypes onRAD51-dependent HR pathways wasdemonstrated by using a dominant-negativeRAD51 protein to suppress mitotic recombinationin WRN and control cells: the suppression ofRAD51-dependent recombination led tosignificantly improved survival of WRN cellsfollowing DNA damage. These results define a", "metadata": {}}
+{"_id": "6710713", "title": "", "text": "Risk factors at medical school for subsequentprofessional misconduct: multicentreretrospective case-control studyOBJECTIVE Todetermine whether there are risk factors in adoctor's time at medical school that areassociated with subsequent professionalmisconduct. DESIGN Matched case-controlstudy. Setting Records from medical schools andthe General Medical Council (GMC).PARTICIPANTS 59 doctors who had graduatedfrom any one of eight medical schools in theUnited Kingdom in 1958-97 and had a provedfinding of serious professional misconduct inGMC proceedings in 1999-2004 (cases); 236controls (four for each case) were selected bysystematic sampling from matching graduationcohorts. Case-control status was revealed by theGMC after completion of data entry. MAINOUTCOME MEASURE Odds ratios for being a\"case,\" with multivariable conditional logisticregression of potential risk factors includingpre-admission characteristics and progress", "metadata": {}}
+{"_id": "6712836", "title": "", "text": "MiD49 and MiD51, new components of themitochondrial fission machinery.Mitochondriaform intricate networks through fission andfusion events. Here, we identify mitochondrialdynamics proteins of 49 and 51 kDa (MiD49 andMiD51, respectively) anchored in themitochondrial outer membrane. MiD49/51 formfoci and rings around mitochondria similar to thefission mediator dynamin-related protein 1(Drp1). MiD49/51 directly recruit Drp1 to themitochondrial surface, whereas their knockdownreduces Drp1 association, leading to unopposedfusion. Overexpression of MiD49/51 seems tosequester Drp1 from functioning at mitochondriaand cause fused tubules to associate with actin.Thus, MiD49/51 are new mediators ofmitochondrial division affecting Drp1 action atmitochondria.", "metadata": {}}
+{"_id": "6717533", "title": "", "text": "Maximal activation of transcription by statl andstat3 requires both tyrosine and serinephosphorylationStat1 and Stat3 are latenttranscriptional factors activated initially throughphosphorylation on single tyrosine residuesinduced by cytokine and growth factoroccupation of cell surface receptors. Here weshow that phosphorylation on a single serine(residue 727) in each protein is also required formaximal transcriptional activity. Both cytokinesand growth factors are capable of inducing theserine phosphorylation of Stat1 and Stat3. Theseexperiments show that gene activation by Stat1and Stat3, which obligatorily require tyrosinephosphorylation to become active, also dependsfor maximal activation on one or more of themany serine kinases.", "metadata": {}}
+{"_id": "6718824", "title": "", "text": "Protein restriction during pregnancy affectsmaternal liver lipid metabolism and fetal brainlipid composition in the rat.Suboptimaldevelopmental environments program offspringto lifelong metabolic problems. The aim of thisstudy was to determine the impact of proteinrestriction in pregnancy on maternal liver lipidmetabolism at 19 days of gestation (dG) and itseffect on fetal brain development. Control (C)and restricted (R) mothers were fed withisocaloric diets containing 20 and 10% of casein.At 19 dG, maternal blood and livers and fetallivers and brains were collected. Serum insulinand leptin levels were determinate in mothers.Maternal and fetal liver lipid and fetal brain lipidquantification were performed. Maternal liverand fetal brain fatty acids were quantified by gaschromatography. In mothers, liver desaturaseand elongase mRNAs were measured by RT-PCR.Maternal body and liver weights were similar inboth groups. However, fat body composition,including liver lipids, was lower in R mothers. A", "metadata": {}}
+{"_id": "6722522", "title": "", "text": "Heparan sulfate proteoglycans mediateinternalization and propagation of specificproteopathic seeds.Recent experimentalevidence suggests that transcellular propagationof fibrillar protein aggregates drives theprogression of neurodegenerative diseases in aprion-like manner. This phenomenon is now welldescribed in cell and animal models and involvesthe release of protein aggregates into theextracellular space. Free aggregates then enterneighboring cells to seed further fibrillization.The mechanism by which aggregatedextracellular proteins such as tau andα-synuclein bind and enter cells to triggerintracellular fibril formation is unknown. Priorwork indicates that prion protein aggregates bindheparan sulfate proteoglycans (HSPGs) on thecell surface to transmit pathologic processes.Here, we find that tau fibril uptake also occursvia HSPG binding. This is blocked in cultured cellsand primary neurons by heparin, chlorate,heparinase, and genetic knockdown of a key", "metadata": {}}
+{"_id": "6723450", "title": "", "text": "Effects of Bifidobacterium animalis administeredduring lactation on allergic and autoimmuneresponses in rodents.Probiotics are promoted asbeing beneficial to health and positive effects onthe immune system have been reported.Beneficial immune effects have been attributedto several mechanisms, including stimulating Thelper 1 (Th1) immunity. To explore the effectsof the probiotic Bifidobacterium animalis on Th1-and Th2-mediated immune responses, twodifferent animal models representing either Th1-or Th2-mediated immune responses were used:a rat model for experimental autoimmuneencephalomyelitis (EAE) (Th1) and a mousemodel for respiratory allergy induced byovalbumin (OVA) (Th2). B. animalisadministration started when the mice or ratswere 2 weeks old. Respiratory allergy or EAEwere induced when the animals were 6-7 weeksold. In the allergy model, B. animalis modestlyreduced the number of infiltrating eosinophilsand lymphocytes in the lungs, but no effects on", "metadata": {}}
+{"_id": "6729465", "title": "", "text": "Planar Cell Polarity Signaling Pathway inCongenital Heart DiseasesCongenital heartdisease (CHD) is a common cardiac disorder inhumans. Despite many advances in theunderstanding of CHD and the identification ofmany associated genes, the fundamentaletiology for the majority of cases remainsunclear. The planar cell polarity (PCP) signalingpathway, responsible for tissue polarity inDrosophila and gastrulation movements andcardiogenesis in vertebrates, has been shown toplay multiple roles during cardiac differentiationand development. The disrupted function of PCPsignaling is connected to some CHDs. Here, wesummarize our current understanding of howPCP factors affect the pathogenesis of CHD.", "metadata": {}}
+{"_id": "6748318", "title": "", "text": "Cost-effectiveness of human papillomavirusvaccination and screening inSpain.BACKGROUND In Spain, prophylacticvaccination against human papillomavirus (HPV)types 16 and 18 is being offered free-of-chargeto one birth cohort of girls aged 11-14.Screening is opportunistic (annual/biannual)contributing to social and geographicaldisparities. METHODS A multi-HPV-typemicrosimulation model was calibrated toepidemiologic data from Spain utilisinglikelihood-based methods to assess the healthand economic impact of adding HPV vaccinationto cervical cancer screening. Strategies included(1) screening alone of women over age 25,varying frequency (every 1-5 years) and test(cytology, HPV DNA testing); (2) HPV vaccinationof 11-year-old girls combined with screening.Outcomes included lifetime cancer risk, lifeexpectancy, lifetime costs, number of clinicalprocedures and incremental cost-effectivenessratios. RESULTS After the introduction of HPV", "metadata": {}}
+{"_id": "6751418", "title": "", "text": "Dosimetry and risk estimates of radioiodinetherapy for large, multinodulargoiters.UNLABELLED In patients with a large,multinodular goiter (> 100 g), radiationabsorbed doses in the thyroid, surroundingtissues and remainder of the body wereestimated after therapeutic administration of131I(3.7 MBq or 100 microCi/g of thyroid tissueretained at 24 hr). METHODSThermoluminescent dosimeter (TLD)measurements were performed on 23 patients(12 euthyroid and 1I hyperthyroid; thyroidweight 222 +/- 72 g; 2.1 +/- 0.9 GBq 131I) onthe skin over the thyroid, over thesubmandibular gland and over the parotid gland.Thyroid radioactivity measurements were donedaily in 6 euthyroid and 6 hyperthyroid patients(thyroid weight 204 +/- 69 g; 1.9 +/- 0.9 GBq131I). An iodine biokinetic model and the MIRDmethodology were used to estimate absorbeddoses in organs. Cancer risks were calculatedusing ICRP Publication 60. RESULTS Cumulated", "metadata": {}}
+{"_id": "6766459", "title": "", "text": "RBM3 regulates temperature sensitivemiR-142–5p and miR-143 (thermomiRs), whichtarget immune genes and control feverFever iscommonly used to diagnose disease and isconsistently associated with increased mortalityin critically ill patients. However, the molecularcontrols of elevated body temperature are poorlyunderstood. We discovered that the expressionof RNA-binding motif protein 3 (RBM3), known torespond to cold stress and to modulate microRNA(miRNA) expression, was reduced in 30 patientswith fever, and in THP-1-derived macrophagesmaintained at a fever-like temperature (40 °C).Notably, RBM3 expression is reduced duringfever whether or not infection is demonstrable.Reduced RBM3 expression resulted in increasedexpression of RBM3-targetedtemperature-sensitive miRNAs, we termedthermomiRs. ThermomiRs such as miR-142-5pand miR-143 in turn target endogenous pyrogensincluding IL-6, IL6ST, TLR2, PGE2 and TNF tocomplete a negative feedback mechanism, which", "metadata": {}}
+{"_id": "6767133", "title": "", "text": "Patient preferences and expectations for care:determinants in patients with lumbarintervertebral disc herniation.STUDY DESIGNProspective observational cohort. OBJECTIVE Todescribe the baseline characteristics of patientswith a diagnosis of intervertebral disc herniationwho had different treatment preferences and therelationship of specific expectations with thosepreferences. SUMMARY OF BACKGROUND DATAData were gathered from the observationalcohort of the Spine Patient Outcomes ResearchTrial (SPORT). Patients in the observationalcohort met eligibility requirements identical tothose of the randomized cohort, but declinedrandomization, receiving instead the treatmentof their choice. METHODS Baseline preferenceand expectation data were acquired at the timeof enrollment of the patient, before exposure tothe informed consent process. Univariateanalyses were performed using a t test forcontinuous variables and chi for categoricalvariables. Multivariate analyses were also", "metadata": {}}
+{"_id": "6767271", "title": "", "text": "Cord factor and peptidoglycan recapitulate theTh17-promoting adjuvant activity ofmycobacteria through mincle/CARD9 signalingand the inflammasome.Although adjuvants arecritical vaccine components, their modes ofaction are poorly understood. In this study, weinvestigated the mechanisms by which theheat-killed mycobacteria in CFA promote Th17CD4(+) T cell responses. We found that IL-17secretion by CD4(+) T cells following CFAimmunization requires MyD88 and IL-1β/IL-1Rsignaling. Through measurement of Ag-specificresponses after adoptive transfer of OTII cells,we confirmed that MyD88-dependent signalingcontrols Th17 differentiation rather than simplyproduction of IL-17. Additional experimentsshowed that CFA-induced Th17 differentiationinvolves IL-1β processing by the inflammasome,as mice lacking caspase-1, ASC, or NLRP3 exhibitpartially defective responses after immunization.Biochemical fractionation studies furtherrevealed that peptidoglycan is the major", "metadata": {}}
+{"_id": "6776834", "title": "", "text": "OPA1 gene therapy prevents retinal ganglion cellloss in a Dominant Optic Atrophy mousemodelDominant optic atrophy (DOA) is a rareprogressive and irreversible blinding diseasewhich is one of the most frequent forms ofhereditary optic neuropathy. DOA is mainlycaused by dominant mutation in the OPA1 geneencoding a large mitochondrial GTPase withcrucial roles in membrane dynamics and cellsurvival. Hereditary optic neuropathies arecommonly characterized by the degeneration ofretinal ganglion cells, leading to the optic nerveatrophy and the progressive loss of visual acuity.Up to now, despite increasing advances in theunderstanding of the pathological mechanisms,DOA remains intractable. Here, we tested theefficiency of gene therapy on agenetically-modified mouse model reproducingDOA vision loss. We performed intravitrealinjections of an Adeno-Associated Virus carryingthe human OPA1 cDNA under the control of thecytomegalovirus promotor. Our results provide", "metadata": {}}
+{"_id": "6784372", "title": "", "text": "Multiple degradation pathways regulate versatileCIP/KIP CDK inhibitors.The mammalian CIP/KIPfamily of cyclin-dependent kinase (CDK)inhibitors (CKIs) comprises threeproteins--p21(Cip1/WAF1), p27(Kip1), andp57(Kip2)--that bind and inhibit cyclin-CDKcomplexes, which are key regulators of the cellcycle. CIP/KIP CKIs have additional independentfunctions in regulating transcription, apoptosisand actin cytoskeletal dynamics. These divergentfunctions are performed in distinct cellularcompartments and contribute to the seeminglycontradictory observation that the CKIs can bothsuppress and promote cancer. Multiple ubiquitinligases (E3s) direct the proteasome-mediateddegradation of p21, p27 and p57. This reviewanalyzes recent data highlighting our currentunderstanding of how distinct E3 pathwaysregulate subpopulations of the CKIs to controltheir diverse functions.", "metadata": {}}
+{"_id": "6788835", "title": "", "text": "Dislocation of a type I membrane proteinrequires interactions betweenmembrane-spanning segments within the lipidbilayer.The human cytomegalovirus geneproduct US11 causes rapid degradation of class Imajor histocompatibility complex (MHCI) heavychains by inducing their dislocation from theendoplasmic reticulum (ER) and subsequentdegradation by the proteasome. This set ofreactions resembles the endogenous cellularquality control pathway that removes misfoldedor unassembled proteins from the ER. We showthat the transmembrane domain (TMD) of US11is essential for MHCI heavy chain dislocation, butdispensable for MHCI binding. A Gln residue atposition 192 in the US11 TMD is crucial for theubiquitination and degradation of MHCI heavychains. Cells that express US11 TMD mutantsallow formation of MHCI-beta2m complexes, buttheir rate of egress from the ER is significantlyimpaired. Further mutagenesis data areconsistent with the presence of an alpha-helical", "metadata": {}}
+{"_id": "6790197", "title": "", "text": "Prostate cancer-associated gene expressionalterations determined from needlebiopsies.PURPOSE To accurately identify geneexpression alterations that differentiateneoplastic from normal prostate epithelium usingan approach that avoids contamination byunwanted cellular components and is notcompromised by acute gene expression changesassociated with tumor devascularization andresulting ischemia. EXPERIMENTAL DESIGNApproximately 3,000 neoplastic and benignprostate epithelial cells were isolated using lasercapture microdissection from snap-frozenprostate biopsy specimens provided by 31patients who subsequently participated in aclinical trial of preoperative chemotherapy. cDNAsynthesized from amplified total RNA washybridized to custom-made microarrayscomposed of 6,200 clones derived from theProstate Expression Database. Expressiondifferences for selected genes were verified usingquantitative reverse transcription-PCR. RESULTS", "metadata": {}}
+{"_id": "6793674", "title": "", "text": "Circulating trimethylamine N\u0000oxide and the riskof cardiovascular diseases: a systematic reviewand meta\u0000analysis of 11 prospective cohortstudiesCirculating trimethylamine N-oxide(TMAO), a canonical metabolite from gut flora,has been related to the risk of cardiovasculardisorders. However, the association betweencirculating TMAO and the risk of cardiovascularevents has not been quantitatively evaluated.We performed a systematic review andmeta-analysis of all available cohort studiesregarding the association between baselinecirculating TMAO and subsequent cardiovascularevents. Embase and PubMed databases weresearched for relevant cohort studies. The overallhazard ratios for the developing of cardiovascularevents (CVEs) and mortality were extracted.Heterogeneity among the included studies wasevaluated with Cochran's Q Test and I2 statistics.A random-effect model or a fixed-effect modelwas applied depending on the heterogeneity.Subgroup analysis and meta-regression were", "metadata": {}}
+{"_id": "6796297", "title": "", "text": "PDGF-BB secreted by preosteoclasts inducesangiogenesis during coupling withosteogenesisOsteogenesis during bone modelingand remodeling is coupled with angiogenesis. Arecent study showed that a specific vesselsubtype, strongly positive for CD31 andendomucin (CD31hiEmcnhi), couplesangiogenesis and osteogenesis. Here, we foundthat platelet-derived growth factor-BB(PDGF-BB) secreted by preosteoclasts inducesCD31hiEmcnhi vessel formation during bonemodeling and remodeling. Mice with depletion ofPDGF-BB in the tartrate-resistant acidphosphatase–positive cell lineage showsignificantly lower trabecular and cortical bonemass, serum and bone marrow PDGF-BBconcentrations, and fewer CD31hiEmcnhi vesselscompared to wild-type mice. In the ovariectomy(OVX)-induced osteoporotic mouse model, serumand bone marrow levels of PDGF-BB andnumbers of CD31hiEmcnhi vessels aresignificantly lower compared to sham-operated", "metadata": {}}
+{"_id": "6807122", "title": "", "text": "Discovery of endothelial to mesenchymaltransition as a source for carcinoma-associatedfibroblasts.Activated fibroblasts are associatedwith many different tumors. Myofibroblasts,activated fibroblasts, and perivascularmesenchymal cells such as pericytes play a rolein cancer progression. Many studies suggest thatmyofibroblasts facilitate tumor growth andcancer progression. The source formyofibroblasts and other activated fibroblastswithin the tumors is still debated. Although denovo activation of quiescent fibroblasts intoalpha-smooth muscle actin (alpha SMA)-positivemyofibroblasts is one likely source, epithelial tomesenchymal transition and bone marrowrecruitment are also evolving as possiblemechanisms for the emergence of aheterogeneous population ofcarcinoma-associated fibroblasts. Here, we showthat transforming growth factor-beta1 couldinduce proliferating endothelial cells to undergo aphenotypic conversion into fibroblast-like cells.", "metadata": {}}
+{"_id": "6812319", "title": "", "text": "ERCC1 and MUS81–EME1 promote sisterchromatid separation by processing latereplication intermediates at common fragile sitesduring mitosisChromosomal instability (CIN) is ahallmark of tumour initiation and progression.Some genomic regions are particularly unstableunder replication stress, notably common fragilesites (CFSs) whose rearrangements in tumourcells contribute to cancer development. Recentwork has shown that the Fanconi anaemia(FANC) pathway plays a role in preventingdefective chromosome segregation and CINunder conditions of replication stress. Strikingly,FANCD2 is recruited to regions hosting CFSs onmetaphase chromosomes. To decipher themechanisms protecting CFSs in G2/M, wesearched for proteins that co-localize withFANCD2 on mitotic chromosomes, and identifiedXPF–ERCC1 and MUS81–EME1, twostructure-specific endonucleases. We show thatdepletion of either ERCC1 or MUS81–EME1affects accurate processing of replication", "metadata": {}}
+{"_id": "6820680", "title": "", "text": "Engineered RNA viral synthesis ofmicroRNAs.MicroRNAs (miRNAs) are shortnoncoding RNAs that exert posttranscriptionalgene silencing and regulate gene expression. Inaddition to the hundreds of conserved cellularmiRNAs that have been identified, miRNAs ofviral origin have been isolated and found tomodulate both the viral life cycle and the cellulartranscriptome. Thus far, detection ofvirus-derived miRNAs has been largely limited toDNA viruses, suggesting that RNA viruses maybe unable to exploit this aspect of transcriptionalregulation. Lack of RNA virus-produced miRNAshas been attributed to the replicative constraintsthat would incur following RNase III processingof a genomic hairpin. To ascertain whether thegeneration of viral miRNAs is limited to DNAviruses, we investigated whether influenza viruscould be designed to deliver functional miRNAswithout affecting replication. Here, we describe amodified influenza A virus that expresses cellularmicroRNA-124 (miR-124). Insertion of the", "metadata": {}}
+{"_id": "6826100", "title": "", "text": "The developmental potential of iPSCs is greatlyinfluenced by reprogramming factorselection.Induced pluripotent stem cells (iPSCs)are commonly generated by transduction ofOct4, Sox2, Klf4, and Myc (OSKM) into cells.Although iPSCs are pluripotent, they frequentlyexhibit high variation in terms of quality, asmeasured in mice by chimera contribution andtetraploid complementation. Reliably high-qualityiPSCs will be needed for future therapeuticapplications. Here, we show that one majordeterminant of iPSC quality is the combination ofreprogramming factors used. Based on tetraploidcomplementation, we found that ectopicexpression of Sall4, Nanog, Esrrb, and Lin28(SNEL) in mouse embryonic fibroblasts (MEFs)generated high-quality iPSCs more efficientlythan other combinations of factors includingOSKM. Although differentially methylatedregions, transcript number of master regulators,establishment of specific superenhancers, andglobal aneuploidy were comparable between", "metadata": {}}
+{"_id": "6826636", "title": "", "text": "GiardiaDB and TrichDB: integrated genomicresources for the eukaryotic protist pathogensGiardia lamblia and TrichomonasvaginalisGiardiaDB (http://GiardiaDB.org) andTrichDB (http://TrichDB.org) house the genomedatabases for Giardia lamblia and Trichomonasvaginalis, respectively, and represent the latestadditions to the EuPathDB (http://EuPathDB.org)family of functional genomic databases.GiardiaDB and TrichDB employ the sameframework as other EuPathDB sites (CryptoDB,PlasmoDB and ToxoDB), supporting fullyintegrated and searchable databases.Genomic-scale data available via these resourcesmay be queried based on BLAST searches,annotation keywords and gene ID searches, GOterms, sequence motifs and other proteincharacteristics. Functional queries may also beformulated, based on transcript and proteinexpression data from a variety of platforms.Phylogenetic relationships may also beinterrogated. The ability to combine the results", "metadata": {}}
+{"_id": "6828370", "title": "", "text": "A coding-independent function of gene andpseudogene mRNAs regulates tumour biologyThecanonical role of messenger RNA (mRNA) is todeliver protein-coding information to sites ofprotein synthesis. However, given thatmicroRNAs bind to RNAs, we hypothesized thatRNAs could possess a regulatory role that relieson their ability to compete for microRNA binding,independently of their protein-coding function.As a model for the protein-coding-independentrole of RNAs, we describe the functionalrelationship between the mRNAs produced by thePTEN tumour suppressor gene and itspseudogene PTENP1 and the criticalconsequences of this interaction. We find thatPTENP1 is biologically active as it can regulatecellular levels of PTEN and exert agrowth-suppressive role. We also show that thePTENP1 locus is selectively lost in human cancer.We extended our analysis to other cancer-relatedgenes that possess pseudogenes, such asoncogenic KRAS. We also demonstrate that the", "metadata": {}}
+{"_id": "6836086", "title": "", "text": "Identification of a Multicomponent ComplexRequired for Outer Membrane Biogenesis inEscherichia coliGram-negative bacteria have anouter membrane (OM) that functions as a barrierto protect the cell from toxic compounds such asantibiotics and detergents. The OM is a highlyasymmetric bilayer composed of phospholipids,glycolipids, and proteins. Assembly of thisessential organelle occurs outside the cytoplasmin an environment that lacks obvious energysources such as ATP, and the mechanismsinvolved are poorly understood. We describe theidentification of a multiprotein complex requiredfor the assembly of proteins in the OM ofEscherichia coli. We also demonstrate geneticinteractions between genes encodingcomponents of this protein assembly complexand imp, which encodes a protein involved in theassembly of lipopolysaccharides (LPS) in the OM.These genetic interactions suggest a role forYfgL, one of the lipoprotein components of theprotein assembly complex, in a homeostatic", "metadata": {}}
+{"_id": "6841927", "title": "", "text": "Transtheoretical model-based multiple behaviorintervention for weight management:effectiveness on a populationbasis.BACKGROUND The increasing prevalence ofoverweight and obesity underscores the need forevidence-based, easily disseminableinterventions for weight management that canbe delivered on a population basis. TheTranstheoretical Model (TTM) offers a promisingtheoretical framework for multiple behaviorweight management interventions. METHODSOverweight or obese adults (BMI 25-39.9;n=1277) were randomized to no-treatmentcontrol or home-based, stage-matched multiplebehavior interventions for up to three behaviorsrelated to weight management at 0, 3, 6, and 9months. All participants were re-assessed at 6,12, and 24 months. RESULTS Significanttreatment effects were found for healthy eating(47.5% versus 34.3%), exercise (44.90% versus38.10%), managing emotional distress (49.7%versus 30.30%), and untreated fruit and", "metadata": {}}
+{"_id": "6847208", "title": "", "text": "Autoinduction and signal transduction in theregulation of staphylococcal virulence.Theaccessory genes of Staphylococcus aureus,including those involved in pathogenesis, arecontrolled by a complex regulatory network thatincludes at least four two-component systems,one of which, agr, is a quorum sensor, analternative sigma factor and a large set oftranscription factors, including at least two of thesuperantigen genes, tst and seb. Theseregulatory genes are hypothesized to act in atime- and population density-dependent mannerto integrate signals received from the externalenvironment with the internal metabolicmachinery of the cell, in order to achieve theproduction of particular subsets ofaccessory/virulence factors at the time and inquantities that are appropriate to the needs ofthe organism at any given location. From thestandpoint of pathogenesis, the regulatoryagenda is presumably tuned to particular sites inthe host organism. To address this hypothesis, it", "metadata": {}}
+{"_id": "6853699", "title": "", "text": "Macrophages in the Pathogenesis ofAtherosclerosisIn atherosclerosis, theaccumulation of apolipoprotein B-lipoproteins inthe matrix beneath the endothelial cell layer ofblood vessels leads to the recruitment ofmonocytes, the cells of the immune system thatgive rise to macrophages and dendritic cells.Macrophages derived from these recruitedmonocytes participate in a maladaptive,nonresolving inflammatory response thatexpands the subendothelial layer due to theaccumulation of cells, lipid, and matrix. Somelesions subsequently form a necrotic core,triggering acute thrombotic vascular disease,including myocardial infarction, stroke, andsudden cardiac death. This Review discusses thecentral roles of macrophages in each of thesestages of disease pathogenesis.", "metadata": {}}
+{"_id": "6863070", "title": "", "text": "Three-dimensional superresolution colocalizationof intracellular protein superstructures and thecell surface in live Caulobactercrescentus.Recently, single-molecule imagingand photocontrol have enabled superresolutionoptical microscopy of cellular structures beyondAbbe's diffraction limit, extending the frontier ofnoninvasive imaging of structures within livingcells. However, live-cell superresolution imaginghas been challenged by the need to imagethree-dimensional (3D) structures relative totheir biological context, such as the cellularmembrane. We have developed a technique,termed superresolution by power-dependentactive intermittency and points accumulation forimaging in nanoscale topography (SPRAIPAINT)that combines imaging of intracellular enhancedYFP (eYFP) fusions (SPRAI) with stochasticlocalization of the cell surface (PAINT) to imagetwo different fluorophores sequentially with onlyone laser. Simple light-induced blinking of eYFPand collisional flux onto the cell surface by Nile", "metadata": {}}
+{"_id": "6876224", "title": "", "text": "Overweight prevalence among youth in theUnited States: Why so many differentnumbers?Several recent publications havepresented different estimates for the prevalenceof overweight among youth in the United States.Prevalence estimates range from 11–24%,despite describing the same results from thethird National Health and Nutrition ExaminationSurvey (NHANES III). This paper discusses thevariety and evolution of different overweightprevalence estimates. Issues of definition,measurements, criteria selection and comparisongroups are considered and implications forestimates of the prevalence of overweight amongyouth are explored. Reference percentiles forbody mass index (BMI) from several publicationsare compared. The differences in publishedestimates from NHANES III are noted andexplained.", "metadata": {}}
+{"_id": "6896063", "title": "", "text": "Senescence and aging: the critical roles ofp53p53 functions as a transcription factorinvolved in cell-cycle control, DNA repair,apoptosis and cellular stress responses.However, besides inducing cell growth arrest andapoptosis, p53 activation also modulates cellularsenescence and organismal aging. Senescence isan irreversible cell-cycle arrest that has a crucialrole both in aging and as a robust physiologicalantitumor response, which counteractsoncogenic insults. Therefore, via the regulationof senescence, p53 contributes to tumor growthsuppression, in a manner strictly dependent byits expression and cellular context. In thisreview, we focus on the recent advances on thecontribution of p53 to cellular senescence and itsimplication for cancer therapy, and we willdiscuss p53’s impact on animal lifespan.Moreover, we describe p53-mediated regulationof several physiological pathways that couldmediate its role in both senescence and aging.", "metadata": {}}
+{"_id": "6903077", "title": "", "text": "Asymmetric cryo-EM reconstruction of phageMS2 reveals genome structure in situInsingle-stranded ribonucleic acid (RNA) viruses,virus capsid assembly and genome packagingare intertwined processes. Using cryo-electronmicroscopy and single particle analysis wedetermined the asymmetric virion structure ofbacteriophage MS2, which includes 178 copies ofthe coat protein, a single copy of the A-proteinand the RNA genome. This reveals that in situ,the viral RNA genome can adopt a definedconformation. The RNA forms a branchednetwork of stem-loops that almost all allocatenear the capsid inner surface, whilepredominantly binding to coat protein dimersthat are located in one-half of the capsid. Thissuggests that genomic RNA is highly involved ingenome packaging and virion assembly.", "metadata": {}}
+{"_id": "6910577", "title": "", "text": "Harnessing transposons for cancer genediscoveryRecently, it has become possible tomobilize the Tc1/mariner transposon, SleepingBeauty (SB), in mouse somatic cells atfrequencies high enough to induce cancer.Tumours result from SB insertional mutagenesisof cancer genes, thus facilitating theidentification of the genes and signallingpathways that drive tumour formation. Aconditional SB transposition system has alsobeen developed that makes it possible to limitwhere SB mutagenesis occurs, providing ameans to selectively model many types ofhuman cancer. SB mutagenesis has alreadyidentified a large collection of known cancergenes in addition to a plethora of new candidatecancer genes and potential drug targets.", "metadata": {}}
+{"_id": "6913227", "title": "", "text": "MicroRNA-Containing T-Regulatory-Cell-DerivedExosomes Suppress Pathogenic T Helper 1CellsFoxp3(+) T regulatory (Treg) cells preventinflammatory disease but the mechanistic basisof suppression is not understood completely.Gene silencing by RNA interference can act in acell-autonomous and non-cell-autonomousmanner, providing mechanisms of intercellularregulation. Here, we demonstrate thatnon-cell-autonomous gene silencing, mediatedby miRNA-containing exosomes, is a mechanismemployed by Treg cells to suppressT-cell-mediated disease. Treg cells transferredmicroRNAs (miRNA) to various immune cells,including T helper 1 (Th1) cells, suppressing Th1cell proliferation and cytokine secretion. Use ofDicer-deficient or Rab27a and Rab27bdouble-deficient Treg cells to disrupt miRNAbiogenesis or the exosomal pathway,respectively, established a requirement formiRNAs and exosomes for Treg-cell-mediatedsuppression. Transcriptional analysis and miRNA", "metadata": {}}
+{"_id": "6917133", "title": "", "text": "Estimating risk curves for first-degree relativesof patients with Alzheimer’s disease: The REVEALstudyPurpose: The REVEAL study is arandomized, controlled study of the psychologicaland behavioral impact of APOE disclosure in arisk assessment protocol provided to first degreerelatives of patients with Alzheimer’s disease.The protocol presents risk information ascumulative incidence curves. This articledescribes how these curves were estimated.Methods: Curves were calculated using Bayes’rule to compute the posterior survival curvesincorporating APOE information. Results: Acombination of survival data from the MIRAGEstudy and gender- and age-specific APOE oddsratios were used to create risk curves for malesand females within each of the 6 APOEgenotypes. Conclusion: Utilizing comparativegenotype relative risk information and survivaldata from family studies, estimates of gender-,age-, and genotype-specific risk can begenerated for use in a risk assessment research", "metadata": {}}
+{"_id": "6923795", "title": "", "text": "Up-regulation of endothelial nitric-oxide synthaseby endothelium-derived hyperpolarizing factorinvolves mitogen-activated protein kinase andprotein kinase C signaling pathways.CytochromeP450 (P450)-dependent metabolites ofarachidonic acid, the epoxyeicosatrienoic acids(EETs), are proposed to be endothelium-derivedhyperpolarizing factors (EDHF) that affectvascular tone; however, the effects of EDHF onendothelial-derived nitric oxide biosynthesisremain unknown. We examined the regulation ofendothelial nitric-oxide synthase (eNOS) byEDHF and investigated the relevant signalingpathways involved. The P450 epoxygenasesCYP102 F87V mutant, CYP2C11-CYPOR, andCYP2J2 were transfected into cultured bovineaortic endothelial cells, and the effects ofendogenously formed or exogenously appliedEETs on eNOS expression and activity wereassessed. Transfection with the P450epoxygenases led to increased eNOS proteinexpression, an effect that was attenuated by", "metadata": {}}
+{"_id": "6923961", "title": "", "text": "Prostaglandin E2 promotes intestinal tumorgrowth via DNA methylationAlthough aberrantDNA methylation is considered to be one of thekey ways by which tumor-suppressor andDNA-repair genes are silenced during tumorinitiation and progression, the mechanismsunderlying DNA methylation alterations in cancerremain unclear. Here we show that prostaglandinE(2) (PGE(2)) silences certain tumor-suppressorand DNA-repair genes through DNA methylationto promote tumor growth. These findingsuncover a previously unrecognized role forPGE(2) in the promotion of tumor progression.", "metadata": {}}
+{"_id": "6936141", "title": "", "text": "Nef is physically recruited into the immunologicalsynapse and potentiates T cell activation earlyafter TCR engagement.The HIV-1 protein Nefenhances viral pathogenicity and acceleratesdisease progression in vivo. Nef potentiates T cellactivation by an unknown mechanism, probablyby optimizing the intracellular environment forHIV replication. Using a new T cell reportersystem, we have found that Nef more thandoubles the number of cells expressing thetranscription factors NF-kappaB and NFAT afterTCR stimulation. This Nef-induced priming of TCRsignaling pathways occurred independently ofcalcium signaling and involved a very proximalstep before protein kinase C activation.Engagement of the TCR by MHC-bound Agtriggers the formation of the immunologicalsynapse by recruiting detergent-resistantmembrane microdomains, termed lipid rafts.Approximately 5-10% of the total cellular pool ofNef is localized within lipid rafts. Using confocaland real-time microscopy, we found that Nef in", "metadata": {}}
+{"_id": "6944800", "title": "", "text": "Microenvironmental regulation of tumorprogression and metastasisCancers develop incomplex tissue environments, which they dependon for sustained growth, invasion andmetastasis. Unlike tumor cells, stromal cell typeswithin the tumor microenvironment (TME) aregenetically stable and thus represent anattractive therapeutic target with reduced risk ofresistance and tumor recurrence. However,specifically disrupting the pro-tumorigenic TME isa challenging undertaking, as the TME hasdiverse capacities to induce both beneficial andadverse consequences for tumorigenesis.Furthermore, many studies have shown that themicroenvironment is capable of normalizingtumor cells, suggesting that re-education ofstromal cells, rather than targeted ablation perse, may be an effective strategy for treatingcancer. Here we discuss the paradoxical roles ofthe TME during specific stages of cancerprogression and metastasis, as well as recenttherapeutic attempts to re-educate stromal cells", "metadata": {}}
+{"_id": "6945285", "title": "", "text": "Bezafibrate in men with lower extremity arterialdisease: randomised controlled trial.OBJECTIVETo assess the effect of bezafibrate on the risk ofcoronary heart disease and stroke in men withlower extremity arterial disease. DESIGN Doubleblind placebo controlled randomised trial.SETTING 85 general practices and nine hospitalvascular clinics. PARTICIPANTS 1568 men, meanage 68.2 years (range 35 to 92) at recruitment.INTERVENTIONS Bezafibrate 400 mg daily (783men) or placebo (785 men). MAIN OUTCOMEMEASURES Combination of coronary heartdisease and of stroke. All coronary events, fataland non-fatal coronary events separately, andstrokes alone (secondary end points). RESULTSBezafibrate did not reduce the incidence ofcoronary heart disease and stroke. There were150 and 160 events in the active and placebogroups respectively (relative risk 0.96, 95%confidence interval 0.76 to 1.21). There were 90and 111 major coronary events in the active andplacebo groups respectively (0.81, 0.60 to 1.08),", "metadata": {}}
+{"_id": "6945691", "title": "", "text": "The modulation of human natural killer cellactivity by prostaglandins.Prostaglandins (PGs)have been implicated as a regulator of tumorgrowth in mice and humans. Since natural killercell (NK) cytotoxicity may be an importantcomponent of immune surveillance againstcancer, it is appropriate to study whether theamount of PGs produced by tumors may besufficient to suppress NK activity. Accordingly,the effect of various PGs on the NK activity ofhuman peripheral mononuclear cells wasinvestigated. The percentage cytotoxicity wasmeasured by the release of Cr51 from labeledK562 and other target cells. At very highconcentrations of PG (10(-6) M), suppressionwas seen with PGE2, PGD2, PGA2, and PGF2alpha. However, at concentrations of PG in thephysiologic range (10(-8) M), significantsuppression was seen with PGE2 and PGD2 only.The percentage suppression with PGE2 rangedfrom 77% to 9.5% over a range ofconcentrations from 10(-5) to 10(-9) M (45% at", "metadata": {}}
+{"_id": "6947286", "title": "", "text": "Association analysis between anterior-pharynxdefective-1 genes polymorphisms andAlzheimer's disease.Recent biological studiesindicate the importance of anterior-pharynxdefective-1 (APH-1) proteins in Alzheimer'sdisease (AD) pathogenesis. We scanned APH-1genes for the presence of sequence variations bydenaturing high performance liquidchromatography and analyzed their distributionin an Italian sample of 113 AD patients and 132controls. We found six different polymorphisms:three of them, all in APH-1b, predict anaminoacid substitution (T27I, V199L and F217L);the others are either silent or in non-codingregions. None of them is significantly associatedwith the disease; data stratification by theapolipoprotein E epsilon4 carrier status show atrend for coexistence of the transversionc+651T>G (F217L) with the epsilon4 allele. Ourdata suggest that polymorphisms in APH-1a/bcoding regions are not linked with higher risk forsporadic AD in our Italian population sample.", "metadata": {}}
+{"_id": "6948886", "title": "", "text": "Dynamic epigenetic regulation of glioblastomatumorigenicity through LSD1 modulation of MYCexpression.The available evidence suggests thatthe lethality of glioblastoma is driven by smallsubpopulations of cells that self-renew andexhibit tumorigenicity. It remains unclearwhether tumorigenicity exists as a staticproperty of a few cells or as a dynamicallyacquired property. We used tumor-sphere andxenograft formation as assays for tumorigenicityand examined subclones isolated fromestablished and primary glioblastoma lines. Ourresults indicate that glioblastoma tumorigenicityis largely deterministic, yet the property can beacquired spontaneously at low frequencies.Further, these dynamic transitions are governedby epigenetic reprogramming through thelysine-specific demethylase 1 (LSD1). LSDdepletion increases trimethylation of histone 3lysine 4 at the avian myelocytomatosis viraloncogene homolog (MYC) locus, which elevatesMYC expression. MYC, in turn, regulates", "metadata": {}}
+{"_id": "6955746", "title": "", "text": "Auditory Cortex Tracks Both Auditory and VisualStimulus Dynamics Using Low-FrequencyNeuronal Phase ModulationIntegratinginformation across sensory domains to constructa unified representation of multi-sensory signalsis a fundamental characteristic of perception inecological contexts. One provocative hypothesisderiving from neurophysiology suggests thatthere exists early and direct cross-modal phasemodulation. We provide evidence, based onmagnetoencephalography (MEG) recordings fromparticipants viewing audiovisual movies, thatlow-frequency neuronal information lies at thebasis of the synergistic coordination ofinformation across auditory and visual streams.In particular, the phase of the 2-7 Hz delta andtheta band responses carries robust (in singletrials) and usable information (for parsing thetemporal structure) about stimulus dynamics inboth sensory modalities concurrently. Theseexperiments are the first to show in humans thata particular cortical mechanism, delta-theta", "metadata": {}}
+{"_id": "6957332", "title": "", "text": "The diagnosis and management ofgastro-oesophageal reflux ininfants.Gastro-oesophageal reflux (GOR) andgastro-oesophageal reflux disease (GORD) occurfrequently during the first months of life.Gastro-oesophageal reflux may be a primarygastro-intestinal motility disorder, but it mayalso be secondary to other conditions such ascow's milk protein allergy. Objective diagnosiscan be difficult because there may be absence ofcorrelation between history, results of pHmonitoring and histology. Severe GORD maycause minor symptoms, and minor GOR maycause severe symptoms. Several differenttherapeutic interventions exist. Simply stated,thickened formula reduces regurgitation andalginates and proton pump inhibitors can be usedto decrease acid GOR, depending on the severityof the GORD. Efficacy data of prokinetic drugsare either lacking or disappointing. Regardingside-effects, interest has been focused oncisapride, although other molecules have similar", "metadata": {}}
+{"_id": "6961811", "title": "", "text": "Increased sensitivity of antigen-experienced Tcells through the enrichment of oligomeric T cellreceptor complexes.Although memory T cellsrespond more vigorously to stimulation and theyare more sensitive to low doses of antigen thannaive T cells, the molecular basis of thisincreased sensitivity remains unclear. We havepreviously shown that the T cell receptor (TCR)exists as different-sized oligomers on the surfaceof resting T cells and that large oligomers arepreferentially activated in response to lowantigen doses. Through biochemistry andelectron microscopy, we now showed thatpreviously stimulated and memory T cells havemore and larger TCR oligomers at the cellsurface than their naive counterparts.Reconstitution of cells and mice with a pointmutant of the CD3ζ subunit, which impairs TCRoligomer formation, demonstrated that theincreased size of TCR oligomers was directlyresponsible for the increased sensitivity ofantigen-experienced T cells. Thus, we propose", "metadata": {}}
+{"_id": "6962472", "title": "", "text": "G*Power 3: a flexible statistical power analysisprogram for the social, behavioral, andbiomedical sciences.G*Power (Erdfelder, Faul, &Buchner, 1996) was designed as a generalstand-alone power analysis program forstatistical tests commonly used in social andbehavioral research. G*Power 3 is a majorextension of, and improvement over, theprevious versions. It runs on widely usedcomputer platforms (i.e., Windows XP, WindowsVista, and Mac OS X 10.4) and covers manydifferent statistical tests of the t, F, and chi2 testfamilies. In addition, it includes power analysesfor z tests and some exact tests. G*Power 3provides improved effect size calculators andgraphic options, supports both distribution-basedand design-based input modes, and offers alltypes of power analyses in which users might beinterested. Like its predecessors, G*Power 3 isfree.", "metadata": {}}
+{"_id": "6969753", "title": "", "text": "Dynamic interactions of cortactin and membranetype 1 matrix metalloproteinase at invadopodia:defining the stages of invadopodia formation andfunction.Metastatic tumor cells that activelymigrate and invade surrounding tissues rely oninvadopodia to degrade extracellular matrix(ECM) barriers. Invadopodia are membraneprotrusions that localize enzymes required forECM degradation. Little is known about theformation, function, and regulation ofinvadopodia. Here, we show that invadopodiahave two distinct aspects: (a) structural fororganizing the cellular actin cytoskeleton to formmembrane protrusions and (b) functional forusing proteolytic enzyme(s) for ECMdegradation. Small interfering RNA (siRNA)inhibition established that organization ofinvadopodia structure requires cortactin,whereas protease inhibitor studies identifiedmembrane type 1 matrix metalloproteinase(MT1-MMP) as the key invadopodial enzymeresponsible for gelatin matrix degradation in the", "metadata": {}}
+{"_id": "6974477", "title": "", "text": "PEP-FOLD: an updated de novo structureprediction server for both linear and disulfidebonded cyclic peptidesIn the context of therenewed interest of peptides as therapeutics, it isimportant to have an on-line resource for 3Dstructure prediction of peptides with well-definedstructures in aqueous solution. We present anupdated version of PEP-FOLD allowing thetreatment of both linear and disulphide bondedcyclic peptides with 9-36 amino acids. The servermakes possible to define disulphide bonds andany residue-residue proximity under theguidance of the biologists. Using a benchmark of34 cyclic peptides with one, two and threedisulphide bonds, the best PEP-FOLD modelsdeviate by an average RMS of 2.75 Å from thefull NMR structures. Using a benchmark of 37linear peptides, PEP-FOLD locates lowest-energyconformations deviating by 3 Å RMS from theNMR rigid cores. The evolution of PEP-FOLDcomes as a new on-line service to supersede theprevious server. The server is available at: http:", "metadata": {}}
+{"_id": "6985854", "title": "", "text": "Discrimination of speech stimuli based onneuronal response phase patterns depends onacoustics but not comprehension.Speech stimuligive rise to neural activity in the listener that canbe observed as waveforms usingmagnetoencephalography. Although waveformsvary greatly from trial to trial due to activityunrelated to the stimulus, it has beendemonstrated that spoken sentences can bediscriminated based on theta-band (3-7 Hz)phase patterns in single-trial responsewaveforms. Furthermore, manipulations of thespeech signal envelope and fine structure thatreduced intelligibility were found to producecorrelated reductions in discriminationperformance, suggesting a relationship betweentheta-band phase patterns and speechcomprehension. This study investigates thenature of this relationship, hypothesizing thattheta-band phase patterns primarily reflectcortical processing of low-frequency (<40 Hz)modulations present in the acoustic signal and", "metadata": {}}
+{"_id": "6993046", "title": "", "text": "Breathing more with weaker respiratory musclesin pulmonary arterial hypertension.Exertionalfatigue and dyspnoea limit the daily activities ofpatients with pulmonary arterial hypertension 1.These symptoms are usually explained by theinability of the overloaded right ventricle toperfuse the lungs and to adapt systemic oxygendelivery to oxygen demand. Accordingly,pulmonary hypertension patients present withreductions in peak oxygen uptake, anaerobicthreshold, oxygen pulse, ventilatory efficiencyand 6-min walk distance 2–8. Thisergospirometric profile is strikingly similar to thatof congestive heart failure 8–12, furthersupporting the notion of impaired cardiac outputadaptation to peripheral oxygen requirements asthe main cause of decreased exercise capacity.However, in both pulmonary hypertension andheart failure, ergospirometric variables and walkdistances are better correlated to functional classand prognosis than to haemodynamic function 3,6, 7, 10–12. In addition, impaired skeletal", "metadata": {}}
+{"_id": "7005276", "title": "", "text": "Acetic Acid Activates the AMP-Activated ProteinKinase Signaling Pathway to Regulate LipidMetabolism in Bovine HepatocytesThe effect ofacetic acid on hepatic lipid metabolism inruminants differs significantly from that inmonogastric animals. Therefore, the aim of thisstudy was to investigate the regulationmechanism of acetic acid on the hepatic lipidmetabolism in dairy cows. The AMP-activatedprotein kinase (AMPK) signaling pathway plays akey role in regulating hepatic lipid metabolism.In vitro, bovine hepatocytes were cultured andtreated with different concentrations of sodiumacetate (neutralized acetic acid) and BML-275(an AMPKα inhibitor). Acetic acid consumed alarge amount of ATP, resulting in an increase inAMPKα phosphorylation. The increase in AMPKαphosphorylation increased the expression andtranscriptional activity of peroxisomeproliferator-activated receptor α, whichupregulated the expression of lipid oxidationgenes, thereby increasing lipid oxidation in", "metadata": {}}
+{"_id": "7011850", "title": "", "text": "Unawareness of hypoglycaemia and inadequatehypoglycaemic counterregulation: no causalrelation with diabetic autonomicneuropathy.OBJECTIVE To examine thetraditional view that unawareness ofhypoglycaemia and inadequate hypoglycaemiccounterregulation in insulin dependent diabetesmellitus are manifestations of autonomicneuropathy. DESIGN Perspective assessment ofunawareness of hypoglycaemia and detailedassessment of autonomic neuropathy in patientswith insulin dependent diabetes according to theadequacy of their hypoglycaemiccounterregulation. SETTING One routine diabeticunit in a university teaching hospital. PATIENTS23 Patients aged 21-52 with insulin dependentdiabetes mellitus (seven with symptomssuggesting autonomic neuropathy, nine with aserious clinical problem with hypoglycaemia, andseven without symptoms of autonomicneuropathy and without problems withhypoglycaemia) and 10 controls with a similar", "metadata": {}}
+{"_id": "7020505", "title": "", "text": "Genetic Abnormalities in Chronic LymphocyticLeukemia: Where We Are and Where WeGoChromosomal abnormalities in chroniclymphocytic leukemia (CLL) are detected in up to80% of patients. Among them, deletions of 11q,13q, 17p, and trisomy 12 have a knownprognostic value and play an important role inCLL pathogenesis and evolution, determiningpatients outcome and therapeutic strategies.Standard methods used to identify thesegenomic aberrations include both conventionalG-banding cytogenetics (CGC) and fluorescencein situ hybridization (FISH). Although FISHanalyses have been implemented as the goldstandard, CGC allows the identification ofchromosomal translocations and complexkaryotypes, the latest associated with pooroutcome. Genomic arrays have a higherresolution that allows the detection of crypticabnormalities, although these have not beenfully implemented in routine laboratories. In thelast years, next generation sequencing (NGS)", "metadata": {}}
+{"_id": "7028976", "title": "", "text": "Epidermal growth factor receptor expressionidentifies functionally and molecularly distincttumor-initiating cells in human glioblastomamultiforme and is required forgliomagenesis.Epidermal growth factor receptor(EGFR) is a known diagnostic and, althoughcontroversial, prognostic marker of humanglioblastoma multiforme (GBM). However, itsfunctional role and biological significance in GBMremain elusive. Here, we show that multiple GBMcell subpopulations could be purified from thespecimens of patients with GBM and from cancerstem cell (CSC) lines based on the expression ofEGFR and of other putative CSC markers. Allthese subpopulations are molecularly andfunctionally distinct, are tumorigenic, and needto express EGFR to promote experimentaltumorigenesis. Among them, EGFR-expressingtumor-initiating cells (TIC) display the mostmalignant functional and molecular phenotype.Accordingly, modulation of EGFR expression bygain-of-function and loss-of-function strategies", "metadata": {}}
+{"_id": "7029990", "title": "", "text": "Stress-induced apoptosis associated with nullmutation of ADAR1 RNA editing deaminasegene.One type of RNA editing involves theconversion of adenosine residues into inosine indouble-stranded RNA through the action ofadenosine deaminases acting on RNA (ADAR).A-to-I RNA editing of the coding sequence couldresult in synthesis of proteins not directlyencoded in the genome. ADAR edits alsonon-coding sequences of target RNAs, such asintrons and 3'-untranslated regions, which mayaffect splicing, translation, and mRNA stability.Three mammalian ADAR gene family members(ADAR1-3) have been identified. Here weinvestigated phenotypes of mice homozygous forADAR1 null mutation. Although live ADAR1-/-embryos with normal gross appearance could berecovered up to E11.5, widespread apoptosiswas detected in many tissues. Fibroblastsderived from ADAR1-/- embryos were also proneto apoptosis induced by serum deprivation. Ourresults demonstrate an essential requirement for", "metadata": {}}
+{"_id": "7034001", "title": "", "text": "Outcome of multipair donor kidney exchange bya web-based algorithm.Donor kidney exchange isan established method to overcomeincompatibility of donor-recipient pairs (DRP). Acomputerized algorithm was devised to exchangedonor kidney and was tested in a multicentersetting. The algorithm was made according tothe consensus of participating centers. It makesall possible exchange combinations not onlybetween two incompatible DRP but also circularlyamong three DRP and selects an optimum set ofexchange combinations, considering severalfactors that can affect the outcome of theexchanged transplant. The algorithm wasimplemented as a web-based program, andmatching was performed five times. Fifty-threeDRP were enrolled from five transplant centers.The numbers of DRP that were enrolled in eachmatching were 38 (25:13), 39 (34:5), 33 (31:2),32 (28:4), and 34 (30:4) (carryover:newcomer).The numbers of generated exchangecombinations were 4:11, 3:17, 2:12, 2:3, and", "metadata": {}}
+{"_id": "7036529", "title": "", "text": "Light Activation of Channelrhodopsin-2 inExcitable Cells of Caenorhabditis elegansTriggers Rapid Behavioral ResponsesFor studyingthe function of specific neurons in their nativecircuitry, it is desired to precisely control theiractivity. This often requires dissection to allowaccurate electrical stimulation orneurotransmitter application , and it is thusinherently difficult in live animals, especially insmall model organisms. Here, we employedchannelrhodopsin-2 (ChR2), a directlylight-gated cation channel from the green algaChlamydomonas reinhardtii, in excitable cells ofthe nematode Caenorhabditis elegans, to triggerspecific behaviors, simply by illumination.Channelrhodopsins are 7-transmembrane-helixproteins that resemble the light-driven protonpump bacteriorhodopsin , and they also utilizethe chromophore all-trans retinal, but to open anintrinsic cation pore. In muscle cells,light-activated ChR2 evoked strong,simultaneous contractions, which were reduced", "metadata": {}}
+{"_id": "7039855", "title": "", "text": "Neuronal activity regulates remyelination viaglutamate signalling to oligodendrocyteprogenitorsMyelin regeneration can occurspontaneously in demyelinating diseases such asmultiple sclerosis (MS). However, the underlyingmechanisms and causes of its frequent failureremain incompletely understood. Here we show,using an in-vivo remyelination model, thatdemyelinated axons are electrically active andgenerate de novo synapses with recruitedoligodendrocyte progenitor cells (OPCs), which,early after lesion induction, sense neuronalactivity by expressing AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)/kainatereceptors. Blocking neuronal activity, axonalvesicular release or AMPA receptors indemyelinated lesions results in reducedremyelination. In the absence of neuronalactivity there is a \u00006-fold increase in OPCnumber within the lesions and a reducedproportion of differentiated oligodendrocytes.These findings reveal that neuronal activity and", "metadata": {}}
+{"_id": "7042304", "title": "", "text": "The threshold for polyglutamine-expansionprotein aggregation and cellular toxicity isdynamic and influenced by aging inCaenorhabditis elegans.Studies of the mutantgene in Huntington's disease, and for eightrelated neurodegenerative disorders, haveidentified polyglutamine (polyQ) expansions as abasis for cellular toxicity. This finding has led to adisease hypothesis that protein aggregation andcellular dysfunction can occur at a threshold ofapproximately 40 glutamine residues. Here, wetest this hypothesis by expression offluorescently tagged polyQ proteins (Q29, Q33,Q35, Q40, and Q44) in the body wall muscle cellsof Caenorhabditis elegans and show that youngadults exhibit a sharp boundary at 35-40glutamines associated with the appearance ofprotein aggregates and loss of motility.Surprisingly, genetically identical animalsexpressing near-threshold polyQ repeatsexhibited a high degree of variation in theappearance of protein aggregates and cellular", "metadata": {}}
+{"_id": "7046487", "title": "", "text": "Inflammation meets cancer, with NF-κB as thematchmakerInflammation is a fundamentalprotective response that sometimes goes awryand becomes a major cofactor in thepathogenesis of many chronic human diseases,including cancer. Here we review theevolutionary relationship and opposing functionsof the transcription factor NF-κB in inflammationand cancer. Although it seems to fulfill adistinctly tumor-promoting role in many types ofcancer, NF-κB has a confounding role in certaintumors. Understanding the activity and functionof NF-κB in the context of tumorigenesis iscritical for its successful taming, an importantchallenge for modern cancer biology.", "metadata": {}}
+{"_id": "7059897", "title": "", "text": "IgBLAST: an immunoglobulin variable domainsequence analysis toolThe variable domain of animmunoglobulin (IG) sequence is encoded bymultiple genes, including the variable (V) gene,the diversity (D) gene and the joining (J) gene.Analysis of IG sequences typically requiresidentification of each gene, as well as acomparison of sequence variations in the contextof defined regions. General purpose tools, suchas the BLAST program, have only limited use forsuch tasks, as the rearranged nature of an IGsequence and the variable length of each generequires multiple rounds of BLAST searches for asingle IG sequence. Additionally, manualassembly of different genes is difficult anderror-prone. To address these issues and tofacilitate other common tasks in analysing IGsequences, we have developed the sequenceanalysis tool IgBLAST(http://www.ncbi.nlm.nih.gov/igblast/). With thistool, users can view the matches to the germlineV, D and J genes, details at rearrangement", "metadata": {}}
+{"_id": "7074001", "title": "", "text": "Evidence into practice. Application ofpsychological models of change inevidence-based implementation.Psychiatristshave long recognised that routine clinicalpractice needs to be shaped and informed byexternal evidence (Lewis, 1958). Psychiatricresearchers were among the first to utilisemulti-centre randomised controlled trials(demonstrating the effectiveness ofantipsychotics), and psychologists were amongthe first in the health field to develop techniquesof meta-analysis. Social workers, too, point totheir tradition with the publication of one of theearliest controlled trials (Lehrman, 1949).", "metadata": {}}
+{"_id": "7093809", "title": "", "text": "Wnt signaling establishes anteroposteriorneuronal polarity and requires retromer in C.elegans.Secreted Wnt proteins influence neuralconnectivity by regulating axon guidance,dendritic morphogenesis and synapse formation.We report a new role for Wnt and Frizzledproteins in establishing the anteroposteriorpolarity of the mechanosensory neurons ALM andPLM in C. elegans. Disruption of Wnt signalingleads to a complete inversion of ALM and PLMpolarity: the anterior process adopts the length,branching pattern and synaptic properties of thewild-type posterior process, and vice versa.Different but overlapping sets of Wnt proteinsregulate neuronal polarity in different bodyregions. Wnts act directly on PLM via the FrizzledLIN-17. In addition, we show that they areneeded for axon branching and anteriorlydirected axon growth. We also find that theretromer, a conserved protein complex thatmediates transcytosis and endosome-to-Golgiprotein trafficking, plays a key role in Wnt", "metadata": {}}
+{"_id": "7098463", "title": "", "text": "Adjustable gastric banding and conventionaltherapy for type 2 diabetes: a randomizedcontrolled trial.CONTEXT Observational studiessuggest that surgically induced loss of weightmay be effective therapy for type 2 diabetes.OBJECTIVE To determine if surgically inducedweight loss results in better glycemic control andless need for diabetes medications thanconventional approaches to weight loss anddiabetes control. DESIGN, SETTING, ANDPARTICIPANTS Unblinded randomized controlledtrial conducted from December 2002 throughDecember 2006 at the University ObesityResearch Center in Australia, with generalcommunity recruitment to established treatmentprograms. Participants were 60 obese patients(BMI >30 and <40) with recently diagnosed (<2years) type 2 diabetes. INTERVENTIONSConventional diabetes therapy with a focus onweight loss by lifestyle change vs laparoscopicadjustable gastric banding with conventionaldiabetes care. MAIN OUTCOME MEASURES", "metadata": {}}
+{"_id": "7111021", "title": "", "text": "Integration of antiretroviral therapy withtuberculosis treatment.BACKGROUND Wepreviously reported that integrating antiretroviraltherapy (ART) with tuberculosis treatmentreduces mortality. However, the timing for theinitiation of ART during tuberculosis treatmentremains unresolved. METHODS We conducted athree-group, open-label, randomized, controlledtrial in South Africa involving 642 ambulatorypatients, all with tuberculosis (confirmed by apositive sputum smear for acid-fast bacilli),human immunodeficiency virus infection, and aCD4+ T-cell count of less than 500 per cubicmillimeter. Findings in the earlier-ART group(ART initiated within 4 weeks after the start oftuberculosis treatment, 214 patients) andlater-ART group (ART initiated during the first 4weeks of the continuation phase of tuberculosistreatment, 215 patients) are presented here.RESULTS At baseline, the median CD4+ T-cellcount was 150 per cubic millimeter, and themedian viral load was 161,000 copies per", "metadata": {}}
+{"_id": "7114092", "title": "", "text": "From bloodjournal.hematologylibrary.org atPENN STATE UNIVERSITY on February 23, 2013.For personal use only.Megakaryocyte (MK) is thenaturally polyploid cell that gives rise toplatelets. Polyploidization occurs by endomitosis,which was a process considered to be anincomplete mitosis aborted in anaphase. Here,we used time-lapse confocal video microscopy tovisualize the endomitotic process of primaryhuman megakaryocytes. Our results show thatthe switch from mitosis to endomitosiscorresponds to a late failure of cytokinesisaccompanied by a backward movement of the 2daughter cells. No abnormality was observed inthe central spindle of endomitotic MKs. A furrowformation was present, but the contractile ringwas abnormal because accumulation ofnonmuscle myosin IIA was lacking. In addition, adefect in cell elongation was observed in dipolarendomitotic MKs during telophase. RhoA andF-actin were partially concentrated at the site offurrowing. Inhibition of the Rho/Rock pathway", "metadata": {}}
+{"_id": "7115651", "title": "", "text": "Key role for IL-21 in experimental autoimmuneuveitis.IL-21 is a pleiotropic type 1 cytokine thatshares the common cytokine receptor γ-chain,γ(c), with IL-2, IL-4, IL-7, IL-9, and IL-15. IL-21is most homologous to IL-2. These cytokines areencoded by adjacent genes, but they arefunctionally distinct. Whereas IL-2 promotesdevelopment of regulatory T cells and confersprotection from autoimmune disease, IL-21promotes differentiation of Th17 cells and isimplicated in several autoimmune diseases,including type 1 diabetes and systemic lupuserythematosus. However, the roles of IL-21 andIL-2 in CNS autoimmune diseases such asmultiple sclerosis and uveitis have beencontroversial. Here, we generatedIl21-mCherry/Il2-emGFP dual-reportertransgenic mice and showed that development ofexperimental autoimmune uveitis (EAU)correlated with the presence of T cellscoexpressing IL-21 and IL-2 into the retina.Furthermore, Il21r(-/-) mice were more resistant", "metadata": {}}
+{"_id": "7116734", "title": "", "text": "Nicotinamide Phosphoribosyltransferase/VisfatinDoes Not Catalyze Nicotinamide MononucleotideFormation in Blood PlasmaNicotinamide (Nam)phosphoribosyltransferase (NAMPT) is therate-limiting enzyme in mammalian NADsynthesis, catalyzing nicotinamidemononucleotide (NMN) formation from Nam and5-phosphoribosyl 1-pyrophosphate (PRPP).NAMPT has also been described as anadipocytokine visfatin with a variety of actions,although physiological significance of this proteinremains unclear. It has been proposed thatpossible actions of visfatin are mediated throughthe extracellular formation of NMN. However, wedid not detect NMN in mouse blood plasma, evenwith a highly specific and sensitive liquidchromatography/tandem mass spectrometry.Furthermore, there is no or little ATP, theactivator of NAMPT, in extracellular spaces. Wethus questioned whether visfatin catalyzes the insitu formation of NMN under such extracellularmilieus. To address this question, we here", "metadata": {}}
+{"_id": "7137057", "title": "", "text": "Hepatitis B virus replication is regulated by theacetylation status of hepatitis B viruscccDNA-bound H3 and H4histones.BACKGROUND & AIMS HBV covalentlyclosed circular DNA (cccDNA), the replicativeintermediate responsible for persistent HBVinfection of hepatocytes, is the template fortranscription of all viral mRNAs. Nuclear cccDNAaccumulates as a stable episome organized intominichromosomes by histone and nonhistoneproteins. In this study we investigated, by anewly developed sensitive and specific assay, therelationship between viral replication and HBVchromatin assembly, transcription, andinteraction with viral and cellular regulatoryproteins. METHODS To achieve this aim wecoupled a quantitative chromatinimmunoprecipitation (ChIP) technique to anestablished method that allows the amplificationof virion-encapsidated HBV genomes aftertransfection of linear HBV DNA into humanhepatoma HuH7 cells. The cccDNA-ChIP", "metadata": {}}
+{"_id": "7142113", "title": "", "text": "Visualization of cell cycle in mouse embryos withFucci2 reporter directed by Rosa26promoter.Fucci technology makes possible thedistinction between live cells in the G(1) andS/G(2)/M phases by dual-color imaging. Thistechnology relies upon ubiquitylation-mediatedproteolysis, and transgenic mice expressing Fucciprovide a powerful model system with which tostudy the coordination of the cell cycle anddevelopment. The mice were initially generatedusing the CAG promoter; lines expressing theG(1) and S/G(2)/M phase probes that emittedorange (mKO2) and green (mAG) fluorescence,respectively, were separately constructed. Owingto cell type-biased strength of the CAG promoteras well as the positional effects of randomtransgenesis, however, we noticed somevariability in Fucci expression levels. To controlmore reliably the expression of cell cycle probes,we used different genetic approaches to createtwo types of reporter mouse lines with Fucci2and Rosa26 transcriptional machinery. Fucci2 is", "metadata": {}}
+{"_id": "7145763", "title": "", "text": "Tit-for-Tat: Type VI Secretion SystemCounterattack during Bacterial Cell-CellInteractionsThe bacterial type VI secretionsystem (T6SS) is a dynamic organelle thatbacteria use to target prey cells for inhibition viatranslocation of effector proteins. Time-lapsefluorescence microscopy has documentedstriking dynamics of opposed T6SS organelles inadjacent sister cells of Pseudomonas aeruginosa.Such cell-cell interactions have been termed\"T6SS dueling\" and likely reflect a biologicalprocess that is driven by T6SS antibacterialattack. Here, we show that T6SS duelingbehavior strongly influences the ability of P.aeruginosa to prey upon heterologous bacterialspecies. We show that, in the case of P.aeruginosa, T6SS-dependent killing of eitherVibrio cholerae or Acinetobacter baylyi is greatlystimulated by T6SS activity occurring in thoseprey species. Our data suggest that, in P.aeruginosa, T6SS organelle assembly and lethalcounterattack are regulated by a signal that", "metadata": {}}
+{"_id": "7150238", "title": "", "text": "The effects of LY2405319, an FGF21 analog, inobese human subjects with type 2diabetes.Fibroblast growth factor 21 (FGF21) is arecently discovered metabolic regulator.Exogenous FGF21 produces beneficial metaboliceffects in animal models; however, thetranslation of these observations to humans hasnot been tested. Here, we studied the effects ofLY2405319 (LY), a variant of FGF21, in arandomized, placebo-controlled, double-blindproof-of-concept trial in patients with obesity andtype 2 diabetes. Patients received placebo or 3,10, or 20 mg of LY daily for 28 days. LYtreatment produced significant improvements indyslipidemia, including decreases in low-densitylipoprotein cholesterol and triglycerides andincreases in high-density lipoprotein cholesteroland a shift to a potentially less atherogenicapolipoprotein concentration profile. Favorableeffects on body weight, fasting insulin, andadiponectin were also detected. However, only atrend toward glucose lowering was observed.", "metadata": {}}
+{"_id": "7151961", "title": "", "text": "Visualization of recombination intermediatesproduced by RAD52-mediated single-strandannealing.Double-strand breaks (DSBs) occurfrequently during DNA replication. They are alsocaused by ionizing radiation, chemical damage oras part of the series of programmed events thatoccur during meiosis. In yeast, DSB repairrequires RAD52, a protein that plays a criticalrole in homologous recombination. Here wedescribe the actions of human RAD52 protein ina model system for single-strand annealing(SSA) using tailed (i.e. exonuclease resected)duplex DNA molecules. Purified human RAD52protein binds resected DSBs and promotesassociations between complementary DNAtermini. Heteroduplex intermediates of theserecombination reactions have been visualized byelectron microscopy, revealing the specificbinding of multiple rings of RAD52 to theresected termini and the formation of largeprotein complexes at heteroduplex joints formedby RAD52-mediated annealing.", "metadata": {}}
+{"_id": "7155555", "title": "", "text": "Crucial Role of Interferon Consensus SequenceBinding Protein, but neither of InterferonRegulatory Factor 1 nor of Nitric Oxide Synthesisfor Protection Against Murine ListeriosisListeriamonocytogenes is widely used as a model tostudy immune responses against intracellularbacteria. It has been shown that neutrophils andmacrophages play an important role to restrictbacterial replication in the early phase of primaryinfection in mice, and that the cytokinesinterferon-γ (IFN-γ) and tumor necrosis factor-α(TNF-α) are essential for protection. However,the involved signaling pathways and effectormechanisms are still poorly understood. Thisstudy investigated mouse strains deficient for theIFN-dependent transcription factors interferonconsensus sequence binding protein (ICSBP),interferon regulatory factor (IRF)1 or 2 for theircapacity to eliminate Listeria in vivo and in vitroand for production of inducible reactive nitrogenintermediates (RNI) or reactive oxygenintermediates (ROI) in macrophages. ICSBP−/−", "metadata": {}}
+{"_id": "7157436", "title": "", "text": "Neuronal replacement from endogenousprecursors in the adult brain after strokeIn theadult brain, new neurons are continuouslygenerated in the subventricular zone and dentategyrus, but it is unknown whether these neuronscan replace those lost following damage ordisease. Here we show that stroke, caused bytransient middle cerebral artery occlusion inadult rats, leads to a marked increase of cellproliferation in the subventricular zone.Stroke-generated new neurons, as well asneuroblasts probably already formed before theinsult, migrate into the severely damaged area ofthe striatum, where they express markers ofdeveloping and mature, striatal medium-sizedspiny neurons. Thus, stroke inducesdifferentiation of new neurons into thephenotype of most of the neurons destroyed bythe ischemic lesion. Here we show that the adultbrain has the capacity for self-repair after insultscausing extensive neuronal death. If the newneurons are functional and their formation can", "metadata": {}}
+{"_id": "7165938", "title": "", "text": "Overexpression of the circadian clock geneBmal1 increases sensitivity to oxaliplatin incolorectal cancer.PURPOSE The circadian clockgene Bmal1 is involved in cancer cellproliferation and DNA damage sensitivity. Theaim of this study was to explore the effect ofBmal1 on oxaliplatin sensitivity and to determineits clinical significance in colorectal cancer.EXPERIMENTAL DESIGN Three colorectal cancercell lines, HCT116, THC8307 and HT29, wereused. The Bmal1-mediated control of colorectalcancer cell proliferation was tested in vitro and invivo. MTT and colony formation assays wereperformed to determine the sensitivity ofcolorectal cancer cells to oxaliplatin. Flowcytometry was used to examine changes in thecell-cycle distribution and apoptosis rate.Proteins expressed downstream of Bmal1 uponits overexpression were determined by Westernblotting. Immunohistochemistry was used toanalyze Bmal1 expression in 82 archivedcolorectal cancer tumors from patients treated", "metadata": {}}
+{"_id": "7177329", "title": "", "text": "Evolution of an HIV glycan–dependent broadlyneutralizing antibody epitope through immuneescapeNeutralizing antibodies are likely to play acrucial part in a preventative HIV-1 vaccine.Although efforts to elicit broadlycross-neutralizing (BCN) antibodies byvaccination have been unsuccessful, a minorityof individuals naturally develop these antibodiesafter many years of infection. How suchantibodies arise, and the role of viral evolution inshaping these responses, is unknown. Here weshow, in two HIV-1–infected individuals whodeveloped BCN antibodies targeting the glycan atAsn332 on the gp120 envelope, that this glycanwas absent on the initial infecting virus.However, this BCN epitope evolved within 6months, through immune escape from earlierstrain-specific antibodies that resulted in a shiftof a glycan to position 332. Both viruses thatlacked the glycan at amino acid 332 wereresistant to the Asn332-dependent BCNmonoclonal antibody PGT128 (ref. 8), whereas", "metadata": {}}
+{"_id": "7185591", "title": "", "text": "Sir2-Independent Life Span Extension by CalorieRestriction in YeastCalorie restriction slows agingand increases life span in many organisms. Inyeast, a mechanistic explanation has beenproposed whereby calorie restriction slows agingby activating Sir2. Here we report theidentification of a Sir2-independent pathwayresponsible for a majority of the longevity benefitassociated with calorie restriction. Deletion ofFOB1 and overexpression of SIR2 have beenpreviously found to increase life span byreducing the levels of toxic rDNA circles in agedmother cells. We find that combining calorierestriction with either of these geneticinterventions dramatically enhances longevity,resulting in the longest-lived yeast strainreported thus far. Further, calorie restrictionresults in a greater life span extension in cellslacking both Sir2 and Fob1 than in cells whereSir2 is present. These findings indicate that Sir2and calorie restriction act in parallel pathways topromote longevity in yeast and, perhaps, higher", "metadata": {}}
+{"_id": "7198295", "title": "", "text": "The Effect of Submaximal Exercise Preceded bySingle Whole-Body Cryotherapy on the Markersof Oxidative Stress and Inflammation in Blood ofVolleyball PlayersThe aim of the study was todetermine the effect of single whole-bodycryotherapy (WBC) session applied prior tosubmaximal exercise on the activity ofantioxidant enzymes, the concentration of lipidperoxidation products, total oxidative status, andthe level of cytokines in blood of volleyballplayers. The study group consisted of 18 maleprofessional volleyball players, who weresubjected to extremely cold air (-130°C) prior toexercise performed on cycloergometer. Bloodsamples were taken five times: before WBC,after WBC procedure, after exercise preceded bycryotherapy (WBC exercise), and before andafter exercise without WBC (control exercise).The activity of catalase statistically significantlyincreased after control exercise. Moreover, theactivity of catalase and superoxide dismutasewas lower after WBC exercise than after control", "metadata": {}}
+{"_id": "7209559", "title": "", "text": "Incidence of childhood distal forearm fracturesover 30 years: a population-basedstudy.CONTEXT The incidence of distal forearmfractures in children peaks around the time ofthe pubertal growth spurt, possibly becausephysical activity increases at the time of atransient deficit in cortical bone mass due to theincreased calcium demand during maximalskeletal growth. Changes in physical activity ordiet may therefore influence risk of forearmfracture. OBJECTIVE To determine whether therehas been a change in the incidence of distalforearm fractures in children in recent years.DESIGN, SETTING, AND PATIENTSPopulation-based study among Rochester, Minn,residents younger than 35 years with distalforearm fractures in 1969-1971, 1979-1981,1989-1991, and 1999-2001. MAIN OUTCOMEMEASURE Estimated incidence of distal forearmfractures in 4 time periods. RESULTSComparably age- and sex-adjusted annualincidence rates per 100 000 increased from", "metadata": {}}
+{"_id": "7211056", "title": "", "text": "Tolerance of whole-genome doubling propagateschromosomal instability and accelerates cancergenome evolution.UNLABELLED The contributionof whole-genome doubling to chromosomalinstability (CIN) and tumor evolution is unclear.We use long-term culture of isogenic tetraploidcells from a stable diploid colon cancerprogenitor to investigate how a genome-doublingevent affects genome stability over time. Rarecells that survive genome doubling demonstrateincreased tolerance to chromosome aberrations.Tetraploid cells do not exhibit increasedfrequencies of structural or numerical CIN perchromosome. However, the tolerant phenotypein tetraploid cells, coupled with a doubling ofchromosome aberrations per cell, allowschromosome abnormalities to evolve specificallyin tetraploids, recapitulating chromosomalchanges in genomically complex colorectaltumors. Finally, a genome-doubling event isindependently predictive of poor relapse-freesurvival in early-stage disease in two", "metadata": {}}
+{"_id": "7221410", "title": "", "text": "Alzheimer’s Disease Risk Gene CD33 InhibitsMicroglial Uptake of Amyloid BetaThetransmembrane protein CD33 is a sialicacid-binding immunoglobulin-like lectin thatregulates innate immunity but has no knownfunctions in the brain. We have previously shownthat the CD33 gene is a risk factor forAlzheimer's disease (AD). Here, we observedincreased expression of CD33 in microglial cellsin AD brain. The minor allele of the CD33 SNPrs3865444, which confers protection against AD,was associated with reductions in both CD33expression and insoluble amyloid beta 42 (Aβ42)levels in AD brain. Furthermore, the numbers ofCD33-immunoreactive microglia were positivelycorrelated with insoluble Aβ42 levels and plaqueburden in AD brain. CD33 inhibited uptake andclearance of Aβ42 in microglial cell cultures.Finally, brain levels of insoluble Aβ42 as well asamyloid plaque burden were markedly reduced inAPP(Swe)/PS1(ΔE9)/CD33(-/-) mice. Therefore,CD33 inactivation mitigates Aβ pathology and", "metadata": {}}
+{"_id": "7223604", "title": "", "text": "Aluminum fluoride stimulates surface protrusionsin cells overexpressing the ARF6 GTPaseTo studythe effector function of the ADP- ribosylationfactor (ARF) 6 GTP-binding protein, wetransfected HeLa cells with wild-type,epitope-tagged ARF6. Previously shown toindirectly activate the ARF1 GTPase, aluminumfluoride (AIF) treatment of ARF6-transfectedcells resulted in a redistribution of both ARF6 andactin to discrete sites on the plasma membrane,which became increasingly protrusive over time.The effects of AIF were reversible, specific tocells transfected with wild-type ARF6, andresembled the cellular protrusions observed incells expressing the GTPase defective mutant ofARF6. Importantly, the protrusions observed incells transfected with ARF6 were distinct fromthe enhanced stress fibers and membrane rufflesobserved in cells transfected with RhoA andRac1, respectively. In cells forming protrusions,there was an apparent stimulation ofmacropinocytosis and membrane recycling within", "metadata": {}}
+{"_id": "7224632", "title": "", "text": "A longitudinal diffusion tensor imaging studyassessing white matter fiber tracts aftersports-related concussion.The extent ofstructural injury in sports-related concussion(SRC) is central to the course of recovery,long-term effects, and the decision to return toplay. In the present longitudinal study, we useddiffusion tensor imaging (DTI) to assess whitematter (WM) fiber tract integrity within 2 days, 2weeks, and 2 months of concussive injury.Participants were right-handed male varsitycontact-sport athletes (20.2±1.0 years of age)with a medically diagnosed SRC (no loss ofconsciousness). They were compared toright-handed male varsity non-contact-sportathletes serving as controls (19.9±1.7 years).We found significantly increased radial diffusivity(RD) in concussed athletes (n=12; paired t-test,tract-based spatial statistics; p<0.025) at 2days, when compared to the 2-week postinjurytime point. The increase was found in a cluster ofright hemisphere voxels, spanning the posterior", "metadata": {}}
+{"_id": "7224723", "title": "", "text": "HIV–1 Infects Multipotent Progenitor CellsCausing Cell Death and Establishing LatentCellular ReservoirsHIV causes a chronic infectioncharacterized by depletion of CD4(+) Tlymphocytes and the development ofopportunistic infections. Despite drugs thatinhibit viral spread, HIV infection has beendifficult to cure because of uncharacterizedreservoirs of infected cells that are resistant tohighly active antiretroviral therapy (HAART) andthe immune response. Here we used CD34(+)cells from infected people as well as in vitrostudies of wild-type HIV to show infection andkilling of CD34(+) multipotent hematopoieticprogenitor cells (HPCs). In some HPCs, wedetected latent infection that stably persisted incell culture until viral gene expression wasactivated by differentiation factors. A uniquereporter HIV that directly detects latentlyinfected cells in vitro confirmed the presence ofdistinct populations of active and latentlyinfected HPCs. These findings have major", "metadata": {}}
+{"_id": "7225911", "title": "", "text": "The human long non-coding RNA-RoR is a p53repressor in response to DNA damageIt is wellknown that upon stress, the level of the tumorsuppressor p53 is remarkably elevated.However, despite extensive studies, theunderlying mechanism involving importantinter-players for stress-induced p53 regulation isstill not fully understood. We present evidencethat the human lincRNA-RoR (RoR) is a strongnegative regulator of p53. Unlike MDM2 thatcauses p53 degradation through theubiquitin-proteasome pathway, RoR suppressesp53 translation through direct interaction withthe heterogeneous nuclear ribonucleoprotein I(hnRNP I). Importantly, a 28-base RoR sequencecarrying hnRNP I binding motifs is essential andsufficient for p53 repression. We further showthat RoR inhibits p53-mediated cell cycle arrestand apoptosis. Finally, we demonstrate aRoR-p53 autoregulatory feedback loop wherep53 transcriptionally induces RoR expression.Together, these results suggest that the", "metadata": {}}
+{"_id": "7227763", "title": "", "text": "Experimental and clinical studies on lactate andpyruvate as indicators of the severity of acutecirculatory failure (shock).The increase in lactate(L) and pyruvate (P) content of arterial bloodduring experimental and clinical shock states andthe extent to which such increases serve asmeasures of oxygen deficit and irreversibleinjury were investigated on an empirical basis. Astandardized method for production ofhemorrhagic shock in the Wistar rat wasemployed. During a 4-hour bleeding period,oxygen consumption of the rat was reduced toapproximately 40% of control value, pH wasreduced from 7.39 to 7.08, and a concurrentincrease in L from 0.80 to 6.06 mm and in P from0.07 to 0.18 mm were observed. Cumulativeoxygen debt correlated with log L (r = 0.50; P <0.0005) and both were significantly related tosurvival. Correlation of cumulative oxygen debtand survival, both with P and with computedvalues of the lactate pyruvate ratio (L/P) andexcess lactate (XL), were of no higher", "metadata": {}}
+{"_id": "7228140", "title": "", "text": "Virtual microdissection identifies distinct tumor-and stroma-specific subtypes of pancreatic ductaladenocarcinomaPancreatic ductaladenocarcinoma (PDAC) remains a lethal diseasewith a 5-year survival rate of 4%. A key hallmarkof PDAC is extensive stromal involvement, whichmakes capturing precise tumor-specificmolecular information difficult. Here we haveovercome this problem by applying blind sourceseparation to a diverse collection of PDAC geneexpression microarray data, including data fromprimary tumor, metastatic and normal samples.By digitally separating tumor, stromal andnormal gene expression, we have identified andvalidated two tumor subtypes, including a'basal-like' subtype that has worse outcome andis molecularly similar to basal tumors in bladderand breast cancers. Furthermore, we define'normal' and 'activated' stromal subtypes, whichare independently prognostic. Our resultsprovide new insights into the molecularcomposition of PDAC, which may be used to", "metadata": {}}
+{"_id": "7230315", "title": "", "text": "Inducible nitric oxide synthase in pulmonaryalveolar macrophages from patients withtuberculosisThe high-output pathway of nitricoxide production helps protect mice frominfection by several pathogens, includingMycobacterium tuberculosis. However, based onstudies of cells cultured from blood, it iscontroversial whether human mononuclearphagocytes can express the correspondinginducible nitric oxide synthase (iNOS;NOS2). Thepresent study examined alveolar macrophagesfixed directly after bronchopulmonary lavage. Anaverage of 65% of the macrophages from 11 of11 patients with untreated, culture-positivepulmonary tuberculosis reacted with an antibodydocumented herein to be monospecific forhuman NOS2. In contrast, a mean of 10% ofbronchoalveolar lavage cells were positive fromeach of five clinically normal subjects.Tuberculosis patients' macrophages displayeddiaphorase activity in the same proportion thatthey stained for NOS2, under assay conditions", "metadata": {}}
+{"_id": "7239105", "title": "", "text": "The use of mouse models to understand andimprove cognitive deficits in DownsyndromeRemarkable advances have been madein recent years towards therapeutics forcognitive impairment in individuals with Downsyndrome (DS) by using mouse models. In thisreview, we briefly describe the phenotypes ofmouse models that represent outcome targetsfor drug testing, the behavioral tests used toassess impairments in cognition and the knownmechanisms of action of several drugs that arebeing used in preclinical studies or are likely tobe tested in clinical trials. Overlaps in thedistribution of targets and in the pathways thatare affected by these diverse drugs in thetrisomic brain suggest new avenues for DSresearch and drug development.", "metadata": {}}
+{"_id": "7260461", "title": "", "text": "position-specific gap penaltiesThe sensitivity ofthe commonly used progressive multiplesequence alignment method has been greatlyimproved for the alignment of divergent proteinsequences. Firstly, individual weights areassigned to each sequence in a partial alignmentin order to down-weight near-duplicatesequences and up-weight the most divergentones. Secondly, amino acid substitution matricesare varied at different alignment stagesaccording to the divergence of the sequences tobe aligned. Thirdly, residue-specific gap penaltiesand locally reduced gap penalties in hydrophilicregions encourage new gaps in potential loopregions rather than regular secondary structure.Fourthly, positions in early alignments wheregaps have been opened receive locally reducedgap penalties to encourage the opening up ofnew gaps at these positions. These modificationsare incorporated into a new program, CLUSTALW which is freely available.", "metadata": {}}
+{"_id": "7261402", "title": "", "text": "Pedestrian Detection via Periodic MotionAnalysisWe describe algorithms for detectingpedestrians in videos acquired by infrared (andcolor) sensors. Two approaches are proposedbased on gait. The first employs computationallyefficient periodicity measurements. Unlike othermethods, it estimates a periodic motionfrequency using two cascading hypothesistesting steps to filter out non-cyclic pixels so thatit works well for both radial and lateral walkingdirections. The extraction of the period isefficient and robust with respect to sensor noiseand cluttered background. In order to integrateshape and motion, we convert the cyclic patterninto a binary sequence by Maximal Principal GaitAngle (MPGA) fitting in the second method. Itdoes not require alignment and continuouslyestimates the period using a Phase-locked Loop.Both methods are evaluated by experimentalresults that measure performance as a functionof size, movement direction, frame rate andsequence length.", "metadata": {}}
+{"_id": "7264949", "title": "", "text": "Seroepidemiological survey of feline retrovirusinfections in cats in Taiwan in 1993 and 1994.Inorder to investigate the prevalence of infectionswith three feline retroviruses felineimmunodeficiency virus (FIV), feline leukemiavirus (FeLV) and feline syncytial virus (FSV) inTaiwan, we collected a total of 75 blood samplesfrom cats from veterinary hospitals, a breedingcattery and a homeless shelter in 1993 and1994. We examined the presences of anti-FIVand FSV antibodies and FeLV-p27 antigen inthese samples by the indirectimmunofluorescence and/or enzyme-linkedimmunosorbent assays. All of the serum samplespositive for FIV were obtained from homelesscats and the overall FIV positive rate was 4%.The overall positive rates of FSV and FeLV were28% and 1.3%, respectively. From these results,together with previous seroepidemiologicalsurveys by others, it was revealed that theprevalence of FIV and FeLV infections appearedto be lower in Taiwan than in the United States", "metadata": {}}
+{"_id": "7268522", "title": "", "text": "Notch targets and their regulation.The proteolyticcleavages elicited by activation of the Notchreceptor release an intracellular fragment, Notchintracellular domain, which enters the nucleus toactivate the transcription of targets. Changes intranscription are therefore a major output of thispathway. However, the Notch outputs clearlydiffer from cell type to cell type. In this reviewwe discuss current understanding of Notchtargets, the mechanisms involved in theirtranscriptional regulation, and what mightunderlie the activation of different sets of targetsin different cell types.", "metadata": {}}
+{"_id": "7277084", "title": "", "text": "Extraction and Analysis of Multiple PeriodicMotions in Video SequencesThe analysis ofperiodic or repetitive motions is useful in manyapplications, such as the recognition andclassification of human and animal activities.Existing methods for the analysis of periodicmotions first extract motion trajectories usingspatial information and then determine if theyare periodic. These approaches are mostly basedon feature matching or spatial correlation, whichare often infeasible, unreliable, orcomputationally demanding. In this paper, wepresent a new approach, based on the time-frequency analysis of the video sequence as awhole. Multiple periodic trajectories are extractedand their periods are estimated simultaneously.The objects that are moving in a periodic mannerare extracted using the spatial domaininformation. Experiments with synthetic and realsequences display the capabilities of thisapproach.", "metadata": {}}
+{"_id": "7281161", "title": "", "text": "MicroRNA-21 is up-regulated in allergic airwayinflammation and regulates IL-12p35expression.Allergic airway inflammation ischaracterized by marked in situ changes in geneand protein expression, yet the role ofmicroRNAs (miRNAs), a new family of key mRNAregulatory molecules, in this process has not yetbeen reported. Using a highly sensitivemicroarray-based approach, we identified 21miRNAs with differential expression betweendoxycycline-induced lung-specific IL-13transgenic mice (with allergic airwayinflammation) and control mice. In particular, weobserved overexpression of miR-21 andunderexpression of miR-1 in the induced IL-13transgenic mice compared with control mice.These findings were validated in two independentmodels of allergen-induced allergic airwayinflammation and in IL-4 lung transgenic mice.Although IL-13-induced miR-21 expression wasIL-13Ralpha1 dependent, allergen-inducedmiR-21 expression was mediated mainly", "metadata": {}}
+{"_id": "7285256", "title": "", "text": "COPD: epidemiology, prevalence, morbidity andmortality, and disease heterogeneity.COPDcontinues to cause a heavy health and economicburden both in the United States and around theworld. Some of the risk factors for COPD arewell-known and include smoking, occupationalexposures, air pollution, airwayhyperresponsiveness, asthma, and certaingenetic variations, although many questions,such as why < 20% of smokers developsignificant airway obstruction, remain. Precisedefinitions of COPD vary and are frequentlydependent on an accurate diagnosis of theproblem by a physician. These differences in thedefinition of COPD can have large effects on theestimates of COPD in the population.Furthermore, evidence that COPD representsseveral different disease processes withpotentially different interventions continues toemerge. In most of the world, COPD prevalenceand mortality are still increasing and likely willcontinue to rise in response to increases in", "metadata": {}}
+{"_id": "7299977", "title": "", "text": "Changing geographic ranges of ticks andtick-borne pathogens: drivers, mechanisms andconsequences for pathogen diversityThegeographic ranges of ticks and tick-bornepathogens are changing due to global and localenvironmental (including climatic) changes. Inthis review we explore current knowledge of thedrivers for changes in the ranges of ticks andtick-borne pathogen species and strains viaeffects on their basic reproduction number (R 0),and the mechanisms of dispersal that allow ticksand tick-borne pathogens to invade suitableenvironments. Using the expanding geographicdistribution of the vectors and agent of Lymedisease as an example we then investigate whatcould be expected of the diversity of tick-bornepathogens during the process of rangeexpansion, and compare this with what iscurrently being observed. Lastly we explore howhistoric population and range expansions andcontractions could be reflected in thephylogeography of ticks and tick-borne", "metadata": {}}
+{"_id": "7317051", "title": "", "text": "Mutant KRAS is a druggable target for pancreaticcancer.Pancreatic ductal adenocarcinoma (PDA)represents an unmet therapeutic challenge. PDAis addicted to the activity of the mutated KRASoncogene which is considered so far anundruggable therapeutic target. We propose anapproach to target KRAS effectively in patientsusing RNA interference. To meet this challenge,we have developed a local prolonged siRNAdelivery system (Local Drug EluteR, LODER)shedding siRNA against the mutated KRAS(siG12D LODER). The siG12D LODER wasassessed for its structural, release, and deliveryproperties in vitro and in vivo. The effect of thesiG12D LODER on tumor growth was assessed ins.c. and orthotopic mouse models. KRASsilencing effect was further assessed on theKRAS downstream signaling pathway. TheLODER-encapsulated siRNA was stable and activein vivo for 155 d. Treatment of PDA cells withsiG12D LODER resulted in a significant decreasein KRAS levels, leading to inhibition of", "metadata": {}}
+{"_id": "7324039", "title": "", "text": "Trimmomatic: a flexible trimmer for Illuminasequence dataMOTIVATION Although manynext-generation sequencing (NGS) readpreprocessing tools already existed, we could notfind any tool or combination of tools that met ourrequirements in terms of flexibility, correcthandling of paired-end data and highperformance. We have developed Trimmomaticas a more flexible and efficient preprocessingtool, which could correctly handle paired-enddata. RESULTS The value of NGS readpreprocessing is demonstrated for bothreference-based and reference-free tasks.Trimmomatic is shown to produce output that isat least competitive with, and in many casessuperior to, that produced by other tools, in allscenarios tested. AVAILABILITY ANDIMPLEMENTATION Trimmomatic is licensed underGPL V3. It is cross-platform (Java 1.5+ required)and available at http://www.usadellab.org/cms/index.php?page=trimmomatic   CONTACTusadel@bio1.rwth-aachen.de   SUPPLEMENTARY", "metadata": {}}
+{"_id": "7343711", "title": "", "text": "Basics of PD-1 in self-tolerance, infection, andcancer immunitySuccessful cancer treatmentrequires understanding host immune responseagainst tumor cells. PD-1 belongs to the CD28superfamily of receptors that work as“checkpoints” of immune activation. PD-1maintains immune self-tolerance to preventautoimmunity and controls T-cell reaction duringinfection to prevent excessive tissue damage.Tumor cells that arise from normal tissue acquiremutations that can be targeted by lymphocytes.Accumulating lines of evidence suggest thattumor cells evade host immune attack byexpressing physiological PD-1 ligands andstimulating PD-1 on the lymphocytes. Based onthis idea, researchers have successfullydemonstrated that systemic administration ofmonoclonal antibodies that inhibit the binding ofPD-1 to the ligands reactivated T cells andaugmented the anti-cancer immune response. Inthis review, I summarize the basics of T-cellbiology and its regulation by PD-1 and discuss", "metadata": {}}
+{"_id": "7357135", "title": "", "text": "Dissociation of β1- and β2-adrenergic receptorsubtypes in the retrieval of cocaine-associatedmemory.Drug seeking is maintained byencounters with drug-associated cues, anddisrupting retrieval of these drug-cueassociations would reduce the risk of relapse.Retrieval of cocaine-associated memories isdependent on β-adrenergic receptor (β-AR)activation, and blockade of these receptorsinduces a persistent retrieval deficit. Whetherretrieval of cocaine-associated memory ismediated by a specific β-AR subtype, however,remains unclear. Using a cocaine conditionedplace preference (CPP) procedure, we examinedwhether retrieval of a cocaine CPP memory ismediated collectively by β1- and β2-ARs, or byone of these β-AR subtypes alone. We show thatco-blockade of β1- and β2-ARs abolished CPPexpression on that and subsequent drug-freeCPP tests, resulting in a long-lasting retrievaldeficit that prevented subsequentcocaine-induced reinstatement. To dissociate the", "metadata": {}}
+{"_id": "7370282", "title": "", "text": "Podoplanin-Rich Stromal Networks InduceDendritic Cell Motility via Activation of the C-typeLectin Receptor CLEC-2To initiate adaptiveimmunity, dendritic cells (DCs) move fromparenchymal tissues to lymphoid organs bymigrating along stromal scaffolds that display theglycoprotein podoplanin (PDPN). PDPN isexpressed by lymphatic endothelial andfibroblastic reticular cells and promotesblood-lymph separation during development byactivating the C-type lectin receptor, CLEC-2, onplatelets. Here, we describe a role for CLEC-2 inthe morphodynamic behavior and motility ofDCs. CLEC-2 deficiency in DCs impaired theirentry into lymphatics and trafficking to andwithin lymph nodes, thereby reducing T cellpriming. CLEC-2 engagement of PDPN wasnecessary for DCs to spread and migrate alongstromal surfaces and sufficient to inducemembrane protrusions. CLEC-2 activationtriggered cell spreading via downregulation ofRhoA activity and myosin light-chain", "metadata": {}}
+{"_id": "7373120", "title": "", "text": "The Public Health Responsibility Deal: brokeringa deal for public health, but on whoseterms?UNLABELLED Coalitions of multinationalfood and drink businesses have pledged toreformulate their products and to market themresponsibly. Largely business-led andself-regulated, the integrity of these voluntaryinitiatives has been questioned. The PublicHealth Responsibility Deal in England is anexample of a voluntary initiative that isgovernment-led. Does this approach provideevidence that with public leadership there ispotential for voluntary actions to delivermeaningful results for public health? METHODSThe subject of the research is the caloriereduction initiative of the Responsibility Deal.Source material was obtained primarily througha series of UK Freedom of Information requestsand comprises previously unpublishedDepartment of Health documentation relating torelevant meetings held during 2011 and 2012.RESULTS The Responsibility Deal approach to", "metadata": {}}
+{"_id": "7373453", "title": "", "text": "Role of endothelial shear stress in the naturalhistory of coronary atherosclerosis and vascularremodeling: molecular, cellular, and vascularbehavior.Although the entire coronary tree isexposed to the atherogenic effect of the systemicrisk factors, atherosclerotic lesions form atspecific arterial regions, where low andoscillatory endothelial shear stress (ESS) occur.Low ESS modulates endothelial gene expressionthrough complex mechanoreception andmechanotransduction processes, inducing anatherogenic endothelial phenotype and formationof an early atherosclerotic plaque. Each earlyplaque exhibits an individual natural history ofprogression, regression, or stabilization, which isdependent not only on the formation andprogression of atherosclerosis but also on thevascular remodeling response. Although thepathophysiologic mechanisms involved in theremodeling of the atherosclerotic wall areincompletely understood, the dynamic interplaybetween local hemodynamic milieu, low ESS in", "metadata": {}}
+{"_id": "7386360", "title": "", "text": "Schistosoma mansoni worms induce anergy of Tcells via selective up-regulation of programmeddeath ligand 1 on macrophages.Infectiouspathogens can selectively stimulate activation orsuppression of T cells to facilitate their survivalwithin humans. In this study we demonstratethat the trematode parasite Schistosomamansoni has evolved with two distinctmechanisms to suppress T cell activation. Duringthe initial 4- to 12-wk acute stages of a worminfection both CD4(+) and CD8(+) T cells areanergized. In contrast, infection with male andfemale worms induced T cell anergy at 4 wk,which was replaced after egg laying by T cellsuppression via a known NO-dependentmechanism, that was detected for up to 40 wkafter infection. Worm-induced anergy wasmediated by splenic F4/80(+) macrophages(Mphi) via an IL-4-, IL-13-, IL-10-, TGF-beta-,and NO-independent, but cell contact-dependent,mechanism. F4/80(+) Mphi isolated fromworm-infected mice were shown to induce", "metadata": {}}
+{"_id": "7396492", "title": "", "text": "Thawing Frozen Robust Multi-array Analysis(fRMA)BACKGROUND A novel method ofmicroarray preprocessing--Frozen RobustMulti-array Analysis (fRMA)--has recently beendeveloped. This algorithm allows the user topreprocess arrays individually while retaining theadvantages of multi-array preprocessingmethods. The frozen parameter estimatesrequired by this algorithm are generated using alarge database of publicly available arrays.Curation of such a database and creation of thefrozen parameter estimates is time-consuming;therefore, fRMA has only been implemented onthe most widely used Affymetrix platforms.RESULTS We present an R package, frmaTools,that allows the user to quickly create his or herown frozen parameter vectors. We describe howthis package fits into a preprocessing workflowand explore the size of the training datasetneeded to generate reliable frozen parameterestimates. This is followed by a discussion ofspecific situations in which one might wish to", "metadata": {}}
+{"_id": "7399084", "title": "", "text": "Transcriptional repressor Blimp-1 is essential forT cell homeostasis and self-toleranceT cellhomeostasis is crucial for a functional immunesystem, as the accumulation of T cells resultingfrom lack of regulatory T cells or an inability toshut down immune responses can lead toinflammation and autoimmune pathology. Herewe show that Blimp-1, a transcriptional repressorthat is a 'master regulator' of terminal B celldifferentiation, was expressed in a subset ofantigen-experienced CD4+ and CD8+ T cells.Mice reconstituted with fetal liver stem cellsexpressing a mutant Blimp-1 lacking theDNA-binding domain developed a lethalmultiorgan inflammatory disease caused by anaccumulation of effector and memory T cells.These data identify Blimp-1 as an essentialregulator of T cell homeostasis and suggest thatBlimp-1 regulates both B cell and T celldifferentiation.", "metadata": {}}
+{"_id": "7416873", "title": "", "text": "Nuclear repositioning of the VSG promoter duringdevelopmental silencing in TrypanosomabruceiInterphase nuclear repositioning ofchromosomes has been implicated in theepigenetic regulation of RNA polymerase (pol) IItranscription. However, little is known about thenuclear position–dependent regulation of RNApol I–transcribed loci. Trypanosoma brucei is anexcellent model system to address this questionbecause its two main surface protein genes,procyclin and variant surface glycoprotein (VSG),are transcribed by pol I and undergo distincttranscriptional activation or downregulationevents during developmental differentiation.Although the monoallelically expressed VSGlocus is exclusively localized to an extranucleolarbody in the bloodstream form, in this study, wereport that nonmutually exclusive procyclingenes are located at the nucleolar periphery.Interestingly, ribosomal DNA loci and pol Itranscription activity are restricted to similarperinucleolar positions. Upon developmental", "metadata": {}}
+{"_id": "7419612", "title": "", "text": "An administrative claims measure suitable forprofiling hospital performance on the basis of30-day all-cause readmission rates amongpatients with heart failure.BACKGROUNDReadmission soon after hospital discharge is anexpensive and often preventable event forpatients with heart failure. We present a modelapproved by the National Quality Forum for thepurpose of public reporting of hospital-levelreadmission rates by the Centers for Medicare &Medicaid Services. METHODS AND RESULTS Wedeveloped a hierarchical logistic regressionmodel to calculate hospital risk-standardized30-day all-cause readmission rates for patientshospitalized with heart failure. The model wasderived with the use of Medicare claims data fora 2004 cohort and validated with the use ofclaims and medical record data. The unadjustedreadmission rate was 23.6%. The final modelincluded 37 variables, had discrimination rangingfrom 15% observed 30-day readmission rate inthe lowest predictive decile to 37% in the upper", "metadata": {}}
+{"_id": "7421677", "title": "", "text": "Queueing up for enzymatic processing:correlated signaling through coupleddegradationHigh-throughput technologies haveled to the generation of complex wiring diagramsas a post-sequencing paradigm for depicting theinteractions between vast and diverse cellularspecies. While these diagrams are useful foranalyzing biological systems on a large scale, adetailed understanding of the molecularmechanisms that underlie the observed networkconnections is critical for the furtherdevelopment of systems and synthetic biology.Here, we use queueing theory to investigate how'waiting lines' can lead to correlations betweenprotein 'customers' that are coupled solelythrough a downstream set of enzymatic'servers'. Using the E. coli ClpXP degradationmachine as a model processing system, weobserve significant cross-talk between twonetworks that are indirectly coupled through acommon set of processors. We further illustratethe implications of enzymatic queueing using a", "metadata": {}}
+{"_id": "7426741", "title": "", "text": "The histone demethylases Jhdm1a/1b enhancesomatic cell reprogramming in avitamin-C-dependent manner.Reprogramming ofsomatic cells into induced pluripotent stem cells(iPSCs) resets the epigenome to anembryonic-like state. Vitamin C enhances thereprogramming process, but the underlyingmechanisms are unclear. Here we show that thehistone demethylases Jhdm1a/1b are keyeffectors of somatic cell reprogrammingdownstream of vitamin C. We first observed thatvitamin C induces H3K36me2/3 demethylation inmouse embryonic fibroblasts in culture andduring reprogramming. We then identifiedJhdm1a/1b, two known vitamin-C-dependentH3K36 demethylases, as potent regulators ofreprogramming through gain- andloss-of-function approaches. Furthermore, wefound that Jhdm1b accelerates cell cycleprogression and suppresses cell senescenceduring reprogramming by repressing theInk4/Arf locus. Jhdm1b also cooperates with", "metadata": {}}
+{"_id": "7433668", "title": "", "text": "Preexisting helminth infection induces inhibitionof innate pulmonary anti-tuberculosis defense byengaging the IL-4 receptor pathwayTuberculosisand helminthic infections coexist in many partsof the world, yet the impact of helminth-elicitedTh2 responses on the ability of the host tocontrol Mycobacterium tuberculosis (Mtb)infection has not been fully explored. We showthat mice infected with the intestinal helminthNippostrongylus brasiliensis (Nb) exhibit atransitory impairment of resistance to airborneMtb infection. Furthermore, a second dose of Nbinfection substantially increases the bacterialburden in the lungs of co-infected mice.Interestingly, the Th2 response in the co-infectedanimals did not impair the onset anddevelopment of the protective Mtb-specific Th1cellular immune responses. However, thehelminth-induced Th2 environment resulted inthe accumulation of alternatively activatedmacrophages (AAMs) in the lung. Co-infectedmice lacking interleukin (IL) 4Rα exhibited", "metadata": {}}
+{"_id": "7438803", "title": "", "text": "Archaea in biogeochemical cycles.Archaeaconstitute a considerable fraction of the microbialbiomass on Earth. Like Bacteria they haveevolved a variety of energy metabolisms usingorganic and/or inorganic electron donors andacceptors, and many of them are able to fixcarbon from inorganic sources. Archaea thus playcrucial roles in the Earth's global geochemicalcycles and influence greenhouse gas emissions.Methanogenesis and anaerobic methaneoxidation are important steps in the carboncycle; both are performed exclusively byanaerobic archaea. Oxidation of ammonia tonitrite is performed by Thaumarchaeota. Theyrepresent the only archaeal group that resides inlarge numbers in the global aerobic terrestrialand marine environments on Earth.Sulfur-dependent archaea are confined mostly tohot environments, but metal leaching byacidophiles and reduction of sulfate byanaerobic, nonthermophilic methane oxidizershave a potential impact on the environment. The", "metadata": {}}
+{"_id": "7447120", "title": "", "text": "Novel proteinaceous infectious particles causescrapie.After infection and a prolongedincubation period, the scrapie agent causes adegenerative disease of the central nervoussystem in sheep and goats. Six lines of evidenceincluding sensitivity to proteases demonstratethat this agent contains a protein that is requiredfor infectivity. Although the scrapie agent isirreversibly inactivated by alkali, five procedureswith more specificity for modifying nucleic acidsfailed to cause inactivation. The agent showsheterogeneity with respect to size, apparently aresult of its hydrophobicity; the smallest formmay have a molecular weight of 50,000 or less.Because the novel properties of the scrapieagent distinguish it from viruses, plasmids, andviroids, a new term \"prion\" is proposed to denotea small proteinaceous infectious particle which isresistant to inactivation by most procedures thatmodify nucleic acids. Knowledge of the scrapieagent structure may have significance forunderstanding the causes of several", "metadata": {}}
+{"_id": "7451018", "title": "", "text": "Viral Carcinogenesis.Cancer has been recognizedfor thousands of years. Egyptians believed thatcancer occurred at the will of the gods.Hippocrates believed human disease resultedfrom an imbalance of the four humors: blood,phlegm, yellow bile, and black bile with cancerbeing caused by excess black bile. The lymphtheory of cancer replaced the humoral theoryand the blastema theory replaced the lymphtheory. Rudolph Virchow was the first torecognize that cancer cells like all cells camefrom other cells and believed chronic irritationcaused cancer. At the same time there was abelief that trauma caused cancer, though itnever evolved after many experiments inducingtrauma. The birth of virology occurred in 1892when Dimitri Ivanofsky demonstrated thatdiseased tobacco plants remained infective afterfiltering their sap through a filter that trappedbacteria. Martinus Beijerinck would call the tinyinfective agent a virus and both Dimitri Ivanofskyand Marinus Beijerinck would become the fathers", "metadata": {}}
+{"_id": "7451607", "title": "", "text": "Monitoring spatiotemporal biogenesis ofmacromolecular assemblies by pulse-chaseepitope labeling.Many cellular proteins performtheir roles within macromolecular assemblies.Hence, an understanding of how thesemultiprotein complexes form is a fundamentalquestion in cell biology. We developed atranslation-controlled pulse-chase system thatallows time-resolved isolation of newly formingmultiprotein complexes in chemical quantitiessuitable for biochemical and cell biologicalanalysis. The \"pulse\" is triggered by an unnaturalamino acid, which induces immediate translationof an amber stop codon repressed mRNAencoding the protein of interest with a built-intag for detection and purification. The \"chase\" iselicited by stopping translation of this bait via ariboswitch in the respective mRNA. Over thecourse of validating our method, we discovered adistinct time-resolved assembly step during NPCbiogenesis and could directly monitor thespatiotemporal maturation of preribosomes via", "metadata": {}}
+{"_id": "7454794", "title": "", "text": "Statins in the primary prevention ofcardiovascular diseaseStatins are widely used inthe evidence-based lowering of cardiovasculardisease (CVD) risk. The use of these drugs forsecondary prevention of CVD is well founded, buttheir expanding use in primary prevention—inindividuals without documented CVD—has raisedsome concerns. Firstly, evidence suggests that,in primary prevention, statins substantiallydecrease CVD morbidity, but only moderatelyreduce CVD mortality. Secondly, long-term statinuse might cause adverse effects, such as incidentdiabetes mellitus. Thirdly, the cost-effectivenessof such a strategy is unclear, and has to bebalanced against the risk of 'overmedicating' thegeneral population. Data clearly support the useof statins for primary prevention in high-riskindividuals, in whom the strategy iscost-effective and the benefits exceed the risks.Whether primary prevention is beneficial inindividuals at low or moderate risk is not certain.Therefore, the prescription of statins for primary", "metadata": {}}
+{"_id": "7465900", "title": "", "text": "Acetylation of apurinic/apyrimidinicendonuclease-1 regulates Helicobacterpylori-mediated gastric epithelial cellapoptosis.BACKGROUND & AIMS Helicobacterpylori-induced gastric epithelial cell (GEC)apoptosis is a complex process that includesactivation of the tumor suppressor p53.p53-mediated apoptosis involves p53 activation,bax transcription, and cytochrome c release frommitochondria. Apurinic/apyrimidinicendonuclease-1 (APE-1) regulates transcriptionalactivity of p53, and H pylori induce APE-1expression in human GECs. H pylori infectionincreases intracellular calcium ion concentration[Ca2+]i of GECs, which induces APE-1acetylation. We investigated the effects of Hpylori infection and APE-1 acetylation on GECapoptosis. METHODS AGS cells (wild-type or withsuppressed APE-1), KATO III cells, and cellsisolated from gastric biopsy specimens wereinfected with H pylori. Effects were examined byimmunoblotting, real-time reverse-transcription", "metadata": {}}
+{"_id": "7468449", "title": "", "text": "A beginning of the end: new insights into thefunctional organization of telomeresEver sincethe first demonstration of their repetitivesequence and unique replication pathway,telomeres have beguiled researchers with howthey function in protecting chromosome ends. Ofcourse much has been learned over the years,and we now appreciate that telomeres arecomprised of the multimeric protein/DNAshelterin complex and that the formation oft-loops provides protection from DNA damagemachinery. Deriving their name from D-loops,t-loops are generated by the insertion of the 3'overhang into telomeric repeats facilitated by thebinding of TRF2. Recent studies have uncoverednovel forms of chromosome end-structure thatmay implicate telomere organization in cellularprocesses beyond its essential role in telomereprotection and homeostasis. In particular, wehave recently described that t-loops form in aTRF2-dependent manner at interstitial telomererepeat sequences, which we termed interstitial", "metadata": {}}
+{"_id": "7481159", "title": "", "text": "Biochemical analysis of TssK, a core componentof the bacterial Type VI secretion system,reveals distinct oligomeric states of TssK andidentifies a TssK–TssFGsubcomplexGram-negative bacteria use the TypeVI secretion system (T6SS) to inject toxicproteins into rival bacteria or eukaryotic cells.However, the mechanism of the T6SS isincompletely understood. In the present study,we investigated a conserved component of theT6SS, TssK, using the antibacterial T6SS ofSerratia marcescens as a model system. TssKwas confirmed to be essential for effectorsecretion by the T6SS. The native protein,although not an integral membrane protein,appeared to localize to the inner membrane,consistent with its presence within amembrane-anchored assembly. RecombinantTssK purified from S. marcescens was found toexist in several stable oligomeric forms, namelytrimer, hexamer and higher-order species.Native-level purification of TssK identified TssF", "metadata": {}}
+{"_id": "7482674", "title": "", "text": "Involvement of ER Stress in Dysmyelination ofPelizaeus-Merzbacher Disease with PLP1Missense Mutations Shown by iPSC-DerivedOligodendrocytesPelizaeus-Merzbacher disease(PMD) is a form of X-linked leukodystrophycaused by mutations in the proteolipid protein 1(PLP1) gene. Although PLP1 proteins withmissense mutations have been shown toaccumulate in the rough endoplasmic reticulum(ER) in disease model animals and cell linestransfected with mutant PLP1 genes, the exactpathogenetic mechanism of PMD has notpreviously been clarified. In this study, weestablished induced pluripotent stem cells(iPSCs) from two PMD patients carrying missensemutation and differentiated them intooligodendrocytes in vitro. In the PMDiPSC-derived oligodendrocytes, mislocalization ofmutant PLP1 proteins to the ER and anassociation between increased susceptibility toER stress and increased numbers of apoptoticoligodendrocytes were observed. Moreover,", "metadata": {}}
+{"_id": "7485455", "title": "", "text": "Using Routine Surveillance Data to Estimate theEpidemic Potential of Emerging Zoonoses:Application to the Emergence of US Swine OriginInfluenza A H3N2v VirusBACKGROUND Prior toemergence in human populations, zoonoses suchas SARS cause occasional infections in humanpopulations exposed to reservoir species. Therisk of widespread epidemics in humans can beassessed by monitoring the reproduction numberR (average number of persons infected by ahuman case). However, until now, estimating Rrequired detailed outbreak investigations ofhuman clusters, for which resources andexpertise are not always available. Additionally,existing methods do not correct for importantselection and under-ascertainment biases. Here,we present simple estimation methods thatovercome many of these limitations. METHODSAND FINDINGS Our approach is based on aparsimonious mathematical model of diseasetransmission and only requires data collectedthrough routine surveillance and standard case", "metadata": {}}
+{"_id": "7486516", "title": "", "text": "Independently Evolving Species in AsexualBdelloid RotifersAsexuals are an important testcase for theories of why species exist. If asexualclades displayed the same pattern of discretevariation as sexual clades, this would challengethe traditional view that sex is necessary fordiversification into species. However, criticalevidence has been lacking: all putative exampleshave involved organisms with recent or ongoinghistories of recombination and have relied onvisual interpretation of patterns of genetic andphenotypic variation rather than on formal testsof alternative evolutionary scenarios. Here weshow that a classic asexual clade, the bdelloidrotifers, has diversified into distinct evolutionaryspecies. Intensive sampling of the genus Rotariareveals the presence of well-separated geneticclusters indicative of independent evolution.Moreover, combined genetic and morphologicalanalyses reveal divergent selection in feedingmorphology, indicative of niche divergence.Some of the morphologically coherent groups", "metadata": {}}
+{"_id": "7487927", "title": "", "text": "The Ribosome Biogenesis Factor Nol11 IsRequired for Optimal rDNA Transcription andCraniofacial Development in XenopusTheproduction of ribosomes is ubiquitous andfundamental to life. As such, it is surprising thatdefects in ribosome biogenesis underlie agrowing number of symptomatically distinctinherited disorders, collectively calledribosomopathies. We previously determined thatthe nucleolar protein, NOL11, is essential foroptimal pre-rRNA transcription and processing inhuman tissue culture cells. However, the role ofNOL11 in the development of a multicellularorganism remains unknown. Here, we reveal acritical function for NOL11 in vertebrate ribosomebiogenesis and craniofacial development. Nol11is strongly expressed in the developing cranialneural crest (CNC) of both amphibians andmammals, and knockdown of Xenopus nol11results in impaired pre-rRNA transcription andprocessing, increased apoptosis, and abnormaldevelopment of the craniofacial cartilages.", "metadata": {}}
+{"_id": "7488455", "title": "", "text": "Genomic Nucleosome Organization Reconstitutedwith Pure ProteinsChromatin remodelers regulategenes by organizing nucleosomes aroundpromoters, but their individual contributions areobfuscated by the complex in vivo milieu offactor redundancy and indirect effects.Genome-wide reconstitution of promoternucleosome organization with purified proteinsresolves this problem and is therefore a criticalgoal. Here, we reconstitute four stages ofnucleosome architecture using purifiedcomponents: yeast genomic DNA, histones,sequence-specific Abf1/Reb1, and remodelersRSC, ISW2, INO80, and ISW1a. We identifydirect, specific, and sufficient contributions thatin vivo observations validate. First, RSC clearspromoters by translating poly(dA:dT) intodirectional nucleosome removal. Second, partialredundancy is recapitulated where INO80 alone,or ISW2 at Abf1/Reb1sites, positions +1nucleosomes. Third, INO80 and ISW2 each aligndownstream nucleosomal arrays. Fourth, ISW1a", "metadata": {}}
+{"_id": "7489663", "title": "", "text": "Identification of splenic reservoir monocytes andtheir deployment to inflammatory sites.A currentparadigm states that monocytes circulate freelyand patrol blood vessels but differentiateirreversibly into dendritic cells (DCs) ormacrophages upon tissue entry. Here we showthat bona fide undifferentiated monocytes residein the spleen and outnumber their equivalents incirculation. The reservoir monocytes assemble inclusters in the cords of the subcapsular red pulpand are distinct from macrophages and DCs. Inresponse to ischemic myocardial injury, splenicmonocytes increase their motility, exit the spleenen masse, accumulate in injured tissue, andparticipate in wound healing. These observationsuncover a role for the spleen as a site for storageand rapid deployment of monocytes and identifysplenic monocytes as a resource that the bodyexploits to regulate inflammation.", "metadata": {}}
+{"_id": "7492250", "title": "", "text": "Prox1 Is Required for Granule Cell Maturationand Intermediate Progenitor Maintenance DuringBrain NeurogenesisThe dentate gyrus has animportant role in learning and memory, andadult neurogenesis in the subgranular zone ofthe dentate gyrus may play a role in theacquisition of new memories. The homeoboxgene Prox1 is expressed in the dentate gyrusduring embryonic development and adultneurogenesis. Here we show that Prox1 isnecessary for the maturation of granule cells inthe dentate gyrus during development and forthe maintenance of intermediate progenitorsduring adult neurogenesis. We also demonstratethat Prox1-expressing intermediate progenitorsare required for adult neural stem cellself-maintenance in the subgranular zone; thus,we have identified a previously unknown non-cellautonomous regulatory feedback mechanismthat controls adult neurogenesis in this region ofthe mammalian brain. Finally, we show that theectopic expression of Prox1 induces premature", "metadata": {}}
+{"_id": "7492420", "title": "", "text": "The abbreviated pluripotent cell cycle.Humanembryonic stem cells (hESCs) and inducedpluripotent stem cells proliferate rapidly anddivide symmetrically producing equivalentprogeny cells. In contrast, lineage committedcells acquire an extended symmetrical cell cycle.Self-renewal of tissue-specific stem cells issustained by asymmetric cell division where oneprogeny cell remains a progenitor while thepartner progeny cell exits the cell cycle anddifferentiates. There are three principal contextsfor considering the operation and regulation ofthe pluripotent cell cycle: temporal, regulatory,and structural. The primary temporal contextthat the pluripotent self-renewal cell cycle ofhESCs is a short G1 period without reducingperiods of time allocated to S phase, G2, andmitosis. The rules that govern proliferation inhESCs remain to be comprehensivelyestablished. However, several lines of evidencesuggest a key role for the naïve transcriptome ofhESCs, which is competent to stringently", "metadata": {}}
+{"_id": "7506409", "title": "", "text": "Senescent growth arrest in mesenchymal stemcells is bypassed by Wip1-mediateddownregulation of intrinsic stress signalingpathways.Human mesenchymal stem cells(hMSCs) have been widely studied as a source ofprimary adult stem cells for cell therapy becauseof their multidifferentiation potential; however,the growth arrest (also known as \"prematuresenescence\") often found in hMSCs cultured invitro has been a major obstacle to the in-depthcharacterization of these cells. In addition, theinability to maintain constant cell growthhampers the development of additional geneticmodifications aimed at achieving desired levelsof differentiation to specific tissues; however, themolecular mechanisms that govern thisphenomenon remain unclear, with the exceptionof a few studies demonstrating that induction ofp16INK4a is responsible for this senescence-likeevent. Here, we observed that the prematuregrowth arrest in hMSCs occurs in parallel withthe induction of p16INK4a, following abrogation", "metadata": {}}
+{"_id": "7514614", "title": "", "text": "Understanding the Odd Science ofAgingEvolutionary considerations suggest agingis caused not by active gene programming but byevolved limitations in somatic maintenance,resulting in a build-up of damage. Ecologicalfactors such as hazard rates and food availabilityinfluence the trade-offs between investing ingrowth, reproduction, and somatic survival,explaining why species evolved different lifespans and why aging rate can sometimes bealtered, for example, by dietary restriction. Tounderstand the cell and molecular basis of agingis to unravel the multiplicity of mechanismscausing damage to accumulate and the complexarray of systems working to keep damage atbay.", "metadata": {}}
+{"_id": "7521113", "title": "", "text": "Fate mapping reveals origins and dynamics ofmonocytes and tissue macrophages underhomeostasis.Mononuclear phagocytes, includingmonocytes, macrophages, and dendritic cells,contribute to tissue integrity as well as to innateand adaptive immune defense. Emergingevidence for labor division indicates thatmanipulation of these cells could beartherapeutic potential. However, specificontogenies of individual populations and theoverall functional organization of this cellularnetwork are not well defined. Here we report afate-mapping study of the murine monocyte andmacrophage compartment taking advantage ofconstitutive and conditional CX(3)CR1promoter-driven Cre recombinase expression.We have demonstrated that majortissue-resident macrophage populations,including liver Kupffer cells and lung alveolar,splenic, and peritoneal macrophages, areestablished prior to birth and maintainthemselves subsequently during adulthood", "metadata": {}}
+{"_id": "7547329", "title": "", "text": "Dealing with substantial heterogeneity inCochrane reviews. Cross-sectionalstudyBACKGROUND Dealing with heterogeneityin meta-analyses is often tricky, and there is onlylimited advice for authors on what to do. Weinvestigated how authors addressed differentdegrees of heterogeneity, in particular whetherthey used a fixed effect model, which assumesthat all the included studies are estimating thesame true effect, or a random effects modelwhere this is not assumed. METHODS Wesampled randomly 60 Cochrane reviews from2008, which presented a result in its firstmeta-analysis with substantial heterogeneity (I2greater than 50%, i.e. more than 50% of thevariation is due to heterogeneity rather thanchance). We extracted information on choice ofstatistical model, how the authors had handledthe heterogeneity, and assessed themethodological quality of the reviews in relationto this. RESULTS The distribution ofheterogeneity was rather uniform in the whole I2", "metadata": {}}
+{"_id": "7548577", "title": "", "text": "Antagonistic Controls of Autophagy and GlycogenAccumulation by Snf1p, the Yeast Homolog ofAMP-Activated Protein Kinase, and theCyclin-DependentIn the yeast Saccharomycescerevisiae, glycogen is accumulated as acarbohydrate reserve when cells are deprived ofnutrients. Yeast mutated in SNF1, a geneencoding a protein kinase required for glucosederepression, has diminished glycogenaccumulation and concomitant inactivation ofglycogen synthase. Restoration of synthesis in ansnf1 strain results only in transient glycogenaccumulation, implying the existence of otherSNF1-dependent controls of glycogen storage. Agenetic screen revealed that two genes involvedin autophagy, APG1 and APG13, may beregulated by SNF1. Increased autophagic activitywas observed in wild-type cells entering thestationary phase, but this induction was impairedin an snf1 strain. Mutants defective forautophagy were able to synthesize glycogenupon approaching the stationary phase, but were", "metadata": {}}
+{"_id": "7549811", "title": "", "text": "Preferential binding of a kinesin-1 motor toGTP-tubulin–rich microtubules underliespolarized vesicle transportPolarized transport inneurons is fundamental for the formation ofneuronal circuitry. A motor domain-containingtruncated KIF5 (a kinesin-1) recognizes axonalmicrotubules, which are enriched in EB1 bindingsites, and selectively accumulates at the tips ofaxons. However, it remains unknown what cueKIF5 recognizes to result in this selectiveaccumulation. We found that axonalmicrotubules were preferentially stained by theanti-GTP-tubulin antibody hMB11.Super-resolution microscopy combined with EMimmunocytochemistry revealed that hMB11 waslocalized at KIF5 attachment sites. In addition,EB1, which binds preferentially toguanylyl-methylene-diphosphate (GMPCPP)microtubules in vitro, recognized hMB11 bindingsites on axonal microtubules. Further, expressionof hMB11 antibody in neurons disrupted theselective accumulation of truncated KIF5 in the", "metadata": {}}
+{"_id": "7552147", "title": "", "text": "Developmental biology of the pancreas.Thepancreas is an organ containing two distinctpopulations of cells, the exocrine cells thatsecrete enzymes into the digestive tract, and theendocrine cells that secrete hormones into thebloodstream. It arises from the endoderm as adorsal and a ventral bud which fuse together toform the single organ. Mammals, birds, reptilesand amphibians have a pancreas with similarhistology and mode of development, while insome fish, the islet cells are segregated asBrockmann bodies. Invertebrates do not have apancreas, but comparable endocrine cells may befound in the gut or the brain. The earlypancreatic bud shows uniform expression of thehomeobox gene IPF-1 (also known as IDX-1,STF-1 or PDX), which when mutated to inactivityleads to total absence of the organ. Theoccurrence of heterotopic pancreas in theembryo, and also the metaplasias that can bedisplayed by a regenerating pancreas in theadult, both suggest that only a few gene", "metadata": {}}
+{"_id": "7552215", "title": "", "text": "Long term pharmacotherapy for obesity andoverweight: updated meta-analysis.OBJECTIVETo summarise the long term efficacy ofanti-obesity drugs in reducing weight andimproving health status. DESIGN Updatedmeta-analysis of randomised trials. DATASOURCES Medline, Embase, the Cochranecontrolled trials register, the Current Sciencemeta-register of controlled trials, and referencelists of identified articles. All data sources weresearched from December 2002 (end date of lastsearch) to December 2006. STUDIES REVIEWEDDouble blind randomised placebo controlled trialsof approved anti-obesity drugs used in adults(age over 18) for one year or longer. RESULTS30 trials of one to four years' duration met theinclusion criteria: 16 orlistat (n=10 631participants), 10 sibutramine (n=2623), and fourrimonabant (n=6365). Of these, 14 trials werenew and 16 had previously been identified.Attrition rates averaged 30-40%. Compared withplacebo, orlistat reduced weight by 2.9 kg (95%", "metadata": {}}
+{"_id": "7560876", "title": "", "text": "The centrosome cycle: Centriole biogenesis,duplication and inherentasymmetriesCentrosomes aremicrotubule-organizing centres of animal cells.They influence the morphology of themicrotubule cytoskeleton, function as the basefor the primary cilium and serve as a nexus forimportant signalling pathways. At the core of atypical centrosome are two cylindricalmicrotubule-based structures termed centrioles,which recruit a matrix of associatedpericentriolar material. Cells begin the cell cyclewith exactly one centrosome, and the duplicationof centrioles is constrained such that it occursonly once per cell cycle and at a specific site inthe cell. As a result of this duplicationmechanism, the two centrioles differ in age andmaturity, and thus have different functions; forexample, the older of the two centrioles caninitiate the formation of a ciliary axoneme. Wediscuss spatial aspects of the centrosomeduplication cycle, the mechanism of centriole", "metadata": {}}
+{"_id": "7568596", "title": "", "text": "Osteoclasts control reactivation of dormantmyeloma cells by remodelling the endostealnicheMultiple myeloma is largely incurable,despite development of therapies that targetmyeloma cell-intrinsic pathways. Disease relapseis thought to originate from dormant myelomacells, localized in specialized niches, which resisttherapy and repopulate the tumour. However,little is known about the niche, and how it exertscell-extrinsic control over myeloma celldormancy and reactivation. In this study, wetrack individual myeloma cells by intravitalimaging as they colonize the endosteal niche,enter a dormant state and subsequently becomeactivated to form colonies. We demonstrate thatdormancy is a reversible state that is switched'on' by engagement with bone-lining cells orosteoblasts, and switched 'off' by osteoclastsremodelling the endosteal niche. Dormantmyeloma cells are resistant to chemotherapythat targets dividing cells. The demonstrationthat the endosteal niche is pivotal in controlling", "metadata": {}}
+{"_id": "7581911", "title": "", "text": "Human embryonic stem cells with biological andepigenetic characteristics similar to those ofmouse ESCs.Human and mouse embryonic stemcells (ESCs) are derived from blastocyst-stageembryos but have very different biologicalproperties, and molecular analyses suggest thatthe pluripotent state of human ESCs isolated sofar corresponds to that of mouse-derived epiblaststem cells (EpiSCs). Here we rewire the identityof conventional human ESCs into a moreimmature state that extensively shares definingfeatures with pluripotent mouse ESCs. This wasachieved by ectopic induction of Oct4, Klf4, andKlf2 factors combined with LIF and inhibitors ofglycogen synthase kinase 3beta (GSK3beta) andmitogen-activated protein kinase (ERK1/2)pathway. Forskolin, a protein kinase A pathwayagonist which can induce Klf4 and Klf2expression, transiently substitutes for therequirement for ectopic transgene expression. Incontrast to conventional human ESCs, theseepigenetically converted cells have growth", "metadata": {}}
+{"_id": "7583104", "title": "", "text": "IDEAL in meshes for prolapse, urinaryincontinence, and hernia repair.PURPOSE Meshsurgeries are counted among the mostfrequently applied surgical procedures. Despiteglobal spread of mesh applying surgeries, thereis no current systematic analysis of incidenceand possible prevention of adverse events aftermesh implantation. MATERIALS AND METHODSBased on the recommendations of IDEAL an invitro test system for biocompatibility of surgicalmeshes has been generated (Innovation).Coating strategies for biocompatibilityoptimization have been developed(Development). The native and modifiedalloplastic materials have been tested in ananimal model over 2 years (Exploration andAssessment and Long-term study). RESULTS In3 meshes, implanted in sheep and explanted at 4different time points (a, 3 months; b, 6 months;c, 12 months; and d, 24 months) over 24months, thickness of inflammatory tissue (TVT a,35 µm; b, 32 µm; c, 33 µm; d, 28 µm; UltraPro,", "metadata": {}}
+{"_id": "7583161", "title": "", "text": "Heterotopic of bone marrow. Analysis ofprecursor cells for osteogenic and hematopoietictissues.In semisyngeneic heterotopic bonemarrow transplants the donor or recipient originof cells of osteogenic and hematopoietic tissueswas identified by chromosome markers (T6) andby reverse transplantation into the initial donorline. In syngeneic and semisyngeneic grafts ofbone marrow under the renal capsule bone andbone marrow are formed. In allogeneic graftsonly bone is formed; this bone is subsequentlyresorbed. In 14-month semisyngeneictransplants the bone marrow consists of recipientcells. This is true for both the proliferating pooland the stem cells of hematopoietic tissue. At thesame time, osteogenic precursor cells and bonetissue in these transplants are of donor origin. Adiscussion is presented of the interrelationshipbetween determinated osteogenic precursor cells(preosteoblasts) and hematopoietic stem cells(or their descendants) in which osteogenesis isinducible.", "metadata": {}}
+{"_id": "7583725", "title": "", "text": "TRPM7 is required for breast tumor cellmetastasis.TRPM7 encodes a Ca2+-permeablenonselective cation channel with kinase activity.TRPM7 has been implicated in control of celladhesion and migration, but whether TRPM7activity contributes to cancer progression has notbeen established. Here we report that high levelsof TRPM7 expression independently predict pooroutcome in breast cancer patients and that it isfunctionally required for metastasis formation ina mouse xenograft model of human breastcancer. Mechanistic investigation revealed thatTRPM7 regulated myosin II-based cellulartension, thereby modifying focal adhesionnumber, cell-cell adhesion and polarized cellmovement. Our findings therefore suggest thatTRPM7 is part of a mechanosensory complexadopted by cancer cells to drive metastasisformation.", "metadata": {}}
+{"_id": "7595742", "title": "", "text": "Frailty Syndrome: A Transitional State in aDynamic ProcessFrailty has long been consideredsynonymous with disability and comorbidity, tobe highly prevalent in old age and to confer ahigh risk for falls, hospitalization and mortality.However, it is becoming recognized that frailtymay be a distinct clinical syndrome with abiological basis. The frailty process appears to bea transitional state in the dynamic progressionfrom robustness to functional decline. During thisprocess, total physiological reserves decreaseand become less likely to be sufficient for themaintenance and repair of the ageing body.Central to the clinical concept of frailty is that nosingle altered system alone defines it, but thatmultiple systems are involved. Clinical consensusregarding the phenotype which constitutesfrailty, drawing upon the opinions of numerousauthors, shows the characteristics to includewasting (loss of both muscle mass and strengthand weight loss), loss of endurance, decreasedbalance and mobility, slowed performance,", "metadata": {}}
+{"_id": "7602348", "title": "", "text": "Progression of preclinical diastolic dysfunction tothe development of symptoms.BACKGROUNDPreclinical diastolic dysfunction (PDD) has beendefined as subjects with normal systolic function,diastolic dysfunction but no symptoms of heartfailure (HF). The clinical phenotype and naturalhistory of the syndrome remains poorly defined.This study's objective was to determine theclinical phenotype and progression to HF in agroup of patients with normal systolic functionand moderate or severe diastolic dysfunction asdeterminate by Doppler criteria without anyclinical diagnosis of HF according to theFramingham criteria or any symptoms of HF,specifically dyspnoea, oedema or fatigue at thetime of echocardiography. METHODS The authorsused resources of the Mayo Clinicechocardiography database to consecutivelyselect among patients who had anechocardiogram in 2005, a cohort with moderateor severe diastolic dysfunction by Doppler criteriaand EF >or=50%. Patients could not have a", "metadata": {}}
+{"_id": "7613033", "title": "", "text": "Aspirin in the chemoprevention of colorectalneoplasia: an overview.Considerable evidencesupports the effectiveness of aspirin forchemoprevention of colorectal cancer (CRC) inaddition to its well-established benefits in theprevention of vascular disease. Epidemiologicstudies have consistently observed an inverseassociation between aspirin use and risk of CRC.A recent pooled analysis of a long-term posttrialfollow-up of nearly 14,000 patients from fourrandomized, cardiovascular disease preventiontrials showed that daily aspirin treatment forabout five years was associated with a 34%reduction in 20-year CRC mortality. A separatemetaanalysis of nearly 3,000 patients with ahistory of colorectal adenoma or cancer in fourrandomized adenoma prevention trials showedthat aspirin reduced the occurrence of advancedadenomas by 28% and any adenoma by 17%.Aspirin has also been shown to be beneficial in aclinical trial of patients with Lynch syndrome, ahereditary CRC syndrome; in those treated with", "metadata": {}}
+{"_id": "7621534", "title": "", "text": "Chemokine receptor trio: CXCR3, CXCR4 andCXCR7 crosstalk via CXCL11 andCXCL12.Although chemokines are wellestablished to function in immunity andendothelial cell activation and proliferation, arapidly growing literature suggests that CXCChemokine receptors CXCR3, CXCR4 and CXCR7are critical in the development and progressionof solid tumors. The effect of these chemokinereceptors in tumorigenesis is mediated viainteractions with shared ligands I-TAC (CXCL11)and SDF-1 (CXCL12). Over the last decade,CXCR4 has been extensively reported to beoverexpressed in most human solid tumors andhas earned considerable attention towardelucidating its role in cancer metastasis. Toenrich the existing armamentarium ofanti-cancerous agents, many inhibitors ofCXCL12-CXCR4 axis have emerged as additionalor alternative agents for neo-adjuvanttreatments and even many of them are inpreclinical and clinical stages of their", "metadata": {}}
+{"_id": "7622767", "title": "", "text": "Human Cyclin a Is Required for Mitosis until MidProphaseWe have used microinjection andtime-lapse video microscopy to study the role ofcyclin A in mitosis. We have injected purified,active cyclin A/cyclin-dependent kinase 2 (CDK2)into synchronized cells at specific points in thecell cycle and assayed its effect on cell division.We find that cyclin A/CDK2 will drive G2 phasecells into mitosis within 30 min of microinjection,up to 4 h before control cells enter mitosis. Oftenthis premature mitosis is abnormal; thechromosomes do not completely condense anddaughter cells fuse. Remarkably, microinjectingcyclin A/CDK2 into S phase cells has no effect onprogress through the following G2 phase ormitosis. In complementary experiments we havemicroinjected the amino terminus ofp21Cip1/Waf1/Sdi1 (p21N) into cells to inhibitcyclin A/CDK2 activity. We find that p21N willprevent S phase or G2 phase cells from enteringmitosis, and will cause early prophase cells toreturn to interphase. These results suggest that", "metadata": {}}
+{"_id": "7627167", "title": "", "text": "Brief, four-session group CBT reduces bingeeating behaviors among bariatric surgerycandidates.BACKGROUND The objective of thisstudy was to evaluate the effectiveness of abrief, 4-session cognitive behavioral, grouppsychotherapy for binge eating among bariatricsurgery candidates at an academic medicalcenter. Binge eating behaviors have been linkedto poorer outcomes among bariatric surgerypatients, and binge eating disorder have beconsidered a contraindication in surgeryprograms, some of which have mandatedpreoperative binge eating treatment. However,no previous studies have examined whether apreoperative binge eating intervention couldsuccessfully reduce binge eating behaviorsamong severely obese bariatric surgerycandidates. METHODS A total of 243 bariatricsurgery candidates completed a brief cognitivebehavioral group treatment for binge eatingbehaviors and were administered the BingeEating Scale and reported the number of weekly", "metadata": {}}
+{"_id": "7639744", "title": "", "text": "Influence of smoking cessation after diagnosis ofearly stage lung cancer on prognosis: systematicreview of observational studies withmeta-analysisOBJECTIVE To systematicallyreview the evidence that smoking cessation afterdiagnosis of a primary lung tumour affectsprognosis. DESIGN Systematic review withmeta-analysis. DATA SOURCES CINAHL (from1981), Embase (from 1980), Medline (from1966), Web of Science (from 1966), CENTRAL(from 1977) to December 2008, and referencelists of included studies. STUDY SELECTIONRandomised controlled trials or observationallongitudinal studies that measured the effect ofquitting smoking after diagnosis of lung canceron prognostic outcomes, regardless of stage atpresentation or tumour histology, were included.DATA EXTRACTION Two researchersindependently identified studies for inclusion andextracted data. Estimates were combined byusing a random effects model, and the I(2)statistic was used to examine heterogeneity. Life", "metadata": {}}
+{"_id": "7640058", "title": "", "text": "Epigenetic reprogramming and inducedpluripotency.The cloning of animals from adultcells has demonstrated that the developmentalstate of adult cells can be reprogrammed intothat of embryonic cells by uncharacterizedfactors within the oocyte. More recently,transcription factors have been identified thatcan induce pluripotency in somatic cells withoutthe use of oocytes, generating inducedpluripotent stem (iPS) cells. iPS cells provide aunique platform to dissect the molecularmechanisms that underlie epigeneticreprogramming. Moreover, iPS cells can teach usabout principles of normal development anddisease, and might ultimately facilitate thetreatment of patients by custom-tailored celltherapy.", "metadata": {}}
+{"_id": "7640792", "title": "", "text": "Sex differences in mortality following acutecoronary syndromes.CONTEXT Conflictinginformation exists about whether sex differencesmodulate short-term mortality following acutecoronary syndromes (ACS). OBJECTIVES Toinvestigate the relationship between sex and30-day mortality in ACS, and to determinewhether this relationship was modified by clinicalsyndrome or coronary anatomy using a largedatabase across the spectrum of ACS andadjusting for potentially confounding clinicalcovariates. DESIGN, SETTING, ANDPARTICIPANTS A convenience sample of patientspooled from 11 independent, international,randomized ACS clinical trials between 1993 and2006 whose databases are maintained at theDuke Clinical Research Institute, Durham, NorthCarolina. Of 136 247 patients, 38 048 (28%)were women; 102 004 (26% women) withST-segment elevation myocardial infarction(STEMI), 14 466 (29% women) with non-STEMI(NSTEMI), and 19 777 (40% women) with", "metadata": {}}
+{"_id": "7643848", "title": "", "text": "Membrane topology of the 60-kDa Oxa1phomologue from Escherichia coli.We havecharacterized the membrane topology of a60-kDa inner membrane protein from Escherichiacoli that is homologous to the recently identifiedOxa1p protein in Saccharomyces cerevisiaemitochondria implicated in the assembly ofmitochondrial inner membrane proteins.Hydrophobicity and alkaline phosphatase fusionanalyses suggest a membrane topology with sixtransmembrane segments, including anN-terminal signal-anchor sequence not presentin mitochondrial Oxa1p. In contrast to partialN-terminal fusion protein constructs, thefull-length protein folds into a protease-resistantconformation, suggesting that important foldingdeterminants are present in the C-terminal partof the molecule.", "metadata": {}}
+{"_id": "7645565", "title": "", "text": "Identifying and Characterizing Interplay betweenHepatitis B Virus X Protein and Smc5/6HepatitisB X protein (HBx) plays an essential role in thehepatitis B virus (HBV) replication cycle, but thefunction of HBx has been elusive until recently. Itwas recently shown that transcription from theHBV genome (covalently-closed circular DNA,cccDNA) is inhibited by the structuralmaintenance of chromosome 5/6 complex(Smc5/6), and that a key function of HBx is toredirect the DNA-damage binding protein 1(DDB1) E3 ubiquitin ligase to target this complexfor degradation. By doing so, HBx alleviatestranscriptional repression by Smc5/6 andstimulates HBV gene expression. In this review,we discuss in detail how the interplay betweenHBx and Smc5/6 was identified andcharacterized. We also discuss what is knownregarding the repression of cccDNA transcriptionby Smc5/6, the timing of HBx expression, andthe potential role of HBx in promotinghepatocellular carcinoma (HCC).", "metadata": {}}
+{"_id": "7647224", "title": "", "text": "Hepatitis C Virus (HCV) Vertical Transmission in12-Month-Old Infants Born to HCV-InfectedWomen and Assessment of Maternal RiskFactorsBackground. Hepatitis C virus (HCV) is anunderappreciated cause of pediatric liver disease,most frequently acquired by vertical transmission(VT). Current guidelines that include the optionof screening infants for HCV RNA at 1-2 monthsare based on data prior to current real-timepolymerase chain reaction (PCR)-based testing.Previous studies have demonstrated VT rates of4%-15% and an association with high maternalviral load. We evaluated HCV RNA in infants withHCV VT and assessed maternal risk factors in aprospective cohort in Cairo, Egypt. Methods.Pregnant women were screened for HCV fromDecember 2012 to March 2014. For those withHCV viremia, their infants were tested at 12months for HCV RNA using real-time PCR.Maternal risk factors assessed for HCV VTassociation included HCV RNA levels, mode ofdelivery, and maternal IL28B genotype. Results.", "metadata": {}}
+{"_id": "7650066", "title": "", "text": "Long-term follow-up of cervical disease inwomen screened by cytology and HPV testing:results from the HART studyBACKGROUNDSeveral studies have shown that testing forhigh-risk human papillomavirus (HPV) typesresults in an improved sensitivity for CIN2+,compared with cytology, although with asomewhat lower specificity. METHODS Weobtained follow-up results, with at least onesmear after participation in the HART study,which compared HPV testing (HC-II) withcytology as a primary screening modality.RESULTS With a median follow-up of 6 years, 42additional cases of CIN2+ were identified;women who were HPV positive at baseline weremore likely to develop CIN2+ than those whowere HPV negative (hazard ratio (HR) 17.2; 95%confidence interval (CI) (9.3-31.6)) and the riskincreased with increasing viral load. Comparedwith HPV-negative women (relative light unit(RLU) <1), the HR (95% CI) was 5.4 (1.6, 18.2)for 1-10 RLU and 25.5 (13.6, 47.9) for RLU > or", "metadata": {}}
+{"_id": "7655029", "title": "", "text": "The Burden of Trachoma in Ayod County ofSouthern SudanBACKGROUND Blindness due totrachoma is avoidable through Surgery,Antibiotics, Facial hygiene and Environmentalimprovements (SAFE). Recent surveys haveshown trachoma to be a serious cause ofblindness in Southern Sudan. We conducted thissurvey in Ayod County of Jonglei State toestimate the need for intervention activities toeliminate blinding trachoma. METHODOLOGYAND FINDINGS A cross-sectional two-stagecluster random survey was conducted inNovember 2006. All residents of selectedhouseholds were clinically assessed for trachomausing the World Health Organization (WHO)simplified grading scheme. A total of 2,335people from 392 households were examined, ofwhom 1,107 were over 14 years of age.Prevalence of signs of active trachoma in children1-9 years of age was: trachomatousinflammation follicular (TF) = 80.1% (95%confidence interval [CI], 73.9-86.3);", "metadata": {}}
+{"_id": "7662206", "title": "", "text": "A Century of Cholesterol and Coronaries: FromPlaques to Genes to StatinsOne-fourth of alldeaths in industrialized countries result fromcoronary heart disease. A century of researchhas revealed the essential causative agent:cholesterol-carrying low-density lipoprotein(LDL). LDL is controlled by specific receptors(LDLRs) in liver that remove it from blood.Mutations that eliminate LDLRs raise LDL andcause heart attacks in childhood, whereasmutations that raise LDLRs reduce LDL anddiminish heart attacks. If we are to eliminatecoronary disease, lowering LDL should be theprimary goal. Effective means to achieve thisgoal are currently available. The key questionsare: who to treat, when to treat, and how long totreat.", "metadata": {}}
+{"_id": "7662395", "title": "", "text": "Perinatal mortality in rural China: retrospectivecohort study.OBJECTIVES To explore the use oflocal civil registration data to assess the perinatalmortality in a typical rural county in a lessdeveloped province in China, 1999-2000.DESIGN Retrospective cohort study. Pregnanciesin a cohort of women followed from registrationof pregnancy to outcome of infant seven daysafter birth. SETTING Routine family planningrecords in 20 rural townships in eastern China.SUBJECTS 3697 pregnancies registered by thelocal family planning system during 1999. MAINOUTCOME MEASURES Abortions, stillbirths, earlyneonatal mortality, perinatal mortality. RESULTSOnly three cases were lost to follow up. Theaverage age of the women at pregnancy was25.9 years. Three hundred and twelvepregnancies were aborted and 240 ended inmiscarriage (total 552, 15%). The perinatalmortality rate was 69 per 1000 births, the rate ofstillbirth was 24 per 1000 births, and the earlyneonatal mortality was 46 per 1000 live births.", "metadata": {}}
+{"_id": "7666498", "title": "", "text": "Genetic disruption of aurora B uncovers anessential role for aurora C during earlymammalian development.Mitosis is controlled bymultiple kinases that drive cell cycle progressionand prevent chromosome mis-segregation.Aurora kinase B interacts with survivin, borealinand incenp to form the chromosomal passengercomplex (CPC), which is involved in theregulation of microtubule-kinetochoreattachments and cytokinesis. Whereas geneticablation of survivin, borealin or incenp results inearly lethality at the morula stage, we show herethat aurora B is dispensable for CPC functionduring early cell divisions and aurora B-nullembryos are normally implanted. This is due to acrucial function of aurora C during these earlyembryonic cycles. Expression of aurora Cdecreases during late blastocyst stages resultingin post-implantation defects in aurora B-nullembryos. These defects correlate with abundantprometaphase figures and apoptotic cell death ofthe aurora B-deficient inner cell mass.", "metadata": {}}
+{"_id": "7681810", "title": "", "text": "NuSAP is essential for chromatin-induced spindleformation during early embryogenesis.Mitoticspindle assembly is mediated by two processes:a centrosomal and a chromosomal pathway.RanGTP regulates the latter process by releasingmicrotubule-associated proteins from inhibitorycomplexes. NuSAP, a microtubule- andDNA-binding protein, is a target of RanGTP andpromotes the formation of microtubules nearchromosomes. However, the contribution ofNuSAP to cell proliferation in vivo is unknown.Here, we demonstrate that the expression ofNuSAP highly correlates with cell proliferationduring embryogenesis and adult life, making it areliable marker of proliferating cells. Additionally,we show that NuSAP deficiency in mice leads toearly embryonic lethality. Spindle assembly inNuSAP-deficient cells is highly inefficient andchromosomes remain dispersed in the mitoticcytoplasm. As a result of sustained spindlecheckpoint activity, the cells are unable toprogress through mitosis, eventually leading to", "metadata": {}}
+{"_id": "7688110", "title": "", "text": "E2F-6: a novel member of the E2F family is aninhibitor of E2F-dependent transcriptionThe E2Ffamily of transcription factors are essential forthe regulation of genes required for appropriateprogression through the cell cycle. Five membersof the E2F family have been previously reported,namely E2F1-5. All five are key elements intranscriptional regulation of essential genes, andthey can be divided into two functional groups,those that induce S-phase progression whenoverexpressed in quiescent cells (E2Fs 1–3), andthose that do not (E2Fs 4–5). Here, we describethe identification of a novel member of thisfamily, which we refer to as E2F-6. E2F-6 sharessignificant homology with E2Fs 1–5, especiallywithin the DNA binding, heterodimerization andmarked box domains. Unlike E2Fs 1–5, E2F-6lacks a transactivation and a pocket proteinbinding domain, hence, forms a unique thirdgroup within the E2F family. E2F-6 is a nuclearprotein that can form heterodimers with the DPproteins (both DP-1 and DP-2) in vitro and in", "metadata": {}}
+{"_id": "7708803", "title": "", "text": "Enhancement of hippocampal pyramidal cellexcitability by the novel selectiveslow-afterhyperpolarization channel blocker3-(triphenylmethylaminomethyl)pyridine(UCL2077).The slow afterhyperpolarization(sAHP) in hippocampal neurons has beenimplicated in learning and memory. However, itsprecise role in cell excitability and centralnervous system function has not been explicitlytested for 2 reasons: 1) there are, at present, noselective inhibitors that effectively reduce theunderlying current in vivo or in intact in vitrotissue preparations, and 2) although it is knownthat a small conductance K(+) channel thatactivates after a rise in [Ca(2+)](i) underlies thesAHP, the exact molecular identity remainsunknown. We show that3-(triphenylmethylaminomethyl)pyridine(UCL2077), a novel compound, suppressed thesAHP present in hippocampal neurons in culture(IC(50) = 0.5 microM) and in the slicepreparation (IC(50) approximately 10 microM).", "metadata": {}}
+{"_id": "7711685", "title": "", "text": "Lessons from sudden coronary death: acomprehensive morphological classificationscheme for atherosclerotic lesions.This reviewwill reconsider the current paradigm forunderstanding the critical, final steps in theprogression of atherosclerotic lesions. Thatscheme, largely an outgrowth of observations ofautopsy tissues by Davies and colleagues,1 2asserts that the cause of death in atheroscleroticcoronary artery disease is rupture of anadvanced atherosclerotic lesion. Although thisassumption may be partially true, recent autopsystudies suggest that it is incomplete. Toreconsider this paradigm, we reexamined themorphological classification scheme for lesionsproposed by the American Heart Association(AHA).3 4 This scheme is difficult to use for 2reasons. First, it uses a very long list of romannumerals modified by letter codes that aredifficult to remember. Second, it implies anorderly, linear pattern of lesion progression. Thistends to be ambiguous, because it is not clear", "metadata": {}}
+{"_id": "7717468", "title": "", "text": "Loss of allergen 1 confers a hypervirulentphenotype that resembles mucoid switchvariants of Cryptococcus neoformans.Microbialsurvival in a host is usually dependent on theability of a pathogen to undergo changes thatpromote escape from host defense mechanisms.The human-pathogenic fungus Cryptococcusneoformans undergoes phenotypic switching invivo that promotes persistence in tissue. Bymicroarray and real-time PCR analyses, theallergen 1 gene (ALL1) was found to bedownregulated in the hypervirulent mucoidswitch variant, both during logarithmic growthand during intracellular growth in macrophages.The ALL1 gene encodes a small cytoplasmicprotein that is involved in capsule formation.Growth of an all1Delta gene deletion mutant wasnormal. Similar to cells of the mucoid switchvariant, all1Delta cells produced a largerpolysaccharide capsule than cells of the smoothparent and the complemented strain produced,and the enlarged capsule inhibited macrophage", "metadata": {}}
+{"_id": "7729656", "title": "", "text": "Lessons from more than 80 structures of theGluA2 ligand-binding domain in complex withagonists, antagonists and allostericmodulators.Ionotropic glutamate receptors(iGluRs) constitute a family of ligand-gated ionchannels that are essential for mediating fastsynaptic transmission in the central nervoussystem. These receptors play an important rolefor the development and function of the nervoussystem, and are essential in learning andmemory. However, iGluRs are also implicated inor have causal roles for several brain disorders,e.g. epilepsy, Alzheimer's disease, Parkinson'sdisease and schizophrenia. Their involvement inneurological diseases has stimulated widespreadinterest in their structure and function. Since thefirst publication in 1998 of the structure of arecombinant soluble protein comprising theligand-binding domain of GluA2 extensive studieshave afforded numerous crystal structures ofwildtype and mutant proteins including differentligands. The structural information obtained", "metadata": {}}
+{"_id": "7734150", "title": "", "text": "Diaphragm Atrophy and Contractile Dysfunctionin a Murine Model of PulmonaryHypertensionPulmonary hypertension (PH)causes loss of body weight and inspiratory(diaphragm) muscle dysfunction. A model of PHinduced by drug (monocrotaline, MCT) has beenextensively used in mice to examine the etiologyof PH. However, it is unclear if PH induced byMCT in mice reproduces the loss of body weightand diaphragm muscle dysfunction seen inpatients. This is a pre-requisite for widespreaduse of mice to examine mechanisms of cachexiaand diaphragm abnormalities in PH. Thus, wemeasured body and soleus muscle weight, foodintake, and diaphragm contractile properties inmice after 6-8 weeks of saline (control) or MCT(600 mg/kg) injections. Body weightprogressively decreased in PH mice, while foodintake was similar in both groups. PH decreased(P<0.05) diaphragm maximal isometric specificforce, maximal shortening velocity, and peakpower. Protein carbonyls in whole-diaphragm", "metadata": {}}
+{"_id": "7735859", "title": "", "text": "Identification of an anti-inflammatory proteinfrom Faecalibacterium prausnitzii, a commensalbacterium deficient in Crohn'sdisease.BACKGROUND Crohn's disease(CD)-associated dysbiosis is characterised by aloss of Faecalibacterium prausnitzii, whoseculture supernatant exerts an anti-inflammatoryeffect both in vitro and in vivo. However, thechemical nature of the anti-inflammatorycompounds has not yet been determined.METHODS Peptidomic analysis using massspectrometry was applied to F. prausnitziisupernatant. Anti-inflammatory effects ofidentified peptides were tested in vitro directlyon intestinal epithelial cell lines and on cell linestransfected with a plasmid construction codingfor the candidate protein encompassing thesepeptides. In vivo, the cDNA of the candidateprotein was delivered to the gut by recombinantlactic acid bacteria to prevent dinitrobenzenesulfonic acid (DNBS)-colitis in mice. RESULTSThe seven peptides, identified in the F.", "metadata": {}}
+{"_id": "7736860", "title": "", "text": "Calcium store sensor stromal-interactionmolecule 1-dependent signaling plays animportant role in cervical cancer growth,migration, and angiogenesis.Store-operatedCa(2+) entry (SOCE) is the principal Ca(2+)entry mechanism in nonexcitable cells.Stromal-interaction molecule 1 (STIM1) is anendoplasmic reticulum Ca(2+) sensor thattriggers SOCE activation. However, the role ofSTIM1 in regulating cancer progression remainscontroversial and its clinical relevance is unclear.Here we show that STIM1-dependent signaling isimportant for cervical cancer cell proliferation,migration, and angiogenesis. STIM1overexpression in tumor tissue is noted in 71%cases of early-stage cervical cancer. In tumortissues, the level of STIM1 expression issignificantly associated with the risk ofmetastasis and survival. EGF-stimulated cancercell migration requires STIM1 expression andEGF increases the interaction between STIM1and Orai1 in juxta-membrane areas, and thus", "metadata": {}}
+{"_id": "7751726", "title": "", "text": "A feasibility study for a randomised controlledtrial of the Positive Reappraisal CopingIntervention, a novel supportive technique forrecurrent miscarriageINTRODUCTION Recurrentmiscarriage (RM) is diagnosed when a womanhas had three or more miscarriages. Increasedlevels of distress and anxiety are common duringthe waiting period of any subsequentpregnancies, posing a significant threat topsychological well-being. However, only limitedsupport and therapy are available for thesewomen, and many are left to cope alone. ThePositive Reappraisal Coping Intervention (PRCI)is a novel self-administered supportive techniquewhich has been shown to be effective in patientsawaiting the outcome of in vitro fertilisationtreatment. The primary objective of this study isto assess the feasibility and effectiveness of thePRCI in improving quality of life in the difficultwaiting period which women with previous RMendure before an ongoing pregnancy can beconfirmed. METHODS AND ANALYSIS A", "metadata": {}}
+{"_id": "7757997", "title": "", "text": "Report of the National Heart, Lung, and BloodInstitute Workshop on Lipoprotein(a) andCardiovascular Disease: recent advances andfuture directions.It has been estimated thatapproximately 37% of the US population judgedto be at high risk for developing coronary arterydisease (CAD), based on the National CholesterolEducation Program guidelines, have increasedplasma lipoprotein(a) [Lp(a)], whereas Lp(a) isincreased in only 14% of those judged to be atlow risk. Therefore, the importance ofestablishing a better understanding of therelative contribution of Lp(a) to the risk burdenfor CAD and other forms of vascular disease, aswell as the underlying mechanisms, is clearlyevident. However, the structural complexity andsize heterogeneity of Lp(a) have hindered thedevelopment of immunoassays to accuratelymeasure Lp(a) concentrations in plasma. Thelarge intermethod variation in Lp(a) values hasmade it difficult to compare data from differentclinical studies and to achieve a uniform", "metadata": {}}
+{"_id": "7764903", "title": "", "text": "Classification, functions, and clinical relevance ofextracellular vesicles.Both eukaryotic andprokaryotic cells release small,phospholipid-enclosed vesicles into theirenvironment. Why do cells release vesicles?Initial studies showed that eukaryotic vesiclesare used to remove obsolete cellular molecules.Although this release of vesicles is beneficial tothe cell, the vesicles can also be a danger totheir environment, for instance in blood, wherevesicles can provide a surface supportingcoagulation. Evidence is accumulating thatvesicles are cargo containers used by eukaryoticcells to exchange biomolecules astransmembrane receptors and geneticinformation. Because also bacteria communicateto each other via extracellular vesicles, theintercellular communication via extracellularcargo carriers seems to be conserved throughoutevolution, and therefore vesicles are likely to bea highly efficient, robust, and economic mannerof exchanging information between cells.", "metadata": {}}
+{"_id": "7766808", "title": "", "text": "Estimating the sample mean and standarddeviation from the sample size, median, rangeand/or interquartile rangeIn systematic reviewsand meta-analysis, researchers often pool theresults of the sample mean and standarddeviation from a set of similar clinical trials. Anumber of the trials, however, reported thestudy using the median, the minimum andmaximum values, and/or the first and thirdquartiles. Hence, in order to combine results, onemay have to estimate the sample mean andstandard deviation for such trials. In this paper,we propose to improve the existing literature inseveral directions. First, we show that thesample standard deviation estimation in Hozo etal. (2005) has some serious limitations and isalways less satisfactory in practice. Inspired bythis, we propose a new estimation method byincorporating the sample size. Second, wesystematically study the sample mean andstandard deviation estimation problem undermore general settings where the first and third", "metadata": {}}
+{"_id": "7795952", "title": "", "text": "Fascin protein is critical for transforming growthfactor β protein-induced invasion and filopodiaformation in spindle-shaped tumor cells.Fascin,an actin-bundling protein overexpressed in allcarcinomas, has been associated with poorprognosis, shorter survival, and more metastaticdiseases. It is believed that fascin facilitatestumor metastasis by promoting the formation ofinvasive membrane protrusions. However, themechanisms by which fascin is overexpressed intumors are not clear. TGFβ is a cytokine secretedby tumor and mesenchymal cells and promotesmetastasis in many late stage tumors. Thepro-metastasis mechanisms of TGFβ remain tobe fully elucidated. Here we demonstrated thatTGFβ induced fascin expression inspindle-shaped tumor cells through the canonicalSmad-dependent pathway. Fascin was critical forTGFβ-promoted filopodia formation, migration,and invasion in spindle tumor cells. Moreimportantly, fascin expression significantlycorrelates with TGFβ1 and TGFβ receptor I levels", "metadata": {}}
+{"_id": "7808055", "title": "", "text": "DNA methylation age of human tissues and celltypesBACKGROUND It is not yet known whetherDNA methylation levels can be used to accuratelypredict age across a broad spectrum of humantissues and cell types, nor whether the resultingage prediction is a biologically meaningfulmeasure. RESULTS I developed a multi-tissuepredictor of age that allows one to estimate theDNA methylation age of most tissues and celltypes. The predictor, which is freely available,was developed using 8,000 samples from 82Illumina DNA methylation array datasets,encompassing 51 healthy tissues and cell types.I found that DNA methylation age has thefollowing properties: first, it is close to zero forembryonic and induced pluripotent stem cells;second, it correlates with cell passage number;third, it gives rise to a highly heritable measureof age acceleration; and, fourth, it is applicableto chimpanzee tissues. Analysis of 6,000 cancersamples from 32 datasets showed that all of theconsidered 20 cancer types exhibit significant", "metadata": {}}
+{"_id": "7813993", "title": "", "text": "Whole-body MR vascular screening detectsunsuspected concomitant vascular disease incoronary heart disease patientsCoronary heartdisease (CHD) patients often showatherosclerotic vascular disease in other vascularterritories. We evaluated how often whole-bodyMR imaging detects concomitant arterialpathologies in CHD patients, and how often thesepathologies were not known to the patientspreviously. Of 4,814 participants in thepopulation-based Heinz Nixdorf Recall Study,327 reported CHD (i.e., previous coronarybypass surgery, angioplasty); of those, 160patients (mean age 66.4 years) were examinedusing MR of the brain, the heart (excluding thecoronary arteries), and whole-body MRangiography. The prevalence of each vascularpathology was assessed, correlated to the othersand compared to patients’ histories. Of the 160CHD patients, 16 (10%) showed MR signs ofstroke, and 77 (48.1%) had a stenosis >50% inat least one extracerebral peripheral artery", "metadata": {}}
+{"_id": "7820043", "title": "", "text": "Key role of Ubc5 and lysine-63 polyubiquitinationin viral activation of IRF3.The mitochondrialantiviral signaling protein (MAVS; also known asIPS-1, VISA, and CARDIF) is essential for innateimmune response against RNA viruses. MAVStransduces signals from the cytosolic RIG-I-likereceptors, which bind to viral RNAs. But howMAVS activates downstream transcription factorssuch as IRF3 to induce type-I interferons is notwell understood. We have established a cell-freesystem in which mitochondria derived fromvirus-infected cells activate IRF3 in the cytosol.Fractionation of the cytosol led to theidentification of Ubc5 as a ubiquitin-conjugatingenzyme (E2) required for IRF3 activation. Usingan inducible RNAi strategy, we demonstrate thatcatalytically active Ubc5 is required for IRF3activation by viral infection. The activation ofIRF3 also requires two ubiquitin-binding domainsof NEMO. Furthermore, we show thatreplacement of endogenous ubiquitin with itsK63R mutant abolishes viral activation of IRF3,", "metadata": {}}
+{"_id": "7821634", "title": "", "text": "Profiling of residual breast cancers afterneoadjuvant chemotherapy identifies DUSP4deficiency as a mechanism of drugresistanceNeoadjuvant chemotherapy (NAC)induces a pathological complete response (pCR)in \u000030% of patients with breast cancer.However, many patients have residual cancerafter chemotherapy, which correlates with ahigher risk of metastatic recurrence and pooreroutcome than those who achieve a pCR. Wehypothesized that molecular profiling of tumorsafter NAC would identify genes associated withdrug resistance. Digital transcript counting wasused to profile surgically resected breast cancersafter NAC. Low concentrations of dual specificityprotein phosphatase 4 (DUSP4), an ERKphosphatase, correlated with high post-NACtumor cell proliferation and with basal-like breastcancer (BLBC) status. BLBC had higher DUSP4promoter methylation and gene expressionpatterns of Ras-ERK pathway activation relativeto other breast cancer subtypes. DUSP4", "metadata": {}}
+{"_id": "7834603", "title": "", "text": "Age-related behaviors have distincttranscriptional profiles in Caenorhabditiselegans.There has been a great deal of interestin identifying potential biomarkers of aging.Biomarkers of aging would be useful to predictpotential vulnerabilities in an individual that mayarise well before they are chronologicallyexpected, due to idiosyncratic aging rates thatoccur between individuals. Prior attempts toidentify biomarkers of aging have often relied onthe comparisons of long-lived animals to awild-type control. However, the effect ofinterventions in model systems that prolonglifespan (such as single gene mutations or caloricrestriction) can sometimes be difficult tointerpret due to the manipulation itself havingmultiple unforeseen consequences onphysiology, unrelated to aging itself. The searchfor predictive biomarkers of aging therefore isproblematic, and the identification of metricsthat can be used to predict either physiological orchronological age would be of great value. One", "metadata": {}}
+{"_id": "7837879", "title": "", "text": "Synchronization of Diffusively-ConnectedNonlinear Systems: Results Based onContractions with Respect to GeneralNormsContraction theory provides an elegantway to analyze the behavior of certain nonlineardynamical systems. In this paper, we discuss theapplication of contraction to synchronization ofdiffusively interconnected components describedby nonlinear differential equations. We provideestimates of convergence of the difference instates between components, in the cases of line,complete, and star graphs, and Cartesianproducts of such graphs. We base our approachon contraction theory, using matrix measuresderived from norms that are not induced by innerproducts. Such norms are the most appropriatein many applications, but proofs cannot relyupon Lyapunov-like linear matrix inequalities,and different techniques, such as the use of thePerron-Frobenious Theorem in the cases of L1 orL∞ norms, must be introduced.", "metadata": {}}
+{"_id": "7838799", "title": "", "text": "GeneTrack--a genomic data processing andvisualization framework.MOTIVATIONHigh-throughput 'ChIP-chip' and 'ChIP-seq'methodologies generate sufficiently large datasets that analysis poses significant informaticschallenges, particularly for research groups withmodest computational support. To address thischallenge, we devised a software platform forstoring, analyzing and visualizing high resolutiongenome-wide binding data. GeneTrackautomates several steps of a typical dataprocessing pipeline, including smoothing andpeak detection, and facilitates dissemination ofthe results via the web. Our software is freelyavailable via the Google Project Hostingenvironment athttp://genetrack.googlecode.com", "metadata": {}}
+{"_id": "7840442", "title": "", "text": "Multisite optical recording of excitability in theenteric nervous system.A multisite opticalrecording technique consisting of an array of 464photodiodes was used to measure dynamicchanges in transmembrane potentials (Vm) ofguinea-pig and mouse enteric neurones stainedwith the voltage-sensitive dye Di-8-ANEPPS.Optical recordings of Vm changes in entericneurones which were evoked by depolarizingcurrent pulses or synaptic activation mirrored theVm changes measured intracellularly in the sameneurone. Action potentials had fractional changein fluorescence of -0.09 +/- 0.06% and theirpeak to peak noise level was 20 +/- 14% of theaction potential amplitude. Optical recordingsafter electrical stimulation of interganglionicnerve strands revealed slow EPSPs, nicotinergicsupra- and subthreshold fast EPSPs as well aspropagation of action potentials alonginterganglionic strands. Local application ofacetylcholine onto a single ganglion inducedreproducibly and dose dependently action", "metadata": {}}
+{"_id": "7848113", "title": "", "text": "Telomere-bound TRF1 and TRF2 stall thereplication fork at telomeric repeats.Vertebratetelomeres consist of tandem repeats of T2AG3and associated proteins including the telomericDNA-binding proteins, TRF1 and TRF2. It hasbeen proposed that telomeres assume twointerswitchable states, the open state that isaccessible to various trans-acting factors and theclosed state that excludes those factors. TRF1and TRF2 are believed to promote the formationof the closed state. However, little is knownabout how those two states influence DNAreplication. We analyzed the effects of TRF1 andTRF2 on telomeric replication both in vitro and invivo. By exploiting the in vitro replication systemof linear SV40 DNA, we found that telomericrepeats are a poor replication template.Moreover, the addition of recombinant TRF1 andTRF2 significantly stalled the replication forkprogression at telomeric repeats. When TRF1was overexpressed in HeLa cells, cells with 4NDNA content were accumulated. Furthermore,", "metadata": {}}
+{"_id": "7850867", "title": "", "text": "Margination of white blood cells in microcapillaryflow.Margination of white blood cells (WBCs)towards vessel walls is an essential preconditionfor their efficient adhesion to the vascularendothelium. We perform numerical simulationswith a two-dimensional blood flow model toinvestigate the dependence of WBC marginationon hydrodynamic interactions of blood cells withthe vessel walls, as well as on their collectivebehavior and deformability. We find WBCmargination to be optimal in intermediate rangesof red blood cell (RBC) volume fractions and flowrates, while, beyond these ranges, it issubstantially attenuated. RBC aggregationenhances WBC margination, while WBCdeformability reduces it. These results arecombined in state diagrams, which identify WBCmargination for a wide range of flow and cellsuspension conditions.", "metadata": {}}
+{"_id": "7852582", "title": "", "text": "Lung cancer treatment waiting times and tumourgrowth.We report a single-centre prospectiveaudit of 29 lung cancer patients who wereawaiting radical (potentially curative)radiotherapy. This was the total numberassessed as suitable for radical treatment by oneconsultant during 1999. At the time ofassessment they had been newly diagnosed andstaged with a computed tomographic (CT) scanof chest. They had a subsequent CT scan prior tostarting treatment for the purpose of planningthe radiation fields. We have now measuredtumour size on the diagnostic scans andcompared this with the size on the planningscans. We have documented the delay betweendiagnostic and planning CT scanning and thetotal time between first hospital visit and startingtreatment. Two patients had progression ofsymptoms while on the waiting list, making themunfit for radical treatment, and another four hadtumour progression on planning CT such that thetumour volume was too large for radical", "metadata": {}}
+{"_id": "7860396", "title": "", "text": "Functional coupling of RNAP II transcription tospliceosome assembly.The pathway of geneexpression in higher eukaryotes involves a highlycomplex network of physical and functionalinteractions among the different machinesinvolved in each step of the pathway. Here weestablished an efficient in vitro system todetermine how RNA polymerase II (RNAP II)transcription is functionally coupled to pre-mRNAsplicing. Strikingly, our data show that nascentpre-messenger RNA (pre-mRNA) synthesized byRNAP II is immediately and quantitativelydirected into the spliceosome assembly pathway.In contrast, nascent pre-mRNA synthesized byT7 RNA polymerase is quantitatively assembledinto the nonspecific H complex, which consists ofheterogeneous nuclear ribonucleoprotein(hnRNP) proteins and is inhibitory forspliceosome assembly. Consequently, RNAP IItranscription results in a dramatic increase inboth the kinetics of splicing and overall yield ofspliced mRNA relative to that observed for T7", "metadata": {}}
+{"_id": "7869794", "title": "", "text": "Calicum microdomains form within neutrophils atthe neutrophil–tumor cell synapse: role inantibody-dependent target cell apoptosisCa2+messages are broadly important in cellular signaltransduction. In immune cells, Ca2+ signaling isan essential step in many forms of activation.Neutrophil-mediated antibody-dependentcell-mediated cytotoxicity (ADCC) is one form ofleukocyte activation that plays an important rolein tumor cell killing in vitro and in patient care.Using fluorescence methodologies, we found thatneutrophils exhibit Ca2+ signals during ADCCdirected against breast fibrosarcoma cells.Importantly, these signals were localized toCa2+ microdomains at the neutrophil-to-tumorcell interface where they display dynamicfeatures such as movement, fusion, and fission.These signals were blocked by the intracellularCa2+ buffer BAPTA. At the neutrophil–tumor cellsynapse, the neutrophil’s cytoplasm wasenriched in STIM1, a crucial mediator of Ca2+signaling, whereas the Ca2+-binding proteins", "metadata": {}}
+{"_id": "7873737", "title": "", "text": "Platelet glycoprotein IIb/IIIa inhibitors reducemortality in diabetic patients withnon-ST-segment-elevation acute coronarysyndromes.BACKGROUND Diabetes mellitus is amajor risk factor for adverse outcomes afteracute coronary syndromes (ACS). Because thisdisease may be associated with increasedplatelet aggregation, we investigated whetherdiabetic patients with ACS derive particularbenefit from platelet glycoprotein (GP) IIb/IIIareceptor inhibition. METHODS AND RESULTS Weperformed a meta-analysis of the diabeticpopulations enrolled in the 6 large-scale plateletGP IIb/IIIa inhibitor ACS trials: PRISM,PRISM-PLUS, PARAGON A, PARAGON B,PURSUIT, and GUSTO IV. Among 6458 diabeticpatients, platelet GP IIb/IIIa inhibition wasassociated with a significant mortality reductionat 30 days, from 6.2% to 4.6% (OR 0.74; 95%CI 0.59 to 0.92; P=0.007). Conversely, 23 072nondiabetic patients had no survival benefit(3.0% versus 3.0%). The interaction between", "metadata": {}}
+{"_id": "7875158", "title": "", "text": "Glucose deprivation-induced cytotoxicity andalterations in mitogen-activated protein kinaseactivation are mediated by oxidative stress inmultidrug-resistant human breast carcinomacells.We previously observed that glucosedeprivation induces cell death inmultidrug-resistant human breast carcinomacells (MCF-7/ADR). As a follow up we wished totest the hypothesis that metabolic oxidativestress was the causative process or at least thelink between causative processes behind thecytotoxicity. In the studies described here, wedemonstrate that mitogen-activated proteinkinase (MAPK) was activated within 3 min ofbeing in glucose-free medium and remainedactivated for 3 h. Glucose deprivation for 2-4 halso caused oxidative stress as evidenced by a3-fold greater steady state concentration ofoxidized glutathione and a 3-fold increase inpro-oxidant production. Glucose and glutamatetreatment rapidly suppressed MAPK activationand rescued cells from cytotoxicity. Glutamate", "metadata": {}}
+{"_id": "7878807", "title": "", "text": "A structural basis for kinetochore recruitment ofthe Ndc80 complex via two distinct centromerereceptors.The Ndc80 complex is the keymicrotubule-binding element of the kinetochore.In contrast to the well-characterized interactionof Ndc80-Nuf2 heads with microtubules, little isknown about how the Spc24-25 heterodimerconnects to centromeric chromatin. Here, wepresent molecular details of Spc24-25 in complexwith the histone-fold protein Cnn1/CENP-Tillustrating how this connection ultimately linksmicrotubules to chromosomes. The conservedNdc80 receptor motif of Cnn1 is bound as an αhelix in a hydrophobic cleft at the interfacebetween Spc24 and Spc25. Point mutations thatdisrupt the Ndc80-Cnn1 interaction also abrogatebinding to the Mtw1 complex and are lethal inyeast. We identify a Cnn1-related motif in theDsn1 subunit of the Mtw1 complex, necessary forNdc80 binding and essential for yeast growth.Replacing this region with the Cnn1 peptiderestores viability demonstrating functionality of", "metadata": {}}
+{"_id": "7898952", "title": "", "text": "Feedback Circuit among INK4 TumorSuppressors Constrains Human GlioblastomaDevelopmentWe have developed a nonheuristicgenome topography scan (GTS) algorithm tocharacterize the patterns of genomic alterationsin human glioblastoma (GBM), identifyingfrequent p18(INK4C) and p16(INK4A)codeletion. Functional reconstitution ofp18(INK4C) in GBM cells null for bothp16(INK4A) and p18(INK4C) resulted in impairedcell-cycle progression and tumorigenic potential.Conversely, RNAi-mediated depletion ofp18(INK4C) in p16(INK4A)-deficient primaryastrocytes or established GBM cells enhancedtumorigenicity in vitro and in vivo. Furthermore,acute suppression of p16(INK4A) in primaryastrocytes induced a concomitant increase inp18(INK4C). Together, these findings uncover afeedback regulatory circuit in the astrocyticlineage and demonstrate a bona fide tumorsuppressor role for p18(INK4C) in human GBMwherein it functions cooperatively with other", "metadata": {}}
+{"_id": "7915836", "title": "", "text": "The SMC5/6 complex maintains telomere lengthin ALT cancer cells through SUMOylation oftelomere-binding proteinsMost cancer cellsactivate telomerase to elongate telomeres andachieve unlimited replicative potential. Somecancer cells cannot activate telomerase and usetelomere homologous recombination (HR) toelongate telomeres, a mechanism termedalternative lengthening of telomeres (ALT). Ahallmark of ALT cells is the recruitment oftelomeres to PML bodies (termed APBs). Here,we show that the SMC5/6 complex localizes toAPBs in ALT cells and is required for targetingtelomeres to APBs. The MMS21 SUMO ligase ofthe SMC5/6 complex SUMOylates multipletelomere-binding proteins, including TRF1 andTRF2. Inhibition of TRF1 or TRF2 SUMOylationprevents APB formation. Depletion of SMC5/6subunits by RNA interference inhibits telomereHR, causing telomere shortening and senescencein ALT cells. Thus, the SMC5/6 complexfacilitates telomere HR and elongation in ALT", "metadata": {}}
+{"_id": "7925817", "title": "", "text": "Dynein pulls microtubules without rotating itsstalk.Dynein is a microtubule motor that powersmotility of cilia and flagella. There is evidencethat the relative sliding of the doubletmicrotubules is due to a conformational changein the motor domain that moves a microtubulebound to the end of an extension known as thestalk. A predominant model for the movementinvolves a rotation of the head domain, with itsstalk, toward the microtubule plus end. However,stalks bound to microtubules have been difficultto observe. Here, we present the clearest viewsso far of stalks in action, by observing seaurchin, outer arm dynein molecules bound tomicrotubules, with a new method, \"cryo-positivestain\" electron microscopy. The dynein moleculesin the complex were shown to be active in invitro motility assays. Analysis of the electronmicrographs shows that the stalk angles relativeto microtubules do not change significantlybetween the ADP.vanadate and no-nucleotidestates, but the heads, together with their stalks,", "metadata": {}}
+{"_id": "7929932", "title": "", "text": "The INO80 chromatin remodeling complex intranscription, replication and repair.The Ino80ATPase is a member of the SNF2 family ofATPases and functions as an integral componentof a multisubunit ATP-dependent chromatinremodeling complex. Although INO80 complexesfrom yeast and higher eukaryotes share acommon core of conserved subunits, thecomplexes have diverged substantially duringevolution and have acquired new subunits withapparently species-specific functions. Recentstudies have shown that the INO80 complexcontributes to a wide variety ofchromatin-dependent nuclear transactions,including transcription, DNA repair and DNAreplication.", "metadata": {}}
+{"_id": "7944381", "title": "", "text": "VEX1 controls the allelic exclusion required forantigenic variation in trypanosomes.Allelicexclusion underpins antigenic variation andimmune evasion in African trypanosomes. Thesebloodstream parasites use RNA polymerase-I(pol-I) to transcribe just one telomeric variantsurface glycoprotein (VSG) gene at a time,producing superabundant and switchable VSGcoats. We identified trypanosome VSGexclusion-1 (VEX1) using a genetic screen fordefects in telomere-exclusive expression. VEX1was sequestered by the active VSG and silencingof other VSGs failed when VEX1 was eitherectopically expressed or depleted, indicatingpositive and negative regulation, respectively.Positive regulation affected VSGs andnontelomeric pol-I-transcribed genes, whereasnegative regulation primarily affected VSGs.Negative regulation by VEX1 also affectedtelomeric pol-I-transcribed reporter constructs,but only when they contained blocks of sequencesharing homology with a pol-I-transcribed locus.", "metadata": {}}
+{"_id": "7948486", "title": "", "text": "Kruppel-like factor 2 (KLF2) regulates monocytedifferentiation and functions in mBSA andIL-1β-induced arthritis.Kruppel-like factor 2(KLF2) plays an important role in the regulationof a variety of immune cells, includingmonocytes. We have previously shown that KLF2inhibits proinflammatory activation ofmonocytes. However, the role of KLF2 in arthritisis yet to be investigated. In the current study,we show that recruitment of significantly greaternumbers of inflammatory subset ofCD11b(+)F4/80(+)Ly6C+ monocytes to theinflammatory sites in KLF2 hemizygous micecompared to the wild type littermate controls. Inparallel, inflammatory mediators, MCP-1, Cox-2and PAI-1 were significantly up-regulated inbone marrow-derived monocytes isolated fromKLF2 hemizygous mice, in comparison towild-type controls. Methylated-BSA andIL-1β-induced arthritis was more severe in KLF2hemizygous mice as compared to the littermatewild type controls. Consistent with this", "metadata": {}}
+{"_id": "7965928", "title": "", "text": "Relationship of collegiate football experience andconcussion with hippocampal volume andcognitive outcomes.IMPORTANCE Concussionand subconcussive impacts have been associatedwith short-term disrupted cognitive performancein collegiate athletes, but there are limited dataon their long-term neuroanatomic and cognitiveconsequences. OBJECTIVE To assess therelationships of concussion history and years offootball experience with hippocampal volume andcognitive performance in collegiate footballathletes. DESIGN, SETTING, AND PARTICIPANTSCross-sectional study conducted between June2011 and August 2013 at a US psychiatricresearch institute specializing in neuroimagingamong collegiate football players with a historyof clinician-diagnosed concussion (n = 25),collegiate football players without a history ofconcussion (n = 25), and non-football-playing,age-, sex-, and education-matched healthycontrols (n = 25). EXPOSURES History ofclinician-diagnosed concussion and years of", "metadata": {}}
+{"_id": "7968532", "title": "", "text": "STING and the innate immune response tonucleic acids in the cytosolCytosolic detection ofpathogen-derived nucleic acids is critical for theinitiation of innate immune defense againstdiverse bacterial, viral and eukaryotic pathogens.Conversely, inappropriate responses to cytosolicnucleic acids can produce severe autoimmunepathology. The host protein STING has beenidentified as a central signaling molecule in theinnate immune response to cytosolic nucleicacids. STING seems to be especially critical forresponses to cytosolic DNA and the uniquebacterial nucleic acids called 'cyclicdinucleotides'. Here we discuss advances in theunderstanding of STING and highlight the manyunresolved issues in the field.", "metadata": {}}
+{"_id": "7970974", "title": "", "text": "Global Assessment of Genomic Regions Requiredfor Growth in MycobacteriumtuberculosisIdentifying genomic elementsrequired for viability is central to ourunderstanding of the basic physiology ofbacterial pathogens. Recently, the combinationof high-density mutagenesis and deepsequencing has allowed for the identification ofrequired and conditionally required genes inmany bacteria. Genes, however, make up only apart of the complex genomes of importantbacterial pathogens. Here, we use an unbiasedanalysis to comprehensively identify genomicregions, including genes, domains, andintergenic elements, required for the optimalgrowth of Mycobacterium tuberculosis, a majorglobal health pathogen. We found that severalproteins jointly contain both domains requiredfor optimal growth and domains that aredispensable. In addition, many non-codingregions, including regulatory elements andnon-coding RNAs, are critical for mycobacterial", "metadata": {}}
+{"_id": "7975937", "title": "", "text": "Cyclooxygenase-Dependent Tumor Growththrough Evasion of ImmunityThe mechanisms bywhich melanoma and other cancer cells evadeanti-tumor immunity remain incompletelyunderstood. Here, we show that the growth oftumors formed by mutant Braf(V600E) mousemelanoma cells in an immunocompetent hostrequires their production of prostaglandin E2,which suppresses immunity and fuelstumor-promoting inflammation. Genetic ablationof cyclooxygenases (COX) or prostaglandin Esynthases in Braf(V600E) mouse melanomacells, as well as in Nras(G12D) melanoma or inbreast or colorectal cancer cells, renders themsusceptible to immune control and provokes ashift in the tumor inflammatory profile towardclassic anti-cancer immune pathways. Thismouse COX-dependent inflammatory signature isremarkably conserved in human cutaneousmelanoma biopsies, arguing for COX activity as adriver of immune suppression across species.Pre-clinical data demonstrate that inhibition of", "metadata": {}}
+{"_id": "7986878", "title": "", "text": "Anti-alphav integrin monoclonal antibodyintetumumab enhances the efficacy of radiationtherapy and reduces metastasis of human cancerxenografts in nude rats.We previously reportedthat intetumumab (CNTO 95), a fully humananti-αv integrin monoclonal antibody, is aradiosensitizer in mice with xenograft tumors.Because intetumumab does not cross-react withmouse integrins, but has cross-reactivity with ratintegrins, we next studied the potentialcombined use of radiation therapy andintetumumab in human cancer xenograft modelsin nude rats to assess effects on both tumor cellsand the tumor microenvironment. Nude ratsbearing human head and neck cancer andnon-small cell lung cancer (NSCLC) xenograftswere treated with intetumumab and fractionatedlocal tumor radiotherapy. Effects on tumorgrowth and metastasis, blood perfusion,oxygenation, and gastrointestinal toxicity werestudied. Intetumumab alone had a moderateeffect on tumor growth. When combined with", "metadata": {}}
+{"_id": "7988832", "title": "", "text": "Methylomic trajectories across human fetal braindevelopment.Epigenetic processes play a keyrole in orchestrating transcriptional regulationduring development. The importance of DNAmethylation in fetal brain development ishighlighted by the dynamic expression of denovo DNA methyltransferases during theperinatal period and neurodevelopmental deficitsassociated with mutations in the methyl-CpGbinding protein 2 (MECP2) gene. However, ourknowledge about the temporal changes to theepigenome during fetal brain development has,to date, been limited. We quantifiedgenome-wide patterns of DNA methylation at \u0000400,000 sites in 179 human fetal brain samples(100 male, 79 female) spanning 23 to 184 dpost-conception. We identified highly significantchanges in DNA methylation across fetal braindevelopment at >7% of sites, with anenrichment of loci becoming hypomethylatedwith fetal age. Sites associated withdevelopmental changes in DNA methylation", "metadata": {}}
+{"_id": "7997337", "title": "", "text": "Synaptic Determinants of Rett SyndromeThere ismounting evidence showing that the structuraland molecular organization of synapticconnections is affected both in human patientsand in animal models of neurological andpsychiatric diseases. As a consequence of theseexperimental observations, it has beenintroduced the concept of synapsopathies, anotion describing brain disorders of synapticfunction and plasticity. A close correlationbetween neurological diseases and synapticabnormalities is especially relevant for thosesyndromes including also mental retardation intheir symptomatology, such as Rett syndrome(RS). RS (MIM312750) is an X-linked dominantneurological disorder that is caused in themajority of cases by mutations inmethyl-CpG-binding protein 2 (MeCP2). Thisreview will focus on the current knowledge of thesynaptic alterations produced by mutations ofthe gene MeCP2 in mouse models of RS and willhighlight prospects experimental therapies", "metadata": {}}
+{"_id": "8002529", "title": "", "text": "Depressive symptoms and physical decline incommunity-dwelling older persons.CONTEXTSignificant symptoms of depression are commonin the older community-dwelling population.Although depressive symptoms and disabilitymay commonly occur in the same person,whether depressive symptoms contribute tosubsequent functional decline has not beenelucidated. OBJECTIVE To determine whetherdepressive symptoms in older persons increasethe risk of subsequent decline in physicalfunction as measured by objectiveperformance-based tests. DESIGN A 4-yearprospective cohort study. SETTING Thecommunities of Iowa and Washington counties,Iowa. PARTICIPANTS A total of 1286 personsaged 71 years and older who completed a shortbattery of physical performance tests in 1988and again 4 years later. MAIN OUTCOMEMEASURES Baseline depressive symptoms wereassessed by the Center for EpidemiologicalStudies Depression Scale. Physical performance", "metadata": {}}
+{"_id": "8002887", "title": "", "text": "Foxk proteins repress the initiation ofstarvation-induced atrophy and autophagyprogramsAutophagy is the primary catabolicprocess triggered in response to starvation.Although autophagic regulation within thecytosolic compartment is well established, it isbecoming clear that nuclear events also regulatethe induction or repression of autophagy.Nevertheless, a thorough understanding of themechanisms by which sequence-specifictranscription factors modulate expression ofgenes required for autophagy is lacking. Here,we identify Foxk proteins (Foxk1 and Foxk2) astranscriptional repressors of autophagy in musclecells and fibroblasts. Interestingly, Foxk1/2 serveto counter-balance another forkheadtranscription factor, Foxo3, which induces anoverlapping set of autophagic and atrophictargets in muscle. Foxk1/2 specifically recruitsSin3A-HDAC complexes to restrict acetylation ofhistone H4 and expression of critical autophagygenes. Remarkably, mTOR promotes the", "metadata": {}}
+{"_id": "8005007", "title": "", "text": "PRRSV receptors and their roles in virusinfectionPorcine reproductive and respiratorysyndrome virus (PRRSV) has a restricted celltropism and prefers to invade well-differentiatedcells of the monocyte/macrophage lineage, suchas pulmonary alveolar macrophages and Africangreen monkey kidney cell line MA-104 and itsderivatives, such as Marc-145, Vero andCL-2621. PRRSV infection of the host cellsactually is a receptor-mediated endocytosis andreplication process. The presence and absence ofthe cellular receptors decide whether the celllines are permissive or non-permissive to PRRSVinfection. Several PRRSV non-permissive celllines, such as BHK-21, PK-15 and CHO-K1, havebeen shown to become sensitive to the virusinfection upon expression of the recombinantreceptor proteins. Up to now, heparin sulfate,sialoadhesin, CD163, CD151 and vimentin havebeen identified as the important PRRSV receptorsvia their involvement in virus attachment,internalization or uncoating. Each receptor is", "metadata": {}}
+{"_id": "8006440", "title": "", "text": "Kinetic Analysis Reveals the Fate of a MicroRNAfollowing Target Regulation in MammalianCellsConsiderable details about microRNA(miRNA) biogenesis and regulation have beenuncovered, but little is known about the fate ofthe miRNA subsequent to target regulation. Togain insight into this process, we carried outkinetic analysis of a miRNA's turnover followingtermination of its biogenesis and duringregulation of a target that is not subject toAgo2-mediated catalytic cleavage. Byquantitating the number of molecules of themiRNA and its target in steady state and in thecourse of its decay, we found that each miRNAmolecule was able to regulate at least two targettranscripts, providing in vivo evidence that themiRNA is not irreversibly sequestered with itstarget and that the nonslicing pathway of miRNAregulation is multiple-turnover. Using deepsequencing, we further show that miRNArecycling is limited by target regulation, whichpromotes posttranscriptional modifications to the", "metadata": {}}
+{"_id": "8025177", "title": "", "text": "Estimation of nuclear DNA content in plantsusing flow cytometryFlow cytometry (FCM) usingDNA-selective fluorochromes is now theprevailing method for the measurement ofnuclear DNA content in plants. Ease of samplepreparation and high sample throughput make itgenerally better suited than other methods suchas Feulgen densitometry to estimate genomesize, level of generative polyploidy, nuclearreplication state and endopolyploidy(polysomaty). Here we present four protocols forsample preparation (suspensions of intact cellnuclei) and describe the analysis of nuclear DNAamounts using FCM. We consider the chemicalsand equipment necessary, the measurementprocess, data analysis, and describe the mostfrequent problems encountered with plantmaterial such as the interference of secondarymetabolites. The purpose and requirement ofinternal and external standardization arediscussed. The importance of using a correctterminology for DNA amounts and genome size is", "metadata": {}}
+{"_id": "8037453", "title": "", "text": "Predictive value of bone resorption and formationmarkers in cancer patients with bone metastasesreceiving the bisphosphonate zoledronicacid.PURPOSE Three large, randomized trials ofpatients with bone metastases recentlydemonstrated that zoledronic acid reduces therisk of skeletal-related events. These trialsprovide an opportunity for investigating thecorrelation between bone metabolism and clinicaloutcome during bisphosphonate therapy.PATIENTS AND METHODS Urinary measurementsof N-telopeptide (Ntx) and serum bone alkalinephosphatase (BAP) were obtained in 1,824bisphosphonate-treated patients-1,462 withzoledronic acid (breast, 490; prostate, 411;myeloma, 210; non-small-cell lung, 183; other,168) and 362 with pamidronate (breast, 254;myeloma, 108). This exploratory cohort analysisgrouped patients by baseline and most recentlevels of Ntx as low (< 50 nmol/mmolcreatinine), moderate (50 to 99 nmol/mmolcreatinine), or high (> or = 100 nmol/mmol", "metadata": {}}
+{"_id": "8038329", "title": "", "text": "Role of CD28-B7 interactions in generation andmaintenance of CD8 T cell memory.Although therole of CD28-B7 interaction in the activation ofnaive T cells is well established, its importance inthe generation and maintenance of T cellmemory is not well understood. In this study, weexamined the requirement for CD28-B7interactions in primary T cell activation andimmune memory. Ag-specific CD8 T cellresponses were compared between wild-type(+/+) and CD28-deficient (CD28(-/-)) micefollowing an acute infection with lymphocyticchoriomeningitis virus (LCMV). During theprimary response, there was a substantialactivation and expansion of LCMV-specific CD8 Tcells in both +/+ and CD28(-/-) mice. However,the magnitude of the primary CD8 T cellresponse to both dominant and subdominantLCMV CTL epitopes was approximately 2- to3-fold lower in CD28(-/-) mice compared with+/+ mice; the lack of CD28-mediatedcostimulation did not lead to preferential", "metadata": {}}
+{"_id": "8042158", "title": "", "text": "Systematic reviews from astronomy to zoology:myths and misconceptions.Systematic literaturereviews are widely used as an aid to evidencebased decision making. For example, reviews ofrandomised controlled trials are regularly used toanswer questions about the effectiveness ofhealthcare interventions. The high profile ofsystematic reviews as a cornerstone of evidencebased medicine, however, has led to severalmisconceptions about their purpose andmethods. Among these is the belief thatsystematic reviews are applicable only torandomised controlled trials and that they areincapable of dealing with other forms ofevidence, such as from non-randomised studiesor qualitative research. The systematic literaturereview is a method of locating, appraising, andsynthesising evidence. The value of regularlyupdated systematic reviews in the assessment ofeffectiveness of healthcare interventions wasdramatically illustrated by Antman andcolleagues, who showed that review articles", "metadata": {}}
+{"_id": "8063697", "title": "", "text": "Acellular pertussis vaccines protect againstdisease but fail to prevent infection andtransmission in a nonhuman primatemodel.Pertussis is a highly contagiousrespiratory illness caused by the bacterialpathogen Bordetella pertussis. Pertussis rates inthe United States have been rising and reached a50-y high of 42,000 cases in 2012. Althoughpertussis resurgence is not completelyunderstood, we hypothesize that currentacellular pertussis (aP) vaccines fail to preventcolonization and transmission. To test ourhypothesis, infant baboons were vaccinated at 2,4, and 6 mo of age with aP or whole-cellpertussis (wP) vaccines and challenged with B.pertussis at 7 mo. Infection was followed byquantifying colonization in nasopharyngealwashes and monitoring leukocytosis andsymptoms. Baboons vaccinated with aP wereprotected from severe pertussis-associatedsymptoms but not from colonization, did notclear the infection faster than naïve animals, and", "metadata": {}}
+{"_id": "8065561", "title": "", "text": "Specific and cooperative binding of E. colisingle-stranded DNA binding protein tomRNA.Fluorometric titration of E. colisingle-stranded DNA binding protein with variousRNAs showed that the protein specifically andcooperatively binds to its own mRNA. Thebinding inhibited in vitro expression of ssb andbla but not nusA. This inhibition takes place at aphysiological concentration of SSB. The functionof the protein in gene regulation is discussed.", "metadata": {}}
+{"_id": "8069939", "title": "", "text": "ACAM2000™: The new smallpox vaccine forUnited States Strategic NationalStockpileSmallpox was eradicated more than 30years ago, but heightened concerns overbioterrorism have brought smallpox andsmallpox vaccination back to the forefront. Thepreviously licensed smallpox vaccine in theUnited States, Dryvax (Wyeth Laboratories,Inc.), was highly effective, but the supply wasinsufficient to vaccinate the entire current USpopulation. Additionally, Dryvax had aquestionable safety profile since it consisted of apool of vaccinia virus strains with varyingdegrees of virulence, and was grown on the skinof calves, an outdated technique that poses anunnecessary risk of contamination. The USgovernment has therefore recently supporteddevelopment of an improved live vaccinia virussmallpox vaccine. This initiative has resulted inthe development of ACAM2000 (Acambis, Inc.),a single plaque-purified vaccinia virus derivativeof Dryvax, aseptically propagated in cell culture.", "metadata": {}}
+{"_id": "8082528", "title": "", "text": "Risk of malignant neoplasms in patients withpulmonary sarcoidosis.BACKGROUND For over20 years the association between sarcoidosis andmalignancy, particularly lymphoma and lungcancer, has been disputed with misclassificationbeing the major concern. The aim of the presentstudy was to analyse the incidence ofmalignancies in a cohort of patients withsarcoidosis by linkage to a nationwide populationbased cancer register. METHODS The cohortcomprised 254 patients followed for a median of25 years until death, emigration, or 31December 1992, whichever came first. Theexpected number of cancer cases was calculatedusing the annual age and sex specific cancerrates from the Danish Cancer Registry. RESULTSThirty six cancers were registered, three of whichwere misclassified as sarcoidosis, leaving 33cancers compared with 23 expected(standardised incidence ratio (SIR) = 1.4; 95%CI 0.99 to 2.0). Five lung cancers were observedcompared with 2.5 expected, yielding an SIR of", "metadata": {}}
+{"_id": "8083310", "title": "", "text": "Rps14 haploinsufficiency causes a block inerythroid differentiation mediated by S100A8and S100A9Impaired erythropoiesis in thedeletion 5q (del(5q)) subtype of myelodysplasticsyndrome (MDS) has been linked toheterozygous deletion of RPS14, which encodesthe ribosomal protein small subunit 14. Wegenerated mice with conditional inactivation ofRps14 and demonstrated an erythroiddifferentiation defect that is dependent on thetumor suppressor protein p53 (encoded by Trp53in mice) and is characterized by apoptosis at thetransition from polychromatic to orthochromaticerythroblasts. This defect resulted inage-dependent progressive anemia,megakaryocyte dysplasia and loss ofhematopoietic stem cell (HSC) quiescence. Asassessed by quantitative proteomics, mutanterythroblasts expressed higher levels of proteinsinvolved in innate immune signaling, notably theheterodimeric S100 calcium-binding proteinsS100a8 and S100a9. S100a8—whose expression", "metadata": {}}
+{"_id": "8087082", "title": "", "text": "A Microtubule Interactome: Complexes withRoles in Cell Cycle and MitosisThe microtubule(MT) cytoskeleton is required for many aspectsof cell function, including the transport ofintracellular materials, the maintenance of cellpolarity, and the regulation of mitosis. Thesefunctions are coordinated by MT-associatedproteins (MAPs), which work in concert with eachother, binding MTs and altering their properties.We have used a MT cosedimentation assay,combined with 1D and 2D PAGE and massspectrometry, to identify over 250 MAPs fromearly Drosophila embryos. We have taken twocomplementary approaches to analyse thecellular function of novel MAPs isolated using thisapproach. First, we have carried out an RNAinterference (RNAi) screen, identifying 21previously uncharacterised genes involved in MTorganisation. Second, we have undertaken abioinformatics analysis based on binary proteininteraction data to produce putative interactionnetworks of MAPs. By combining both", "metadata": {}}
+{"_id": "8093935", "title": "", "text": "Structure of the Guanine Nucleotide ExchangeFactor Sec7 Domain of Human Arno and Analysisof the Interaction with ARF GTPaseSec7-relatedguanine nucleotide exchange factors (GEFs)initiate vesicle budding from the Golgi membranesurface by converting the GTPase ARF to aGTP-bound, membrane-associated form. Herewe report the crystal structure of the catalyticSec7 homology domain of Arno, a human GEF forARF1, determined at 2.2 angstroms resolution.The Sec7 domain is an elongated, all-helicalprotein with a distinctive hydrophobic groovethat is phylogenetically conserved.Structure-based mutagenesis identifies thegroove and an adjacent conserved loop as theARF-interacting surface. The sites of Sec7domain interaction on ARF1 have subsequentlybeen mapped, by protein footprintingexperiments, to the switch 1 and switch 2GTPase regions, leading to a model for theinteraction between ARF GTPases and Sec7domain exchange factors.", "metadata": {}}
+{"_id": "8122346", "title": "", "text": "Brief Communication Repeated CocaineAdministration Increases Voltage-SensitiveCalcium Currents in Response to MembraneDepolarization in Medial Prefrontal CortexPyramidal NeuronsThe medial prefrontal cortex(mPFC) plays a critical role in cocaine addiction.However, evidence to elucidate how the mPFC isfunctionally involved in cocaine addiction remainsincomplete. Recent studies have revealed thatrepeated cocaine administration induces variousneuroadaptations in pyramidal mPFC neurons,including a reduction in voltage-gated K+currents (VGKCs) and a possible increase involtage-sensitive Ca2+ currents (I(Ca)). Here,we performed both current-clamp recordings inbrain slices and voltage-clamp recordings infreshly dissociated cells to determine whetherI(Ca) is altered in mPFC pyramidal neurons afterchronic cocaine treatment with a short-term orlong-term withdrawal. In addition, a critical roleof VGKCs in regulating the generation of Ca2+plateau potential was also studied in mPFC", "metadata": {}}
+{"_id": "8126244", "title": "", "text": "Rational Extension of the Ribosome BiogenesisPathway Using Network-GuidedGeneticsBiogenesis of ribosomes is an essentialcellular process conserved across all eukaryotesand is known to require >170 genes for theassembly, modification, and trafficking ofribosome components through multiple cellularcompartments. Despite intensive study, thispathway likely involves many additional genes.Here, we employ network-guided genetics-anapproach for associating candidate genes withbiological processes that capitalizes on recentadvances in functional genomic and proteomicstudies-to computationally identify additionalribosomal biogenesis genes. We experimentallyevaluated >100 candidate yeast genes in abattery of assays, confirming involvement of atleast 15 new genes, including previouslyuncharacterized genes (YDL063C, YIL091C,YOR287C, YOR006C/TSR3, YOL022C/TSR4). Weassociate the new genes with specific aspects ofribosomal subunit maturation, ribosomal particle", "metadata": {}}
+{"_id": "8133050", "title": "", "text": "Quantifying Transmission Investment in MalariaParasitesMany microparasites infect new hostswith specialized life stages, requiring a subset ofthe parasite population to forgo proliferation anddevelop into transmission forms. Transmissionstage production influences infectivity, hostexploitation, and the impact of medicalinterventions like drug treatment. Predicting howparasites will respond to public health efforts onboth epidemiological and evolutionary timescalesrequires understanding transmission strategies.These strategies can rarely be observed directlyand must typically be inferred from infectiondynamics. Using malaria as a case study, we testpreviously described methods for inferringtransmission stage investment against simulateddata generated with a model of within-hostinfection dynamics, where the true transmissioninvestment is known. We show that existingmethods are inadequate and potentially verymisleading. The key difficulty lies in separatingtransmission stages produced by different", "metadata": {}}
+{"_id": "8133180", "title": "", "text": "Roles of induced expression of MAPKphosphatase-2 in tumor development inRET-MEN2A transgenic miceGermline mutationsin the RET tyrosine kinase gene are responsiblefor the development of multiple endocrineneoplasia 2A and 2B (MEN2A and MEN2B).However, knowledge of the fundamentalprinciples that determine the mutantRET-mediated signaling remains elusive. Here,we report increased expression ofmitogen-activated protein kinase phosphatase-2(MKP-2) in carcinomas developed in transgenicmice carrying RET with the MEN2A mutation(RET-MEN2A). The expression of MKP-2 was notonly induced by RET-MEN2A or RET-MEN2Bmutant proteins but also by the activation ofendogenous RET by its ligand, glial cellline-derived neurotrophic factor (GDNF). MKP-2expression was also evident in the MKK-f cellline, which was established from a mammarytumor developed in a RET-MEN2A transgenicmouse. Inhibition of MKP-2 attenuated the in", "metadata": {}}
+{"_id": "8137081", "title": "", "text": "Effects of repeated social stress on leukocytedistribution in bone marrow, peripheral bloodand spleenLeukocyte trafficking between thevarious body compartments has an importantsurveillance function that ensures the detectionof antigen and enables the immune system toinitiate a rapid and effective response. Repeatedsocial defeat of group-housed male mice inducedby daily, acute encounters with an aggressiveconspecific substantially altered leukocytetrafficking and led to a gradual redistribution ofimmune cells in bone marrow, peripheral bloodand spleen. Recurrent exposure to the stressorover a period of 2, 4 or 6 consecutive days wasassociated with cell mobilization and increasedmyelopoiesis in the bone marrow that wasparalleled by an accumulation of neutrophils andmonocytes in circulation and spleen. Substantialdepletion of B cells in bone marrow and bloodwas associated with an increase in splenic B cellsindicating a redirection of this cell type to thespleen. In contrast, T cells were markedly", "metadata": {}}
+{"_id": "8144920", "title": "", "text": "Lentivirally transduced dendritic cells as a toolfor cancer immunotherapy.BACKGROUNDDendritic cells (DC) are the professionalantigen-presenting cells of the immune system,fully equipped to prime naive T cells and thusessential components for cancer immunotherapy.METHODS We tested the influence of severalelements (cPPT, trip, WPRE, SIN) on thetransduction efficiency of human DC. Human andmurine DC were transduced withtNGFR-encoding lentiviruses to assess the effectof transduction on phenotype and function.Human DC were transduced with lentivirusesencoding huIi80MAGE-A3 and murine DC withhuIi80tOVA to test antigen presentation.RESULTS A self-inactivating (SIN) lentiviralvector containing the trip element was mostefficient in transducing human DC. Thetransduction of DC with trip/SIN tNGFR encodinglentiviral vectors at MOI 15 resulted in stablegene expression in up to 94.6% (murine) and88.2% (human) of the mature DC, without", "metadata": {}}
+{"_id": "8148122", "title": "", "text": "Global Reorganization of Replication DomainsDuring Embryonic Stem Cell DifferentiationDNAreplication in mammals is regulated via thecoordinate firing of clusters of replicons thatduplicate megabase-sized chromosomesegments at specific times during S-phase.Cytogenetic studies show that these \"repliconclusters\" coalesce as subchromosomal units thatpersist through multiple cell generations, but themolecular boundaries of such units haveremained elusive. Moreover, the extent to whichchanges in replication timing occur duringdifferentiation and their relationship totranscription changes has not been rigorouslyinvestigated. We have constructedhigh-resolution replication-timing profiles inmouse embryonic stem cells (mESCs) before andafter differentiation to neural precursor cells. Wedemonstrate that chromosomes can besegmented into multimegabase domains ofcoordinate replication, which we call \"replicationdomains,\" separated by transition regions whose", "metadata": {}}
+{"_id": "8148304", "title": "", "text": "Molecular characterization of the yeast meioticregulatory gene RIM1.In the yeastSaccharomyces cerevisiae, genetic studiessuggest that the RIM1 gene encodes a positiveregulator of meiosis. rim1 mutations causereduced expression of IME1, which is required forexpression of many meiotic genes, and thus leadto a partial defect in meiosis and sporeformation. We report the sequence of RIM1 andfunctional analysis of its coding region. The RIM1gene product (RIM1) contains three regionssimilar to C2H2 zinc fingers. Serine substitutionsfor cysteine in each of the putative zinc fingersabolish RIM1 function. The carboxyl-terminus ofRIM1 is enriched in acidic amino acids and isrequired for full RIM1 activity. RIM1 also containstwo putative cAMP-dependent protein kinase(cAPK) phosphorylation sites. At one site,substitution of alanine for serine does not affectRIM1 activity; at the other site, this substitutionimpairs activity. This analysis of RIM1 suggeststhat the protein may function as a transcriptional", "metadata": {}}
+{"_id": "8150638", "title": "", "text": "Butyrate greatly enhances derivation of humaninduced pluripotent stem cells by promotingepigenetic remodeling and the expression ofpluripotency-associated genes.We report herethat butyrate, a naturally occurring fatty acidcommonly used as a nutritional supplement anddifferentiation agent, greatly enhances theefficiency of induced pluripotent stem (iPS) cellderivation from human adult or fetal fibroblasts.After transient butyrate treatment, the iPS cellderivation efficiency is enhanced by 15- to51-fold using either retroviral or piggyBactransposon vectors expressing 4 to 5reprogramming genes. Butyrate stimulation ismore remarkable (>100- to 200-fold) onreprogramming in the absence of either KLF4 orMYC transgene. Butyrate treatment did notnegatively affect properties of iPS cell linesestablished by either 3 or 4 retroviral vectors ora single piggyBac DNA transposon vector. Thesecharacterized iPS cell lines, including thosederived from an adult patient with sickle cell", "metadata": {}}
+{"_id": "8182950", "title": "", "text": "Nanoparticle conjugation of CpG enhancesadjuvancy for cellular immunity and memoryrecall at low dose.In subunit vaccines, strongCD8(+) T-cell responses are desired, yet theyare elusive at reasonable adjuvant doses. Weshow that targeting adjuvant to the lymph node(LN) via ultrasmall polymeric nanoparticles(NPs), which rapidly drain to the LN afterintradermal injection, greatly enhances adjuvantefficacy at low doses. Coupling CpG-B or CpG-Coligonucleotides to NPs led to betterdual-targeting of adjuvant and antigen(codelivered on separate NPs) incross-presenting dendritic cells compared withfree adjuvant. This led to enhanced dendritic cellmaturation and T helper 1 (Th1)-cytokinesecretion, in turn driving stronger effectorCD8(+) T-cell activation with enhanced cytolyticprofiles and, importantly, more powerful memoryrecall. With only 4 μg CpG, NP-CpG-B couldsubstantially protect mice from syngeneic tumorchallenge, even after 4 mo of vaccination,", "metadata": {}}
+{"_id": "8185080", "title": "", "text": "Induction of pluripotent stem cells by definedfactors is greatly improved by small-moleculecompoundsReprogramming of mouse and humansomatic cells can be achieved by ectopicexpression of transcription factors, but with lowefficiencies. We report that DNAmethyltransferase and histone deacetylase(HDAC) inhibitors improve reprogrammingefficiency. In particular, valproic acid (VPA), anHDAC inhibitor, improves reprogrammingefficiency by more than 100-fold, using Oct4-GFPas a reporter. VPA also enables efficientinduction of pluripotent stem cells withoutintroduction of the oncogene c-Myc.", "metadata": {}}
+{"_id": "8190282", "title": "", "text": "Noninvasive ventilation for treatment of acuterespiratory failure in patients undergoing solidorgan transplantation: a randomizedtrial.CONTEXT Noninvasive ventilation (NIV) hasbeen associated with lower rates of endotrachealintubation in populations of patients with acuterespiratory failure. OBJECTIVE To compare NIVwith standard treatment using supplementaloxygen administration to avoid endotrachealintubation in recipients of solid organtransplantation with acute hypoxemic respiratoryfailure. DESIGN AND SETTING Prospectiverandomized study conducted at a 14-bed,general intensive care unit of a universityhospital. PATIENTS Of 238 patients whounderwent solid organ transplantation fromDecember 1995 to October 1997, 51 weretreated for acute respiratory failure. Of these, 40were eligible and 20 were randomized to eachgroup. INTERVENTION Noninvasive ventilation vsstandard treatment with supplemental oxygenadministration. MAIN OUTCOME MEASURES The", "metadata": {}}
+{"_id": "8202880", "title": "", "text": "BIOINFORMATICS APPLICATIONSNOTESUMMARY MADE4, microarray ade4, is asoftware package that facilitates multivariateanalysis of microarray gene-expression data.MADE4 accepts a wide variety ofgene-expression data formats. MADE4 takesadvantage of the extensive multivariatestatistical and graphical functions in the Rpackage ade4, extending these for application tomicroarray data. In addition, MADE4 providesnew graphical and visualization tools that aid ininterpretation of multivariate analysis ofmicroarray data.", "metadata": {}}
+{"_id": "8208212", "title": "", "text": "Dual and opposing roles of primary cilia inmedulloblastoma developmentRecent work hasshown that primary cilia are essential forHedgehog (Hh) signaling during mammaliandevelopment. It is also known that aberrant Hhsignaling can lead to cancer, but the role ofprimary cilia in oncogenesis is not known.Cerebellar granule neuron precursors (GNPs) cangive rise to medulloblastomas, the most commonmalignant brain tumor in children. The primarycilium and Hh signaling are required for GNPproliferation. We asked whether primary cilia inGNPs have a role in medulloblastoma growth inmice. Genetic ablation of primary cilia blockedmedulloblastoma formation when this tumor wasdriven by a constitutively active Smoothenedprotein (Smo), an upstream activator of Hhsignaling. In contrast, removal of cilia wasrequired for medulloblastoma growth by aconstitutively active glioma-associated oncogenefamily zinc finger-2 (GLI2), a downstreamtranscription factor. Thus, primary cilia are either", "metadata": {}}
+{"_id": "8210189", "title": "", "text": "RAS genes in Saccharomyces cerevisiae: signaltransduction in search of a pathway.Ras proteinsin budding yeasts initially appeared to regulateinitiation of the cell cycle in response to nutrientavailability. More recent work, while clarifyingthe mechanism of Ras-mediated signaltransduction, has undermined our notion of thesignal Ras transmits. We now suspect that Rashelps to coordinate cellular metabolism and massaccumulation, but what Ras responds to is notclear.", "metadata": {}}
+{"_id": "8219248", "title": "", "text": "Use of synthetic peptides to locate novel integrinalpha2beta1-binding motifs in human collagenIII.A set of 57 synthetic peptides encompassingthe entire triplehelical domain of human collagenIII was used to locate binding sites for thecollagen-binding integrin alpha(2)beta(1). Thecapacity of the peptides to supportMg(2+)-dependent binding of several integrinpreparations was examined. Wild-type integrins(recombinant alpha(2) I-domain,alpha(2)beta(1) purified from plateletmembranes, and recombinant solublealpha(2)beta(1) expressed as analpha(2)-Fos/beta(1)-Jun heterodimer) boundwell to only three peptides, two containingGXX'GER motifs (GROGER and GMOGER, whereO is hydroxyproline) and one containing twoadjacent GXX'GEN motifs (GLKGEN andGLOGEN). Two mutant alpha(2) I-domains weretested: the inactive T221A mutant, whichrecognized no peptides, and the constitutivelyactive E318W mutant, which bound a larger", "metadata": {}}
+{"_id": "8227227", "title": "", "text": "Locations of cerebral infarctions in tuberculousmeningitisThe locations of cerebral infarctionswere studied in 14 patients with tuberculousmeningitis (TBM) and 173 patients withnoninflammatory ischemic stroke (IS). Inpatients with TBM, 75% of infarctions occurred inthe “TB zone” supplied by medial striate andthalamoperforating arteries; only 11% occurredin the “IS zone” supplied by lateral striate,anterior choroidal and thalamogeniculatearteries. In patients with IS 29% of infarctionsoccurred in the IS zone, 29% in the subcorticalwhite matter, and 24% in (or involving) thecerebral cortex. Only 11% occurred in the TBzone. Bilaterally symmetrical infarctions of theTB zone were common with TMB (71%) but rarewith IS (5%).", "metadata": {}}
+{"_id": "8246090", "title": "", "text": "TRP channels of intracellular membranes.Ionchannels are classically understood to regulatethe flux of ions across the plasma membrane inresponse to a variety of environmental andintracellular cues. Ion channels serve a numberof functions in intracellular membranes as well.These channels may be temporarily localized tointracellular membranes as a function of theirbiosynthetic or secretory pathways, i.e., en routeto their destination location. Intracellularmembrane ion channels may also be located inthe endocytic pathways, either being recycledback to the plasma membrane or targeted to thelysosome for degradation. Several channels doparticipate in intracellular signal transduction;the most well known example is the inositol1,4,5-trisphosphate receptor (IP(3)R) in theendoplasmic reticulum. Some organellarintracellular membrane channels are required forthe ionic homeostasis of their residingorganelles. Several newly-discoveredintracellular membrane Ca(2+) channels actually", "metadata": {}}
+{"_id": "8246922", "title": "", "text": "the Development of Autoimmune Myocarditis inMice by anBACKGROUND Interleukin (IL)-12exerts a potent proinflammatory effect bystimulating T-helper (Th) 1 responses. This effectis believed to be mediated primarily through theactivation of STAT4 and subsequent productionof interferon (IFN)-gamma. Methods andResults- We examined the role of IL-12 receptor(IL-12R) signaling in the development of murineexperimental autoimmune myocarditis (EAM)induced by cardiac myosin immunization. BothIL-12Rbeta1-deficient mice and STAT4-deficientmice were resistant to the induction ofmyocarditis. Treatment with exogenous IL-12exacerbated disease. We questioned whetherIFN-gamma is required for thedisease-promoting activity of IL-12. On thecontrary, we found that IFN-gamma suppressesEAM. Lack of IFN-gamma due to either depletionwith an antibody or a genetic deficiencyexacerbated myocarditis. Spleens fromIFN-gamma-deficient mice immunized with", "metadata": {}}
+{"_id": "8247469", "title": "", "text": "The Viral and Cellular MicroRNA Targetome inLymphoblastoid Cell LinesEpstein-Barr virus(EBV) is a ubiquitous human herpesvirus linkedto a number of B cell cancers andlymphoproliferative disorders. During latentinfection, EBV expresses 25 viral pre-microRNAs(miRNAs) and induces the expression of specifichost miRNAs, such as miR-155 and miR-21,which potentially play a role in viral oncogenesis.To date, only a limited number of EBV miRNAtargets have been identified; thus, the role ofEBV miRNAs in viral pathogenesis and/orlymphomagenesis is not well defined. Here, weused photoactivatable ribonucleoside-enhancedcrosslinking and immunoprecipitation (PAR-CLIP)combined with deep sequencing andcomputational analysis to comprehensivelyexamine the viral and cellular miRNA targetomein EBV strain B95-8-infected lymphoblastoid celllines (LCLs). We identified 7,827miRNA-interaction sites in 3,492 cellular 3'UTRs.531 of these sites contained seed matches to", "metadata": {}}
+{"_id": "8247597", "title": "", "text": "Mitochondrial Dysfunction Leads to NuclearGenome Instability via an Iron-Sulfur ClusterDefectMutations and deletions in themitochondrial genome (mtDNA), as well asinstability of the nuclear genome, are involved inmultiple human diseases. Here, we report that inSaccharomyces cerevisiae, loss of mtDNA leadsto nuclear genome instability, through a processof cell-cycle arrest and selection we define as acellular crisis. This crisis is not mediated by theabsence of respiration, but instead correlateswith a reduction in the mitochondrial membranepotential. Analysis of cells undergoing this crisisidentified a defect in iron-sulfur cluster (ISC)biogenesis, which requires normal mitochondrialfunction. We found that downregulation ofnonmitochondrial ISC protein biogenesis wassufficient to cause increased genomic instabilityin cells with intact mitochondrial function. Theseresults suggest mitochondrial dysfunctionstimulates nuclear genome instability byinhibiting the production of ISC-containing", "metadata": {}}
+{"_id": "8250852", "title": "", "text": "Replisome stall events have shaped thedistribution of replication origins in the genomesof yeastsDuring S phase, the entire genomemust be precisely duplicated, with no sections ofDNA left unreplicated. Here, we develop a simplemathematical model to describe the probabilityof replication failing due to the irreversiblestalling of replication forks. We show that theprobability of complete genome replication ismaximized if replication origins are evenlyspaced, the largest inter-origin distances areminimized, and the end-most origins arepositioned close to chromosome ends. We showthat origin positions in the yeast Saccharomycescerevisiae genome conform to all threepredictions thereby maximizing the probability ofcomplete replication if replication forks stall.Origin positions in four otheryeasts-Kluyveromyces lactis, Lachancea kluyveri,Lachancea waltii and Schizosaccharomycespombe-also conform to these predictions.Equating failure rates at chromosome ends with", "metadata": {}}
+{"_id": "8267678", "title": "", "text": "Regulation of chromatin by histonemodificationsChromatin is not an inert structure,but rather an instructive DNA scaffold that canrespond to external cues to regulate the manyuses of DNA. A principle component of chromatinthat plays a key role in this regulation is themodification of histones. There is anever-growing list of these modifications and thecomplexity of their action is only just beginningto be understood. However, it is clear thathistone modifications play fundamental roles inmost biological processes that are involved in themanipulation and expression of DNA. Here, wedescribe the known histone modifications, definewhere they are found genomically and discusssome of their functional consequences,concentrating mostly on transcription where themajority of characterisation has taken place.", "metadata": {}}
+{"_id": "8290760", "title": "", "text": "Single-Cell Expression Analyses during CellularReprogramming Reveal an Early Stochastic and aLate Hierarchic PhaseDuring cellularreprogramming, only a small fraction of cellsbecome induced pluripotent stem cells (iPSCs).Previous analyses of gene expression duringreprogramming were based on populations ofcells, impeding single-cell level identification ofreprogramming events. We utilized two geneexpression technologies to profile 48 genes insingle cells at various stages during thereprogramming process. Analysis of early stagesrevealed considerable variation in geneexpression between cells in contrast to latestages. Expression of Esrrb, Utf1, Lin28, andDppa2 is a better predictor for cells to progressinto iPSCs than expression of the previouslysuggested reprogramming markers Fbxo15,Fgf4, and Oct4. Stochastic gene expression earlyin reprogramming is followed by a latehierarchical phase with Sox2 being the upstreamfactor in a gene expression hierarchy. Finally,", "metadata": {}}
+{"_id": "8290953", "title": "", "text": "Scaffold-based three-dimensional humanfibroblast culture provides a structural matrixthat supports angiogenesis in infarcted hearttissue.BACKGROUND We have developedtechniques to implant angiogenic patches ontothe epicardium over regions of infarcted cardiactissue to stimulate revascularization of thedamaged tissue. These experiments used ascaffold-based 3D human dermal fibroblastculture (3DFC) as an epicardial patch. The 3DFCcontains viable cells that secrete angiogenicgrowth factors and has previously been shown tostimulate angiogenic activity. The hypothesistested was that a viable 3DFC cardiac patchwould stimulate an angiogenic response withinan area of infarcted cardiac tissue. METHODSAND RESULTS A coronary occlusion of a branchof the left anterior descending coronary arterywas performed by thermal ligation in severecombined immunodeficient mice. 3DFCs with orwithout viable cells were sized to the damagedarea, implanted in replicate mice onto the", "metadata": {}}
+{"_id": "8294009", "title": "", "text": "Global tuberculosis control: lessons learnt andfuture prospectsTuberculosis (TB) is an ancientdisease, but not a disease of the past. Afterdisappearing from the world public healthagenda in the 1960s and 1970s, TB returned inthe early 1990s for several reasons, including theemergence of the HIV/AIDS pandemic andincreases in drug resistance. More than 100years after the discovery of the tubercle bacillusby Robert Koch, what is the status of TB controlworldwide? Here, we review the evolution ofglobal TB control policies, including DOTS(directly observed therapy, short course) and theStop TB Strategy, and assess whether thechallenges and obstacles faced by the publichealth community worldwide in developing andimplementing this strategy can aid future actiontowards the elimination of TB.", "metadata": {}}
+{"_id": "8298120", "title": "", "text": "Global prevalence of glaucoma and projections ofglaucoma burden through 2040: a systematicreview and meta-analysis.PURPOSE Glaucoma isthe leading cause of global irreversible blindness.Present estimates of global glaucoma prevalenceare not up-to-date and focused mainly onEuropean ancestry populations. Wesystematically examined the global prevalence ofprimary open-angle glaucoma (POAG) andprimary angle-closure glaucoma (PACG), andprojected the number of affected people in 2020and 2040. DESIGN Systematic review andmeta-analysis. PARTICIPANTS Data from 50population-based studies (3770 POAG casesamong 140,496 examined individuals and 786PACG cases among 112 398 examinedindividuals). METHODS We searched PubMed,Medline, and Web of Science forpopulation-based studies of glaucoma prevalencepublished up to March 25, 2013. HierarchicalBayesian approach was used to estimate thepooled glaucoma prevalence of the population", "metadata": {}}
+{"_id": "8300657", "title": "", "text": "Gastrointestinal tract as a major site of CD4+ Tcell depletion and viral replication in SIVinfection.Human and simian immunodeficiencyvirus (HIV and SIV) replicate optimally inactivated memory CD4(+) T cells, a cell typethat is abundant in the intestine. SIV infection ofrhesus monkeys resulted in profound andselective depletion of CD4+ T cells in theintestine within days of infection, before anysuch changes in peripheral lymphoid tissues. Theloss of CD4+ T cells in the intestine occurredcoincident with productive infection of largenumbers of mononuclear cells at this site. Theintestine appears to be a major target for SIVreplication and the major site of CD4+ T cell lossin early SIV infection.", "metadata": {}}
+{"_id": "8305686", "title": "", "text": "Interaction of streptavidin-based peptide-MHColigomers (tetramers) with cell-surface TCRs.Thebinding of oligomeric peptide-MHC (pMHC)complexes to cell surface TCR can be consideredto approximate TCR-pMHC interactions atcell-cell interfaces. In this study, we analyzed theequilibrium binding of streptavidin-based pMHColigomers (tetramers) and their dissociationkinetics from CD8(pos) T cells from 2C-TCRtransgenic mice and from T cell hybridomas thatexpressed the 2C TCR or a high-affinity mutant(m33) of this TCR. Our results show that thetetramers did not come close to saturatingcell-surface TCR (binding only 10-30% ofcell-surface receptors), as is generally assumedin deriving affinity values (K(D)), in part becauseof dissociative losses from tetramer-stained cells.Guided by a kinetic model, the oligomerdissociation rate and equilibrium constants wereseen to depend not only on monovalentassociation and dissociation rates (k(off) andk(on)), but also on a multivalent association rate", "metadata": {}}
+{"_id": "8317408", "title": "", "text": "Human monocyte characteristics are altered inhypercholesterolaemia.Peripheral bloodmonocytes are involved during atherogenesis inadhering to endothelium, migrating into thesubendothelial space and taking-up lipoproteinsto become macrophage/foam cells. We haveassessed whether peripheral blood monocytecharacteristics are altered in humanhyperlipidaemia in age/sex/smoking statusmatched pairs of patients and controls.Monocytes from the hypercholesterolaemicpatients, as opposed to the controls, were moresensitive to stimulation by the agonist,N-formyl-methionyl-leucyl-phenylalanine, withrespect to chemokinesis (stimulation index 1.48+/- 0.17 vs. 1.10 +/- 0.14), chemotaxis (4.05+/- 0.55 vs. 2.72 +/- 0.24) and adhesion toporcine aortic endothelial monolayers (1.26 +/-0.05 vs. 1.17 +/- 0.06). The patients' monocytetotal surface expression of the adhesionglycoprotein CD11b/CD18 (37.5 +/- 7.1 vs. 36.0+/- 7.1), but not CD11c/CD18 (31.6 +/- 7.2 vs.", "metadata": {}}
+{"_id": "8318286", "title": "", "text": "Adult Mammalian Neural Stem Cells andNeurogenesis: Five Decades Later.Adult somaticstem cells in various organs maintainhomeostatic tissue regeneration and enhanceplasticity. Since its initial discovery five decadesago, investigations of adult neurogenesis andneural stem cells have led to an established andexpanding field that has significantly influencedmany facets of neuroscience, developmentalbiology, and regenerative medicine. Here wereview recent progress and focus on questionsrelated to adult mammalian neural stem cellsthat also apply to other somatic stem cells. Wefurther discuss emerging topics that are guidingthe field toward better understanding adultneural stem cells and ultimately applying theseprinciples to improve human health.", "metadata": {}}
+{"_id": "8318922", "title": "", "text": "Relationship of ambulatory blood pressure andthe heart rate profile with renal functionparameters in hypertensive patients with chronickidney disease.Strict blood pressure (BP) controlis reportedly important for the management ofhypertensive patients with chronic kidneydisease (CKD). The purpose of thiscross-sectional study was to examine whetherthe variables of ambulatory BP and the heartrate (HR) profile, central hemodynamics, andarterial stiffness were closely related to the renalfunction parameters (urine albumin excretionrate [UACR] and estimated glomerular filtrationrate [eGFR]) observed in 25 consecutivehospitalized hypertensive patients with CKD.There were significant positive relationshipsbetween UACR and 24-hour, daytime, andnighttime ambulatory systolic BP. In addition,there were significant negative relationshipsbetween UACR and 24-hour and daytime HRvariability. The circulating B-type natriureticpeptide level and hemoglobin A1c were also", "metadata": {}}
+{"_id": "8325952", "title": "", "text": "The frequency and immunodominance ofislet-specific CD8+ T-cell responses change aftertype 1 diabetes diagnosis andtreatment.OBJECTIVE Islet-reactive CD8(+)T-cells play a key role in the pathogenesis oftype 1 diabetes in the NOD mouse. Thepredominant T-cell specificities change overtime, but whether similar shifts also occur afterclinical diagnosis and insulin treatment in type 1diabetic patients is unknown. RESEARCH DESIGNAND METHODS We took advantage of a recentlyvalidated islet-specific CD8(+) T-cellgamma-interferon enzyme-linked immunospot(ISL8Spot) assay to follow responses againstpreproinsulin (PPI), GAD, insulinoma-associatedprotein 2 (IA-2), and islet-specificglucose-6-phosphatase catalytic subunit-relatedprotein (IGRP) epitopes in 15 HLA-A2(+) adulttype 1 diabetic patients close to diagnosis and ata second time point 7-16 months later. RESULTSCD8(+) T-cell reactivities were less frequent atfollow-up, as 28.6% of responses tested positive", "metadata": {}}
+{"_id": "8327914", "title": "", "text": "A Protein Inventory of Human RibosomeBiogenesis Reveals an Essential Function ofExportin 5 in 60S Subunit ExportThe assembly ofribosomal subunits in eukaryotes is a complex,multistep process so far mostly studied in yeast.In S. cerevisiae, more than 200 factors includingribosomal proteins and trans-acting factors arerequired for the ordered assembly of 40S and60S ribosomal subunits. To date, only fewhuman homologs of these yeast ribosomesynthesis factors have been characterized. Here,we used a systematic RNA interference (RNAi)approach to analyze the contribution of 464candidate factors to ribosomal subunit biogenesisin human cells. The screen was based on visualreadouts, using inducible, fluorescent ribosomalproteins as reporters. By performingcomputer-based image analysis utilizingsupervised machine-learning techniques, weobtained evidence for a functional link of 153human proteins to ribosome synthesis. Our datashow that core features of ribosome assembly", "metadata": {}}
+{"_id": "8331432", "title": "", "text": "Binding of the winged-helix transcription factorHNF3 to a linker histone site on thenucleosome.The transcription factor HNF3 andlinker histones H1 and H5 possess winged-helixDNA-binding domains, yet HNF3 and other forkhead-related proteins activate genes duringdevelopment whereas linker histones compactDNA in chromatin and repress gene expression.We compared how the two classes of factorsinteract with chromatin templates and found thatHNF3 binds DNA at the side of nucleosome cores,similarly to what has been reported for linkerhistone. A nucleosome structural binding site forHNF3 is occupied at the albumin transcriptionalenhancer in active and potentially activechromatin, but not in inactive chromatin in vivo.While wild-type HNF3 protein does not compactDNA extending from the nucleosome, as doeslinker histone, site-directed mutants of HNF3 cancompact nucleosomal DNA if they contain basicamino acids at positions previously shown to beessential for nucleosomal DNA compaction by", "metadata": {}}
+{"_id": "8352137", "title": "", "text": "Rapid recent growth and divergence of ricenuclear genomes.By employing the nuclear DNAof the African rice Oryza glaberrima as areference genome, the timing, natures,mechanisms, and specificities of recent sequenceevolution in the indica and japonica subspecies ofOryza sativa were identified. The data indicatethat the genome sizes of both indica andjaponica have increased substantially, >2% and>6%, respectively, since their divergence from acommon ancestor, mainly because of theamplification of LTR-retrotransposons. However,losses of all classes of DNA sequence throughunequal homologous recombination andillegitimate recombination have attenuated thegrowth of the rice genome. Small deletions havebeen particularly frequent throughout thegenome. In >1 Mb of orthologous regions thatwe analyzed, no cases of complete geneacquisition or loss from either indica or japonicawere found, nor was any example of precisetransposon excision detected. The sequences", "metadata": {}}
+{"_id": "8354687", "title": "", "text": "Detection of an autoreactive T-cell populationwithin the polyclonal repertoire that undergoesdistinct autoimmune regulator (Aire)-mediatedselection.The autoimmune regulator (Aire) playsa critical role in central tolerance by promotingthe display of tissue-specific antigens in thethymus. To study the influence of Aire on thymicselection in a physiological setting, we usedtetramer reagents to detect autoreactive T cellsspecific for the Aire-dependent tissue-specificantigen interphotoreceptor retinoid-bindingprotein (IRBP), in the polyclonal repertoire. Twoclass II tetramer reagents were designed toidentify T cells specific for two different peptideepitopes of IRBP. Analyses of the polyclonalT-cell repertoire showed a high frequency ofactivated T cells specific for both IRBP tetramersin Aire(-/-) mice, but not in Aire(+/+) mice.Surprisingly, although one tetramer-bindingT-cell population was efficiently deleted in thethymus in an Aire-dependent manner, thesecond tetramer-binding population was not", "metadata": {}}
+{"_id": "8373753", "title": "", "text": "Spatial and temporal heterogeneity of Anophelesmosquitoes and Plasmodium falciparumtransmission along the Kenyan coast.Theseasonal dynamics and spatial distributions ofAnopheles mosquitoes and Plasmodiumfalciparum parasites were studied for one year at30 villages in Malindi, Kilifi, and Kwale Districtsalong the coast of Kenya. Anopheline mosquitoeswere sampled inside houses at each site onceevery two months and malaria parasiteprevalence in local school children wasdetermined at the end of the entomologicsurvey. A total of 5,476 Anopheles gambiae s.l.and 3,461 An. funestus were collected. Speciesin the An. gambiae complex, identified by apolymerase chain reaction, included 81.9% An.gambiae s.s., 12.8% An. arabiensis, and 5.3%An. merus. Anopheles gambiae s.s. contributedmost to the transmission of P. falciparum alongthe coast as a whole, while An. funestusaccounted for more than 50% of all transmissionin Kwale District. Large spatial heterogeneity of", "metadata": {}}
+{"_id": "8385277", "title": "", "text": "Myelodysplasia and leukemia of Fanconi anemiaare associated with a specific pattern of genomicabnormalities that includes cryptic RUNX1/AML1lesions.Fanconi anemia (FA) is a geneticcondition associated with bone marrow (BM)failure, myelodysplasia (MDS), and acutemyeloid leukemia (AML). We studied 57 FApatients with hypoplastic or aplastic anemia (n =20), MDS (n = 18), AML (n = 11), or no BMabnormality (n = 8). BM samples were analyzedby karyotype, high-density DNA arrays withrespect to paired fibroblasts, and by selectedoncogene sequencing. A specific pattern ofchromosomal abnormalities was found inMDS/AML, which included 1q+ (44.8%), 3q+(41.4%), -7/7q (17.2%), and 11q- (13.8%).Moreover, cryptic RUNX1/AML1 lesions(translocations, deletions, or mutations) wereobserved for the first time in FA (20.7%). Raremutations of NRAS, FLT3-ITD, MLL-PTD, ERGamplification, and ZFP36L2-PRDM16translocation, but no TP53, TET2, CBL, NPM1,", "metadata": {}}
+{"_id": "8386609", "title": "", "text": "Molecular and Cellular Approaches forDiversifying and ExtendingOptogeneticsOptogenetic technologies employlight to control biological processes withintargeted cells in vivo with high temporalprecision. Here, we show that application ofmolecular trafficking principles can expand theoptogenetic repertoire along several long-soughtdimensions. Subcellular and transcellulartrafficking strategies now permit (1) opticalregulation at the far-red/infrared border andextension of optogenetic control across the entirevisible spectrum, (2) increased potency of opticalinhibition without increased light powerrequirement (nanoampere-scalechloride-mediated photocurrents that maintainthe light sensitivity and reversible, step-likekinetic stability of earlier tools), and (3)generalizable strategies for targeting cells basednot only on genetic identity, but also onmorphology and tissue topology, to allowversatile targeting when promoters are not", "metadata": {}}
+{"_id": "8396189", "title": "", "text": "An analysis of the Caenorhabditis elegans lipidraft proteome using geLC-MS/MS.Lipid rafts aremicrodomains of the phospholipid bilayer,proposed to form semi-stable \"islands\" that actas a platform for several important cellularprocesses; major classes of raft-resident proteinsinclude signalling proteins andglycosylphosphatidylinositol (GPI)-anchoredproteins. Proteomic studies into lipid rafts havebeen mainly carried out in mammalian cell linesand single cell organisms. The nematodeCaenorhabditis elegans, the model organism witha well-defined developmental profile, is ideallysuited for the study of this subcellular locale in acomplex developmental context. A study of thelipid raft proteome of C. elegans is presentedhere. A total of 44 proteins were identified fromthe lipid raft fraction using geLC-MS/MS, ofwhich 40 have been determined to be likely raftproteins after analysis of predicted functions.Prediction of GPI-anchoring of the proteins found21 to be potentially modified in this way, two of", "metadata": {}}
+{"_id": "8398627", "title": "", "text": "Geographic distribution of community-acquiredmethicillin-resistant Staphylococcus aureus softtissue infections.PURPOSE The goal of this studyis to look at the geographic growth patterns ofcommunity-acquired methicillin-resistantStaphylococcus aureus (MRSA) infections in ourlocal region and to determine if specificgeographic areas are at increased risk.METHODS After Institution Review Boardapproval (132603-3), a retrospective chartreview was conducted of 614 patients whounderwent incision and drainage of an abscessby a single pediatric surgical practice fromJanuary 2004 to December 2008. In addition,previously published data from 195 patients whounderwent incision and drainage of an abscessfrom January 2000 to December 2003 werereviewed. RESULTS The most commonly culturedorganism found in the pediatric populationundergoing incision and drainage was S aureus(n = 388), of which 258 (66%) were methicillinresistant. This is a 21% increase from the rate of", "metadata": {}}
+{"_id": "8411251", "title": "", "text": "The right place at the right time: chaperoningcore histone variants.Histone proteinsdynamically regulate chromatin structure andepigenetic signaling to maintain cellhomeostasis. These processes require controlledspatial and temporal deposition and eviction ofhistones by their dedicated chaperones. With theevolution of histone variants, a network offunctionally specific histone chaperones hasemerged. Molecular details of the determinantsof chaperone specificity for different histonevariants are only slowly being resolved. Acomplete understanding of these processes isessential to shed light on the genuine biologicalroles of histone variants, their chaperones, andtheir impact on chromatin dynamics.", "metadata": {}}
+{"_id": "8417211", "title": "", "text": "Phosphorylation site mutations inheterochromatin protein 1 (HP1) reduce oreliminate silencing activity.HP1 is an essentialheterochromatin-associated protein inDrosophila. HP1 has dosage-dependent effectson the silencing of euchromatic genes that aremislocalized to heterochromatin and is requiredfor the normal expression of at least twoheterochromatic genes. HP1 is multiplyphosphorylated in vivo, and HP1hyperphosphorylation is correlated withheterochromatin assembly during development.The purpose of this study was to test whetherHP1 phosphorylation modifies biological activityand biochemical properties of HP1. To determinesites of HP1 phosphorylation in vivo and whetherphosphorylation affects any biochemicalproperties of HP1, we expressed Drosophila HP1in lepidopteran cultured cells using arecombinant baculovirus vector.Phosphopeptides were identified bymatrix-assisted laser desorption ionization/time", "metadata": {}}
+{"_id": "8425533", "title": "", "text": "Elimination of paternal mitochondria in mouseembryos occurs through autophagic degradationdependent on PARKIN and MUL1A definingfeature of mitochondria is their maternal mode ofinheritance. However, little is understood aboutthe cellular mechanism through which paternalmitochondria, delivered from sperm, areeliminated from early mammalian embryos.Autophagy has been implicated in nematodes,but whether this mechanism is conserved inmammals has been disputed. Here, we show thatcultured mouse fibroblasts and pre-implantationembryos use a common pathway for eliminationof mitochondria. Both situations utilizemitophagy, in which mitochondria aresequestered by autophagosomes and deliveredto lysosomes for degradation. The E3 ubiquitinligases PARKIN and MUL1 play redundant roles inelimination of paternal mitochondria. Theprocess is associated with depolarization ofpaternal mitochondria and additionally requiresthe mitochondrial outer membrane protein FIS1,", "metadata": {}}
+{"_id": "8426046", "title": "", "text": "Ribosome Profiling Provides Evidence that LargeNoncoding RNAs Do Not Encode ProteinsLargenoncoding RNAs are emerging as an importantcomponent in cellular regulation. Considerableevidence indicates that these transcripts actdirectly as functional RNAs rather than throughan encoded protein product. However, a recentstudy of ribosome occupancy reported that manylarge intergenic ncRNAs (lincRNAs) are bound byribosomes, raising the possibility that they aretranslated into proteins. Here, we show thatclassical noncoding RNAs and 5' UTRs show thesame ribosome occupancy as lincRNAs,demonstrating that ribosome occupancy alone isnot sufficient to classify transcripts as coding ornoncoding. Instead, we define a metric based onthe known property of translation wherebytranslating ribosomes are released uponencountering a bona fide stop codon. We showthat this metric accurately discriminates betweenprotein-coding transcripts and all classes ofknown noncoding transcripts, including lincRNAs.", "metadata": {}}
+{"_id": "8427306", "title": "", "text": "Isolation of a Fusion Transcript, AMLl IETO, WithSimilarity toWe have developed a restriction mapof the chromosome 21 breakpoint regioninvolved in t(8;21)(q22;q22.3) acutemyelogenous leukemia (AML) and have isolateda genomic junction clone containing chromosome8 and 21 material. Using probes from theseregions, rearrangements have been identified ineach of nine cases of t(8;21) AML examined. Inaddition, we have isolated cDNA clones from at(8;21) AML cDNA library that contain fusedsequences from chromosome 8 and 21. Thechromosome 8 component, referred to as ETO(for eight twenty-one), is encoded over a largegenomic region, as suggested by the analysis ofcorresponding yeast artificial chromosomes(YACs). The DNA sequence of the chromosome21 portion of the fusion transcript is derived fromthe normal AML1 gene. A striking similarity (67%identity over 387 bp, with a corresponding 69%amino acid identity) was detected between AML1and the Drosophila segmentation gene, runt. The", "metadata": {}}
+{"_id": "8428837", "title": "", "text": "Treatment of spondyloarthropathy with5-aminosalicylic acid (mesalazine): an opentrial.OBJECTIVE Ankylosing spondylitis (AS) andspondyloarthropathy (SpA) are inflammatorydiseases of unknown etiology. Variousexogenous and endogenous (inherited) factorsplay a role in their development. Sulfasalazine(SSZ) is generally accepted as a diseasemodifying drug in the treatment of AS and SpA.Which part of SSZ, 5-acetylsalicylic acid (5-ASA,mesalazine) or sulfapyridine (SP), is the effectivemoiety is unknown. As the bowel, colon, and theileum play an important role in the developmentof AS and SpA, it may be possible that 5-ASA isthe effective moiety, with a similar mode ofaction as in the treatment of inflammatory boweldisease. To determine the efficacy of 5-ASA anopen pilot study was done in 2 groups of patientswith SpA.   METHODS Twenty patients with SpA,who were taking SSZ, were switched to 5-ASA(Pentasa), and 19 patients with active SpA weretreated with 5-ASA without previous", "metadata": {}}
+{"_id": "8428935", "title": "", "text": "Relationship of physical activity and televisionwatching with body weight and level of fatnessamong children: results from the Third NationalHealth and Nutrition ExaminationSurvey.CONTEXT Physical inactivity contributesto weight gain in adults, but whether thisrelationship is true for children of different ethnicgroups is not well established. OBJECTIVE Toassess participation in vigorous activity andtelevision watching habits and their relationshipto body weight and fatness in US children.DESIGN Nationally representative cross-sectionalsurvey with an in-person interview and medicalexamination. SETTING AND PARTICIPANTSBetween 1988 and 1994, 4063 children aged 8through 16 years were examined as part of theNational Health and Nutrition ExaminationSurvey III. Mexican Americans and non-Hispanicblacks were oversampled to produce reliableestimates for these groups. MAIN OUTCOMEMEASURES Episodes of weekly vigorous activityand daily hours of television watched, and their", "metadata": {}}
+{"_id": "8446259", "title": "", "text": "Vascular Calcification in Chronic Kidney Diseaseis Induced by Bone Morphogenetic Protein-2 viaa Mechanism Involving the Wnt/β-CateninPathwayBackground: Vascular calcification (VC),in which vascular smooth muscle cells (VSMCs)undergo a phenotypic transformation intoosteoblast-like cells, is one of the emergent riskfactors for the accelerated atherosclerosisprocess characteristic of chronic kidney disease(CKD). Phosphate is an important regulator ofVC. Methods: The expression of different smoothmuscle cell or osteogenesis markers in responseto high concentrations of phosphate orexogenous bone morphogenetic protein 2(BMP-2) was examined by qRT-PCR and westernblotting in rat VSMCs. Osteocalcin secretion wasmeasured by radioimmunoassay. Differentiationand calcification of VSMCs were examined byalkaline phosphatase (ALP) activity assay andAlizarin staining. Short hairpin RNA-mediatedsilencing of β-catenin was performed to examinethe involvement of Wnt/β-catenin signaling in", "metadata": {}}
+{"_id": "8446324", "title": "", "text": "Advances in brain tumor surgery.Advances in thefields of molecular and translational research,oncology, and surgery have emboldened themedical community to believe that intrinsic braintumors may be treatable. Intraoperative imagingand brain mapping allow operations adjacent toeloquent cortex and more radical resection oftumors with increased confidence and safety.Despite these advances, the infiltrating edge of aneoplasm and distant microscopic satellitelesions will never be amendable to a surgicalcure. Indeed, it is continued research into thedelivery of an efficacious chemobiologic agentthat will eventually allows us to manage thisprimary cause of treatment failure.", "metadata": {}}
+{"_id": "8447873", "title": "", "text": "Systematic review of controlled clinical trials ofgastric lavage in acute organophosphoruspesticide poisoning.BACKGROUNDOrganophosphorus pesticide (OP) self-poisoningis a major problem in the developing rural world.There is little clinical trial data to guide therapy,hindering the identification of best therapy.Despite the recognition of adverse effects,gastric lavage is commonly done in Asia. Weaimed to identify studies assessing itseffectiveness. METHOD We systematicallysearched the literature for controlled clinicalstudies that assessed the effect of gastric lavagein OP pesticide self-poisoning. RESULTS All 56studies identified were Chinese and reportedbenefit from the intervention studied, includingmultiple gastric lavages, use of norepinephrineor pralidoxime in the lavage fluid, concurrenttreatment with naloxone or scopolamine,insertion of the gastric tube via a laparotomyincision, and lavage later than 12 hpost-ingestion. However, only 23 were RCTs and", "metadata": {}}
+{"_id": "8453819", "title": "", "text": "Integrin activation by Fam38A uses a novelmechanism of R-Ras targeting to theendoplasmic reticulum.The integrin family ofheterodimeric cell-surface receptors arefundamental in cell-cell and cell-matrix adhesion.Changes to either integrin-ligand affinity orintegrin gene expression are central to a varietyof disease processes, including inflammation,cardiovascular disease and cancer. In screeningfor novel activators of integrin-ligand affinity weidentified the previously uncharacterisedmulti-transmembrane domain protein Fam38A,located at the endoplasmic reticulum (ER). siRNAknockdown of Fam38A in epithelial cellsinactivates endogenous beta1 integrin, reducingcell adhesion. Fam38A mediates integrinactivation by recruiting the small GTPase R-Rasto the ER, which activates the calcium-activatedprotease calpain by increasing Ca(2+) releasefrom cytoplasmic stores. Fam38A-inducedintegrin activation is blocked by inhibition ofeither R-Ras or calpain activity, or by siRNA", "metadata": {}}
+{"_id": "8458567", "title": "", "text": "Convergence of 9-cis retinoic acid andperoxisome proliferator signalling pathwaysthrough heterodimer formation of theirreceptorsPEROXISOMES are cytoplasmicorganelles which are important in mammals inmodulation of lipid homeostasis, including themetabolism of long-chain fatty acids andconversion of cholesterol to bile salts (reviewedin refs 1 and 2). Amphipathic carboxylates suchas clofibric acid have been used in man ashypolipidaemic agents and in rodents theystimulate the proliferation of peroxisomes. Theseagents, termed peroxisome proliferators, andall-trans retinoic acid activate genes involved inperoxisomal-mediated β-oxidation of fattyacids1–4. Here we show that the receptoractivated by peroxisome proliferators5 and theretinoid X receptor-α (ref. 6) form a heterodimerthat activates acyl-CoA oxidase gene expressionin response to either clofibric acid or the retinoidX receptor-α ligand, 9-cis retinoic acid, anall-trans retinoic acid metabolite7,8;", "metadata": {}}
+{"_id": "8460275", "title": "", "text": "The Utilization of Extracellular Proteins asNutrients Is Suppressed by mTORC1Despitebeing surrounded by diverse nutrients,mammalian cells preferentially metabolizeglucose and free amino acids. Recently,Ras-induced macropinocytosis of extracellularproteins was shown to reduce a transformedcell's dependence on extracellular glutamine.Here, we demonstrate that proteinmacropinocytosis can also serve as an essentialamino acid source. Lysosomal degradation ofextracellular proteins can sustain cell survivaland induce activation of mTORC1 but fails toelicit significant cell accumulation. Unlike itsgrowth-promoting activity underamino-acid-replete conditions, we discoveredthat mTORC1 activation suppresses proliferationwhen cells rely on extracellular proteins as anamino acid source. Inhibiting mTORC1 results inincreased catabolism of endocytosed proteinsand enhances cell proliferation duringnutrient-depleted conditions in vitro and within", "metadata": {}}
+{"_id": "8476213", "title": "", "text": "A general model to explore complex dominancepatterns in plant sporophytic self-incompatibilitysystems.We developed a general model ofsporophytic self-incompatibility under negativefrequency-dependent selection allowing complexpatterns of dominance among alleles. We usedthis model deterministically to investigate theeffects on equilibrium allelic frequencies of thenumber of dominance classes, the number ofalleles per dominance class, the asymmetry indominance expression between pollen and pistil,and whether selection acts on male fitness onlyor both on male and on female fitnesses. Weshow that the so-called \"recessive effect\" occursunder a wide variety of situations. We foundemerging properties of finite population modelswith several alleles per dominance class such asthat higher numbers of alleles are maintained inmore dominant classes and that the number ofdominance classes can evolve. We alsoinvestigated the occurrence of homozygousgenotypes and found that substantial proportions", "metadata": {}}
+{"_id": "8477699", "title": "", "text": "Metabolic Reprograming in MacrophagePolarizationStudying the metabolism of immunecells in recent years has emphasized the tightlink existing between the metabolic state and thephenotype of these cells. Macrophages inparticular are a good example of thisphenomenon. Whether the macrophage obtainsits energy through glycolysis or throughoxidative metabolism can give rise to differentphenotypes. Classically activated or M1macrophages are key players of the first line ofdefense against bacterial infections and areknown to obtain energy through glycolysis.Alternatively activated or M2 macrophages onthe other hand are involved in tissue repair andwound healing and use oxidative metabolism tofuel their longer-term functions. Metabolicintermediates, however, are not just a source ofenergy but can be directly implicated in aparticular macrophage phenotype. In M1macrophages, the Krebs cycle intermediatesuccinate regulates HIF1α, which is responsible", "metadata": {}}
+{"_id": "8494570", "title": "", "text": "Characterization of constitutive CTCF/cohesinloci: a possible role in establishing topologicaldomains in mammalian genomesBACKGROUNDRecent studies suggested thathuman/mammalian genomes are divided intolarge, discrete domains that are units ofchromosome organization. CTCF, a CCCTCbinding factor, has a diverse role in genomeregulation including transcriptional regulation,chromosome-boundary insulation, DNAreplication, and chromatin packaging. It remainsunclear whether a subset of CTCF binding sitesplays a functional role inestablishing/maintaining chromatin topologicaldomains. RESULTS We systematically analysedthe genomic, transcriptomic and epigeneticprofiles of the CTCF binding sites in 56 humancell lines from ENCODE. We identified ~24,000CTCF sites (referred to as constitutive sites) thatwere bound in more than 90% of the cell lines.Our analysis revealed: 1) constitutive CTCF lociwere located in constitutive open chromatin and", "metadata": {}}
+{"_id": "8496132", "title": "", "text": "Regulation of Bcl-2 expression by HuR in HL60leukemia cells and A431 carcinomacells.Overexpression of the proto-oncogene bcl-2promotes abnormal cell survival by inhibitingapoptosis. Expression of bcl-2 is determined, inpart, by regulatory mechanisms that control thestability of bcl-2 mRNA. Elements in the3'-untranslated region of bcl-2 mRNA have beenshown to play a role in regulating the stability ofthe message. Previously, it was found that theRNA binding proteins nucleolin and Ebp1 have arole in stabilizing bcl-2 mRNA in HL60 cells. Here,we have identified HuR as a component of bcl-2messenger ribonucleoprotein (mRNP) complexes.RNA coimmunoprecipitation assays showed thatHuR binds to bcl-2 mRNA in vivo. We alsoobserved an RNA-dependent coprecipitation ofHuR and nucleolin, suggesting that the twoproteins are present in common mRNPcomplexes. Moreover, nucleolin and HuR bindconcurrently to bcl-2 AU-rich element (ARE) RNAin vitro, suggesting separate binding sites for", "metadata": {}}
+{"_id": "8502193", "title": "", "text": "The Worldwide Variation in Avian Clutch Sizeacross Species and SpaceTraits such as clutchsize vary markedly across species andenvironmental gradients but have usually beeninvestigated from either a comparative or ageographic perspective, respectively. Weanalyzed the global variation in clutch size across5,290 bird species, excluding brood parasitesand pelagic species. We integrated intrinsic(morphological, behavioural), extrinsic(environmental), and phylogenetic effects in acombined model that predicts up to 68% of theinterspecific variation in clutch size. We thenapplied the same species-level model to predictmean clutch size across 2,521 assemblagesworldwide and found that it explains theobserved eco-geographic pattern very well.Clutches are consistently largest in cavity nestersand in species occupying seasonal environments,highlighting the importance of offspring andadult mortality that is jointly expressed inintrinsic and extrinsic correlates. The findings", "metadata": {}}
+{"_id": "8509018", "title": "", "text": "Diastolic heart failure--abnormalities in activerelaxation and passive stiffness of the leftventricle.BACKGROUND Patients with signs andsymptoms of heart failure and a normal leftventricular ejection fraction are said to havediastolic heart failure. It has traditionally beenthought that the pathophysiological cause ofheart failure in these patients is an abnormalityin the diastolic properties of the left ventricle;however, this hypothesis remains largelyunproven. METHODS We prospectively identified47 patients who met the diagnostic criteria fordefinite diastolic heart failure; all the patientshad signs and symptoms of heart failure, anormal ejection fraction, and an increased leftventricular end-diastolic pressure. Ten patientswho had no evidence of cardiovascular diseaseserved as controls. Left ventricular diastolicfunction was assessed by means of cardiaccatheterization and echocardiography. RESULTSThe patients with diastolic heart failure hadabnormal left ventricular relaxation and", "metadata": {}}
+{"_id": "8512633", "title": "", "text": "The lncRNAs PCGEM1 and PRNCR1 are notimplicated in castration resistant prostatecancerLong noncoding RNAs (IncRNAs) areincreasingly implicated in cancer biology,contributing to essential cancer cell functionssuch as proliferation, invasion, and metastasis.In prostate cancer, several lncRNAs have beennominated as critical actors in diseasepathogenesis. Among these, expression ofPCGEM1 and PRNCR1 has been identified as apossible component in disease progressionthrough the coordination of androgen receptor(AR) signaling (Yang et al., Nature 2013, see ref.[1]). However, concerns regarding therobustness of these findings have beensuggested. Here, we sought to evaluate whetherPCGEM1 and PRNCR1 are associated withprostate cancer. Through a comprehensiveanalysis of RNA-sequencing data (RNA-seq), wefind evidence that PCGEM1 but not PRNCR1 isassociated with prostate cancer. We employ alarge cohort of >230 high-risk prostate cancer", "metadata": {}}
+{"_id": "8519911", "title": "", "text": "p38MAPK controls expression of multiple cellcycle inhibitors and islet proliferation withadvancing age.Aging is a complex organismalprocess that is controlled by genetic,environmental, and behavioral factors.Accumulating evidence supports a role fordifferent cell cycle inhibitors in mammalianaging. Little is known, however, about theupstream signals that induce their expression.Here, we explore the role of p38MAPK bygenerating a dominant-negative allele (p38(AF))in which activating phosphorylation sites Thr180and Tyr182 are mutated. Heterozygous p38(AF)mice show a marked attenuation ofp38-dependent signaling and age-inducedexpression of multiple cell cycle inhibitors indifferent organs, including pancreatic islets. As aresult, aged p38(AF/+) mice show enhancedproliferation and regeneration of islets whencompared to wild-type littermates. We furtherfind an age-related reduction in expression of thep38-specific phosphatase Wip1. Wip1-deficient", "metadata": {}}
+{"_id": "8520041", "title": "", "text": "ACTA PSYCHIATRICAOBJECTIVE We explored thesubjective effects associated with olanzapine,risperidone and older antipsychotics. METHODWe conducted a content analysis of an Internetdatabase of comments about prescribedmedications. RESULTS We analysed 223comments on risperidone, 170 on olanzapine and46 relating to three older antipsychotics. Thepredominant subjective effects produced by alldrugs consisted of sedation, cognitiveimpairment and emotional flattening orindifference. Connections appeared betweenthese effects and Parkinsonian-like symptomswith the older drugs, sexual impairment withrisperidone and metabolic effects witholanzapine. The experience of akathisia wasfrequently linked to suicidal thoughts. Somerespondents described how the drugs' subjectiveeffects helped to reduce symptoms of mania,psychosis and anxiety. CONCLUSION Thegeneralisability of Internet data is uncertain.However, the data suggest that adverse", "metadata": {}}
+{"_id": "8524891", "title": "", "text": "White matter hyperintensities are a core featureof Alzheimer's disease: Evidence from thedominantly inherited Alzheimernetwork.OBJECTIVE White matterhyperintensities (WMHs) are areas of increasedsignal on T2-weighted magnetic resonanceimaging (MRI) scans that most commonly reflectsmall vessel cerebrovascular disease. IncreasedWMH volume is associated with risk andprogression of Alzheimer's disease (AD). Theseobservations are typically interpreted asevidence that vascular abnormalities play anadditive, independent role contributing tosymptom presentation, but not core features ofAD. We examined the severity and distribution ofWMH in presymptomatic PSEN1, PSEN2, and APPmutation carriers to determine the extent towhich WMH manifest in individuals geneticallydetermined to develop AD. METHODS The studycomprised participants (n = 299; age = 39.03 ±10.13) from the Dominantly Inherited AlzheimerNetwork, including 184 (61.5%) with a mutation", "metadata": {}}
+{"_id": "8529693", "title": "", "text": "Maternal and child undernutrition: consequencesfor adult health and human capitalIn this paperwe review the associations between maternaland child undernutrition with human capital andrisk of adult diseases in low-income andmiddle-income countries. We analysed data fromfive long-standing prospective cohort studiesfrom Brazil, Guatemala, India, the Philippines,and South Africa and noted that indices ofmaternal and child undernutrition (maternalheight, birthweight, intrauterine growthrestriction, and weight, height, and body-massindex at 2 years according to the new WHOgrowth standards) were related to adultoutcomes (height, schooling, income or assets,offspring birthweight, body-mass index, glucoseconcentrations, blood pressure). We undertooksystematic reviews of studies from low-incomeand middle-income countries for these outcomesand for indicators related to blood lipids,cardiovascular disease, lung and immunefunction, cancers, osteoporosis, and mental", "metadata": {}}
+{"_id": "8533245", "title": "", "text": "Ubiquitin-dependent intramembrane rhomboidprotease promotes ERAD of membraneproteins.The ER-associated degradation (ERAD)pathway serves as an important cellularsafeguard by directing incorrectly folded andunassembled proteins from the ER to theproteasome. Still, however, little is known aboutthe components mediating ERAD of membraneproteins. Here we show that the evolutionaryconserved rhomboid family protein RHBDL4 is aubiquitin-dependent ER-resident intramembraneprotease that is upregulated upon ER stress.RHBDL4 cleaves single-spanning and polytopicmembrane proteins with unstabletransmembrane helices, leading to theirdegradation by the canonical ERAD machinery.RHBDL4 specifically binds the AAA+-ATPase p97,suggesting that proteolytic processing anddislocation into the cytosol are functionallylinked. The phylogenetic relationship betweenrhomboids and the ERAD factor derlin suggeststhat substrates for intramembrane proteolysis", "metadata": {}}
+{"_id": "8536018", "title": "", "text": "Detection and function of nitric oxide during thehypersensitive response in Arabidopsis thaliana:where there's a will there's a way.Nitric oxide(NO) was identified as a key player in plantdefence responses approximately 20 years agoand a large body of evidence has accumulatedsince then supporting its role as a signallingmolecule. However, there are manydiscrepancies in current NO detection assays andthe enzymatic pathways responsible for itssynthesis have yet to be determined. This hasprovoked strong debates concerning the functionof NO in plants, even questioning its existence inplanta. Here we gather data obtained using themodel pathosystem Arabidopsis/Pseudomonas,which confirms the production of NO during thehypersensitive response and supports is role as atrigger of hypersensitive cell death and amediator of defence gene expression. Finally, wediscuss potential sources of NO synthesis,focusing on the role of nitrite as major substratefor NO production during incompatible", "metadata": {}}
+{"_id": "8538916", "title": "", "text": "The Cytosolic Chaperonin CCT/TRiC and CancerCell ProliferationThe molecular chaperoneCCT/TRiC plays a central role in maintainingcellular proteostasis as it mediates the folding ofthe major cytoskeletal proteins tubulins andactins. CCT/TRiC is also involved in theoncoprotein cyclin E, the Von Hippel-Lindautumour suppressor protein, cyclin B and p21(ras)folding which strongly suggests that it is involvedin cell proliferation and tumor genesis. To assessthe involvement of CCT/TRiC in tumor genesis,we quantified its expression levels and activity in18 cancer, one non-cancer human cell lines anda non-cancer human liver. We show that theexpression levels of CCT/TRiC in cancer cell linesare higher than that in normal cells. However,CCT/TRiC activity does not always correlate withits expression levels. We therefore documentedthe expression levels of CCT/TRiC modulatorsand partners PhLP3, Hop/P60, prefoldin andHsc/Hsp70. Our analysis reveals a functionalinterplay between molecular chaperones that", "metadata": {}}
+{"_id": "8548635", "title": "", "text": "RBP2 Belongs to a Family of Demethylases,Specific for Tri-and Dimethylated Lysine 4 onHistone 3Methylation of histones has beenregarded as a stable modification defining theepigenetic program of the cell, which regulateschromatin structure and transcription. However,the recent discovery of histone demethylases haschallenged the stable nature of histonemethylation. Here we demonstrate that theJARID1 proteins RBP2, PLU1, and SMCX arehistone demethylases specific for di- andtrimethylated histone 3 lysine 4 (H3K4).Consistent with a role for the JARID1 Drosophilahomolog Lid in regulating expression of homeoticgenes during development, we show that RBP2 isdisplaced from Hox genes during embryonic stem(ES) cell differentiation correlating with anincrease of their H3K4me3 levels and expression.Furthermore, we show that mutation or RNAidepletion of the C. elegans JARID1 homologrbr-2 leads to increased levels of H3K4me3during larval development and defects in vulva", "metadata": {}}
+{"_id": "8551160", "title": "", "text": "Mitochondria: Dynamic Organelles in Disease,Aging, and DevelopmentMitochondria are theprimary energy-generating system in mosteukaryotic cells. Additionally, they participate inintermediary metabolism, calcium signaling, andapoptosis. Given these well-establishedfunctions, it might be expected thatmitochondrial dysfunction would give rise to asimple and predictable set of defects in alltissues. However, mitochondrial dysfunction haspleiotropic effects in multicellular organisms.Clearly, much about the basic biology ofmitochondria remains to be understood. Here wediscuss recent work that suggests that thedynamics (fusion and fission) of these organellesis important in development and disease.", "metadata": {}}
+{"_id": "8563659", "title": "", "text": "Persistence of HIV-1 Receptor-Positive Cells afterHSV-2 Reactivation: A Potential Mechanism forIncreased HIV-1 AcquisitionTo explore themechanism by which herpes simplex virus(HSV)-2 infection is related to HIV-1 acquisition,we conducted in situ analysis of the cellularinfiltrate from sequential biopsies of HSV-2lesions from patients on and off antiviral therapy.CD4(+) and CD8(+) T cells and a mixedpopulation of plasmacytoid and myeloid dendriticcells (DCs), including cells expressing the C-typelectin receptor DC-SIGN, persisted at sites ofHSV-2 reactivation for months after healing,even with daily antiviral therapy. The CD4(+) Tcells that persisted reacted to HSV-2 antigen,were enriched for expression of the chemokinereceptor CCR5, and were contiguous to DCsexpressing the interleukin-3 receptor CD123 orDC-SIGN. Ex vivo infection with a CCR5-tropicstrain of HIV-1 revealed greater concentrationsof integrated HIV-1 DNA in cells derived fromhealed genital lesion biopsies than in cells from", "metadata": {}}
+{"_id": "8570317", "title": "", "text": "Chronic daily headache in Taipei, Taiwan:prevalence, follow-up and outcomepredictors.We conducted a two-stagepopulation-based headache survey amongsubjects aged > or = 15 in Taipei, Taiwan.Subjects with chronic daily headache (CDH) inthe past year were identified, interviewed andfollowed-up. CDH was defined as a headachefrequency > 15 days/month, with a duration > 4h/day. Of the 3377 participants, 108 (3.2%)fulfilled the criteria for CDH, with a higherprevalence in women (4.3%) than men (1.9%).TM was the most common subtype (55%),followed by CTTH (44%). Thirty-four per cent ofthe CDH subjects overused analgesics. At the2-year follow-up, 35% of the CDH subjects stillhad CDH. The significant predictors for persistentCDH at follow-up included: older age ( > or = 40years) (RR = 2.4), CDH onset after 32 years (RR= 1.8), CDH duration > or = 6 years (RR = 2.0),medication overuse (RR = 1.8), and \"daily\"headache (RR = 2.1). We found that CDH is not", "metadata": {}}
+{"_id": "8570478", "title": "", "text": "In vivo microtubules are copolymers of availablebeta-tubulin isotypes: localization of each of sixvertebrate beta-tubulin isotypes using polyclonalantibodies elicited by synthetic peptideantigensbeta-Tubulin is encoded in the genomesof higher animals by a small multigene familycomprising approximately seven functionalgenes. These genes produce a family of closelyrelated, but distinct polypeptide isotypes that aredistinguished principally by sequences within theapproximately 15 carboxy-terminal amino acidresidues. By immunizing rabbits with chemicallysynthesized peptides corresponding to thesevariable domain sequences, we have nowprepared polyclonal antibodies specific for eachof six distinct isotypes. Specificity of eachantiserum has been demonstratedunambiguously by antibody binding to bacteriallyproduced, cloned proteins representing eachisotype and by the inhibition of such binding bypreincubation of each antiserum only with theimmunizing peptide and not with heterologous", "metadata": {}}
+{"_id": "8570690", "title": "", "text": "Topiramate for smoking cessation: arandomized, placebo-controlled pilotstudy.INTRODUCTION Topiramate (TOP) blocksglutamate receptors and facilitates GABA(γ-aminobutyric acid) neurotransmission, effectsthat may facilitate smoking cessation. Wecompared the effects of behavioral counselingcombined with (a) TOP, (b) TOP/nicotine patch(TOP/NIC), or (c) placebo (PLC) for smokingcessation. METHODS We conducted a 10-weekrandomized trial in which subjects and researchpersonnel were blinded to TOP versus PLC butnot to the TOP/NIC patch condition. In groupsreceiving TOP, the medication dosage wastitrated gradually up to 200 mg/day. Thesmoking quit date (QD) was scheduled after 2weeks of medication treatment. NIC (21 mg) wasstarted on the QD in subjects randomized to theTOP/NIC condition. The main outcome measurewas the end-of-treatment, 4-week continuousabstinence rate (CAR; biochemically confirmed).RESULTS Fifty-seven subjects were randomized", "metadata": {}}
+{"_id": "8577229", "title": "", "text": "Break-induced DNAreplication.Recombination-dependent DNAreplication, often called break-induced replication(BIR), was initially invoked to explainrecombination events in bacteriophage but it hasrecently been recognized as a fundamentallyimportant mechanism to repair double-strandchromosome breaks in eukaryotes. Thismechanism appears to be critically important inthe restarting of stalled and broken replicationforks and in maintaining the integrity of erodedtelomeres. Although BIR helps preserve genomeintegrity during replication, it also promotesgenome instability by the production of loss ofheterozygosity and the formation ofnonreciprocal translocations, as well as in thegeneration of complex chromosomalrearrangements.", "metadata": {}}
+{"_id": "8582337", "title": "", "text": "The state of US health, 1990-2010: burden ofdiseases, injuries, and risk factors.IMPORTANCEUnderstanding the major health problems in theUnited States and how they are changing overtime is critical for informing national healthpolicy. OBJECTIVES To measure the burden ofdiseases, injuries, and leading risk factors in theUnited States from 1990 to 2010 and to comparethese measurements with those of the 34countries in the Organisation for EconomicCo-operation and Development (OECD)countries. DESIGN We used the systematicanalysis of descriptive epidemiology of 291diseases and injuries, 1160 sequelae of thesediseases and injuries, and 67 risk factors orclusters of risk factors from 1990 to 2010 for 187countries developed for the Global Burden ofDisease 2010 Study to describe the health statusof the United States and to compare US healthoutcomes with those of 34 OECD countries.Years of life lost due to premature mortality(YLLs) were computed by multiplying the number", "metadata": {}}
+{"_id": "8593263", "title": "", "text": "Malaria risk perception, knowledge andprophylaxis practices among travellers of Africanethnicity living in Paris and visiting their countryof origin in sub-Saharan Africa.An observationalprospective cohort study assessed malaria riskperception, knowledge and prophylaxis practicesamong individuals of African ethnicity living inParis and travelling to their country of origin tovisit friends or relatives (VFR). The studycompared two groups of VFR who had visited atravel clinic (TC; n=122) or a travel agency (TA;n=69) before departure. Of the 47% of VFRciting malaria as a health concern, 75% knewthat malaria is mosquito-borne and that bed netsare an effective preventive measure. Perceptionof high malaria risk was greater in the TA group(33%) than in the TC group (7%). Theavailability of a malaria vaccine was mentionedby 35% of VFR, with frequent confusion betweenyellow fever vaccine and malaria prevention.Twenty-nine percent took adequatechemoprophylaxis with complete adherence,", "metadata": {}}
+{"_id": "8595678", "title": "", "text": "Effect modification by population dietary folateon the association between MTHFR genotype,homocysteine, and stroke risk: a meta-analysisof genetic studies and randomisedtrialsBACKGROUND The MTHFR 677C\u0000Tpolymorphism has been associated with raisedhomocysteine concentration and increased risk ofstroke. A previous overview showed that theeffects were greatest in regions with low dietaryfolate consumption, but differentiation betweenthe effect of folate and small-study bias wasdifficult. A meta-analysis of randomised trials ofhomocysteine-lowering interventions showed noreduction in coronary heart disease events orstroke, but the trials were generally set inpopulations with high folate consumption. Weaimed to reduce the effect of small-study biasand investigate whether folate status modifiesthe association between MTHFR 677C\u0000T andstroke in a genetic analysis and meta-analysis ofrandomised controlled trials. METHODS Weestablished a collaboration of genetic studies", "metadata": {}}
+{"_id": "8596357", "title": "", "text": "Porcine circovirus type 2 DNA influencescytoskeleton rearrangements in plasmacytoidand monocyte-derived dendritic cells.Functionaldisruption of dendritic cells (DC) is an importantstrategy for viral pathogens to evade hostdefences. In this context, porcine circovirus type2 (PCV2), a single-stranded DNA virus, impairsplasmacytoid DC (pDC) and conventional DCactivation by certain viruses or Toll-like receptor(TLR) ligands. This inhibitory capacity isassociated with the viral DNA, but theimpairment does not affect all signallingcascades; TLR7 ligation by small chemicalmolecules will still induce interleukin-6 (IL-6)and tumour necrosis factor-α secretion, but notinterferon-α or IL-12. In this study, themolecular mechanisms by which silencing occurswere investigated. PP2, a potent inhibitor of theLyn and Hck kinases, produced a similar profileto the PCV2 DNA interference with cytokinesecretion by pDC, efficiently inhibiting cellactivation induced through TLR9, but not TLR7,", "metadata": {}}
+{"_id": "8596837", "title": "", "text": "Sympathetic neural and cardiovascularresponses during static handgrip exercise inwomen with a history of hypertensivepregnancyWomen with a history of hypertensivepregnancy are at greater risk for futurecardiovascular events; however, the mechanismsfor this increased risk are unknown. Evidencesuggests that an exercise stimulus unmaskslatent hypertensive tendencies, identifyingindividuals at the greatest risk for developingcardiovascular disease. The current studyexamined the hypothesis that women with ahypertensive pregnancy history exhibit anaugmented exercise pressor response.Normotensive women with a history of healthypregnancy (CON; n = 9) and hypertensivepregnancy (HP+; n = 12) were studied duringthe mid-luteal phase of the menstrual cycle.Heart rate (HR), systolic and diastolic bloodpressure (SBP, DBP), and muscle sympatheticnerve activity (MSNA) were measured during acold pressor test (CPT), and, following a", "metadata": {}}
+{"_id": "8604837", "title": "", "text": "Exercise and the immune system: regulation,integration, and adaptation.Stress-inducedimmunological reactions to exercise havestimulated much research into stressimmunology and neuroimmunology. It issuggested that exercise can be employed as amodel of temporary immunosuppression thatoccurs after severe physical stress. Theexercise-stress model can be easily manipulatedexperimentally and allows for the study ofinteractions between the nervous, the endocrine,and the immune systems. This review focuses onmechanisms underlying exercise-inducedimmune changes such as neuroendocrinologicalfactors including catecholamines, growthhormone, cortisol, beta-endorphin, and sexsteroids. The contribution of a metabolic linkbetween skeletal muscles and the lymphoidsystem is also reviewed. The mechanisms ofexercise-associated muscle damage and theinitiation of the inflammatory cytokine cascadeare discussed. Given that exercise modulates the", "metadata": {}}
+{"_id": "8610932", "title": "", "text": "Positive feedback between PU.1 and the cellcycle controls myeloid differentiation.Regulatorygene circuits with positive-feedback loops controlstem cell differentiation, but several mechanismscan contribute to positive feedback. Here, wedissect feedback mechanisms through which thetranscription factor PU.1 controls lymphoid andmyeloid differentiation. Quantitative live-cellimaging revealed that developing B cellsdecrease PU.1 levels by reducing PU.1transcription, whereas developing macrophagesincrease PU.1 levels by lengthening their cellcycles, which causes stable PU.1 accumulation.Exogenous PU.1 expression in progenitorsincreases endogenous PU.1 levels by inducingcell cycle lengthening, implying positive feedbackbetween a regulatory factor and the cell cycle.Mathematical modeling showed that this cellcycle-coupled feedback architecture effectivelystabilizes a slow-dividing differentiated state.These results show that cell cycle durationfunctions as an integral part of a positive", "metadata": {}}
+{"_id": "8629328", "title": "", "text": "Peripheral B cell subsets.Our understanding ofthe origins and the biological functions ofdifferent peripheral B cell subsets continues toevolve. Some understanding has been obtainedregarding the synergy between BCR-derivedsignals and other receptors and signalingpathways that drive the development offollicular, marginal zone, and B-1 B cells, but thisremains a complex and poorly understood issue.More recent information regarding the origins ofB-1 and B-2 B cells, the ability of follicular B cellsto mature both in the bone marrow and thespleen, the existence of a definable precursor forMZ B cells, and the ability of follicular B cells tooccupy two distinct niches are all highlighted inthis review.", "metadata": {}}
+{"_id": "8639034", "title": "", "text": "Human IL-10 is produced by both type 1 helper(Th1) and type 2 helper (Th2) T cell clones andinhibits their antigen-specific proliferation andcytokine production.IL-10 gene transcription andIL-10 protein production was assessed in bothtype 1 (Th1) and type 2 (Th2) CD4+ human Tcell clones by polymerase chain reaction andELISA, respectively. Although Th2 clonesapparently showed higher IL-10 mRNA levels,IL-10 mRNA expression was consistently found inTh1 clones, as well. Likewise, measurable IL-10levels were found in the supernatants of bothTh1 and Th2 clones. The effect of human IL-10(h-IL-10) and viral IL-10 (v-IL-10) on theproliferative response and cytokine production byTh1 and Th2 human clones was alsoinvestigated. Addition in culture of h-IL-10 andv-IL-10 significantly reduced the proliferation ofboth Th1 and Th2 clones in response to thespecific Ag and to PHA, but it had no inhibitoryeffect on the proliferative response of Th1 andTh2 clones to IL-2. h-IL-10 and v-IL-10 also", "metadata": {}}
+{"_id": "8642784", "title": "", "text": "Evaluating strategies for improving ovarianresponse of the poor responder undergoingassisted reproductive techniques.OBJECTIVE Toassess the efficacy of various controlled ovarianhyperstimulation (COH) regimens in the priorpoor-responder patient preparing for assistedreproductive techniques. DESIGNEnglish-language literature review. PATIENT(S)Candidates for assisted reproductive techniqueswho had been defined as having a priorsuboptimal response to standard COH regimens.INTERVENTION(S) A variety of regimes arereviewed, including increased gonadotropindoses, change of gonadotropins, adjunctivegrowth hormone (GH), luteal phase (long) GnRHagonist (GnRH-a) initiation, early follicular phase(flare) GnRH-a initiation, low-dose luteal phase(ultrashort) GnRH-a initiation, progestinpretreatment, and microdose flare GnRH-ainitiation. MAIN OUTCOME MEASURE(S) Maximalserum E(2) levels, follicular development, dose,and duration of gonadotropin therapy, cycle", "metadata": {}}
+{"_id": "8646760", "title": "", "text": "Identification and Functional Characterization ofN-Terminally Acetylated Proteins in DrosophilamelanogasterProtein modifications play a majorrole for most biological processes in livingorganisms. Amino-terminal acetylation ofproteins is a common modification foundthroughout the tree of life: the N-terminus of anascent polypeptide chain becomesco-translationally acetylated, often after theremoval of the initiating methionine residue.While the enzymes and protein complexesinvolved in these processes have beenextensively studied, only little is known aboutthe biological function of such N-terminalmodification events. To identify commonprinciples of N-terminal acetylation, we analyzedthe amino-terminal peptides from proteinsextracted from Drosophila Kc167 cells. Wedetected more than 1,200 mature proteinN-termini and could show that N-terminalacetylation occurs in insects with a similarfrequency as in humans. As the sole true", "metadata": {}}
+{"_id": "8654183", "title": "", "text": "Bax translocation and mitochondrialfragmentation induced by Helicobacterpylori.BACKGROUND AND AIMS Previous in vitroand in vivo studies have revealed an associationbetween Helicobacter pylori infection andapoptosis in gastric epithelial cells. Althoughinvolvement of the Bcl-2 family of proteins aswell as cytochrome c release has beendemonstrated in H pylori induced cell death, theexact role of the mitochondria during this type ofprogrammed cell death has not been fullyelucidated. Therefore, we sought to determinewhether or not Bax translocation andmitochondrial fragmentation occur on exposureof gastric epithelial cells to H pylori, resulting incell death. METHODS Experiments wereperformed with human gastric adenocarcinoma(AGS) cells, AGS cells transfected with theHPV-E6 gene (which inactivates p53 function),AGS-neo cells (transfected with the backboneconstruct), mouse embryonic fibroblasts (MEFs),and p19(ARF) null (ARF(-/-)) MEFs. Cells were", "metadata": {}}
+{"_id": "8659426", "title": "", "text": "Cancer chemoprevention: a rapidly evolvingfieldCancer chemoprevention involves thechronic administration of a synthetic, natural orbiological agent to reduce or delay theoccurrence of malignancy. The potential value ofthis approach has been demonstrated with trialsin breast, prostate and colon cancer. Theparadigm for developing new chemopreventiveagents has changed markedly in the last decadeand now involves extensive preclinicalmechanistic evaluation of agents before clinicaltrials are instituted and a focus on definingbiomarkers of activity that can be used as earlypredictors of efficacy. This review will summarisethe current status of the field ofchemoprevention and highlight potential newdevelopments.", "metadata": {}}
+{"_id": "8665891", "title": "", "text": "Dengue is still an imported disease in China: acase study in Guangzhou.Dengue virus and itsfour serotypes (DENV 1-4) infect approximately390 million people worldwide each year, withmost cases in tropical and subtropical regions.Because of repeated introduction of DENV fromepidemic regions and suitable weatherconditions, many regions have shifted fromhypo-endemicity to hyper-endemicity overrecent decades. Since the first dengue outbreakin 1978, it is crucial to understand the currentsituation in China over nearly 40 years. Thepurpose of the study was to examine whetherdengue in China was endemic or not, which isessential for relevant dengue control andprevention strategy implementation in China.The study, combining epidemiologicalcharacteristics of dengue from the diseasenotification system, phylogenetic andphylogeographic analyses, showed that all fourserotypes had been detected in Guangzhou,China, which was dominated by DENV 1-2. The", "metadata": {}}
+{"_id": "8670178", "title": "", "text": "The UNAIDS Estimation and Projection Package:a software package to estimate and projectnational HIV epidemics.This paper describes theEstimation and Projection Package (EPP) forestimating and projecting HIV prevalence levelsin countries with generalised epidemics. Thepaper gives an overall summary of the softwareand interface. It describes the process of definingand modelling a national epidemic in terms oflocally relevant sub-epidemics and the fourepidemiological parameters used to fit a curve toproduce the prevalence trends in the epidemic. Italso provides an example of using the EPP in acountry with a generalised epidemic. The paperdiscusses the strengths and weaknesses of thesoftware and its envisaged future developments.", "metadata": {}}
+{"_id": "8671456", "title": "", "text": "Oncolytic adenovirus armed with IL-24 Inhibitsthe growth of breast cancer in vitro and invivoBACKGROUND Interleukin-24 (IL-24) is acytokine that belongs to the IL-10 family. It canselectively induce cancer cell apoptosis which hasbeen utilized as a cancer gene therapy strategy.METHODS A recombinant type five adenoviruscontaining IL-24 gene (designatedCNHK600-IL24) was constructed, whosereplication is activated only in tumor cells. Thereplication of CNHK600-IL24 in breast tumorcells and fibroblasts were assessed by TCID50and MTT assay; the secretion of IL-24 wasmeasured by ELISA and western blotting. The invivo anti-tumor effect of CNHK600-IL24 wasinvestigated in nude mice carrying orthotopic ormetastatic breast tumor. RESULTS We observedthat CNHK600-IL24 could replicate efficiently andresulted in high level IL-24 expression andmassive cell death in human breast cancer cellMDA-MB-231 but not in normal fibroblast cellMRC-5. In addition, orthotopic breast tumor", "metadata": {}}
+{"_id": "8672737", "title": "", "text": "Brain stem and cerebellar hyperintense lesions inmigraine.BACKGROUND AND PURPOSEMigraineurs are at increased risk of cerebellarinfarcts and supratentorial white matter lesions.The prevalence, frequency, and distribution ofinfratentorial hyperintense lesions in migraineare unknown. METHODS Migraineurs with aura(n=161), without aura (n=134), and controls(n=140) from a population-based sample ofadults (30 to 60 years of age) were evaluatedwith MRI. RESULTS Infratentorialhyperintensities were identified in 13 of 295(4.4%) migraineurs and in 1 of 140 (0.7%)controls (P=0.04). Twelve cases hadhyperintensities, mostly bilaterally, in the dorsalbasis pontis. Those with infratentorialhyperintensities also had supratentorial whitematter lesions more often. CONCLUSIONS Wefound an increased prevalence of infratentorial(mostly pontine) hyperintensities in migraineursfrom the general population. This extends theknowledge about vulnerable brain regions and", "metadata": {}}
+{"_id": "8677721", "title": "", "text": "NDRG1 promotes growth of hepatocellularcarcinoma cells by directly interacting withGSK-3β and Nur77 to prevent β-catenindegradationThe N-myc downstream regulatedgene 1 (NDRG1) is significantly associated withadvanced tumor stages and poor survival ofhepatocellular carcinoma (HCC), therebyimplicating it as a potential target for HCCtreatment. We aim to further understand itsbiological roles in hepatocarcinogenesis, as ameans to exploit it for therapeutic purposes. Byscreening using the ProtoArray® Human ProteinMicroarrays, we identified glycogen synthasekinase 3β (GSK-3β) and the orphan nuclearreceptor (Nur77) as potential interactionpartners of NDRG1. These interactions wereconfirmed in HCC cell lines in vitro byco-immunoprecipitation; and co-localizations ofNDRG1 with GSK-3β and Nur77 were observedby immunofluorescence staining. Additionally,high levels of NDRG1 competitively bind toGSK-3β and Nur77 to allow β-catenin to escape", "metadata": {}}
+{"_id": "8690595", "title": "", "text": "A tutorial on statistical methods for populationassociation studiesAlthough genetic associationstudies have been with us for many years, evenfor the simplest analyses there is little consensuson the most appropriate statistical procedures.Here I give an overview of statistical approachesto population association studies, includingpreliminary analyses (Hardy–Weinbergequilibrium testing, inference of phase andmissing data, and SNP tagging), and single-SNPand multipoint tests for association. My goal is tooutline the key methods with a brief discussionof problems (population structure and multipletesting), avenues for solutions and some ongoingdevelopments.", "metadata": {}}
+{"_id": "8692744", "title": "", "text": "Identification and Characterization of MultipleTRIM Proteins That Inhibit Hepatitis B VirusTranscriptionTripartite motif (TRIM) proteinsconstitute a family of over 100 members thatshare conserved tripartite motifs and exhibitdiverse biological functions. Several TRIMproteins have been shown to restrict viralinfections and regulate host cellular innateimmune responses. In order to identify TRIMproteins that modulate the infection of hepatitisB virus (HBV), we tested 38 human TRIMs fortheir effects on HBV gene expression, capsidassembly and DNA synthesis in human hepatomacells (HepG2). The study revealed that ectopicexpression of 8 TRIM proteins in HepG2 cellspotently reduced the amounts of secreted HBVsurface and e antigens as well as intracellularcapsid and capsid DNA. Mechanistic analysesfurther demonstrated that the 8 TRIMs not onlyreduced the expression of HBV mRNAs, but alsoinhibited HBV enhancer I and enhancer IIactivities. Studies focused on TRIM41 revealed", "metadata": {}}
+{"_id": "8698208", "title": "", "text": "A mouse Mecp2-null mutation causesneurological symptoms that mimic RettsyndromeRett syndrome (RTT) is an inheritedneurodevelopmental disorder of females thatoccurs once in 10,000–15,000 births. Affectedfemales develop normally for 6–18 months, butthen lose voluntary movements, includingspeech and hand skills. Most RTT patients areheterozygous for mutations in the X-linked geneMECP2 (refs. 3–12), encoding a protein thatbinds to methylated sites in genomic DNA andfacilitates gene silencing. Previous work withMecp2-null embryonic stem cells indicated thatMeCP2 is essential for mouse embryogenesis.Here we generate mice lacking Mecp2 usingCre-loxP technology. Both Mecp2-null mice andmice in which Mecp2 was deleted in brainshowed severe neurological symptoms atapproximately six weeks of age. Compensationfor absence of MeCP2 in other tissues by MeCP1(refs. 19,20) was not apparent in genetic orbiochemical tests. After several months,", "metadata": {}}
+{"_id": "8698857", "title": "", "text": "The p38/MK2-Driven Exchange betweenTristetraprolin and HuR Regulates AU–RichElement–Dependent TranslationTNF expressionof macrophages is under stringent translationalcontrol that depends on the p38 MAPK/MK2pathway and the AU-rich element (ARE) in theTNF mRNA. Here, we elucidate the molecularmechanism of phosphorylation-regulatedtranslation of TNF. We demonstrate thattranslation of the TNF-precursor at the ERrequires expression of the ARE-binding and-stabilizing factor human antigen R (HuR)together with either activity of the p38MAPK/MK2 pathway or the absence of theARE-binding and -destabilizing factortristetraprolin (TTP). We show thatphosphorylation of TTP by MK2 decreases itsaffinity to the ARE, inhibits its ability to replaceHuR, and permits HuR-mediated initiation oftranslation of TNF mRNA. Since translation ofTTP's own mRNA is also regulated by thismechanism, an intrinsic feedback control of the", "metadata": {}}
+{"_id": "8702697", "title": "", "text": "miR-205 hinders the malignant interplaybetween prostate cancer cells and associatedfibroblasts.AIMS Tumor microenvironment is astrong determinant for the acquisition ofmetastatic potential of cancer cells. We haverecently demonstrated that cancer-associatedfibroblasts (CAFs) elicit a redox-dependentepithelial-mesenchymal transition (EMT) inprostate cancer (PCa) cells, driven bycycloxygenase-2/hypoxia-inducible factor-1(HIF-1)/nuclear factor-κB pathway andenhancing tumor aggressiveness. Here, weinvestigated the involvement of microRNAs(miRNAs) in tumor-stroma interplay to identifypossible tools to counteract oxidative stress andmetastasis dissemination. RESULTS We foundthat miR-205 is the most downmodulated miRNAin PCa cells upon CAF stimulation, due to directtranscriptional repression by HIF-1, a knownredox-sensitive transcription factor. Rescueexperiments demonstrated that ectopic miR-205overexpression in PCa cells counteracts", "metadata": {}}
+{"_id": "8708082", "title": "", "text": "The prevention of type 2 diabetesType 2 diabetesmellitus (T2DM) affects more than 7% of adultsin the US and leads to substantial personal andeconomic burden. In prediabetic states insulinsecretion and action—potential targets ofpreventive interventions—are impaired. In trialslifestyle modification (i.e. weight loss andexercise) has proven effective in preventingincident T2DM in high-risk groups, althoughweight loss has the greatest effect. Variousmedications (e.g. metformin, thiazolidinedionesand acarbose) can also prevent or delay T2DM.Whether diabetes-prevention strategies alsoultimately prevent the development of diabeticvascular complications is unknown, butcardiovascular risk factors are favorably affected.Preventive strategies that can be implemented inroutine clinical settings have been developed andevaluated. Widespread application has, however,been limited by local financial considerations,even though cost-effectiveness might beachieved at the population level.", "metadata": {}}
+{"_id": "8712839", "title": "", "text": "The transcriptional landscape of the mammaliangenome.This study describes comprehensivepolling of transcription start and terminationsites and analysis of previously unidentifiedfull-length complementary DNAs derived fromthe mouse genome. We identify the 5' and 3'boundaries of 181,047 transcripts with extensivevariation in transcripts arising from alternativepromoter usage, splicing, and polyadenylation.There are 16,247 new mouse protein-codingtranscripts, including 5154 encoding previouslyunidentified proteins. Genomic mapping of thetranscriptome reveals transcriptional forests,with overlapping transcription on both strands,separated by deserts in which few transcripts areobserved. The data provide a comprehensiveplatform for the comparative analysis ofmammalian transcriptional regulation indifferentiation and development.", "metadata": {}}
+{"_id": "8721150", "title": "", "text": "The Protein Data BankThe Protein Data Bank[PDB; Berman, Westbrook et al. (2000), NucleicAcids Res. 28, 235-242; http://www.pdb.org/] isthe single worldwide archive of primarystructural data of biological macromolecules.Many secondary sources of information arederived from PDB data. It is the starting point forstudies in structural bioinformatics. This articledescribes the goals of the PDB, the systems inplace for data deposition and access, how toobtain further information and plans for thefuture development of the resource. The readershould come away with an understanding of thescope of the PDB and what is provided by theresource.", "metadata": {}}
+{"_id": "8724666", "title": "", "text": "Cell-State-Specific Metabolic Dependency inHematopoiesis and LeukemogenesisThe balancebetween oxidative and nonoxidative glucosemetabolism is essential for a number ofpathophysiological processes. By deletingenzymes that affect aerobic glycolysis withdifferent potencies, we examine how modulatingglucose metabolism specifically affectshematopoietic and leukemic cell populations. Wefind that a deficiency in the M2 pyruvate kinaseisoform (PKM2) reduces the levels of metabolicintermediates important for biosynthesis andimpairs progenitor function without perturbinghematopoietic stem cells (HSCs), whereaslactate dehydrogenase A (LDHA) deletionsignificantly inhibits the function of both HSCsand progenitors during hematopoiesis. Incontrast, leukemia initiation by transformingalleles putatively affecting either HSCs orprogenitors is inhibited in the absence of eitherPKM2 or LDHA, indicating that thecell-state-specific responses to metabolic", "metadata": {}}
+{"_id": "8734695", "title": "", "text": "A transition in brain state duringpropofol-induced unconsciousness.Rhythmicoscillations shape cortical dynamics during activebehavior, sleep, and general anesthesia.Cross-frequency phase-amplitude coupling is aprominent feature of cortical oscillations, but itsrole in organizing conscious and unconsciousbrain states is poorly understood. Usinghigh-density EEG and intracranialelectrocorticography during gradual induction ofpropofol general anesthesia in humans, wediscovered a rapid drug-induced transitionbetween distinct states with oppositephase-amplitude coupling and different corticalsource distributions. One state occurs duringunconsciousness and may be similar to sleepslow oscillations. A second state occurs at theloss or recovery of consciousness and resemblesan enhanced slow cortical potential. Theseresults provide objective electrophysiologicallandmarks of distinct unconscious brain states,and could be used to help improve EEG-based", "metadata": {}}
+{"_id": "8747771", "title": "", "text": "Cohesins and condensins orchestrate the 4Ddynamics of yeast chromosomes during the cellcycleDuplication and segregation ofchromosomes involves dynamic reorganization oftheir internal structure by conservedarchitectural proteins, including the structuralmaintenance of chromosomes (SMC) complexescohesin and condensin. Despite activeinvestigation of the roles of these factors, agenome-wide view of dynamic chromosomearchitecture at both small and large scale duringcell division is still missing. Here, we report thefirst comprehensive 4D analysis of thehigher-order organization of the Saccharomycescerevisiae genome throughout the cell cycle andinvestigate the roles of SMC complexes incontrolling structural transitions. Duringreplication, cohesion establishment promotesnumerous long-range intra-chromosomalcontacts and correlates with the individualizationof chromosomes, which culminates atmetaphase. In anaphase, mitotic chromosomes", "metadata": {}}
+{"_id": "8748720", "title": "", "text": "Genome-wide patterns of divergence and geneflow across a butterfly radiation.The Heliconiusbutterflies are a diverse recent radiationcomprising multiple levels of divergence withongoing gene flow between species. The recentlysequenced genome of Heliconius melpomeneallowed us to investigate the genomic evolutionof this group using dense RAD markersequencing. Phylogenetic analysis of 54individuals robustly supported reciprocalmonophyly of H. melpomene and Heliconiuscydno and refuted previous phylogenetichypotheses that H. melpomene may beparaphylectic with respect to H. cydno.Heliconius timareta also formed a monophyleticclade closely related but distinct from H. cydnowith Heliconius heurippa falling within this clade.We find evidence for genetic admixture betweensympatric populations of the sister clades H.melpomene and H. cydno/timareta, particularlybetween H. cydno and H. melpomene fromCentral America and between H. timareta and H.", "metadata": {}}
+{"_id": "8756719", "title": "", "text": "Randomized, double-blind study of the safety,tolerability, and efficacy of tafenoquine versusmefloquine for malaria prophylaxis innonimmune subjects.This study represents thefirst phase III trial of the safety, tolerability, andeffectiveness of tafenoquine for malariaprophylaxis. In a randomized (3:1),double-blinded study, Australian soldiersreceived weekly malaria prophylaxis with 200 mgtafenoquine (492 subjects) or 250 mgmefloquine (162 subjects) for 6 months on apeacekeeping deployment to East Timor. Afterreturning to Australia, tafenoquine-receivingsubjects received a placebo andmefloquine-receiving subjects received 30 mgprimaquine daily for 14 days. There were noclinically significant differences betweenhematological and biochemical parameters of thetreatment groups. Treatment-related adverseevents for the two groups were similar(tafenoquine, 13.4%; mefloquine, 11.7%). Threesubjects on tafenoquine (0.6%) and none on", "metadata": {}}
+{"_id": "8759633", "title": "", "text": "Domain-wide regulation of DNA replicationtiming during mammalian developmentStudies ofreplication timing provide a handle intopreviously impenetrable higher-order levels ofchromosome organization and their plasticityduring development. Although mechanismsregulating replication timing are not clear, novelgenome-wide studies provide a thorough surveyof the extent to which replication timing isregulated during most of the early cell fatetransitions in mammals, revealing coordinatedchanges of a defined set of 400–800 kbchromosomal segments that involve at least halfthe genome. Furthermore, changes in replicationtime are linked to changes in sub-nuclearorganization and domain-wide transcriptionalpotential, and tissue-specific replication timingprofiles are conserved from mouse to human,suggesting that the program has developmentalsignificance. Hence, these studies have provideda solid foundation for linking megabase levelchromosome structure to function, and suggest a", "metadata": {}}
+{"_id": "8764879", "title": "", "text": "PU.1-mediated upregulation of CSF1R is crucialfor leukemia stem cell potential induced byMOZ-TIF2Leukemias and other cancers possessself-renewing stem cells that help to maintainthe cancer. Cancer stem cell eradication isthought to be crucial for successful anticancertherapy. Using an acute myeloid leukemia (AML)model induced by the leukemia-associatedmonocytic leukemia zinc finger (MOZ)-TIF2fusion protein, we show here that AML can becured by the ablation of leukemia stem cells. TheMOZ fusion proteins MOZ-TIF2 and MOZ-CBPinteracted with the transcription factor PU.1 tostimulate the expression of macrophagecolony–stimulating factor receptor (CSF1R, alsoknown as M-CSFR, c-FMS or CD115). Studiesusing PU.1-deficient mice showed that PU.1 isessential for the ability of MOZ-TIF2 to establishand maintain AML stem cells. Cells expressinghigh amounts of CSF1R (CSF1Rhigh cells), butnot those expressing low amounts of CSF1R(CSF1Rlow cells), showed potent", "metadata": {}}
+{"_id": "8771704", "title": "", "text": "Pharmacological blockage of fibro/adipogenicprogenitor expansion and suppression ofregenerative fibrogenesis is associated withimpaired skeletal muscle regeneration.Acuteskeletal muscle injury triggers an expansion offibro/adipogenic progenitors (FAPs) and atransient stage of fibrogenesis characterized byextracellular matrix deposition. While theperpetuation of such phase can lead topermanent tissue scarring, the consequences ofits suppression remain to be studied. Using amodel of acute muscle damage we were able todetermine that pharmacological inhibition of FAPexpansion by Nilotinib, a tyrosine kinase inhibitorwith potent antifibrotic activity, exerts adetrimental effect on myogenesis duringregeneration. We found that Nilotinib inhibits thedamage-induced expansion of satellite cells invivo, but it does not affect in vitro proliferation,suggesting a non cell-autonomous effect.Nilotinib impairs regenerative fibrogenesis bypreventing the injury-triggered expansion and", "metadata": {}}
+{"_id": "8774475", "title": "", "text": "Deregulation of Scribble Promotes MammaryTumorigenesis and Reveals a Role for CellPolarity in CarcinomaLoss of cell polarity proteinssuch as Scribble induces neoplasia in Drosophilaby promoting uncontrolled proliferation. Inmammals, the role that polarity proteins playduring tumorigenesis is not well understood.Here, we demonstrate that depletion of Scribblein mammary epithelia disrupts cell polarity,blocks three-dimensional morphogenesis, inhibitsapoptosis, and induces dysplasia in vivo thatprogress to tumors after long latency. Loss ofScribble cooperates with oncogenes such asc-myc to transform epithelial cells and inducetumors in vivo by blocking activation of anapoptosis pathway. Like depletion,mislocalization of Scribble from cell-cell junctionwas sufficient to promote cell transformation.Interestingly, spontaneous mammary tumors inmice and humans possess both downregulatedand mislocalized Scribble. Thus, we demonstratethat scribble inhibits breast cancer formation and", "metadata": {}}
+{"_id": "8780599", "title": "", "text": "The Polymeal: a more natural, safer, andprobably tastier (than the Polypill) strategy toreduce cardiovascular disease by more than75%.OBJECTIVE Although the Polypill concept(proposed in 2003) is promising in terms ofbenefits for cardiovascular risk management, thepotential costs and adverse effects are its mainpitfalls. The objective of this study was toidentify a tastier and safer alternative to thePolypill: the Polymeal. METHODS Data on theingredients of the Polymeal were taken from theliterature. The evidence based recipe includedwine, fish, dark chocolate, fruits, vegetables,garlic, and almonds. Data from the Framinghamheart study and the Framingham offspring studywere used to build life tables to model thebenefits of the Polymeal in the generalpopulation from age 50, assuming multiplicativecorrelations. RESULTS Combining the ingredientsof the Polymeal would reduce cardiovasculardisease events by 76%. For men, taking thePolymeal daily represented an increase in total", "metadata": {}}
+{"_id": "8790729", "title": "", "text": "Islet-Like Clusters Derived from MesenchymalStem Cells in Wharton's Jelly of the HumanUmbilical Cord for Transplantation to ControlType 1 DiabetesBACKGROUND There is awidespread interest in developing renewablesources of islet-replacement tissue for type Idiabetes mellitus. Human mesenchymal cellsisolated from the Wharton's jelly of the umbilicalcord (HUMSCs), which can be easily obtainedand processed compared with embryonic andbone marrow stem cells, possess stem cellproperties. HUMSCs may be a valuable source forthe generation of islets. METHODOLOGY ANDPRINCIPAL FINDINGS HUMSCs were induced totransform into islet-like cell clusters in vitrothrough stepwise culturing in neuron-conditionedmedium. To assess the functional stability of theislet-like cell clusters in vivo, these cell clusterswere transplanted into the liver ofstreptozotocin-induced diabetic rats vialaparotomy. Glucose tolerance was measured onweek 12 after transplantation accompanied with", "metadata": {}}
+{"_id": "8814634", "title": "", "text": "Use of perioperative hydroxyethyl starch 6% andalbumin 5% in elective joint arthroplasty andassociation with adverse outcomes: aretrospective population basedanalysisOBJECTIVE To determine whether theperioperative use of hydroxyethyl starch 6% andalbumin 5% in elective joint arthroplasties areassociated with an increased risk forperioperative complications. DESIGNRetrospective cohort study of population baseddata between 2006 and 2013. SETTING Datafrom 510 different hospitals across the UnitedStates participating in the Premier Perspectivedatabase. PARTICIPANTS 1,051,441 patientsundergoing elective total hip and kneearthroplasties. EXPOSURES Perioperative fluidresuscitation with hydroxyethyl starch 6% oralbumin 5%, or neither. MAIN OUTCOMEMEASURES Acute renal failure andthromboembolic, cardiac, and pulmonarycomplications. RESULTS Compared with patientswho received neither colloid, perioperative fluid", "metadata": {}}
+{"_id": "8816869", "title": "", "text": "BMAL1 and CLOCK, Two Essential Components ofthe Circadian Clock, Are Involved in GlucoseHomeostasisCircadian timing is generatedthrough a unique series of autoregulatoryinteractions termed the molecular clock.Behavioral rhythms subject to the molecularclock are well characterized. We demonstrate arole for Bmal1 and Clock in the regulation ofglucose homeostasis. Inactivation of the knownclock components Bmal1 (Mop3) and Clocksuppress the diurnal variation in glucose andtriglycerides. Gluconeogenesis is abolished bydeletion of Bmal1 and is depressed in Clockmutants, but the counterregulatory response ofcorticosterone and glucagon to insulin-inducedhypoglycaemia is retained. Furthermore, ahigh-fat diet modulates carbohydrate metabolismby amplifying circadian variation in glucosetolerance and insulin sensitivity, and mutation ofClock restores the chow-fed phenotype. Bmal1and Clock, genes that function in the coremolecular clock, exert profound control over", "metadata": {}}
+{"_id": "8839502", "title": "", "text": "Mechanisms of progression and regression ofrenal lesions of chronic nephropathies anddiabetes.The incidence of chronic kidneydiseases is increasing worldwide, and theseconditions are emerging as a major public healthproblem. While genetic factors contribute tosusceptibility and progression of renal disease,proteinuria has been claimed as an independentpredictor of outcome. Reduction of urinaryprotein levels by various medications and alow-protein diet limits renal function decline inindividuals with nondiabetic and diabeticnephropathies to the point that remission of thedisease and regression of renal lesions havebeen observed in experimental animals and evenin humans. In animal models, regression ofglomerular structural changes is associated withremodeling of the glomerular architecture.Instrumental to this discovery were 3Dreconstruction studies of the glomerular capillarytuft, which allowed the quantification of sclerosisvolume reduction and capillary regeneration", "metadata": {}}
+{"_id": "8842332", "title": "", "text": "Contemporary type 1 diabetes pregnancyoutcomes: impact of obesity and glycaemiccontrol.OBJECTIVE To compare contemporarypregnancy outcomes in women with and withouttype 1 diabetes, and to examine the effects ofobesity and glycaemic control on theseoutcomes. DESIGN AND SETTING Historicalcohort study in a specialist diabetes andmaternity network in Victoria. PARTICIPANTS Allsingleton births (at least 20 weeks' gestation),2010-2013, were analysed: 107 pregnancies towomen with type 1 diabetes and 27 075pregnancies to women without diabetes. Womenwith type 2 diabetes or gestational diabetes wereexcluded. METHODS Data were extracted fromthe Birthing Outcomes System database;associations between type 1 diabetes andpregnancy outcomes were analysed bymultivariable regression. MAIN OUTCOMEMEASURES Mode of birth; maternal and neonataloutcomes. RESULTS The mean body mass indexwas higher for women with type 1 diabetes than", "metadata": {}}
+{"_id": "8856690", "title": "", "text": "Molecular Mechanisms of Vitamin D ActionThehormonal metabolite of vitamin D,1α,25-dihydroxyvitamin D3 (1,25D), initiatesbiological responses via binding to the vitamin Dreceptor (VDR). When occupied by 1,25D, VDRinteracts with the retinoid X receptor (RXR) toform a heterodimer that binds to vitamin Dresponsive elements in the region of genesdirectly controlled by 1,25D. By recruitingcomplexes of either coactivators or corepressors,ligand-activated VDR-RXR modulates thetranscription of genes encoding proteins thatpromulgate the traditional functions of vitamin D,including signaling intestinal calcium andphosphate absorption to effect skeletal andcalcium homeostasis. Thus, vitamin D action in aparticular cell depends upon the metabolicproduction or delivery of sufficient concentrationsof the 1,25D ligand, expression of adequate VDRand RXR coreceptor proteins, and cell-specificprogramming of transcriptional responses toregulate select genes that encode proteins that", "metadata": {}}
+{"_id": "8858602", "title": "", "text": "Quantitative Temporal Viromics: An Approach toInvestigate Host-Pathogen InteractionAsystematic quantitative analysis of temporalchanges in host and viral proteins throughout thecourse of a productive infection could providedynamic insights into virus-host interaction. Wedeveloped a proteomic technique called\"quantitative temporal viromics\" (QTV), whichemploys multiplexed tandem-mass-tag-basedmass spectrometry. Human cytomegalovirus(HCMV) is not only an important pathogen but aparadigm of viral immune evasion. QTV detailedhow HCMV orchestrates the expression of>8,000 cellular proteins, including 1,200cell-surface proteins to manipulate signalingpathways and counterintrinsic, innate, andadaptive immune defenses. QTV predictednatural killer and T cell ligands, as well as 29viral proteins present at the cell surface,potential therapeutic targets. Temporal profilesof >80% of HCMV canonical genes and 14noncanonical HCMV open reading frames were", "metadata": {}}
+{"_id": "8868863", "title": "", "text": "Interactions between sleep, circadian function,and glucose metabolism: implications for riskand severity of diabetes.Sleep disturbances,including sleep insufficiency and sleepfragmentation, have been linked to abnormalglucose metabolism and increased diabetes risk.Well-controlled laboratory studies have providedinsights regarding the underlying mechanisms.Several large prospective studies suggest thatthese sleep disturbances are associated with anincreased risk of incident diabetes. Obstructivesleep apnea, which combines sleepfragmentation and hypoxemia, is a major riskfactor for insulin resistance and possiblydiabetes. Whether glycemic control in type 2diabetes patients can be improved by treatingsleep apnea remains controversial. Recently,sleep disturbances during pregnancy and theirrelationship to gestational diabetes andhyperglycemia have received considerableattention owing to potential adverse effects onmaternal and fetal health. Additionally, evidence", "metadata": {}}
+{"_id": "8883846", "title": "", "text": "Antibody-Based HIV-1 Vaccines: RecentDevelopments and Future DirectionsThe GlobalHIV Vaccine Enterprise convened a two-dayworkshop in May of 2007 to discuss humoralimmune responses to HIV and approaches todesign vaccines that induce viral neutralizing andother potentially protective antibody responses.The goals of this workshop were to identify keyscientific issues, gaps, and opportunities thathave emerged since the Enterprise Strategic Planwas first published in 2005 [1], and to makerecommendations that Enterprise stakeholderscan use to plan new activities. Most effectiveviral vaccines work, at least in part, bygenerating antibodies that inactivate orneutralize the invading virus, and the existingdata strongly suggest that an optimally effectiveHIV-1 vaccine should elicit potent antiviralneutralizing antibodies. However, unlike acuteviral pathogens, HIV-1 chronically replicates inthe host and evades the antibody response. Thisimmune evasion, along with the large genetic", "metadata": {}}
+{"_id": "8891333", "title": "", "text": "Targeted therapy for cancer stem cells: thepatched pathway and ABC transportersData fromcertain leukemias as well as brain and breastcancer indicate that there is a small population oftumor cells with ‘stem cell’ characteristics andthe capacity for self-renewal. The self-renewingcells have many of the properties of normal stemcells and have been termed ‘cancer stem cells’.These cancer stem cells make up as few as 1%of the cells in a tumor, making them difficult todetect and study. Like normal stem cells, cancerstem cells have a number of propertiespermitting them to survive traditional cancerchemotherapy and radiation therapy. These cellsexpress high levels of ATP-binding cassette(ABC) drug transporters, providing for a level ofresistance; are relatively quiescent; have higherlevels of DNA repair and a lowered ability toenter apoptosis. Combined cancer therapyapproaches targeting the cancer stem cells andthe non-stem cells may be developed withincreased efficacy. Efforts to target the", "metadata": {}}
+{"_id": "8892905", "title": "", "text": "Increased in vivo amyloid-β42 production,exchange, and loss in presenilin mutationcarriers.Alzheimer's disease (AD) is hypothesizedto be caused by an overproduction or reducedclearance of amyloid-β (Aβ) peptide. Autosomaldominant AD (ADAD) caused by mutations in thepresenilin (PSEN) gene have been postulated toresult from increased production of Aβ42compared to Aβ40 in the central nervous system(CNS). This has been demonstrated in rodentmodels of ADAD but not in human mutationcarriers. We used compartmental modeling ofstable isotope labeling kinetic (SILK) studies inhuman carriers of PSEN mutations and relatednoncarriers to evaluate the pathophysiologicaleffects of PSEN1 and PSEN2 mutations on theproduction and turnover of Aβ isoforms. Wecompared these findings by mutation status andamount of fibrillar amyloid deposition asmeasured by positron emission tomography(PET) using the amyloid tracer Pittsburghcompound B (PIB). CNS Aβ42 to Aβ40 production", "metadata": {}}
+{"_id": "8903143", "title": "", "text": "Basic residues in the T-cell receptor ζcytoplasmic domain mediate membraneassociation and modulate signaling.The T-cellreceptor (TCR) consists of a TCRαβ heterodimer,a TCRζ homodimer, and CD3γε and CD3δεheterodimers. The precise mechanism of T-celltriggering following TCR ligand engagementremains elusive. Previous studies reported thatthe cytoplasmic tail of CD3ε binds to the plasmamembrane through a basic residue-rich stretch(BRS) and proposed that dissociation from themembrane is required for phosphorylationthereof. In this report we show that BRS motifswithin the cytoplasmic tail of TCRζ mediateassociation with the plasma membrane and thatTCR engagement results in TCRζ dissociationfrom the membrane. This dissociation requiresphosphorylation of the TCRζ immunoreceptortyrosine-based activation motifs by lymphocytecell-specificprotein tyrosine kinase (Lck) but notζ-chain-associated protein kinase 70 binding.Mutations of the TCRζ BRS motifs that disrupt", "metadata": {}}
+{"_id": "8906858", "title": "", "text": "Policies for alcohol restriction and theirassociation with interpersonal violence: atime-series analysis of homicides in Cali,Colombia.BACKGROUND Cali, Colombia, has ahigh incidence of interpersonal violence deaths.Various alcohol control policies have beenimplemented to reduce alcohol-related problems.The objective of this study was to determinewhether different alcohol control policies wereassociated with changes in the incidence rate ofhomicides. METHODS Ecologic study conductedduring 2004-08 using a time-series design.Policies were implemented with variations inhours of restriction of sales and consumption ofalcohol. Most restrictive policies prohibitedalcohol between 2 a.m. and 10 a.m. for 446non-consecutive days. Moderately restrictivepolicies prohibited alcohol between 3 a.m. and10 a.m. for 1277 non-consecutive days. Laxpolicies prohibited alcohol between 4 a.m. and10 a.m. for 104 non-consecutive days. Inconditional autoregressive negative binomial", "metadata": {}}
+{"_id": "8909176", "title": "", "text": "Effects of SNF1 on Maltose Metabolism andLeavening Ability of Baker's Yeast in LeanDough.Maltose metabolism of baker's yeast(Saccharomyces cerevisiae) in lean dough isnegatively influenced by glucose repression,thereby delaying the dough fermentation. Toimprove maltose metabolism and leaveningability, it is necessary to alleviate glucoserepression. The Snf1 protein kinase is well knownto be essential for the response to glucoserepression and required for transcription ofglucose-repressed genes including themaltose-utilization genes (MAL). In this study,the SNF1 overexpression and deletion industrialbaker's yeast strains were constructed andcharacterized in terms of maltose utilization,growth and fermentation characteristics, mRNAlevels of MAL genes (MAL62 encoding themaltase and MAL61 encoding the maltosepermease) and maltase and maltose permeaseactivities. Our results suggest thatoverexpression of SNF1 was effective to glucose", "metadata": {}}
+{"_id": "8925851", "title": "", "text": "Review articleRibosomopathies compose acollection of disorders in which geneticabnormalities cause impaired ribosomebiogenesis and function, resulting in specificclinical phenotypes. Congenital mutations inRPS19 and other genes encoding ribosomalproteins cause Diamond-Blackfan anemia, adisorder characterized by hypoplastic, macrocyticanemia. Mutations in other genes required fornormal ribosome biogenesis have beenimplicated in other rare congenital syndromes,Schwachman-Diamond syndrome, dyskeratosiscongenita, cartilage hair hypoplasia, andTreacher Collins syndrome. In addition, the 5q-syndrome, a subtype of myelodysplasticsyndrome, is caused by a somatically acquireddeletion of chromosome 5q, which leads tohaploinsufficiency of the ribosomal protein RPS14and an erythroid phenotype highly similar toDiamond-Blackfan anemia. Acquiredabnormalities in ribosome function have beenimplicated more broadly in human malignancies.", "metadata": {}}
+{"_id": "8963413", "title": "", "text": "PD-L1 expression in human cancers and itsassociation with clinical outcomesPD-L1 is animmunoinhibitory molecule that suppresses theactivation of T cells, leading to the progression oftumors. Overexpression of PD-L1 in cancers suchas gastric cancer, hepatocellular carcinoma,renal cell carcinoma, esophageal cancer,pancreatic cancer, ovarian cancer, and bladdercancer is associated with poor clinical outcomes.In contrast, PD-L1 expression correlates withbetter clinical outcomes in breast cancer andmerkel cell carcinoma. The prognostic value ofPD-L1 expression in lung cancer, colorectalcancer, and melanoma is controversial. Blockingantibodies that target PD-1 and PD-L1 haveachieved remarkable response rates in cancerpatients who have PD-L1-overexpressing tumors.However, using PD-L1 as an exclusive predictivebiomarker for cancer immunotherapy isquestionable due to the low accuracy of PD-L1immunohistochemistry staining. Factors thataffect the accuracy of PD-L1", "metadata": {}}
+{"_id": "8979167", "title": "", "text": "Primate cytomegaloviruses encode and expressan IL-10-like protein.An open reading frame(ORF) with homology to interleukin-10 (IL-10)has been identified in rhesus cytomegalovirus(RhCMV). The IL-10-like protein is generatedfrom a multispliced, polyadenylated early genetranscript encompassing part of thecorresponding UL111A ORF of human CMV(HCMV). Immunological analyses confirmexpression of the IL-10-like protein both in tissueculture and in RhCMV-infected rhesus macaques.Conserved ORFs were subsequently identified inhuman, baboon, and African green monkey CMV,and a fully processed transcript has beenmapped in fibroblasts infected with the Townestrain of HCMV. The conservation of thispreviously unrecognized ORF suggests that theprotein may play an essential role in primateCMV persistence and pathogenesis.", "metadata": {}}
+{"_id": "8989616", "title": "", "text": "Genome Sequencing and Analysis of theTasmanian Devil and Its TransmissibleCancerThe Tasmanian devil (Sarcophilusharrisii), the largest marsupial carnivore, isendangered due to a transmissible facial cancerspread by direct transfer of living cancer cellsthrough biting. Here we describe the sequencing,assembly, and annotation of the Tasmanian devilgenome and whole-genome sequences for twogeographically distant subclones of the cancer.Genomic analysis suggests that the cancer firstarose from a female Tasmanian devil and thatthe clone has subsequently genetically divergedduring its spread across Tasmania. The devilcancer genome contains more than 17,000somatic base substitution mutations and bearsthe imprint of a distinct mutational process.Genotyping of somatic mutations in 104geographically and temporally distributedTasmanian devil tumors reveals the pattern ofevolution and spread of this parasitic clonallineage, with evidence of a selective sweep in", "metadata": {}}
+{"_id": "8994465", "title": "", "text": "A Temporarily Distinct Subpopulation ofSlow-Cycling Melanoma Cells Is Required forContinuous Tumor GrowthMelanomas are highlyheterogeneous tumors, but the biologicalsignificance of their different subpopulations isnot clear. Using the H3K4 demethylase JARID1B(KDM5B/PLU-1/RBP2-H1) as a biomarker, wehave characterized a small subpopulation ofslow-cycling melanoma cells that cycle withdoubling times of >4 weeks within the rapidlyproliferating main population. IsolatedJARID1B-positive melanoma cells give rise to ahighly proliferative progeny. Knockdown ofJARID1B leads to an initial acceleration of tumorgrowth followed by exhaustion which suggeststhat the JARID1B-positive subpopulation isessential for continuous tumor growth.Expression of JARID1B is dynamically regulatedand does not follow a hierarchical cancer stemcell model because JARID1B-negative cells canbecome positive and even single melanoma cellsirrespective of selection are tumorigenic. These", "metadata": {}}
+{"_id": "8995263", "title": "", "text": "A map of human circular RNAs in clinicallyrelevant tissuesCellular circular RNAs (circRNAs)are generated by head-to-tail splicing and arepresent in all multicellular organisms studied sofar. Recently, circRNAs have emerged as a largeclass of RNA which can function aspost-transcriptional regulators. It has also beenshown that many circRNAs are tissue- andstage-specifically expressed. Moreover, theunusual stability and expression specificity makecircRNAs important candidates for clinicalbiomarker research. Here, we present a circRNAexpression resource of 20 human tissues highlyrelevant to disease-related research: vascularsmooth muscle cells (VSMCs), human umbilicalvein cells (HUVECs), artery endothelial cells(HUAECs), atrium, vena cava, neutrophils,platelets, cerebral cortex, placenta, and samplesfrom mesenchymal stem cell differentiation. Ineight different samples from a single donor, wefound highly tissue-specific circRNA expression.Circular-to-linear RNA ratios revealed that many", "metadata": {}}
+{"_id": "8997410", "title": "", "text": "Arp2/3 complex inhibition radically alterslamellipodial actin architecture, suspended cellshape, and the cell spreading processRecentstudies have investigated the dendritic actincytoskeleton of the cell edge's lamellipodial (LP)region by experimentally decreasing the activityof the actin filament nucleator and branchformer, the Arp2/3 complex. Here we extendthese studies via pharmacological inhibition ofthe Arp2/3 complex in sea urchin coelomocytes,cells that possess an unusually broad LP regionand display correspondingly exaggeratedcentripetal flow. Using light and electronmicroscopy, we demonstrate that Arp2/3complex inhibition via the drug CK666dramatically altered LP actin architecture, slowedcentripetal flow, drove alamellipodial-to-filopodial shape change insuspended cells, and induced a novel actinstructural organization during cell spreading. Ageneral feature of the CK666 phenotype incoelomocytes was transverse actin arcs, and arc", "metadata": {}}
+{"_id": "9021186", "title": "", "text": "Synergistic Activation of HIV-1 Expression byDeacetylase Inhibitors and Prostratin:Implications for Treatment of Latent InfectionThepersistence of transcriptionally silent butreplication-competent HIV-1 reservoirs in HighlyActive Anti-Retroviral Therapy (HAART)-treatedinfected individuals, represents a major hurdle tovirus eradication. Activation of HIV-1 geneexpression in these cells together with anefficient HAART has been proposed as anadjuvant therapy aimed at decreasing the pool oflatent viral reservoirs. Using the latently-infectedU1 monocytic cell line and latently-infected J-LatT-cell clones, we here demonstrated a strongsynergistic activation of HIV-1 production byclinically used histone deacetylase inhibitors(HDACIs) combined with prostratin, anon-tumor-promoting nuclear factor (NF)-kappaB inducer. In J-Lat cells, we showed thatthis synergism was due, at least partially, to thesynergistic recruitment of unresponsive cells intothe expressing cell population. A combination of", "metadata": {}}
+{"_id": "9038803", "title": "", "text": "Centrosome aberrations: cause or consequenceof cancer progression?Many human tumoursshow centrosome aberrations, indicating anunderlying deregulation of centrosome structure,duplication or segregation. Centrosomesorganize microtubule arrays throughout the cellcycle, thereby influencing both tissuearchitecture and the accuracy of chromosomesegregation. But what are the origins ofcentrosomal abnormalities in tumours, and whatimpact do they have on the generation ofinvasive, genetically unbalanced cells duringcancer progression?", "metadata": {}}
+{"_id": "9047718", "title": "", "text": "Autonomic neuropathy, QT interval lengthening,and unexpected deaths in male diabeticpatientsQT intervals were measured over RRintervals ranging from 500 ms to 1000 ms in 13normal male subjects, 13 male diabetic subjectswithout and 13 with autonomic neuropathy.There was a close linear relationship between QTand RR in all subjects. The slope of theregression line was significantly greater in theautonomic neuropathy group than the normalgroup. Thirty-two male diabetic subjects withvarying degrees of autonomic dysfunction hadrepeat QT measurements 3 (range 2–6) yearslater. QT and QTC lengthened significantly at thesecond visit, unrelated to age or time betweenrecordings, but which corresponded with changesin autonomic function. Of 71 male diabeticsubjects under 60 years followed for 3 years, 13had died, 8 unexpectedly. Of those withautonomic neuropathy, QT and QTC weresignificantly longer in those who subsequentlydied, despite similar ages and duration of", "metadata": {}}
+{"_id": "9056874", "title": "", "text": "Incidence of cancer after immunosuppressivetreatment for heart transplantation.Prolonged orintensive immunosuppressive therapy used afterorgan transplantation is complicated by anincreased incidence of cancer. Strikingdifferences in incidence are observed in heartand heart-lung transplant recipients whencompared with renal transplant patients. Themost significant increase was in the incidence oflymphomas in cardiac versus renal patients.Moreover, a two-fold greater increase of allneoplasms was found in cardiac recipients, withnearly a six-fold increase in visceral tumors.Several factors may account for thesedifferences. In cardiac allograft recipients,intensive immunosuppression is frequently usedto reverse acute rejection and the highestnumber of cardiac transplants was performed inthe era of polypharmacy, usually consisting oftriple therapy.", "metadata": {}}
+{"_id": "9063688", "title": "", "text": "Nucleating actin for invasionThe invasion ofcancer cells into the surrounding tissue is aprerequisite and initial step in metastasis, whichis the leading cause of death from cancer.Invasive cell migration requires the formation ofvarious structures, such as invadopodia andpseudopodia, which require actin assembly thatis regulated by specialized actin nucleationfactors. There is a large variety of different actinnucleators in human cells, such as formins, spireand Arp2/3-regulating proteins, and the list islikely to grow. Studies of the mechanisms ofvarious actin nucleation factors that are involvedin cancer cell function may ultimately providenew treatments for invasive and metastaticdisease.", "metadata": {}}
+{"_id": "9076196", "title": "", "text": "GFI1 and GFI1B control the loss of endothelialidentity of hemogenic endothelium duringhematopoietic commitment.Recent studies haveestablished that during embryonic development,hematopoietic progenitors and stem cells aregenerated from hemogenic endotheliumprecursors through a process termed endothelialto hematopoietic transition (EHT). Thetranscription factor RUNX1 is essential for thisprocess, but its main downstream effectorsremain largely unknown. Here, we report theidentification of Gfi1 and Gfi1b as direct targetsof RUNX1 and critical regulators of EHT. GFI1and GFI1B are able to trigger, in the absence ofRUNX1, the down-regulation of endothelialmarkers and the formation of round cells, amorphologic change characteristic of EHT.Conversely, blood progenitors in Gfi1- andGfi1b-deficient embryos maintain the expressionof endothelial genes. Moreover, those cells arenot released from the yolk sac and disseminatedinto embryonic tissues. Taken together, our", "metadata": {}}
+{"_id": "9091863", "title": "", "text": "An RNA-directed nuclease mediatespost-transcriptional gene silencing in Drosophilacells.In a diverse group of organisms thatincludes Caenorhabditis elegans, Drosophila,planaria, hydra, trypanosomes, fungi and plants,the introduction of double-stranded RNAs inhibitsgene expression in a sequence-specific manner.These responses, called RNA interference orpost-transcriptional gene silencing, may provideanti-viral defence, modulate transposition orregulate gene expression. We have taken abiochemical approach towards elucidating themechanisms underlying this geneticphenomenon. Here we show that'loss-of-function' phenotypes can be created incultured Drosophila cells by transfection withspecific double-stranded RNAs. This coincideswith a marked reduction in the level of cognatecellular messenger RNAs. Extracts of transfectedcells contain a nuclease activity that specificallydegrades exogenous transcripts homologous totransfected double-stranded RNA. This enzyme", "metadata": {}}
+{"_id": "9095394", "title": "", "text": "Expression of basal cell keratin 15 and keratin 19in oral squamous neoplasms represents diversepathophysiologies.Human epithelium containskeratin, which is expressed duringdifferentiation. Depending on the target celltype, different types of keratin are expressed,and their alterations seem to represent changesin cell properties. The basal cells of oralepithelium express keratin 5 (K5), K14, K15 andK19, but their alterations in tumors are unclear.To address this issue and to seek possiblediagnostic application, we examined theexpression of these keratins in oral squamouscell carcinoma (OSCC) and squamousintraepithelial neoplasm (SIN). cDNA microarrayanalysis of 43 OSCC revealed slight upregulationof KRT14, downregulation of KRT15 and KRT19,and unaltered KRT5 expression. There weregreat variations in KRT15 and KRT19 expressionacross each cancer. Well-differentiated OSCCtended to express more KRT15 and less KRT19compared to moderately- or poorly-differentiated", "metadata": {}}
+{"_id": "9095943", "title": "", "text": "Exosomes in Plasma of Patients with OvarianCarcinoma: Potential Biomarkers of TumorProgression and Response toTherapy.BACKGROUND In patients with OvarianCancer (OvCa) exosomes released by tumor cellsare present in the plasma and could be involvedin tumor progression. This study examines theassociation between the exosomepresence/protein content in plasma of OvCapatients and disease outcome, response tostandard therapy and/or tumorresistance totherapies in patients studied at diagnosis andalso serially during and after therapy. DESIGNAND METHODS Exosomes were purified fromOvCa patients' plasma (n=22), patients withbenign tumors (n=10) or (n=10) healthycontrols (NC) using ultracentrifugation.Exosomes were visualized by scanning electronmicroscopy. Their protein content was measured.The presence of MAGE 3/6 and TGF-β1 inexosomes was evaluated in Western blots.RESULTS The OvCa patients' plasma contained", "metadata": {}}
+{"_id": "9110810", "title": "", "text": "Insecticide impregnated curtains to controldomestic transmission of cutaneousleishmaniasis in Venezuela: cluster randomisedtrial.OBJECTIVE To measure the impact ontransmission of leishmaniasis of curtainsimpregnated with insecticide. DESIGN Clusterrandomised controlled trial: household interviewsurvey, observational study of people'sbehaviour, entomological study with light trapcaptures of sandflies inside houses. SETTING 14urban sectors in Trujillo, Venezuela.PARTICIPANTS 2913 inhabitants of 569 houses.INTERVENTION Sectors were paired according totheir 12 month cumulative incidence ofcutaneous leishmaniasis, one sector in each pairwas randomly allocated to receive polyestercurtains impregnated with lambdacyhalothrin(intervention group) while the other sectorreceived curtains without insecticide or nocurtains (control groups). After 12 months afollow up household survey was conducted. MAINOUTCOME MEASURES Reduction in abundance of", "metadata": {}}
+{"_id": "9113824", "title": "", "text": "Chronic pancreatitis is essential for induction ofpancreatic ductal adenocarcinoma by K-Rasoncogenes in adult mice.Pancreatic ductaladenocarcinoma (PDA), one of the deadliesthuman cancers, often involves somatic activationof K-Ras oncogenes. We report that selectiveexpression of an endogenous K-Ras(G12V)oncogene in embryonic cells ofacinar/centroacinar lineage results in pancreaticintraepithelial neoplasias (PanINs) and invasivePDA, suggesting that PDA originates bydifferentiation of acinar/centroacinar cells ortheir precursors into ductal-like cells.Surprisingly, adult mice become refractory toK-Ras(G12V)-induced PanINs and PDA. However,if these mice are challenged with a mild form ofchronic pancreatitis, they develop the fullspectrum of PanINs and invasive PDA. Theseobservations suggest that, during adulthood,PDA stems from a combination of genetic (e.g.,somatic K-Ras mutations) and nongenetic (e.g.,tissue damage) events.", "metadata": {}}
+{"_id": "9122283", "title": "", "text": "Relative roles of direct regeneration versusparacrine effects of human cardiosphere-derivedcells transplanted into infarcted mice.RATIONALEMultiple biological mechanisms contribute to theefficacy of cardiac cell therapy. Most prominentamong these are direct heart muscle and bloodvessel regeneration from transplanted cells, asopposed to paracrine enhancement of tissuepreservation and/or recruitment of endogenousrepair. OBJECTIVE Human cardiac progenitorcells, cultured as cardiospheres (CSps) or asCSp-derived cells (CDCs), have been shown tobe capable of direct cardiac regeneration in vivo.Here we characterized paracrine effects in CDCtransplantation and investigated their relativeimportance versus direct differentiation ofsurviving transplanted cells. METHODS ANDRESULTS In vitro, many growth factors werefound in media conditioned by human adult CSpsand CDCs; CDC-conditioned media exertedantiapoptotic effects on neonatal rat ventricularmyocytes, and proangiogenic effects on human", "metadata": {}}
+{"_id": "9142761", "title": "", "text": "The IC(50) of anti-Pfs25 antibody inmembrane-feeding assay varies amongspecies.Plasmodium falciparum surface protein25 (Pfs25) is a candidate fortransmission-blocking vaccines (TBVs).Anti-Pfs25 antibodies block the development ofoocysts in membrane-feeding assays and wehave shown the activity correlates with antibodytiter. In this study, we purified Pfs25-specificIgGs to convert antibody titer to microg/mL anddetermined the amount of antibody required toinhibit 50% of oocyst development (IC(50)). TheIC(50) were, 15.9, 4.2, 41.2, and85.6microg/mL for mouse, rabbit, monkey andhuman, respectively, and the differences amongspecies were significant. Anti-Pfs25 sera fromrabbit, monkey and human showed differentpatterns of competition against 6 mousemonoclonal antibodies, and the avidity ofantibodies among four species were alsodifferent. These data suggests that informationobtained from animal studies which assess", "metadata": {}}
+{"_id": "9154703", "title": "", "text": "Single-Cell RNA-Seq Reveals Dynamic, RandomMonoallelic Gene Expression in MammalianCellsExpression from both alleles is generallyobserved in analyses of diploid cell populations,but studies addressing allelic expression patternsgenome-wide in single cells are lacking. Here, wepresent global analyses of allelic expressionacross individual cells of mouse preimplantationembryos of mixed background (CAST/EiJ ×C57BL/6J). We discovered abundant (12 to 24%)monoallelic expression of autosomal genes andthat expression of the two alleles occursindependently. The monoallelic expressionappeared random and dynamic because therewas considerable variation among closely relatedembryonic cells. Similar patterns of monoallelicexpression were observed in mature cells. Ourallelic expression analysis also demonstrates thede novo inactivation of the paternal Xchromosome. We conclude that independent andstochastic allelic transcription generatesabundant random monoallelic expression in the", "metadata": {}}
+{"_id": "9159125", "title": "", "text": "Lipopolysaccharide-dependent prostaglandinE(2) production is regulated by theglutathione-dependent prostaglandin E(2)synthase gene induced by the Toll-like receptor4/MyD88/NF-IL6 pathway.Macrophages producea large amount of PGE(2) during inflammation.This lipid mediator modulates various immuneresponses. PGE(2) acts on macrophages andinhibits production of cytokines such asTNF-alpha and IL-12. Membrane-boundglutathione-dependent PGE(2) synthase(mPGES) has been shown to be a terminalenzyme of the cyclooxygenase-2-mediatedPGE(2) biosynthesis. Here we identified mPGESas a molecule that is induced by LPS inmacrophages. The expression of mPGES was notinduced by LPS in mice lacking Toll-like receptor4 or MyD88. Furthermore, mice deficient inNF-IL6 showed neither induction of mPGES norbiosynthesis of PGE(2) in response to LPS,indicating that mPGES expression in response toLPS is regulated by a Toll-like receptor", "metadata": {}}
+{"_id": "9159495", "title": "", "text": "A microRNA feedback loop regulates globalmicroRNA abundance during aging.Expressionlevels of many microRNAs (miRNAs) changeduring aging, notably declining globally in anumber of organisms and tissues across taxa.However, little is known about the mechanismsor the biological relevance for this change. Weinvestigated the network of genes that controlsmiRNA transcription and processing during C.elegans aging. We found that miRNA biogenesisgenes are highly networked with transcriptionfactors and aging-associated miRNAs. Inparticular, miR-71, known to influence life spanand itself up-regulated during aging, repressesalg-1/Argonaute expressionpost-transcriptionally during aging. IncreasedALG-1 abundance in mir-71 loss-of-functionmutants led to globally increased miRNAexpression. Interestingly, these mutantsdemonstrated widespread mRNA expressiondysregulation and diminished levels of variabilityboth in gene expression and in overall life span.", "metadata": {}}
+{"_id": "9160947", "title": "", "text": "Early lymphocyte expansion is severely impairedin interleukin 7 receptor-deficientmiceInterleukin 7 (IL-7) stimulates theproliferation of B cell progenitors, thymocytes,and mature T cells through an interaction with ahigh affinity receptor (IL-7R) belonging to thehematopoietin receptor superfamily. We havefurther addressed the role of IL-7 and itsreceptor during B and T cell development bygenerating mice genetically deficient in IL-7R.Mutant mice display a profound reduction inthymic and peripheral lymphoid cellularity.Analyses of lymphoid progenitor populations inIL-7R-deficient mice define precisely thosedevelopmental stages affected by the mutationand reveal a critical role for IL-7R during earlylymphoid development. Significantly, thesestudies indicate that the phase of thymocyteexpansion occurring before the onset of T cellreceptor gene rearrangement is criticallydependent upon, and mediated by the highaffinity receptor for IL-7.", "metadata": {}}
+{"_id": "9161988", "title": "", "text": "Immune Activation with HIV VaccinesThedevelopment of a safe and effective HIV vaccineis perhaps the most important and challenginggoal remaining in HIV-AIDS research. Recentprogress using a poxvirus vector prime andenvelope protein boost strategy demonstrated amodest but statistically significant level ofefficacy and established the concept that avaccine could prevent HIV infection (1), andapproaches to boost durability and efficacy arecurrently in the planning stages (2). But theresults of two vaccine concepts based onrecombinant adenovirus serotype-5 (rAd5) (3–5)pointed to a potential major problem—that suchvaccines might increase susceptibility to HIVinfection. This also raised the question ofwhether the problem extends to some or all ofthe other recombinant adenovirus vectorscurrently in development or to othervector-based vaccines.", "metadata": {}}
+{"_id": "9164724", "title": "", "text": "Distribution of dystrophin- andutrophin-associated protein complexes duringactivation of human neutrophils.OBJECTIVEDystrophins, utrophins, and their associatedproteins are involved in structural and signalingroles in nonmuscle tissues; however, descriptionof these proteins in neutrophils remainedunexplored. Therefore we characterize thepattern expression, and the cellular distributionof dystrophin and utrophin gene products anddystrophin-associated proteins (i.e.,beta-dystroglycan, alpha-syntrophin, andalpha-dystrobrevins) in relation to actinfilaments in resting and activated withformyl-methionyl-leucyl-phenylalanine humanneutrophils. MATERIALS AND METHODS Restingand fMLP-activated human neutrophils wereanalyzed by immunoblot and by confocalmicroscopy analysis. Immunoprecipitation assayswere performed to corroborate the presence ofprotein complexes. RESULTSImmunoprecipitation assays and confocal", "metadata": {}}
+{"_id": "9167230", "title": "", "text": "Global and regional burden of hospitaladmissions for severe acute lower respiratoryinfections in young children in 2010: asystematic analysisBACKGROUND The annualnumber of hospital admissions and in-hospitaldeaths due to severe acute lower respiratoryinfections (ALRI) in young children worldwide isunknown. We aimed to estimate the incidence ofadmissions and deaths for such infections inchildren younger than 5 years in 2010.METHODS We estimated the incidence ofadmissions for severe and very severe ALRI inchildren younger than 5 years, stratified by ageand region, with data from a systematic reviewof studies published between Jan 1, 1990, andMarch 31, 2012, and from 28 unpublishedpopulation-based studies. We applied theseincidence estimates to population estimates for2010, to calculate the global and regional burdenin children admitted with severe ALRI in thatyear. We estimated in-hospital mortality due tosevere and very severe ALRI by combining", "metadata": {}}
+{"_id": "9169645", "title": "", "text": "Identification of a novel p53 functional domainthat is necessary for mediating apoptosis.Theability of p53 to induce apoptosis requires itssequence-specific DNA binding activity; however,the transactivation-deficient p53(Gln22-Ser23)can still induce apoptosis. Previously, we haveshown that the region between residues 23 and97 in p53 is necessary for such activity. In aneffort to more precisely map a domain necessaryfor apoptosis within the N terminus, we foundthat deletion of the N-terminal 23 amino acidscompromises, but does not abolish, p53induction of apoptosis. Surprisingly,p53(Delta1-42), which lacks the N-terminal 42amino acids and the previously defined activationdomain, retains the ability to induce apoptosis toan even higher level than wild-type p53. A moreextensive deletion, which eliminates theN-terminal 63 amino acids, renders p53completely inert in mediating apoptosis. Inaddition, we found that both p53(Delta1-42) andp53(Gln22-Ser23) can activate a subset of", "metadata": {}}
+{"_id": "9171913", "title": "", "text": "Risk of breast cancer in relation to blood lipids: aprospective study of 31,209 Norwegian womenInthis prospective study, the relationship betweenblood lipids and breast cancer risk wasexamined. Between 1977 and 1983, 31,209Norwegian women, 20 to 54 years of age,attended a health screening carried out by theNorwegian National Health Screening Services.The screening consisted of a questionnaire,anthropometric measurements, and nonfastingblood drawn for analysis of total serumcholesterol (TC), triglyceride (TG), and highdensity lipoprotein (HDL) cholesterol. Lowdensity lipoprotein (LDL) cholesterol wascalculated by the Friedewald's formula. Duringthe seven to 13 years of follow-up, 302 breastcancer cases were identified by linkage to theNorwegian Cancer Registry. After adjustment forsome of the known risk factors of breast cancer,the relative risk of women in the highest quartileof TC compared with women in the lowestquartile was 0.87 (95 percent confidence interval", "metadata": {}}
+{"_id": "9178310", "title": "", "text": "Involvement of lysosomal dysfunction inautophagosome accumulation and earlypathologies in adipose tissue of obesemiceWhether obesity accelerates or suppressesautophagy in adipose tissue is still debatable. Toclarify dysregulation of autophagy and its role inpathologies of obese adipose tissue, we focusedon lysosomal function, protease maturation andactivity, both in vivo and in vitro. First, weshowed that autophagosome formation wasaccelerated, but autophagic clearance wasimpaired in obese adipose tissue. We also foundprotein and activity levels of CTSL (cathepsin L)were suppressed in obese adipose tissue, whilethe activity of CTSB (cathepsin B) wassignificantly enhanced. Moreover, cellularsenescence and inflammasomes were activatedin obese adipose tissue. In 3T3L1 adipocytes,downregulation of CTSL deteriorated autophagicclearance, upregulated expression of CTSB,promoted cellular senescence and activatedinflammasomes. Upregulation of CTSB promoted", "metadata": {}}
+{"_id": "9185195", "title": "", "text": "ARNO regulates VEGF-dependent tissueresponses by stabilizing endothelial VEGFR-2surface expression.AIMS The vascular endothelialgrowth factor (VEGF) stimulates angiogenesis byinduction of vessel permeability, proliferation,and migration of endothelial cells, an importantprocess in ischaemic diseases. ADP-ribosylationfactor (ARF) nucleotide-binding site opener(ARNO) (cytohesin-2) is a guanine exchangefactor important for cellular signalling throughARF GTPases. However, a role for ARNO inVEGF-dependent endothelial processes has so farnot been documented. Therefore, weinvestigated whether ARNO has a role inVEGF-dependent activation of endothelial cellsand thus vessel permeability. METHODS ANDRESULTS ARNO expression was observed inendothelial cells in vitro by RT-PCR, westernblotting, and immunofluorescence as well as exvivo by immunohistochemical staining of mouseaorta. Treatment with the cytohesin inhibitorSecinH3 or with an ARNO siRNA prevented", "metadata": {}}
+{"_id": "9194077", "title": "", "text": "Effects of Hypoxia and Oxidative Stress onExpression of Neprilysin in HumanNeuroblastoma Cells and Rat Cortical Neuronesand AstrocytesPathogenesis of Alzheimer’sdisease (AD), which is characterised byaccumulation of extracellular deposits ofβ-amyloid peptide (Aβ) in the brain, has recentlybeen linked to vascular disorders such asischemia and stroke. Aβ is constantly producedin the brain from amyloid precursor protein (APP)through its cleavage by β- and γ-secretases andcertain Aβ species are toxic for neurones. Thebrain has an endogenous mechanism of Aβremoval via proteolytic degradation and the zincmetalloproteinase neprilysin (NEP) is a criticalregulator of Aβ concentration. Down-regulationof NEP could predispose to AD. By comparing theeffects of hypoxia and oxidative stress onexpression and activity of the Aβ-degradingenzyme NEP in human neuroblastoma NB7 cellsand rat primary cortical neurones we havedemonstrated that hypoxia reduced NEP", "metadata": {}}
+{"_id": "9196472", "title": "", "text": "Genetics and Beyond – The Transcriptome ofHuman Monocytes and DiseaseSusceptibilityBACKGROUND Variability of geneexpression in human may link gene sequencevariability and phenotypes; however,non-genetic variations, alone or in combinationwith genetics, may also influence expressiontraits and have a critical role in physiological anddisease processes. METHODOLOGY/PRINCIPALFINDINGS To get better insight into the overallvariability of gene expression, we assessed thetranscriptome of circulating monocytes, a keycell involved in immunity-related diseases andatherosclerosis, in 1,490 unrelated individualsand investigated its association with >675,000SNPs and 10 common cardiovascular risk factors.Out of 12,808 expressed genes, 2,745expression quantitative trait loci were detected(P<5.78x10(-12)), most of them (90%) beingcis-modulated. Extensive analyses showed thatassociations identified by genome-wideassociation studies of lipids, body mass index or", "metadata": {}}
+{"_id": "9197092", "title": "", "text": "Molecular mechanisms of (-)-epicatechin andchlorogenic acid on the regulation of theapoptotic and survival/proliferation pathways ina human hepatoma cell line.Dietary polyphenolshave been associated with reduced risk ofchronic diseases, but the precise molecularmechanisms of protection remain unclear. Thiswork was aimed at studying the effect of(-)-epicatechin (EC) and chlorogenic acid (CGA)on the regulation of apoptotic andsurvival/proliferation pathways in a humanhepatoma cell line (HepG2). EC or CGAtreatment for 18 h had a slight effect on cellviability and decreased reactive oxygen speciesformation, and EC alone promoted cellproliferation, whereas CGA increased glutathionelevels. Phenols neither induced the caspasecascade for apoptosis nor affected expressionlevels of Bcl-xL or Bax. A sustained activation ofthe major survival signals AKT/PI-3-kinase andERK was shown in EC-treated cells, rather thanin CGA-exposed cells. These data suggest that", "metadata": {}}
+{"_id": "9197786", "title": "", "text": "Wnt5a mediates nerve growth factor-dependentaxonal branching and growth in developingsympathetic neurons.Nerve growth factor (NGF)is a potent survival and axon growth factor forneuronal populations in the peripheral nervoussystem. Although the mechanisms by whichtarget-derived NGF influences survival ofinnervating neurons have been extensivelyinvestigated, its regulation of axonal growth andtarget innervation are just being elucidated.Here, we identify Wnt5a, a member of the Wntfamily of secreted growth factors, as a keydownstream effector of NGF in mediating axonalbranching and growth in developing sympatheticneurons. Wnt5a is robustly expressed insympathetic neurons when their axons areinnervating NGF-expressing targets. NGF:TrkAsignaling enhances neuronal expression ofWnt5a. Wnt5a rapidly induces axon branchingwhile it has a long-term effect on promotingaxon extension. Loss of Wnt5a function revealedthat it is necessary for NGF-dependent axonal", "metadata": {}}
+{"_id": "9199796", "title": "", "text": "The Snf1 kinase controls glucose repression inyeast by modulating interactions between theMig1 repressor and the Cyc8-Tup1co-repressor.Among lower eukaryotes, glucoserepression is a conserved, widely spreadmechanism regulating carbon catabolism. Theyeast Snf1 kinase, the Mig1 DNA-bindingrepressor and the Mig1-interacting co-repressorcomplex Cyc8(Ssn6)-Tup1 are centralcomponents of this pathway. Previousexperiments suggested that cytoplasmictranslocation of Mig1, upon its phosphorylationby Snf1 in the nucleus, is the key regulatory stepfor releasing glucose repression. In this reportwe re-evaluate this model. We establish thecoordinated repressive action of Mig1 andCyc8-Tup1 on GAL1 transcription, but we findthat Cyc8-Tup1 is not tethered by Mig1 to thepromoter DNA. We demonstrate that bothnegative regulators occupy GAL1 continuouslyunder either repression or activation conditions,although the majority of the Mig1 is redistributed", "metadata": {}}
+{"_id": "9211173", "title": "", "text": "ARID1A mutations in endometriosis-associatedovarian carcinomas.BACKGROUND Ovarianclear-cell and endometrioid carcinomas mayarise from endometriosis, but the molecularevents involved in this transformation have notbeen described. METHODS We sequenced thewhole transcriptomes of 18 ovarian clear-cellcarcinomas and 1 ovarian clear-cell carcinomacell line and found somatic mutations in ARID1A(the AT-rich interactive domain 1A [SWI-like]gene) in 6 of the samples. ARID1A encodesBAF250a, a key component of the SWI–SNFchromatin remodeling complex. We sequencedARID1A in an additional 210 ovarian carcinomasand a second ovarian clear-cell carcinoma cellline and measured BAF250a expression bymeans of immunohistochemical analysis in anadditional 455 ovarian carcinomas. RESULTSARID1A mutations were seen in 55 of 119ovarian clear-cell carcinomas (46%), 10 of 33endometrioid carcinomas (30%), and none of the76 high-grade serous ovarian carcinomas.", "metadata": {}}
+{"_id": "9217800", "title": "", "text": "The ALS-associated proteins FUS and TDP-43function together to affect Drosophila locomotionand life span.The fatal adult motor neurondisease amyotrophic lateral sclerosis (ALS)shares some clinical and pathological overlapwith frontotemporal dementia (FTD), anearly-onset neurodegenerative disorder. TheRNA/DNA-binding proteins fused in sarcoma(FUS; also known as TLS) and TAR DNA bindingprotein-43 (TDP-43) have recently been shownto be genetically and pathologically associatedwith familial forms of ALS and FTD. It is currentlyunknown whether perturbation of these proteinsresults in disease through mechanisms that areindependent of normal protein function or via thepathophysiological disruption of molecularprocesses in which they are both critical. Here,we report that Drosophila mutants in which thehomolog of FUS is disrupted exhibit decreasedadult viability, diminished locomotor speed, andreduced life span compared with controls. Thesephenotypes were fully rescued by wild-type", "metadata": {}}
+{"_id": "9225850", "title": "", "text": "Non-canonical PI3K-Cdc42-Pak-Mek-ErkSignaling Promotes Immune-Complex-InducedApoptosis in Human NeutrophilsNeutrophils areperipheral blood leukocytes that represent thefirst line of immune cell defense against bacterialand fungal infections but are also crucial playersin the generation of the inflammatory response.Many neutrophil cell surface receptors regulateimportant cellular processes via activation ofagonist-activated PI3Ks. We show here thatactivation of human neutrophils with insolubleimmune complexes drives a previouslyuncharacterized, PI3K-dependent, non-canonical,pro-apoptotic signaling pathway,FcγR-PI3Kβ/δ-Cdc42-Pak-Mek-Erk. This is a raredemonstration of Ras/Raf-independent activationof Erk and of PI3K-mediated activation of Cdc42.In addition, comparative analysis ofimmune-complex- and fMLF-induced signalinguncovers key differences in pathways used byhuman and murine neutrophils. Thenon-canonical pathway we identify in this study", "metadata": {}}
+{"_id": "9226649", "title": "", "text": "Inflammation-induced tumorigenesis in the colonis regulated by caspase-1 and NLRC4.Chronicinflammation is a known risk factor fortumorigenesis, yet the precise mechanism of thisassociation is currently unknown. Theinflammasome, a multiprotein complex formedby NOD-like receptor (NLR) family members, hasrecently been shown to orchestrate multipleinnate and adaptive immune responses, yet itspotential role in inflammation-induced cancer hasbeen little studied. Using the azoxymethane anddextran sodium sulfate colitis-associatedcolorectal cancer model, we show thatcaspase-1-deficient (Casp1(-/-)) mice haveenhanced tumor formation. Surprisingly, the roleof caspase-1 in tumorigenesis was not throughregulation of colonic inflammation, but ratherthrough regulation of colonic epithelial cellproliferation and apoptosis. Consequently,caspase-1-deficient mice demonstrate increasedcolonic epithelial cell proliferation in early stagesof injury-induced tumor formation and reduced", "metadata": {}}
+{"_id": "9239963", "title": "", "text": "The nuclear receptors SF1 and LRH1 areexpressed in endometrial cancer cells andregulate steroidogenic gene transcription bycooperating with AP-1 factors.Excessiveexposure to estradiol represents the main riskfactor for endometrial cancer. The abnormallyhigh estradiol levels in the endometrium ofwomen with endometrial cancer are most likelydue to overproduction by the tumour itself.Endometrial cancer cells express the genesencoding the steroidogenic enzymes involved inestradiol synthesis. Here we used RT-PCR andWestern blot to show that the nuclear receptorsSF1 and LRH1, two well-known regulators ofsteroidogenic gene expression in gonadal andadrenal cells, are also expressed in endometrialcancer cell lines. By transient transfections, wefound that SF1 and LRH1, but not the relatednuclear receptor NUR77, can activate thepromoters of three human steroidogenic genes:STAR, HSD3B2, and CYP19A1 PII. Similarly,forskolin but not PMA, could activate all three", "metadata": {}}
+{"_id": "9244474", "title": "", "text": "Dietary factors in chronic inflammation: foodtolerances and intolerances of a New ZealandCaucasian Crohn's disease population.Diet isknown to play a major role in the symptoms ofthe inflammatory bowel disease, Crohn's disease(CD). Although no single diet is appropriate to allindividuals, most CD patients are aware of foodsthat provide adverse or beneficial effects. Thisstudy seeks to categorise foods in relation totheir effects on symptoms of CD, in a NewZealand Caucasian population. Four hundred andforty-six subjects from two different centres inNew Zealand were recruited into the study. Anextensive dietary questionnaire (257 food itemsin 15 groups) recorded self-reported dietarytolerances and intolerances. Across each of thefood groups, there were statistically significantdifferences among responses to foods. Atwo-dimensional graphical summary enabledstratification of foods according to the probabilitythat they will be either beneficial or detrimental.A small number of foods are frequently", "metadata": {}}
+{"_id": "9254550", "title": "", "text": "Age as a risk factor for thrombocytopenia andanaemia in children treated for acuteuncomplicated falciparum malaria.BACKGROUND& OBJECTIVES Anaemia is commonly observed inchildren with malaria, but reports on leucocyteand platelet count abnormalities associated withmalaria are inconsistent. This study examinedthe effect of age, gender, parasite density andtemperature on haematological parameters inchildren with acute uncomplicated malaria.METHODS Haematological parameters weredetermined in children with acute uncomplicatedmalaria, and these were correlated with age,sex, temperature and parasite density. Statisticalanalysis was done using SAS 9.1. RESULTS Sixhundred and ninety five children with acuteuncomplicated malaria participated in the study.The mean age was 51.7 months +/- 33.8. Atpresentation, anaemia occurred in 43.8% of thepatients and children <5 yr had a significantlylower haematocrit (28.4% +/- 4.8) than that ofolder children (32.8% +/- 4.8) (p <0.001), but", "metadata": {}}
+{"_id": "9257019", "title": "", "text": "Discovery of endogenous catecholamines inlymphocytes and evidence for catecholamineregulation of lymphocyte function via anautocrine loop.Evidence has been obtained thatcatecholamines and their metabolites are presentin single lymphocytes and extracts of T- andB-cell clones by use of capillary electrophoresiswith electrochemical detection. Pharmacologicalinhibition of tyrosine hydroxylase reducesobserved catecholamine levels, suggestingcatecholamine synthesis by lymphocytes.Intracellular dopamine levels are shown to beincreased by extra-cellular dopamine, suggestinga cellular-uptake mechanism. Furthermore,incubation with either dopamine orL-dihydroxyphenylalanine, a precursor ofdopamine, results in a dose-dependent inhibitionof lymphocyte proliferation and differentiation.Together, these results suggest the presence ofan autocrine loop whereby lymphocytesdown-regulate their own activity.", "metadata": {}}
+{"_id": "9272598", "title": "", "text": "Structure-based drug design identifiespolythiophenes as antiprion compoundsPrionscause transmissible spongiform encephalopathiesfor which no treatment exists. Prions consist ofPrPSc, a misfolded and aggregated form of thecellular prion protein (PrPC). We explore theantiprion properties of luminescent conjugatedpolythiophenes (LCPs) that bind and stabilizeordered protein aggregates. By administering alibrary of structurally diverse LCPs to the brainsof prion-infected mice via osmotic minipumps,we found that antiprion activity required aminimum of five thiophene rings bearingregularly spaced carboxyl side groups.Solid-state nuclear magnetic resonance analysesand molecular dynamics simulations revealedthat anionic side chains interacted withcomplementary, regularly spaced cationicamyloid residues of model prions. These findingsallowed us to extract structural rules governingthe interaction between LCPs and proteinaggregates, which we then used to design a new", "metadata": {}}
+{"_id": "9274291", "title": "", "text": "Comparisons of patient and physicianexpectations for cancer survivorshipcare.PURPOSE To compare expectations forcancer survivorship care between patients andtheir physicians and between primary careproviders (PCPs) and oncologists. METHODSSurvivors and their physicians were surveyed toevaluate for expectations regarding physicianparticipation in primary cancer follow-up,screening for other cancers, general preventivehealth, and management of comorbidities.RESULTS Of 992 eligible survivors and 607physicians surveyed, 535 (54%) and 378 (62%)were assessable, respectively. Among physicianrespondents, 255 (67%) were PCPs and 123(33%) were oncologists. Comparing patientswith their oncologists, expectations were highlydiscrepant for screening for cancers other thanthe index one (agreement rate, 29%), withpatients anticipating significantly more oncologistinvolvement. Between patients and their PCPs,expectations were most incongruent for primary", "metadata": {}}
+{"_id": "9278263", "title": "", "text": "MHC class I antigen presentation: learning fromviral evasion strategiesThe cell surface display ofpeptides by MHC class I molecules tolymphocytes provides the host with an importantsurveillance mechanism to protect againstinvading pathogens. However, in turn, viruseshave evolved elegant strategies to inhibit variousstages of the MHC class I antigen presentationpathway and prevent the display of viralpeptides. This Review highlights how theelucidation of mechanisms of viral immuneevasion is important for advancing ourunderstanding of virus–host interactions and canfurther our knowledge of the MHC class Ipresentation pathway as well as other cellularpathways.", "metadata": {}}
+{"_id": "9283422", "title": "", "text": "T cell receptor-proximal signals are sustained inperipheral microclusters and terminated in thecentral supramolecular activation cluster.T cellreceptor (TCR) signaling is initiated andsustained in microclusters; however, it's notknown whether signaling also occurs in theTCR-rich central supramolecular activationcluster (cSMAC). We showed that the cSMACformed by fusion of microclusters containedmore CD45 than microclusters and is a siteenriched in lysobisphosphatidic acid, a lipidinvolved in sorting ubiquitinated membraneproteins for degradation. Calcium signaling viaTCR was blocked within 2 min by anti-MHCptreatment and 1 min by latrunculin-A treatment.TCR-MHCp interactions in the cSMAC survivedthese perturbations for 10 min and hence werenot sufficient to sustain signaling. TCRmicroclusters were also resistant to disruption byanti-MHCp and latrunculin-A treatments. Wepropose that TCR signaling is sustained bystabilized microclusters and is terminated in the", "metadata": {}}
+{"_id": "9285396", "title": "", "text": "The role of red cell distribution width in theprognosis of patients with gastriccancer.BACKGROUND Although the red celldistribution width (RDW) has been reported as areliable predictor of prognosis in several types ofcancer, to our knowledge the prognostic value ofRDW in gastric carcinoma has not been studied,so far. OBJECTIVE We aimed to investigate therole of red cell distribution width (RDW) inpredicting prognosis in gastric cancer patients.METHODS All gastric cancer patients whounderwent curative surgery (n= 172, 110M/62F)over a five-year study period were evaluated.Data on demographics, preoperative RDW levels,tumor characteristics (early stage: I and II,advanced stage: IIIA-B-C), disease-free (DFS)and overall survival (OS) were retrospectivelyreviewed. Patients were classified as high RDWgroup (RDW ≥ 16, n= 62) or low RDW group(RDW < 16, n= 110). RESULTS Overall mortalityand postoperative 60-day mortality in bothgroups were 55% and 14%, respectively. A", "metadata": {}}
+{"_id": "9288638", "title": "", "text": "Vascular responsiveness in isolated perfusedkidneys of diabetic hypertensive rats.OBJECTIVEThe aim of this study was to investigate whetherdiabetes and hypertension cause additive effectsin the responses to various vasoconstrictor andvasodilator agents, in isolated perfused kidneysobtained from streptozotocin (STZ)-diabeticWistar-Kyoto (WKY) rats and from diabeticspontaneously hypertensive rats (SHR).METHODS SHR and WKY rats were administeredSTZ 55 mg/kg by intravenous injection into alateral tail vein at age 12 weeks. Eight weekslater the kidneys were isolated and perfused viathe left renal artery with a physiological saltsolution. Renal perfusion pressure was measuredcontinuously. Concentration response curveswere plotted for various vasoconstrictor andvasodilator agents. RESULTS Both the diabeticand the hypertensive state were associated withan increased wet kidney weight. The contractileresponses of the renal arterial system tophenylephrine (PhE), serotonin (5-HT) and", "metadata": {}}
+{"_id": "9291596", "title": "", "text": "DNA replication is required To elicit cellularresponses to psoralen-induced DNA interstrandcross-links.Following introduction of DNAinterstrand cross-links (ICLs), mammalian cellsdisplay chromosome breakage or cell cycle delaywith a 4N DNA content. To further understandthe nature of the delay, previously described as aG(2)/M arrest, we developed a protocol togenerate ICLs during specific intervals of the cellcycle. Synchronous populations of G(1), S, andG(2) cells were treated with photoactivated4'-hydroxymethyl-4,5',8-trimethylpsoralen(HMT) and scored for normal passage intomitosis. In contrast to what was found forionizing radiation, ICLs introduced during G(2)did not result in a G(2)/M arrest, mitotic arrest,or chromosome breakage. Rather, subsequentpassage through S phase was required to triggerboth chromosome breakage and arrest in thenext cell cycle. Similarly, ICLs introduced duringG(1) did not cause a G(1)/S arrest. We concludethat DNA replication is required to elicit the", "metadata": {}}
+{"_id": "9291668", "title": "", "text": "DNA methylation and healthy human agingTheprocess of aging results in a host of changes atthe cellular and molecular levels, which includesenescence, telomere shortening, and changes ingene expression. Epigenetic patterns also changeover the lifespan, suggesting that epigeneticchanges may constitute an important componentof the aging process. The epigenetic mark thathas been most highly studied is DNAmethylation, the presence of methyl groups atCpG dinucleotides. These dinucleotides are oftenlocated near gene promoters and associate withgene expression levels. Early studies indicatedthat global levels of DNA methylation increaseover the first few years of life and then decreasebeginning in late adulthood. Recently, with theadvent of microarray and next-generationsequencing technologies, increases in variabilityof DNA methylation with age have beenobserved, and a number of site-specific patternshave been identified. It has also been shown thatcertain CpG sites are highly associated with age,", "metadata": {}}
+{"_id": "9301606", "title": "", "text": "Parathyroid hormone-induced E4BP4/NFIL3down-regulates transcription inosteoblasts.Parathyroid hormone (PTH), a majorregulator of bone metabolism, activates thePTHR1 receptor on the osteoblast plasmamembrane to initiate signaling and inducetranscription of primary response genes.Subsequently, primary genes with transcriptionalactivity regulate expression of downstream PTHtargets. We have identified the adenovirus E4promoter-binding protein/nuclear factorregulated by IL-3 (E4bp4) as a PTH-inducedprimary gene in osteoblasts. E4BP4 is a basicleucine zipper (bZIP) transcription factor thatrepresses or activates transcription innon-osteoblastic cells. We report here that PTHrapidly and transiently induced E4bp4 mRNA inosteoblastic cells and that this induction did notrequire protein synthesis. PTH also inducedE4BP4 protein synthesis and E4BP4 binding to aconsensus but not to a mutant E4BP4 responseelement (EBPRE). E4BP4 overexpression", "metadata": {}}
+{"_id": "9304312", "title": "", "text": "Molecular basis of synaptic vesicle cargorecognition by the endocytic sorting adaptorstonin 2Synaptic transmission depends onclathrin-mediated recycling of synaptic vesicles(SVs). How select SV proteins are targeted forinternalization has remained elusive. Stonins areevolutionarily conserved adaptors dedicated toendocytic sorting of the SV proteinsynaptotagmin. Our data identify the moleculardeterminants for recognition of synaptotagminby stonin 2 or its Caenorhabditis elegansorthologue UNC-41B. The interaction involvesthe direct association of clusters of basic residueson the surface of the cytoplasmic domain ofsynaptotagmin 1 and a beta strand within themu-homology domain of stonin 2. Mutation ofK783, Y784, and E785 to alanine within thisstonin 2 beta strand results in failure of themutant stonin protein to associate withsynaptotagmin, to accumulate at synapses, andto facilitate synaptotagmin internalization.Synaptotagmin-binding-defective UNC-41B is", "metadata": {}}
+{"_id": "9306247", "title": "", "text": "Size separation of circulatory DNA in maternalplasma permits ready detection of fetal DNApolymorphisms.BACKGROUND Analysis of fetalDNA in maternal plasma has recently beenintroduced as a new method for noninvasiveprenatal diagnosis, particularly for the analysis offetal genetic traits, which are absent from thematernal genome, e.g., RHD orY-chromosome-specific sequences. To date, theanalysis of other fetal genetic traits has beenmore problematic because of the overwhelmingpresence of maternal DNA sequences in thecirculation. We examined whether differentbiochemical properties can be discerned betweenfetal and maternal circulatory DNA. METHODSPlasma DNA was examined by agarose gelelectrophoresis. The fractions of fetal andmaternal DNA in size-fractionated fragmentswere assayed by real-time PCR. Thedetermination of paternally and maternallyinherited fetal genetic traits was examined byuse of highly polymorphic", "metadata": {}}
+{"_id": "9310407", "title": "", "text": "The intravascular volume effect of Ringer'slactate is below 20%: a prospective study inhumansINTRODUCTION Isotonic crystalloids playa central role in perioperative fluid management.Isooncotic preparations of colloids (for example,human albumin or hydroxyethyl starch) remainnearly completely intravascular when infused tocompensate for acute blood losses. Recent datawere interpreted to indicate a comparableintravascular volume effect for crystalloids,challenging the occasionally suggestedadvantage of using colloids to treat hypovolemia.General physiological knowledge and clinicalexperience, however, suggest otherwise.METHODS In a prospective study, double-tracerblood volume measurements were performedbefore and after intended normovolemichemodilution in ten female adults,simultaneously substituting the three-foldamount of withdrawn blood with Ringer's lactate.Any originated deficits were substituted with halfthe volume of 20% human albumin, followed by", "metadata": {}}
+{"_id": "9315213", "title": "", "text": "Fibroblast Growth Factor 21 PreventsAtherosclerosis by Suppression of Hepatic SterolRegulatory Element-Binding Protein-2 andInduction of Adiponectin in MiceBACKGROUNDFibroblast growth factor 21 (FGF21) is ametabolic hormone with pleiotropic effects onglucose and lipid metabolism and insulinsensitivity. It acts as a key downstream target ofboth peroxisome proliferator-activated receptor αand γ, the agonists of which have been used forlipid lowering and insulin sensitization,respectively. However, the role of FGF21 in thecardiovascular system remains elusive.METHODS AND RESULTS The roles of FGF21 inatherosclerosis were investigated by evaluatingthe impact of FGF21 deficiency andreplenishment with recombinant FGF21 inapolipoprotein E(-/-) mice. FGF21 deficiencycauses a marked exacerbation of atheroscleroticplaque formation and premature death inapolipoprotein E(-/-) mice, which is accompaniedby hypoadiponectinemia and severe", "metadata": {}}
+{"_id": "9317504", "title": "", "text": "VARNA: Interactive drawing and editing of theRNA secondary structureDESCRIPTION VARNA isa tool for the automated drawing, visualizationand annotation of the secondary structure ofRNA, designed as a companion software for webservers and databases. FEATURES VARNAimplements four drawing algorithms, supportsinput/output using the classic formats dbn, ct,bpseq and RNAML and exports the drawing asfive picture formats, either pixel-based (JPEG,PNG) or vector-based (SVG, EPS and XFIG). Italso allows manual modification and structuralannotation of the resulting drawing using eitheran interactive point and click approach, within aweb server or through command-line arguments.AVAILABILITY VARNA is a free software, releasedunder the terms of the GPLv3.0 license andavailable at http://varna.lri.fr. SUPPLEMENTARYINFORMATION Supplementary data are availableat Bioinformatics online.", "metadata": {}}
+{"_id": "9334631", "title": "", "text": "C-reactive protein decreases interleukin-10secretion in activated human monocyte-derivedmacrophages via inhibition of cyclic AMPproduction.OBJECTIVE C-Reactive protein (CRP),a cardiovascular risk marker, could alsoparticipate in atherosclerosis. Atheroscleroticplaques express CRP and interleukin (IL)-10, amajor antiinflammatory cytokine. IL-10deficiency results in increased lesion formation,whereas IL-10 delivery attenuates lesions. Wetested the effect of CRP on lipopolysaccharide(LPS)-induced IL-10 secretion in humanmonocyte-derived macrophages (HMDMs).METHODS AND RESULTS Incubation of HMDMswith CRP significantly decreased LPS-inducedIL-10 mRNA and intracellular and secreted IL-10protein and destabilized IL-10 mRNA. Also, CRPalone increased secretion of IL-8, IL-6, andtumor necrosis factor from HMDMs and did notinhibit LPS-induced secretion of these cytokines.Fc gamma receptor I antibodies significantlyreversed CRP-mediated IL-10 inhibition. CRP", "metadata": {}}
+{"_id": "9379687", "title": "", "text": "The DNA polymerase activity of Pol ε holoenzymeis required for rapid and efficient chromosomalDNA replication in Xenopus egg extractsDNApolymerase ε (Pol ε) is involved in DNAreplication, repair, and cell-cycle checkpointcontrol in eukaryotic cells. Although the roles ofreplicative Pol α and Pol δ in chromosomal DNAreplication are relatively well understood andwell documented, the precise role of Pol ε inchromosomal DNA replication is not wellunderstood. This study uses a Xenopus eggextract DNA replication system to furtherelucidate the replicative role(s) played by Pol ε.Previous studies show that the initiation timingand elongation of chromosomal DNA replicationare markedly impaired in Pol ε-depleted Xenopusegg extracts, with reduced accumulation ofreplicative intermediates and products. Thisstudy shows that normal replication is restoredby addition of Pol ε holoenzyme to Pol ε-depletedextracts, but not by addition ofpolymerase-deficient forms of Pol ε, including", "metadata": {}}
+{"_id": "9393969", "title": "", "text": "DAF-16/FOXO employs the chromatin remodellerSWI/SNF to promote stress resistance andlongevityOrganisms are constantly challenged bystresses and privations and require adaptiveresponses for their survival. The forkhead box O(FOXO) transcription factor DAF-16 (hereafterreferred to as DAF-16/FOXO) is a central nexusin these responses, but despite its importancelittle is known about how it regulates its targetgenes. Proteomic identification ofDAF-16/FOXO-binding partners in Caenorhabditiselegans and their subsequent functionalevaluation by RNA interference revealed severalcandidate DAF-16/FOXO cofactors, most notablythe chromatin remodeller SWI/SNF.DAF-16/FOXO and SWI/SNF form a complex andglobally co-localize at DAF-16/FOXO targetpromoters. We show that specifically for geneactivation, DAF-16/FOXO depends on SWI/SNF,facilitating SWI/SNF recruitment to targetpromoters, to activate transcription by presumedremodelling of local chromatin. For the animal,", "metadata": {}}
+{"_id": "9394119", "title": "", "text": "Association of type and location of BRCA1 andBRCA2 mutations with risk of breast and ovariancancer.IMPORTANCE Limited information aboutthe relationship between specific mutations inBRCA1 or BRCA2 (BRCA1/2) and cancer riskexists. OBJECTIVE To identify mutation-specificcancer risks for carriers of BRCA1/2. DESIGN,SETTING, AND PARTICIPANTS Observationalstudy of women who were ascertained between1937 and 2011 (median, 1999) and found tocarry disease-associated BRCA1 or BRCA2mutations. The international sample comprised19,581 carriers of BRCA1 mutations and 11,900carriers of BRCA2 mutations from 55 centers in33 countries on 6 continents. We estimatedhazard ratios for breast and ovarian cancerbased on mutation type, function, and nucleotideposition. We also estimated RHR, the ratio ofbreast vs ovarian cancer hazard ratios. A valueof RHR greater than 1 indicated elevated breastcancer risk; a value of RHR less than 1 indicatedelevated ovarian cancer risk. EXPOSURES", "metadata": {}}
+{"_id": "9412420", "title": "", "text": "Endogenous bone marrow MSCs are dynamic,fate-restricted participants in bone maintenanceand regeneration.Mesenchymal stem cells(MSCs) commonly defined by in vitro functionshave entered clinical application despite littledefinition of their function in residence. Here, wereport genetic pulse-chase experiments thatdefine osteoblastic cells as short-lived andnonreplicative, requiring replenishment frombone-marrow-derived, Mx1(+) stromal cells with\"MSC\" features. These cells respond to tissuestress and migrate to sites of injury, supplyingnew osteoblasts during fracture healing. Singlecell transplantation yielded progeny that bothpreserve progenitor function and differentiateinto osteoblasts, producing new bone. They arecapable of local and systemic translocation andserial transplantation. While these cells meetcurrent definitions of MSCs in vitro, they areosteolineage restricted in vivo in growing andadult animals. Therefore, bone-marrow-derivedMSCs may be a heterogeneous population with", "metadata": {}}
+{"_id": "9420732", "title": "", "text": "Dscam and DSCAM: complex genes in simpleanimals, complex animals yet simplegenes.Cadherins and the immunoglobulin (Ig)proteins give rise to a multitude of surfacereceptors, which function as diverse celladhesion molecules (CAMs) or signal-transducingreceptors. These functions are ofteninterdependent, and rely on a high degree ofspecificity in homophilic binding as well asheterophilic interactions. The Drosophila receptorDscam is an exceptional example of homophilicbinding specificity involved in a number ofimportant biological processes, such as neuralwiring and innate immunity. Combinatorial use ofalternatively spliced Ig-domains enables thegeneration of an estimated 18,000isoform-specific homophilic receptor pairs.Although isoform diversity of Dscam is unique toarthropods, recent genetic analysis of vertebrateDSCAM (Down Syndrome Cell AdhesionMolecule) genes has revealed an intriguingconservation of molecular functions underlying", "metadata": {}}
+{"_id": "9433958", "title": "", "text": "Differential innate immune response programs inneuronal subtypes determine susceptibility toinfection in the brain by positive stranded RNAvirusesAlthough susceptibility of neurons in thebrain to microbial infection is a majordeterminant of clinical outcome, little is knownabout the molecular factors governing thisvulnerability. Here we show that two types ofneurons from distinct brain regions showeddifferential permissivity to replication of severalpositive-stranded RNA viruses. Granule cellneurons of the cerebellum and cortical neuronsfrom the cerebral cortex have unique innateimmune programs that confer differentialsusceptibility to viral infection ex vivo and invivo. By transducing cortical neurons with genesthat were expressed more highly in granule cellneurons, we identified threeinterferon-stimulated genes (ISGs; Ifi27, Irg1and Rsad2 (also known as Viperin)) thatmediated the antiviral effects against differentneurotropic viruses. Moreover, we found that the", "metadata": {}}
+{"_id": "9440748", "title": "", "text": "Small-airway obstruction and emphysema inchronic obstructive pulmonarydisease.BACKGROUND The major sites ofobstruction in chronic obstructive pulmonarydisease (COPD) are small airways (<2 mm indiameter). We wanted to determine whetherthere was a relationship between small-airwayobstruction and emphysematous destruction inCOPD. METHODS We used multidetectorcomputed tomography (CT) to compare thenumber of airways measuring 2.0 to 2.5 mm in78 patients who had various stages of COPD, asjudged by scoring on the Global Initiative forChronic Obstructive Lung Disease (GOLD) scale,in isolated lungs removed from patients withCOPD who underwent lung transplantation, andin donor (control) lungs. MicroCT was used tomeasure the extent of emphysema (mean linearintercept), the number of terminal bronchiolesper milliliter of lung volume, and the minimumdiameters and cross-sectional areas of terminalbronchioles. RESULTS On multidetector CT, in", "metadata": {}}
+{"_id": "9451052", "title": "", "text": "Stepwise Histone Replacement by SWR1Requires Dual Activation with Histone H2A.Z andCanonical NucleosomeHistone variantH2A.Z-containing nucleosomes are incorporatedat most eukaryotic promoters. This incorporationis mediated by the conserved SWR1 complex,which replaces histone H2A in canonicalnucleosomes with H2A.Z in an ATP-dependentmanner. Here, we show that promoter-proximalnucleosomes are highly heterogeneous for H2A.Zin Saccharomyces cerevisiae, with substantialrepresentation of nucleosomes containing one,two, or zero H2A.Z molecules. SWR1-catalyzedH2A.Z replacement in vitro occurs in a stepwiseand unidirectional fashion, one H2A.Z-H2B dimerat a time, producing heterotypic nucleosomes asintermediates and homotypic H2A.Znucleosomes as end products. The ATPaseactivity of SWR1 is specifically stimulated byH2A-containing nucleosomes without ensuinghistone H2A eviction. Remarkably, furtheraddition of free H2A.Z-H2B dimer leads to", "metadata": {}}
+{"_id": "9451684", "title": "", "text": "Logic of the yeast metabolic cycle: temporalcompartmentalization of cellularprocesses.Budding yeast grown undercontinuous, nutrient-limited conditions exhibitrobust, highly periodic cycles in the form ofrespiratory bursts. Microarray studies reveal thatover half of the yeast genome is expressedperiodically during these metabolic cycles. Genesencoding proteins having a common functionexhibit similar temporal expression patterns, andgenes specifying functions associated withenergy and metabolism tend to be expressedwith exceptionally robust periodicity. Essentialcellular and metabolic events occur in synchronywith the metabolic cycle, demonstrating that keyprocesses in a simple eukaryotic cell arecompartmentalized in time.", "metadata": {}}
+{"_id": "9460704", "title": "", "text": "Molecular pathways: induction of polyploidy as anovel differentiation therapy forleukemia.Differentiation therapy has emerged asa powerful way to target specific hematologicmalignancies. One of the best examples is theuse of all-trans retinoic acid (ATRA) in acutepromyelocytic leukemia (APL), which hassignificantly improved the outcome for patientswith this specific form of acute myeloid leukemia(AML). In considering how differentiation therapycould be used in other forms of AML, wepredicted that compounds that induce terminaldifferentiation of megakaryocytes would beeffective therapies for the megakaryocytic formof AML, named acute megakaryocytic leukemia(AMKL). We also speculated that such agentswould reduce the burden of abnormalhematopoietic cells in primary myelofibrosis andalter the differentiation of megakaryocytes inmyelodysplastic syndromes. Using ahigh-throughput chemical screening approach,we identified small molecules that promoted", "metadata": {}}
+{"_id": "9478135", "title": "", "text": "Dual mutations in the AML1 and FLT3 genes areassociated with leukemogenesis in acutemyeloblastic leukemia of the M0 subtypePointmutations of the transcription factor AML1 areassociated with leukemogenesis in acutemyeloblastic leukemia (AML). Internal tandemduplications (ITDs) in the juxtamembranedomain and mutations in the second tyrosinekinase domain of the Fms-like tyrosine kinase 3(FLT3) gene represent the most frequent geneticalterations in AML. However, such mutations perse appear to be insufficient for leukemictransformation. To evaluate whether both AML1and FLT3 mutations contribute toleukemogenesis, we analyzed mutations of thesegenes in AML M0 subtype in whom AML1mutations were predominantly observed. Of 51patients, eight showed a mutation in the Runtdomain of the AML1 gene: one heterozygousmissense mutation with normal function, fiveheterozygous frameshift mutations and twobiallelic nonsense or frameshift mutations,", "metadata": {}}
+{"_id": "9483851", "title": "", "text": "Unravelling mechanisms of p53-mediatedtumour suppressionp53 is a crucial tumoursuppressor that responds to diverse stresssignals by orchestrating specific cellularresponses, including transient cell cycle arrest,cellular senescence and apoptosis, which are allprocesses associated with tumour suppression.However, recent studies have challenged therelative importance of these canonical cellularresponses for p53-mediated tumour suppressionand have highlighted roles for p53 in modulatingother cellular processes, including metabolism,stem cell maintenance, invasion and metastasis,as well as communication within the tumourmicroenvironment. In this Opinion article, wediscuss the roles of classical p53 functions, aswell as emerging p53-regulated processes, intumour suppression.", "metadata": {}}
+{"_id": "9486930", "title": "", "text": "Stem cell-related \"self-renewal\" signature andhigh epidermal growth factor receptor expressionassociated with resistance to concomitantchemoradiotherapy in glioblastoma.PURPOSEGlioblastomas are notorious for resistance totherapy, which has been attributed to DNA-repairproficiency, a multitude of deregulated molecularpathways, and, more recently, to the particularbiologic behavior of tumor stem-like cells. Here,we aimed to identify molecular profiles specificfor treatment resistance to the current standardof care of concomitant chemoradiotherapy withthe alkylating agent temozolomide. PATIENTSAND METHODS Gene expression profiles of 80glioblastomas were interrogated for associationswith resistance to therapy. Patients were treatedwithin clinical trials testing the addition ofconcomitant and adjuvant temozolomide toradiotherapy. RESULTS An expression signaturedominated by HOX genes, which comprisesProminin-1 (CD133), emerged as a predictor forpoor survival in patients treated with", "metadata": {}}
+{"_id": "9498458", "title": "", "text": "Heterogeneity Underlies the Emergence ofEGFRT790 Wild-Type Clones Following Treatmentof T790M-Positive Cancers with aThird-Generation EGFR Inhibitor.UNLABELLEDRociletinib is a third-generation EGFR inhibitoractive in lung cancers with T790M, thegatekeeper mutation underlying mostfirst-generation EGFR drug resistance. Webiopsied patients at rociletinib progression toexplore resistance mechanisms. Among 12patients with T790M-positive cancers atrociletinib initiation, six had T790-wild-typerociletinib-resistant biopsies. Two T790-wild-typecancers underwent small cell lung cancertransformation; three T790M-positive cancersacquired EGFR amplification. We documentedT790-wild-type and T790M-positive clonescoexisting within a single pre-rociletinib biopsy.The pretreatment fraction of T790M-positive cellsaffected response to rociletinib. Longitudinalcirculating tumor DNA (ctDNA) analysis revealedan increase in plasma EGFR-activating mutation,", "metadata": {}}
+{"_id": "9500590", "title": "", "text": "Extrathymic Generation of Regulatory T Cells inPlacental Mammals Mitigates Maternal-FetalConflictRegulatory T (Treg) cells, whosedifferentiation and function are controlled by Xchromosome-encoded transcription factor Foxp3,are generated in the thymus (tTreg) andextrathymically (peripheral, pTreg), and theirdeficiency results in fatal autoimmunity. Here,we demonstrate that a Foxp3 enhancer,conserved noncoding sequence 1 (CNS1),essential for pTreg but dispensable for tTreg cellgeneration, is present only in placentalmammals. CNS1 is largely composed ofmammalian-wide interspersed repeats (MIR) thathave undergone retrotransposition during earlymammalian radiation. During pregnancy, pTregcells specific to a model paternal alloantigenwere generated in a CNS1-dependent mannerand accumulated in the placenta. Furthermore,when mated with allogeneic, but not syngeneic,males, CNS1-deficient females showed increasedfetal resorption accompanied by increased", "metadata": {}}
+{"_id": "9505402", "title": "", "text": "Acquired EGFR C797S mutation mediatesresistance to AZD9291 in non–small cell lungcancer harboring EGFR T790MHere we studiedcell-free plasma DNA (cfDNA) collected fromsubjects with advanced lung cancer whosetumors had developed resistance to theepidermal growth factor receptor (EGFR) tyrosinekinase inhibitor (TKI) AZD9291. We firstperformed next-generation sequencing of cfDNAfrom seven subjects and detected an acquiredEGFR C797S mutation in one; expression of thismutant EGFR construct in a cell line rendered itresistant to AZD9291. We then performeddroplet digital PCR on serial cfDNA specimenscollected from 15 AZD9291-treated subjects. Allwere positive for the T790M mutation beforetreatment, but upon developing AZD9291resistance three molecular subtypes emerged:six cases acquired the C797S mutation, fivecases maintained the T790M mutation but didnot acquire the C797S mutation and four caseslost the T790M mutation despite the presence of", "metadata": {}}
+{"_id": "9505448", "title": "", "text": "The Translation Initiation Factor 3f (eIF3f)Exhibits a Deubiquitinase Activity RegulatingNotch ActivationActivation of the mammalianNotch receptor after ligand binding relies on asuccession of events includingmetalloprotease-cleavage, endocytosis,monoubiquitination, and eventually processingby the gamma-secretase, giving rise to a soluble,transcriptionally active molecule. The Notch1receptor was proposed to be monoubiquitinatedbefore its gamma-secretase cleavage; thetargeted lysine has been localized to itssubmembrane domain. Investigating how thisstep might be regulated by a deubiquitinase(DUB) activity will provide new insight forunderstanding Notch receptor activation anddownstream signaling. Animmunofluorescence-based screening of anshRNA library allowed us to identify eIF3f,previously known as one of the subunits of thetranslation initiation factor eIF3, as a DUBtargeting the activated Notch receptor. We show", "metadata": {}}
+{"_id": "9507605", "title": "", "text": "Focal contacts as mechanosensors: externallyapplied local mechanical force induces growth offocal contacts by an mDia1-dependent andROCKindependent mechanismThe transition ofcell–matrix adhesions from the initial punctatefocal complexes into the mature elongated form,known as focal contacts, requires GTPase Rhoactivity. In particular, activation of myosinII–driven contractility by a Rho target known asRho-associated kinase (ROCK) was shown to beessential for focal contact formation. To dissectthe mechanism of Rho-dependent induction offocal contacts and to elucidate the role of cellcontractility, we applied mechanical force tovinculin-containing dot-like adhesions at the celledge using a micropipette. Local centripetalpulling led to local assembly and elongation ofthese structures and to their development intostreak-like focal contacts, as revealed by thedynamics of green fluorescent protein–taggedvinculin or paxillin and interference reflectionmicroscopy. Inhibition of Rho activity by C3", "metadata": {}}
+{"_id": "9513785", "title": "", "text": "Maternal Protein Restriction Affects PostnatalGrowth and the Expression of Key ProteinsInvolved in Lifespan Regulation in MiceWepreviously reported that maternal proteinrestriction in rodents influenced the rate ofgrowth in early life and ultimately affectedlongevity. Low birth weight caused by maternalprotein restriction followed by catch-up growth(recuperated animals) was associated withshortened lifespan whereas protein restrictionand slow growth during lactation (postnatal lowprotein: PLP animals) increased lifespan. We aimto explore the mechanistic basis by which thesedifferences arise. Here we investigated effects ofmaternal diet on organ growth, metabolicparameters and the expression of insulin/IGF1signalling proteins and Sirt1 in muscle of malemice at weaning. PLP mice which experiencedprotein restriction during lactation had lowerfasting glucose (P = 0.038) and insulin levels (P= 0.046) suggesting improved insulin sensitivity.PLP mice had higher relative weights (adjusted", "metadata": {}}
+{"_id": "9538708", "title": "", "text": "‘Short stature in children - a questionnaire forparents’: a new instrument for growthdisorder-specific psychosocial adaptation inchildrenRecent studies report comparablepsychosocial adaptation in children with orwithout a growth disorder. These findings maybe due to a general lack of sensitive and specifictechniques for analysing and comparing theirrespective qualities of life. In this study wepresent a new questionnaire for parents ofshort-statured children. We suggest both aqualitative and quantitative approach providingspecific information about the relative extent ofindividual stress factors and sources of help. Theparents of 442 children with growth retardationresulting from different aetiologies completed thequestionnaire. Aprincipal component analysis ofthe scaled items revealed four dimensions ofpsychosocial adaptation: suffering, futureanxieties, behavioural problems and copingefforts. The index of internal consistencyreliability was sufficient for all scales. The", "metadata": {}}
+{"_id": "9539248", "title": "", "text": "Alphavirus-derived small RNAs modulatepathogenesis in disease vectormosquitoes.Mosquito-borne viruses causesignificant levels of morbidity and mortality inhumans and domesticated animals. Maintenanceof mosquito-borne viruses in nature requires abiological transmission cycle that involvesalternating virus replication in a susceptiblevertebrate and mosquito host. Although thevertebrate infection is acute and often associatedwith disease, continual transmission of theseviruses in nature depends on the establishmentof a persistent, nonpathogenic infection in themosquito vector. An antiviral RNAi response hasbeen shown to limit the replication of RNAviruses in flies. However, the importance of theRNAi pathway as an antiviral defense inmammals is unclear. Differences in the immuneresponses of mammals and mosquitoes mayexplain why these viruses are not generallyassociated with pathology in the invertebratehost. We identified virus-derived small", "metadata": {}}
+{"_id": "9539753", "title": "", "text": "Nuclear RNAi maintains heritable gene silencingin Caenorhabditis elegans.RNA interference(RNAi) is heritable in Caenorhabditis elegans; theprogeny of C. elegans exposed to dsRNA inheritthe ability to silence genes that were targeted byRNAi in the previous generation. Here weinvestigate the mechanism of RNAi inheritance inC. elegans. We show that exposure of animals todsRNA results in the heritable expression ofsiRNAs and the heritable deposition of histone 3lysine 9 methylation (H3K9me) marks inprogeny. siRNAs are detectable before theappearance of H3K9me marks, suggesting thatchromatin marks are not directly inherited but,rather, reestablished in inheriting progeny.Interestingly, H3K9me marks appear moreprominently in inheriting progeny than in animalsdirectly exposed to dsRNA, suggesting thatgerm-line transmission of silencing signals mayenhance the efficiency of siRNA-directedH3K9me. Finally, we show that the nuclear RNAi(Nrde) pathway maintains heritable RNAi", "metadata": {}}
+{"_id": "9547722", "title": "", "text": "Cancer survivors in the United States:prevalence across the survivorship trajectory andimplications for care.BACKGROUND Cancersurvivors represent a growing population,heterogeneous in their need for medical care,psychosocial support, and practical assistance.To inform survivorship research and practice,this manuscript will describe the prevalentpopulation of cancer survivors in terms of overallnumbers and prevalence by cancer site and timesince diagnosis. METHODS Incidence andsurvival data from 1975-2007 were obtainedfrom the Surveillance, Epidemiology, and EndResults Program and population projections fromthe United States Census Bureau. Cancerprevalence for 2012 and beyond was estimatedusing the Prevalence Incidence Approach Model,assuming constant future incidence and survivaltrends but dynamic projections of the U.S.population. RESULTS As of January 1, 2012,approximately 13.7 million cancer survivors wereliving in the United States with prevalence", "metadata": {}}
+{"_id": "9548440", "title": "", "text": "Human aneuploidy: mechanisms and newinsights into an age-old problemTrisomic andmonosomic (aneuploid) embryos account for atleast 10% of human pregnancies and, for womennearing the end of their reproductive lifespan,the incidence may exceed 50%. The errors thatlead to aneuploidy almost always occur in theoocyte but, despite intensive investigation, theunderlying molecular basis has remained elusive.Recent studies of humans and model organismshave shed new light on the complexity of meioticdefects, providing evidence that the age-relatedincrease in errors in the human female is notattributable to a single factor but to an interplaybetween unique features of oogenesis and a hostof endogenous and exogenous factors.", "metadata": {}}
+{"_id": "9550981", "title": "", "text": "The Drosophila hindgut lacks constitutively activeadult stem cells but proliferates in response totissue damage.The adult Drosophila hindgut wasrecently reported to contain active,tissue-replenishing stem cells, like those of themidgut, but located within an anterior ring so asto comprise a single giant crypt. In contrast tothis view, we observed no active stem cells andlittle cell turnover in adult hindgut tissue basedon clonal marking and BrdU incorporationstudies. Again contradicting the previousproposal, we showed that the adult hindgut isnot generated by anterior stem cells duringlarval/pupal development. However, severetissue damage within the hindgut elicits cellproliferation within a ring of putative quiescentstem cells at the anterior of the pylorus. Thus,the hindgut does not provide a model of tissuemaintenance by constitutively active stem cells,but has great potential to illuminate mechanismsof stress-induced tissue repair.", "metadata": {}}
+{"_id": "9555784", "title": "", "text": "Vitamin d deficiency in postmenopausal women -biological correlates.INTRODUCTION Low vitaminD (VD) is associated with secondaryhyperparathyroidism and both contribute todeleterious consequences (reduced bone mineraldensity (BMD), risk of fractures and falls).OBJECTIVE To study the VD status and biologicalcorrelates in a group of postmenopausal women.MATERIAL AND METHODS We studied 123postmenopausal women evaluated in theC.I.Parhon National Institute of Endocrinology,the Pituitary and Neuroendocrine Diseasesdepartment. All cases had been reffered for theevaluation of BMD by the general practitioner.The evaluation included serum measurements oftotal and ionised calcium, phosphorus, alkalinephosphatase (ALP), 25 hydroxi vitaminD(25OHD), parathyroid hormone (PTH),osteocalcin, betacrosslaps. Central DXAosteodensitometry was performed. RESULTS91.9% of cases had 25OHD serum levels below30 ng/ml (74.8% had VD deficiency, 17.1% VD", "metadata": {}}
+{"_id": "9558539", "title": "", "text": "CD44v6 is a marker of constitutive andreprogrammed cancer stem cells driving coloncancer metastasis.Cancer stem cells drive tumorformation and metastasis, but how they acquiremetastatic traits is not well understood. Here, weshow that all colorectal cancer stem cells(CR-CSCs) express CD44v6, which is required fortheir migration and generation of metastatictumors. CD44v6 expression is low in primarytumors but demarcated clonogenic CR-CSCpopulations. Cytokines hepatocyte growth factor(HGF), osteopontin (OPN), and stromal-derivedfactor 1α (SDF-1), secreted from tumorassociated cells, increase CD44v6 expression inCR-CSCs by activating the Wnt/β-cateninpathway, which promotes migration andmetastasis. CD44v6(-) progenitor cells do notgive rise to metastatic lesions but, when treatedwith cytokines, acquire CD44v6 expression andmetastatic capacity. Importantly,phosphatidylinositol 3-kinase (PI3K) inhibitionselectively killed CD44v6 CR-CSCs and reduced", "metadata": {}}
+{"_id": "9559146", "title": "", "text": "Senescent Cells, Tumor Suppression, andOrganismal Aging: Good Citizens, BadNeighborsCells from organisms with renewabletissues can permanently withdraw from the cellcycle in response to diverse stress, includingdysfunctional telomeres, DNA damage, strongmitogenic signals, and disrupted chromatin. Thisresponse, termed cellular senescence, iscontrolled by the p53 and RB tumor suppressorproteins and constitutes a potent anticancermechanism. Nonetheless, senescent cells acquirephenotypic changes that may contribute to agingand certain age-related diseases, includinglate-life cancer. Thus, the senescence responsemay be antagonistically pleiotropic, promotingearly-life survival by curtailing the developmentof cancer but eventually limiting longevity asdysfunctional senescent cells accumulate.", "metadata": {}}
+{"_id": "9580772", "title": "", "text": "Advances in high-resolution imaging--techniquesfor three-dimensional imaging of cellularstructures.A fundamental goal in biology is todetermine how cellular organization is coupled tofunction. To achieve this goal, a betterunderstanding of organelle composition andstructure is needed. Although visualization ofcellular organelles using fluorescence or electronmicroscopy (EM) has become a common tool forthe cell biologist, recent advances are providinga clearer picture of the cell than ever before. Inparticular, advanced light-microscopy techniquesare achieving resolutions below the diffractionlimit and EM tomography provideshigh-resolution three-dimensional (3D) images ofcellular structures. The ability to perform bothfluorescence and electron microscopy on thesame sample (correlative light and electronmicroscopy, CLEM) makes it possible to identifywhere a fluorescently labeled protein is locatedwith respect to organelle structures visualized byEM. Here, we review the current state of the art", "metadata": {}}
+{"_id": "9588931", "title": "", "text": "Quercetin attenuates vascular calcification byinhibiting oxidative stress and mitochondrialfission.Vascular calcification is a strongindependent predictor of increasedcardiovascular morbidity and mortality and has ahigh prevalence among patients with chronickidney disease. The present study investigatedthe effects of quercetin on vascular calcificationcaused by oxidative stress and abnormalmitochondrial dynamics both in vitro and in vivo.Calcifying vascular smooth muscle cells (VSMCs)treated with inorganic phosphate (Pi) exhibitedmitochondrial dysfunction, as demonstrated bydecreased mitochondrial potential and ATPproduction. Disruption of mitochondrial structuralintegrity was also observed in a rat model ofadenine-induced aortic calcification. Increasedproduction of reactive oxygen species, enhancedexpression and phosphorylation of Drp1, andexcessive mitochondrial fragmentation were alsoobserved in Pi-treated VSMCs. These effectswere accompanied by mitochondria-dependent", "metadata": {}}
+{"_id": "9591368", "title": "", "text": "The M/GP5 Glycoprotein Complex of PorcineReproductive and Respiratory Syndrome VirusBinds the Sialoadhesin Receptor in a SialicAcid-Dependent MannerThe porcine reproductiveand respiratory syndrome virus (PRRSV) is amajor threat to swine health worldwide and isconsidered the most significant viral disease inthe swine industry today. In past years, studieson the entry of the virus into its host cell haveled to the identification of a number of essentialvirus receptors and entry mediators. However,viral counterparts for these molecules haveremained elusive and this has made rationaldevelopment of new generation vaccinesimpossible. The main objective of this study wasto identify the viral counterparts for sialoadhesin,a crucial PRRSV receptor on macrophages. Forthis purpose, a soluble form of sialoadhesin wasconstructed and validated. The solublesialoadhesin could bind PRRSV in a sialicacid-dependent manner and could neutralizePRRSV infection of macrophages, thereby", "metadata": {}}
+{"_id": "9599194", "title": "", "text": "A versatile zero background T-vector system forgene cloning and functional genomics.With therecent availability of complete genomicsequences of many organisms, high-throughputand cost-efficient systems for gene cloning andfunctional analysis are in great demand.Although site-specific recombination-basedcloning systems, such as Gateway cloningtechnology, are extremely useful for efficienttransfer of DNA fragments into multipledestination vectors, the two-step cloning processis time consuming and expensive. Here, wereport a zero background TA cloning system thatprovides simple and high-efficiency direct cloningof PCR-amplified DNA fragments with almost noself-ligation. The improved T-vector systemtakes advantage of the restriction enzyme XcmIto generate a T-overhang after digestion and thenegative selection marker gene ccdB to eliminatethe self-ligation background aftertransformation. We demonstrate the feasibilityand flexibility of the technology by developing a", "metadata": {}}
+{"_id": "9600826", "title": "", "text": "GEP100-Arf6-AMAP1-Cortactin PathwayFrequently Used in Cancer Invasion Is Activatedby VEGFR2 to PromoteAngiogenesisAngiogenesis and cancerinvasiveness greatly contribute to cancermalignancy. Arf6 and its effector, AMAP1, arefrequently overexpressed in breast cancer, andconstitute a central pathway to induce theinvasion and metastasis. In this pathway, Arf6 isactivated by EGFR via GEP100. Arf6 is highlyexpressed also in human umbilical veinendothelial cells (HUVECs) and is implicated inangiogenesis. Here, we found that HUVECs alsohighly express AMAP1, and that vascularendothelial growth factor receptor-2 (VEGFR2)recruits GEP100 to activate Arf6. AMAP1functions by binding to cortactin in cancerinvasion and metastasis. We demonstrate thatthe same GEP100-Arf6-AMAP1-cortactin pathwayis essential for angiogenesis activities, includingcell migration and tubular formation, as well asfor the enhancement of cell permeability and", "metadata": {}}
+{"_id": "9604301", "title": "", "text": "Dynamics of Cryptococcusneoformans-Macrophage Interactions Reveal thatFungal Background Influences Outcome duringCryptococcal Meningoencephalitis inHumansUNLABELLED Cryptococcosis is amultifaceted fungal infection with variable clinicalpresentation and outcome. As in many infectiousdiseases, this variability is commonly assigned tohost factors. To investigate whether the diversityof Cryptococcus neoformans clinical (ClinCn)isolates influences the interaction with host cellsand the clinical outcome, we developed andvalidated new quantitative assays using flowcytometry and J774 macrophages. Thephenotype of ClinCn-macrophage interactionswas determined for 54 ClinCn isolates recoveredfrom cerebrospinal fluids (CSF) from 54unrelated patients, based on phagocytic index(PI) and 2-h and 48-h intracellular proliferationindexes (IPH2 and IPH48, respectively). Theirphenotypes were highly variable. Isolatesharboring low PI/low IPH2 and high PI/high IPH2", "metadata": {}}
+{"_id": "9612317", "title": "", "text": "Angiopoietin-2 at high concentration canenhance endothelial cell survival through thephosphatidylinositol 3′-kinase/Akt signaltransduction pathwayThe angiopoietin-Tie2system in endothelial cells is an importantregulator of vasculogenesis and vascularintegrity. High levels of angiopoietin-2 (Ang2)mRNA are observed in vascular activation duringtumorigenesis. Although Ang2 is known to be anaturally occurring antagonist of angiopoietin-1(Ang1) in vivo, the exact function of Ang2 itselfis not known. Here, we found that a highconcentration of Ang2 (800 ng/ml) acts as anapoptosis survival factor for endothelial cellsduring serum deprivation apoptosis. The survivaleffect of high concentration Ang2 was blocked bypre-treatment with soluble Tie2 receptor and thePI 3′-kinase-specific inhibitors, wortmannin andLY294002. Accordingly, 800 ng/ml of Ang2induced phosphorylation of Tie2, the p85 subunitof phosphatidylinositol 3′-kinase (PI 3′-kinase),and serine-threonine kinase Akt at Ser473 in the", "metadata": {}}
+{"_id": "9614443", "title": "", "text": "Lipoxin a4 analogs attenuate induction ofintestinal epithelial proinflammatory geneexpression and reduce the severity of dextransodium sulfate-induced colitis.Theanti-inflammatory eicosanoid lipoxin A(4)(LXA(4)), aspirin-triggered 15-epi-LXA(4), andtheir stable analogs down-regulate IL-8 secretionand subsequent recruitment of neutrophils byintestinal epithelia. In an effort to elucidate themechanism by which these lipid mediatorsmodulate cellular proinflammatory programs, wesurveyed global epithelial gene expression usingcDNA microarrays. LXA(4) analog alone did notsignificantly affect expression of any of the>7000 genes analyzed. However, LXA(4) analogpretreatment attenuated induction ofapproximately 50% of the 125 genesup-regulated in response to thegastroenteritis-causing pathogen Salmonellatyphimurium. A major subset of genes whoseinduction was reduced by LXA(4) analogpretreatment is regulated by NF-kappaB,", "metadata": {}}
+{"_id": "9617381", "title": "", "text": "Serum plant and other noncholesterol sterols,cholesterol metabolism and 22-year mortalityamong middle-aged men.OBJECTIVE To evaluatelong-term prognostic effect of serumnoncholesterol sterols, including plant sterols, inmiddle-aged men with high cardiovasculardisease (CVD) risk, without statins at baseline.METHODS This was a prospective study of 232men (mean age 60 years) at high risk of CVD in1985-1986. Most were hypercholesterolemic, 29(12%) had a history of CVD or cancer, 6 (3%)had diabetes, and 46 (20%) had metabolicsyndrome (MS). Measured noncholesterol sterols(expressed as absolute concentrations or ratiosto serum cholesterol to standardize forcholesterol concentrations) included lathosteroland desmosterol (reflect cholesterol synthesis),and plant sterols (campesterol and sitosterol)and cholestanol (reflect cholesterol absorption).Main outcome measure was total mortality.RESULTS At baseline, markers of cholesterolsynthesis and absorption showed expected", "metadata": {}}
+{"_id": "9622258", "title": "", "text": "Intracoronary autologous cardiac progenitor celltransfer in patients with hypoplastic left heartsyndrome: the TICAP prospective phase 1controlled trial.RATIONALE Hypoplastic left heartsyndrome (HLHS) remains a lethal congenitalcardiac defect. Recent studies have suggestedthat intracoronary administration of autologouscardiosphere-derived cells (CDCs) may improveventricular function. OBJECTIVE The aim of thisstudy was to test whether intracoronary deliveryof CDCs is feasible and safe in patients withhypoplastic left heart syndrome. METHODS ANDRESULTS Between January 5, 2011, and January16, 2012, 14 patients (1.8±1.5 years) wereprospectively assigned to receive intracoronaryinfusion of autologous CDCs 33.4±8.1 days afterstaged procedures (n=7), followed by 7 controlswith standard palliation alone. The primary endpoint was to assess the safety, and thesecondary end point included the preliminaryefficacy to verify the right ventricular ejectionfraction improvements between baseline and 3", "metadata": {}}
+{"_id": "9629682", "title": "", "text": "A Whole Brain Staining, Embedding, and ClearingPipeline for Adult Zebrafish to Visualize CellProliferation and Morphology in 3-DimensionsThefield of macro-imaging has grown considerablywith the appearance of innovative clearingmethods and confocal microscopes with laserscapable of penetrating increasing tissue depths.The ability to visualize and model the growth ofwhole organs as they develop from birth, or withmanipulation, disease or injury, provides newways of thinking about development, tissue-widesignaling, and cell-to-cell interactions. Thezebrafish (Danio rerio) has ascended from apredominantly developmental model to a leadingadult model of tissue regeneration. Theunmatched neurogenic and regenerative capacityof the mature central nervous system, inparticular, has received much attention, howevertools to interrogate the adult brain are sparse. Atpresent there exists no straightforward methodsof visualizing changes in the whole adult brain in3-dimensions (3-D) to examine systemic", "metadata": {}}
+{"_id": "9634465", "title": "", "text": "Single-Construct PolycistronicDoxycycline-Inducible Vectors Improve DirectCardiac Reprogramming and Can Be Used toIdentify the Critical Timing of TransgeneExpressionDirect reprogramming is a promisingapproach in regenerative medicine.Overexpression of the cardiac transcriptionfactors Gata4, Mef2c, and Tbx5 (GMT) or GMTplus Hand2 (GHMT) directly reprogramfibroblasts into cardiomyocyte-like cells (iCMs).However, the critical timing of transgeneexpression and the molecular mechanisms forcardiac reprogramming remain unclear. Theconventional doxycycline (Dox)-inducibletemporal transgene expression systems requiresimultaneous transduction of two vectors(pLVX-rtTA/pLVX-cDNA) harboring the reversetetracycline transactivator (rtTA) and thetetracycline response element (TRE)-controlledtransgene, respectively, leading to inefficientcardiac reprogramming. Herein, we developed asingle-construct-based polycistronic", "metadata": {}}
+{"_id": "9638032", "title": "", "text": "Increasing microtubule acetylation rescuesaxonal transport and locomotor deficits causedby LRRK2 Roc-COR domainmutationsLeucine-rich repeat kinase 2 (LRRK2)mutations are the most common genetic cause ofParkinson's disease. LRRK2 is a multifunctionalprotein affecting many cellular processes and hasbeen described to bind microtubules. Defectivemicrotubule-based axonal transport ishypothesized to contribute to Parkinson'sdisease, but whether LRRK2 mutations affect thisprocess to mediate pathogenesis is not known.Here we find that LRRK2 containing pathogenicRoc-COR domain mutations (R1441C, Y1699C)preferentially associates with deacetylatedmicrotubules, and inhibits axonal transport inprimary neurons and in Drosophila, causinglocomotor deficits in vivo. In vitro, increasingmicrotubule acetylation using deacetylaseinhibitors or the tubulin acetylase αTAT1prevents association of mutant LRRK2 withmicrotubules, and the deacetylase inhibitor", "metadata": {}}
+{"_id": "9641846", "title": "", "text": "G1 arrest and differentiation can occurindependently of Rb family functionThe ability ofprogenitor cells to exit the cell cycle is essentialfor proper embryonic development andhomeostasis, but the mechanisms governing cellcycle exit are still not fully understood. Here, wetested the requirement for the retinoblastoma(Rb) protein and its family members p107 andp130 in G0/G1 arrest and differentiation inmammalian cells. We found that Rb family tripleknockout (TKO) mouse embryos survive untildays 9-11 of gestation. Strikingly, some TKOcells, including in epithelial and neural lineages,are able to exit the cell cycle in G0/G1 anddifferentiate in teratomas and in culture. Thisability of TKO cells to arrest in G0/G1 isassociated with the repression of key E2F targetgenes. Thus, G1 arrest is not always dependenton Rb family members, which illustrates therobustness of cell cycle regulatory networksduring differentiation and allows for theidentification of candidate pathways to inhibit the", "metadata": {}}
+{"_id": "9646449", "title": "", "text": "Induction of ectopic eyes by targeted expressionof the eyeless gene in Drosophila.The Drosophilagene eyeless (ey) encodes a transcription factorwith both a paired domain and a homeodomain.It is homologous to the mouse Small eye (Pax-6)gene and to the Aniridia gene in humans. Thesegenes share extensive sequence identity, theposition of three intron splice sites is conserved,and these genes are expressed similarly in thedeveloping nervous system and in the eye duringmorphogenesis. Loss-of-function mutations inboth the insect and in the mammalian geneshave been shown to lead to a reduction orabsence of eye structures, which suggests thatey functions in eye morphogenesis. By targetedexpression of the ey complementary DNA invarious imaginal disc primordia of Drosophila,ectopic eye structures were induced on thewings, the legs, and on the antennae. Theectopic eyes appeared morphologically normaland consisted of groups of fully differentiatedommatidia with a complete set of photoreceptor", "metadata": {}}
+{"_id": "9648896", "title": "", "text": "mir-1-mediated paracrine effect ofcancer-associated fibroblasts on lung cancer cellproliferation and chemoresistance.Lung cancer isthe leading cause of cancer-related mortality inhumans worldwide. Moreover, the overall 5-yearsurvival rate is only 15%. Pathologically almost80% of all lung cancer cases are non-small celllung cancer (NSCLC). Cancer-associatedfibroblasts (CAFs) have been found to exist in alarge number of NSCLCs. CAFs have been provento promote tumor progression, metastasis andresistance to therapy through paracrine effects inmost solid tumors. In the present study, firstlywe isolated CAFs from patient tissues anddemonstrated that they promoted cellproliferation and chemoresistance to cisplatin inthe lung cancer cell lines A549 and 95D in aparacrine manner. Secondly, using ELISA andquantative PCR, we found that a higher amountof stromal cell-derived factor 1 (SDF-1) existedin the CAFs rather than that observed in thenormal fibroblasts (NFs). Thirdly, we detected", "metadata": {}}
+{"_id": "9650982", "title": "", "text": "Genome-wide association analyses in East Asiansidentify new susceptibility loci for colorectalcancerTo identify new genetic factors forcolorectal cancer (CRC), we conducteda                 genome-wide association study ineast Asians. By analyzing genome-wide data in2,098                 cases and 5,749 controls, weselected 64 promising SNPs for replication inan                 independent set of samples,including up to 5,358 cases and 5,922 controls.We                 identified four SNPs withassociation P values of 8.58×                     10(-7) to 3.77 ×10(-10)                 in the combined analysis ofall east Asian samples. Three of the fourwere                 replicated in a study conductedin 26,060 individuals of European descent,with                 combined P values of 1.22 ×10(-10) for                 rs647161 (5q31.1), 6.64× 10(-9) for rs2423279                 (20p12.3)and 3.06 × 10(-8) forrs10774214                 (12p13.32 near the", "metadata": {}}
+{"_id": "9655347", "title": "", "text": "Long non-coding RNAs as novel players in β cellfunction and type 1 diabetesBACKGROUND Longnon-coding RNAs (lncRNAs) are a sub-classwithin non-coding RNA repertoire that haveemerged as crucial regulators of the geneexpression in various pathophysiologicalconditions. lncRNAs display remarkableversatility and wield their functions throughinteractions with RNA, DNA, or proteins.Accumulating body of evidence based onmultitude studies has highlighted the role oflncRNAs in many autoimmune and inflammatorydiseases, including type 1 diabetes (T1D). Thisreview highlights emerging roles of lncRNAs inimmune and islet β cell function as well as someof the challenges and opportunities inunderstanding the pathogenesis of T1D and itscomplications. CONCLUSION We accentuate thatthe lncRNAs within T1D-loci regions in consortwith regulatory variants and enhancer clustersorchestrate the chromatin remodeling in β cellsand thereby act as cis/trans-regulatory", "metadata": {}}
+{"_id": "9658390", "title": "", "text": "Costs of the COPD. Differences betweenintensive care unit and respiratory intermediatecare unit.INTRODUCTION To assess whetherrespiratory intermediate care units (RICUs) arecost effective alternatives to intensive care units(ICUs) for patients with exacerbation of chronicobstructive pulmonary disease (COPD).PATIENTS AND METHODS Multi-centre,prospective, bottom-up cost study performed in15 ICUs and 6 RICUs. COPD patients stayinglonger than 48 h were recruited; those comingfrom other ICUs/RICUs, with immune-deficiencyor stroke, were excluded. After the ICU samplewas standardised to the RICU distribution of thereason-for-admission and infusion of avasoactive drug on admission, 60 ICU patientsand 65 RICU patients remained, of the original164 recruited. For each patient, besides clinicaldata on admission and discharge, dailyinformation about the resources consumed wererecorded and analysed in terms of their costs.RESULTS Total cost per patient was lower in", "metadata": {}}
+{"_id": "9669099", "title": "", "text": "eRNAs are required for p53-dependent enhanceractivity and gene transcription.Binding within ornearby target genes involved in cell proliferationand survival enables the p53 tumor suppressorgene to regulate their transcription and cell-cycleprogression. Using genome-widechromatin-binding profiles, we describe bindingof p53 also to regions located distantly from anyknown p53 target gene. Interestingly, many ofthese regions possess conserved p53-bindingsites and all known hallmarks of enhancerregions. We demonstrate that these p53-boundenhancer regions (p53BERs) indeed containenhancer activity and interactintrachromosomally with multiple neighboringgenes to convey long-distance p53-dependenttranscription regulation. Furthermore, p53BERsproduce, in a p53-dependent manner, enhancerRNAs (eRNAs) that are required for efficienttranscriptional enhancement of interacting targetgenes and induction of a p53-dependentcell-cycle arrest. Thus, our results ascribe", "metadata": {}}
+{"_id": "9675944", "title": "", "text": "Induction of pluripotent stem cells from mouseembryonic fibroblasts by Oct4 and Klf4 withsmall-molecule compounds.Somatic cells can beinduced into pluripotent stem cells (iPSCs) with acombination of four transcription factors,Oct4/Sox2/Klf4/c-Myc orOct4/Sox2/Nanog/LIN28. This provides anenabling platform to obtain patient-specific cellsfor various therapeutic and research applications.However, several problems remain for thisapproach to be therapeutically relevant due todrawbacks associated with efficiency and viralgenome integration. Recently, it was shown thatneural progenitor cells (NPCs) transduced withOct4/Klf4 can be reprogrammed into iPSCs.However, NPCs express Sox2 endogenously,possibly facilitating reprogramming in theabsence of exogenous Sox2. In this study, weidentified a small-molecule combination,BIX-01294 and BayK8644, that enablesreprogramming of Oct4/Klf4-transduced mouseembryonic fibroblasts, which do not", "metadata": {}}
+{"_id": "9680193", "title": "", "text": "Vps22/EAP30 in ESCRT-II mediates endosomalsorting of growth factor and chemokine receptorsdestined for lysosomal degradation.Theubiquitin-binding protein Hrs and endosomalsorting complex required for transport (ESCRT)-Iand ESCRT-III are involved in sortingendocytosed and ubiquitinated receptors tolysosomes for degradation and efficienttermination of signaling. In this study, we haveinvestigated the role of the ESCRT-II subunitVps22/EAP30 in degradative protein sorting ofubiquitinated receptors. Vps22 transientlyexpressed in HeLa cells was detected inendosomes containing endocytosed epidermalgrowth factor receptors (EGFRs) as well as Hrsand ESCRT-I and ESCRT-III. Depletion of Vps22by small interfering RNA, which wasaccompanied by decreased levels of otherESCRT-II subunits, greatly reduced degradationof EGFR and its ligand EGF as well as thechemokine receptor CXCR4. EGFR accumulatedon the limiting membranes of early endosomes", "metadata": {}}
+{"_id": "9687772", "title": "", "text": "XPG stabilizes TFIIH, allowing transactivation ofnuclear receptors: implications for Cockaynesyndrome in XP-G/CS patients.Mutations in thehuman XPG gene give rise to an inheritedphotosensitive disorder, xerodermapigmentosum (XP) associated with Cockaynesyndrome (XP-G/CS). The clinical features of CSin XP-G/CS patients are difficult to explain on thebasis of a defect in nucleotide excision repair(NER). We found that XPG forms a stablecomplex with TFIIH, which is active intranscription and NER. Mutations in XPG found inXP-G/CS patient cells that prevent theassociation with TFIIH also resulted in thedissociation of CAK and XPD from the core TFIIH.As a consequence, the phosphorylation andtransactivation of nuclear receptors weredisturbed in XP-G/CS as well as xpg(-/-) MEFcells and could be restored by expression ofwild-type XPG. These results provide an insightinto the role of XPG in the stabilization of TFIIHand the regulation of gene expression and", "metadata": {}}
+{"_id": "9696379", "title": "", "text": "Metabolic cycling in single yeast cells fromunsynchronized steady-state populations limitedon glucose or phosphate.Oscillations in patternsof expression of a large fraction of yeast genesare associated with the \"metabolic cycle,\" usuallyseen only in prestarved, continuous cultures ofyeast. We used FISH of mRNA in individual cellsto test the hypothesis that these oscillationshappen in single cells drawn fromunsynchronized cultures growing exponentially inchemostats. Gene-expression data fromsynchronized cultures were used to predictcoincident appearance of mRNAs from pairs ofgenes in the unsynchronized cells. Quantitativeanalysis of the FISH results shows that individualunsynchronized cells growing slowly because ofglucose limitation or phosphate limitation showthe predicted oscillations. We conclude that theyeast metabolic cycle is an intrinsic property ofyeast metabolism and does not depend on eithersynchronization or external limitation of growthby the carbon source.", "metadata": {}}
+{"_id": "9704467", "title": "", "text": "in polyploid speciesWe developed the Yeast GeneOrder Browser (YGOB;http://wolfe.gen.tcd.ie/ygob) to facilitate visualcomparisons and computational analysis ofsynteny relationships in yeasts. The datapresented in YGOB, currently covering sevenspecies, are based on sets of homologous genesthat have been intensively manually curatedbased on both sequence similarity and genomiccontext (synteny). We reconciled differentlaboratories' lists of paralogous Saccharomycescerevisiae gene pairs formed by genomeduplication (ohnologs), and presentnear-exhaustive lists of the ohnolog pairsretained in S. cerevisiae (551, including 22previously unidentified), Saccharomyces castellii(599), and Candida glabrata (404).", "metadata": {}}
+{"_id": "9705208", "title": "", "text": "Immune complex relay by subcapsular sinusmacrophages and non-cognate B cells drivesantibody affinity maturationSubcapsular sinus(SCS) macrophages capture antigens from lymphand present them intact for B cell encounter andfollicular delivery. However, the properties ofSCS macrophages are poorly defined. Here weshow SCS macrophage development dependedon lymphotoxin-alpha1beta2, and the cells hadlow lysosomal enzyme expression and retainedopsonized antigens on their surface. Intravitalimaging revealed immune complexes movingalong macrophage processes into the follicle.Moreover, noncognate B cells relayed antigenopsonized by newly produced antibodies fromthe subcapsular region to the germinal center,and affinity maturation was impaired when thistransport process was disrupted. Thus, wecharacterize SCS macrophages as specializedantigen-presenting cells functioning at the apexof an antigen transport chain that promoteshumoral immunity.", "metadata": {}}
+{"_id": "9724974", "title": "", "text": "Promoter decoding of transcription factordynamics involves a trade-off between noise andcontrol of gene expressionNumeroustranscription factors (TFs) encode informationabout upstream signals in the dynamics of theiractivation, but how downstream genes decodethese dynamics remains poorly understood.Using microfluidics to control thenucleocytoplasmic translocation dynamics of thebudding yeast TF Msn2, we elucidate theprinciples that govern how different promotersconvert dynamical Msn2 input into geneexpression output in single cells. Combiningmodeling and experiments, we classifypromoters according to their signal-processingbehavior and reveal that multiple, distinct geneexpression programs can be encoded in thedynamics of Msn2. We show that both oscillatoryTF dynamics and slow promoter kinetics lead tohigher noise in gene expression. Furthermore,we show that the promoter activation timescaleis related to nucleosome remodeling. Our", "metadata": {}}
+{"_id": "9730755", "title": "", "text": "GaAs nanopillar-array solar cells employing insitu surface passivationArrays of III-Vdirect-bandgap semiconductor nanopillarsrepresent promising photovoltaic candidates dueto their inherent high optical absorptioncoefficients and minimized reflection arising fromlight trapping, efficient charge collection in theradial direction and the ability to synthesize themon low-cost platforms. However, the increasedsurface area results in surface states thathamper the power conversion efficiency. Here,we report the first demonstration of GaAsnanopillar-array photovoltaics employingepitaxial passivation with air mass 1.5 globalpower conversion efficiencies of 6.63%.High-bandgap epitaxial InGaP shells are grown insitu and cap the radial p-n junctions to alleviatesurface-state effects. Under light, thephotovoltaic devices exhibit open-circuit voltagesof 0.44 V, short-circuit current densities of 24.3mA cm(-2) and fill factors of 62% with highexternal quantum efficiencies >70% across the", "metadata": {}}
+{"_id": "9732010", "title": "", "text": "Roles of histone acetylation and chromatinremodeling factor in a meiotic recombinationhotspot.Histone acetyltransferases (HATs) andATP-dependent chromatin remodeling factors(ADCRs) are involved in selective gene regulationvia modulation of local chromatin configuration.Activation of the recombination hotspotade6-M26 of Schizosaccharomyces pombe ismediated by a cAMP responsive element(CRE)-like sequence, M26, and a heterodimericATF/CREB transcription factor, Atf1.Pcr1.Chromatin remodeling occurs meiotically aroundM26. We examined the roles of HATs and ADCRsin chromatin remodeling around M26. HistonesH3 and H4 around M26 were hyperacetylated inan M26- and Atf1-dependent manner early inmeiosis. SpGcn5, the S. pombe homolog ofGcn5p, was required for the majority of histoneH3 acetylation around M26 in vivo. Deletion ofgcn5+ caused a significant delay in chromatinremodeling but only partial reduction of M26meiotic recombination frequency. The snf22+ (a", "metadata": {}}
+{"_id": "9737083", "title": "", "text": "The Somatic Genomic Landscape ofGlioblastomaWe describe the landscape ofsomatic genomic alterations based onmultidimensional and comprehensivecharacterization of more than 500 glioblastomatumors (GBMs). We identify several novelmutated genes as well as complexrearrangements of signature receptors, includingEGFR and PDGFRA. TERT promoter mutations areshown to correlate with elevated mRNAexpression, supporting a role in telomerasereactivation. Correlative analyses confirm thatthe survival advantage of the proneural subtypeis conferred by the G-CIMP phenotype, andMGMT DNA methylation may be a predictivebiomarker for treatment response only inclassical subtype GBM. Integrative analysis ofgenomic and proteomic profiles challenges thenotion of therapeutic inhibition of a pathway asan alternative to inhibition of the target itself.These data will facilitate the discovery oftherapeutic and diagnostic target candidates, the", "metadata": {}}
+{"_id": "9745001", "title": "", "text": "Radioiodine treatment of multinodular non-toxicgoitre.OBJECTIVE To investigate the long termeffect of radioactive iodine on thyroid functionand size in patients with non-toxic multinodulargoitre. DESIGN Consecutive patients withmultinodular non-toxic goitre selected forradioactive iodine treatment and followed for aminimum of 12 months (median 48 months)after an intended dose of 3.7 MBq/g thyroidtissue corrected to a 100% uptake of iodine-131in 24 hours. PATIENTS 69 patients with agrowing multinodular non-toxic goitre causinglocal compression symptoms or cosmeticinconveniences. The treatment was chosenbecause of a high operative risk, previousthyroidectomy, or refusal to be operated on.MAIN OUTCOME MEASUREMENTS Standardthyroid function variables and ultrasonicallydetermined thyroid volume before treatment aswell as 1, 2, 3, 6, and 12 months after treatmentand then once a year. RESULTS 56 patients weretreated with a single dose of 131I, 12 with two", "metadata": {}}
+{"_id": "9748934", "title": "", "text": "Alterations in microRNA-124 and AMPA receptorscontribute to social behavioral deficits infrontotemporal dementiaNeurodegenerativediseases, such as frontotemporal dementia(FTD), are often associated with behavioraldeficits, but the underlying anatomical andmolecular causes remain poorly understood.Here we show that forebrain-specific expressionof FTD-associated mutant CHMP2B in micecauses several age-dependentneurodegenerative phenotypes, including socialbehavioral impairments. The social deficits wereaccompanied by a change in AMPA receptor(AMPAR) composition, leading to an imbalancebetween Ca(2+)-permeable andCa(2+)-impermeable AMPARs. Expression ofmost AMPAR subunits was regulated by thebrain-enriched microRNA miR-124, whoseabundance was markedly decreased in thesuperficial layers of the cerebral cortex of miceexpressing the mutant CHMP2B. We foundsimilar changes in miR-124 and AMPAR levels in", "metadata": {}}
+{"_id": "9752604", "title": "", "text": "Activated AMPK boosts the Nrf2/HO-1 signalingaxis—A role for the unfolded protein responseInlight of the emerging interplay between redoxand metabolic signaling pathways weinvestigated the potential cross talk betweennuclear factor E2-related factor 2 (Nrf2) andAMP-activated kinase (AMPK), central regulatorsof the cellular redox and energy balance,respectively. Making use of xanthohumol (XN) asan activator of both the AMPK and the Nrf2signaling pathway we show that AMPK exerts apositive influence on Nrf2/heme oxygenase(HO)-1 signaling in mouse embryonic fibroblasts.Genetic ablation and pharmacological inhibitionof AMPK blunts Nrf2-dependent HO-1 expressionby XN already at the mRNA level. XN leads toAMPK activation via interference withmitochondrial function and activation of liverkinase B1 as upstream AMPK kinase. Thesubsequent AMPK-mediated enhancement of theNrf2/HO-1 response does not depend oninhibition of the mammalian target of rapamycin,", "metadata": {}}
+{"_id": "9754530", "title": "", "text": "The IDEAL recommendations and urologicalinnovationLike other branches of surgery,Urology has encountered major challenges inaligning the research processes by which newinterventions are assessed with the principles ofEvidence-Based Medicine. This article explainsthe IDEAL framework and recommendations andillustrates how they might affect the evaluationof current controversial urological procedures.From an inside perspective, we provide anoverview of the efforts of the IDEAL WorkingGroup to date with special emphasis on the fieldof Urology. There are clear differences betweendrugs and interventions in the natural history ofinnovations. Since the conventional frameworkfor conducting trials of new treatments is largelybased on the former, the evaluation of surgicalinnovations using the same template canencounter significant problems. Difficulties inperforming randomized controlled trials ofsurgical techniques and the persistence of thecase series as an important feature of the", "metadata": {}}
+{"_id": "9754833", "title": "", "text": "Prolonged conservative care versus early surgeryin patients with sciatica caused by lumbar discherniation: two year results of a randomisedcontrolled trial.OBJECTIVES To evaluate theeffects of early lumbar disc surgery comparedwith prolonged conservative care for patientswith sciatica over two years of follow-up.DESIGN Randomised controlled trial. SETTINGNine Dutch hospitals. PARTICIPANTS 283patients with 6-12 weeks of sciatica.INTERVENTIONS Early surgery or an intended sixmonths of continued conservative treatment,with delayed surgery if needed. MAIN OUTCOMEMEASURES Scores from Roland disabilityquestionnaire for sciatica, visual analogue scalefor leg pain, and Likert self rating scale of globalperceived recovery. RESULTS Of the 141 patientsassigned to undergo early surgery, 125 (89%)underwent microdiscectomy. Of the 142 patientsassigned to conservative treatment, 62 (44%)eventually required surgery, seven doing so inthe second year of follow-up. There was no", "metadata": {}}
+{"_id": "9764256", "title": "", "text": "Human papillomavirus testing for the detectionof high-grade cervical intraepithelial neoplasiaand cancer: final results of the POBASCAMrandomised controlled trial.BACKGROUNDHuman papillomavirus (HPV) testing is moresensitive for the detection of high-grade cervicallesions than is cytology, but detection of HPV byDNA screening in two screening rounds 5 yearsapart has not been assessed. The aim of thisstudy was to assess whether HPV DNA testing inthe first screen decreases detection of cervicalintraepithelial neoplasia (CIN) grade 3 or worse,CIN grade 2 or worse, and cervical cancer in thesecond screening. METHODS In this randomisedtrial, women aged 29-56 years participating inthe cervical screening programme in theNetherlands were randomly assigned to receiveHPV DNA (GP5+/6+-PCR method) and cytologyco-testing or cytology testing alone, fromJanuary, 1999, to September, 2002.Randomisation (in a 1:1 ratio) was done withcomputer-generated random numbers after the", "metadata": {}}
+{"_id": "9767444", "title": "", "text": "Epigenetic therapy activates type I interferonsignaling in murine ovarian cancer to reduceimmunosuppression and tumor burden.Ovariancancer is the most lethal of all gynecologicalcancers, and there is an urgent unmet need todevelop new therapies. Epithelial ovarian cancer(EOC) is characterized by an immunesuppressive microenvironment, and response ofovarian cancers to immune therapies has thusfar been disappointing. We now find, in a mousemodel of EOC, that clinically relevant doses ofDNA methyltransferase and histone deacetylaseinhibitors (DNMTi and HDACi, respectively)reduce the immune suppressivemicroenvironment through type I IFN signalingand improve response to immune checkpointtherapy. These data indicate that the type I IFNresponse is required for effective in vivoantitumorigenic actions of the DNMTi5-azacytidine (AZA). Through type I IFNsignaling, AZA increases the numbers of CD45+immune cells and the percentage of active CD8+", "metadata": {}}
+{"_id": "9769310", "title": "", "text": "IGF2 is parentally imprinted during humanembryogenesis and in the Beckwith–WiedemannsyndromeThe phenomenon of parentalimprinting involves the preferential expression ofone parental allele of a subset of chromosomalgenes and has so far only been documented inthe mouse. We show here, by exploitingsequence polymorphisms in exon nine of thehuman insulin–like growth factor 2 (IGF2) gene,that only the paternally–inherited allele is activein embryonic and extra–embryonic cells fromfirst trimester pregnancies. In addition, only thepaternal allele is expressed in tissues from apatient who suffered from Beckwith–Wiedemannsyndrome. Thus the parental imprinting of IGF2appears to be evolutionarily conserved frommouse to man and has implications for thegeneration of the Beckwith–Wiedemannsyndrome.", "metadata": {}}
+{"_id": "9769684", "title": "", "text": "Safety and reliability of Radio FrequencyIdentification Devices in Magnetic ResonanceImaging and ComputedTomographyBACKGROUND Radio FrequencyIdentification (RFID) devices are becoming moreand more essential for patient safety in hospitals.The purpose of this study was to determinepatient safety, data reliability and signal losswearing on skin RFID devices during magneticresonance imaging (MRI) and computedtomography (CT) scanning. METHODS Sixty RFIDtags of the type I-Code SLI, 13.56 MHz, ISO18000-3.1 were tested: Thirty type 1, an RFIDtag with a 76 x 45 mm aluminum-etchedantenna and 30 type 2, a tag with a 31 x 14 mmcopper-etched antenna. The signal loss, materialmovement and heat tests were performed in a1.5 T and a 3 T MR system. For data integrity,the tags were tested additionally during CTscanning. Standardized function tests wereperformed with all transponders before and afterall imaging studies. RESULTS There was no", "metadata": {}}
+{"_id": "9784254", "title": "", "text": "LXR-Dependent Gene Expression Is Importantfor Macrophage Survival and the Innate ImmuneResponseThe liver X receptors (LXRs) are nuclearreceptors with established roles in the regulationof lipid metabolism. We now show that LXRsignaling not only regulates macrophagecholesterol metabolism but also impactsantimicrobial responses. Mice lacking LXRs arehighly susceptible to infection with theintracellular bacteria Listeria monocytogenes(LM). Bone marrow transplant studies point toaltered macrophage function as the majordeterminant of susceptibility. LXR-nullmacrophages undergo accelerated apoptosiswhen challenged with LM and exhibit defectivebacterial clearance in vivo. These defects result,at least in part, from loss of regulation of theantiapoptotic factor SPalpha, a direct target forregulation by LXRalpha. Expression of LXRalphaor SPalpha in macrophages inhibits apoptosis inthe setting of LM infection. Our resultsdemonstrate that LXR-dependent gene", "metadata": {}}
+{"_id": "9787715", "title": "", "text": "Alterations on peripheral B cell subsets followingan acute uncomplicated clinical malaria infectionin childrenBACKGROUND The effects ofPlasmodium falciparum on B-cell homeostasishave not been well characterized. This studyinvestigated whether an episode of acute malariain young children results in changes in theperipheral B cell phenotype. METHODS Usingflow-cytofluorimetric analysis, the B cellphenotypes found in the peripheral blood ofchildren aged 2-5 years were characterizedduring an episode of acute uncomplicated clinicalmalaria and four weeks post-recovery and inhealthy age-matched controls. RESULTS Therewas a significant decrease in CD19+ Blymphocytes during acute malaria.Characterization of the CD19+ B cell subsets inthe peripheral blood based on expression of IgDand CD38 revealed a significant decrease in thenumbers of naive 1 CD38-IgD+ B cells whilethere was an increase in CD38+IgD- memory 3 Bcells during acute malaria. Further analysis of the", "metadata": {}}
+{"_id": "9791313", "title": "", "text": "SETD2: an epigenetic modifier with tumorsuppressor functionalityIn the past decadeimportant progress has been made in ourunderstanding of the epigenetic regulatorymachinery. It has become clear that geneticaberrations in multiple epigenetic modifierproteins are associated with various types ofcancer. Moreover, targeting the epigenome hasemerged as a novel tool to treat cancer patients.Recently, the first drugs have been reported thatspecifically target SETD2-negative tumors. Inthis review we discuss the studies on theassociated protein, Set domain containing 2(SETD2), a histone modifier for which mutationshave only recently been associated with cancerdevelopment. Our review starts with thestructural characteristics of SETD2 and extendsto its corresponding function by combiningstudies on SETD2 function in yeast, Drosophila,Caenorhabditis elegans, mice, and humans.SETD2 is now generally known as the singlehuman gene responsible for trimethylation of", "metadata": {}}
+{"_id": "9796495", "title": "", "text": "Updated energy budgets for neural computationin the neocortex and cerebellum.The brain'senergy supply determines its informationprocessing power, and generates functionalimaging signals. The energy use on the differentsubcellular processes underlying neuralinformation processing has been estimatedpreviously for the grey matter of the cerebraland cerebellar cortex. However, these estimatesneed reevaluating following recent workdemonstrating that action potentials inmammalian neurons are much more energyefficient than was previously thought. Using thisnew knowledge, this paper provides revisedestimates for the energy expenditure on neuralcomputation in a simple model for the cerebralcortex and a detailed model of the cerebellarcortex. In cerebral cortex, most signaling energy(50%) is used on postsynaptic glutamatereceptors, 21% is used on action potentials, 20%on resting potentials, 5% on presynaptictransmitter release, and 4% on transmitter", "metadata": {}}
+{"_id": "9813098", "title": "", "text": "Plasma homocysteine is a risk factor forrecurrent vascular events in young patients withan ischaemic stroke or TIAYoung patients with anischaemic stroke or transient ischaemic attack(TIA) often have no vascular risk factors.Hyperhomocysteinaemia is an established riskfactor for stroke in elderly patients but it isuncertain whether it is also important for theprognosis of young ischaemic stroke and TIApatients. We examined the possible effect of theplasma homocysteine level on the risk ofrecurrent vascular events in patients between 18and 45 years of age. The study populationconsisted of 161 consecutive patients with arecent cerebral infarction or TIA. Data on theprimary event and the homocysteine level werecollected retrospectively from hospital records.General practitioners and patients werecontacted by telephone to record vascular eventsand the type of medication used during thefollow–up period. Vascular events includedcerebral infarction, TIA, pulmonary embolism,", "metadata": {}}
+{"_id": "9814332", "title": "", "text": "LDL inhibits the mediation of cholesterol effluxfrom macrophage foam cells byapoA-I-containing lipoproteins. A putativemechanism for foam cell formation.Although theaccumulation of cholesterol in macrophagesappears to be an initial step in atherogenesis,low-density lipoprotein (LDL), a major risk factorfor atherosclerosis, does not promote cholesterolaccumulation in macrophages in its native form.On the other hand, apolipoprotein (apo)A-I-containing lipoprotein removes cholesterolfrom cholesterol-loaded macrophages (foamcells) and prevents cholesterol fromaccumulating in the cells. We examined theeffect of LDL on cholesterol removal by twospecies of apoA-I-containing lipoproteins, onecontaining only apoA-I (LpA-I) and the othercontaining apoA-I and apoA-II (LpA-I/A-II).When foam cells were incubated with LpA-I orLpA-I/A-II, cellular cholesterol mass wasreduced. In contrast, when LDL was added, thecholesterol-reducing capacities of these", "metadata": {}}
+{"_id": "9822397", "title": "", "text": "Sugar-sweetened beverages, weight gain, andincidence of type 2 diabetes in young andmiddle-aged women.CONTEXT Sugar-sweetenedbeverages like soft drinks and fruit punchescontain large amounts of readily absorbablesugars and may contribute to weight gain and anincreased risk of type 2 diabetes, but theserelationships have been minimally addressed inadults. OBJECTIVE To examine the associationbetween consumption of sugar-sweetenedbeverages and weight change and risk of type 2diabetes in women. DESIGN, SETTING, ANDPARTICIPANTS Prospective cohort analysesconducted from 1991 to 1999 among women inthe Nurses' Health Study II. The diabetesanalysis included 91,249 women free of diabetesand other major chronic diseases at baseline in1991. The weight change analysis included51,603 women for whom complete dietaryinformation and body weight were ascertained in1991, 1995, and 1999. We identified 741incident cases of confirmed type 2 diabetes", "metadata": {}}
+{"_id": "9831859", "title": "", "text": "Pancreatic stellate cells: partners in crime withpancreatic cancer cells.Pancreatic stellate cells(PSC) produce the stromal reaction in pancreaticcancer, but their role in cancer progression is notfully elucidated. We examined the influence ofPSCs on pancreatic cancer growth using (a) anorthotopic model of pancreatic cancer and (b)cultured human PSCs (hPSC) and humanpancreatic cancer cell lines MiaPaCa-2 andPanc-1. Athymic mice received anintrapancreatic injection of saline, hPSCs,MiaPaCa-2 cells, or hPSCs + MiaPaCa-2. After 7weeks, tumor size, metastases, and tumorhistology were assessed. In vitro studiesassessed the effect of cancer cell secretions onPSC migration and the effect of hPSC secretionson cancer cell proliferation, apoptosis, andmigration. Possible mediators of the effects ofhPSC secretions on cancer cell proliferation wereexamined using neutralizing antibodies.Compared with mice receiving MiaPaCa-2 cellsalone, mice injected with hPSCs + MiaPaCa-2", "metadata": {}}
+{"_id": "9846940", "title": "", "text": "Preoperative statin treatment reduces systemicinflammatory response and myocardial damagein cardiac surgery.OBJECTIVE To determine ifpreoperative statin treatment is associated witha reduction in systemic inflammatory response(SIR) and myocardial damage markers followingcardiac surgery with cardiopulmonary bypass(CPB). METHODS We study a prospective cohortof 138 patients who underwent coronary andvalvular surgery with CPB. We differentiate twostudy groups: patients with (group A, n=72) orwithout (group B, n=66) statins. Plasma levels ofpro-inflammatory interleukins (tumour necrosisfactor-alpha (TNF-alpha), interleukin (IL)-6, IL-8and IL-2R), creatine phosphokinase (CPK),CPK-MB and troponin I were measured beforeand 1, 6, 24 and >72 h after surgery. RESULTSThe baseline, operative and postoperativemorbidity and mortality characteristics weresimilar for both the groups. Group A hadsignificantly lower postoperative levels of IL-6than group B at 6h (68.8+/-5 pg ml(-1) vs", "metadata": {}}
+{"_id": "9872468", "title": "", "text": "MEGA7: Molecular Evolutionary Genetics AnalysisVersion 7.0 for Bigger Datasets.We present thelatest version of the Molecular EvolutionaryGenetics Analysis (Mega) software, whichcontains many sophisticated methods and toolsfor phylogenomics and phylomedicine. In thismajor upgrade, Mega has been optimized for useon 64-bit computing systems for analyzing largerdatasets. Researchers can now explore andanalyze tens of thousands of sequences in MegaThe new version also provides an advancedwizard for building timetrees and includes a newfunctionality to automatically predict geneduplication events in gene family trees. The64-bit Mega is made available in two interfaces:graphical and command line. The graphical userinterface (GUI) is a native Microsoft Windowsapplication that can also be used on Mac OS X.The command line Mega is available as nativeapplications for Windows, Linux, and Mac OS X.They are intended for use in high-throughput andscripted analysis. Both versions are available", "metadata": {}}
+{"_id": "9875570", "title": "", "text": "DNA replication fidelityDNA replication fidelity isa key determinant of genome stability and iscentral to the evolution of species and to theorigins of human diseases. Here we review ourcurrent understanding of replication fidelity, withemphasis on structural and biochemical studiesof DNA polymerases that provide new insightsinto the importance of hydrogen bonding, basepair geometry, and substrate-inducedconformational changes to fidelity. These studiesalso reveal polymerase interactions with the DNAminor groove at and upstream of the active sitethat influence nucleotide selectivity, theefficiency of exonucleolytic proofreading, and therate of forming errors via strand misalignments.We highlight common features that are relevantto the fidelity of any DNA synthesis reaction, andconsider why fidelity varies depending on theenzymes, the error, and the local sequenceenvironment.", "metadata": {}}
+{"_id": "9878167", "title": "", "text": "Viable neutrophils release mitochondrial DNA toform neutrophil extracellular trapsNeutrophilextracellular traps (NETs) represent extracellularstructures able to bind and kill microorganisms.It is believed that they are generated byneutrophils undergoing cell death, allowing thesedying or dead cells to kill microbes. We showthat, following priming withgranulocyte/macrophage colony-stimulatingfactor (GM-CSF) and subsequent short-termtoll-like receptor 4 (TLR4) or complement factor5a (C5a) receptor stimulation, viable neutrophilsare able to generate NETs. Strikingly, NETsformed by living cells contain mitochondrial, butno nuclear, DNA. Pharmacological or geneticapproaches to block reactive oxygen species(ROS) production suggested that NET formationis ROS dependent. Moreover, neutrophilpopulations stimulated with GM-CSF and C5ashowed increased survival compared with restingneutrophils, which did not generate NETs. Inconclusion, mitochondrial DNA release by", "metadata": {}}
+{"_id": "9881829", "title": "", "text": "ATP-driven exchange of histone H2AZ variantcatalyzed by SWR1 chromatin remodelingcomplex.The conserved histone variant H2AZ hasan important role in the regulation of geneexpression and the establishment of a buffer tothe spread of silent heterochromatin. Howhistone variants such as H2AZ are incorporatedinto nucleosomes has been obscure. We havefound that Swr1, a Swi2/Snf2-related adenosinetriphosphatase, is the catalytic core of amultisubunit, histone-variant exchanger thatefficiently replaces conventional histone H2Awith histone H2AZ in nucleosome arrays. Swr1 isrequired for the deposition of histone H2AZ atspecific chromosome locations in vivo, and Swr1and H2AZ commonly regulate a subset of yeastgenes. These findings define a previouslyunknown role for the adenosinetriphosphate-dependent chromatin remodelingmachinery.", "metadata": {}}
+{"_id": "9889151", "title": "", "text": "FACT Disrupts Nucleosome Structure by BindingH2A-H2B with Conserved Peptide Motifs.FACT, aheterodimer of Spt16 and Pob3, is an essentialhistone chaperone. We show that the H2A-H2Bbinding activity that is central to FACT functionresides in short acidic regions near the C terminiof each subunit. Mutations throughout theseregions affect binding and cause correlatedphenotypes that range from mild to lethal, withthe largest individual contributions unexpectedlycoming from an aromatic residue and a nearbycarboxylate residue within each domain. Spt16and Pob3 bind overlapping sites on H2A-H2B,and Spt16-Pob3 heterodimers simultaneouslybind two H2A-H2B dimers, the samestoichiometry as the components of anucleosome. An Spt16:H2A-H2B crystal structureexplains the biochemical and genetic data,provides a model for Pob3 binding, and implies amechanism for FACT reorganization that weconfirm biochemically. Moreover, unexpectedsimilarity to binding of ANP32E and Swr1 with", "metadata": {}}
+{"_id": "9899292", "title": "", "text": "Role of AMP-activated protein kinase inmechanism of metformin action.Metformin is awidely used drug for treatment of type 2diabetes with no defined cellular mechanism ofaction. Its glucose-lowering effect results fromdecreased hepatic glucose production andincreased glucose utilization. Metformin'sbeneficial effects on circulating lipids have beenlinked to reduced fatty liver. AMP-activatedprotein kinase (AMPK) is a major cellularregulator of lipid and glucose metabolism. Herewe report that metformin activates AMPK inhepatocytes; as a result, acetyl-CoA carboxylase(ACC) activity is reduced, fatty acid oxidation isinduced, and expression of lipogenic enzymes issuppressed. Activation of AMPK by metformin oran adenosine analogue suppresses expression ofSREBP-1, a key lipogenic transcription factor. Inmetformin-treated rats, hepatic expression ofSREBP-1 (and other lipogenic) mRNAs andprotein is reduced; activity of the AMPK target,ACC, is also reduced. Using a novel AMPK", "metadata": {}}
+{"_id": "9904546", "title": "", "text": "Interferon alfa therapy for chronic hepatitis B inchildren: a multinational randomized controlledtrial.BACKGROUND & AIMS Treatment of chronichepatitis B with interferon alfa is not approved inchildren. The aim of this study was to evaluatethe safety and efficacy of interferon alfa(IFN-alpha) in children with chronic hepatitis Band increased transaminase levels. METHODSChildren were given either IFN-alpha2b (6megaunits/m2 thrice weekly for 24 weeks) or notreatment. Clearance of markers of viralreplication was evaluated 24 weeks after therapyand after 48 weeks of observation in controls.RESULTS Of 149 children enrolled, 144 wereevaluable (70 treated and 74 controls). Serumhepatitis B e antigen and viral DNA becamenegative in 26% of treated children and 11% ofcontrols (P < 0.05). Serum aminotransferaselevels normalized and liver histology improvedamong responders. Hepatitis B surface antigenbecame undetectable in 10% of treated patientsand 1% of controls. Female gender and", "metadata": {}}
+{"_id": "9909405", "title": "", "text": "ImmTACs for targeted cancer therapy: Why,what, how, and which.Overcomingimmunosuppression and activating a cytotoxic Tcell response has the potential to halt theprogression of cancer and, in somecircumstances, eradicate it. Designingtherapeutic interventions that achieve this goalhas proven challenging, but now a greaterunderstanding of the complexities of immuneresponses is beginning to produce some notablebreakthroughs. ImmTACs (immune-mobilisingmonoclonal TCRs against cancer) are a new classof bispecific reagents, based on solublemonoclonal T cell receptors, which have beenengineered to possess extremely high affinity forcognate tumour antigen. In this way, ImmTACsovercome the problem of low affinitytumour-specific T cells imposed by thymicselection and provide access to the large numberof antigens presented as peptide-HLA complexes.Once bound to tumour cells the anti-CD3 effectorend of the ImmTAC drives recruitment of", "metadata": {}}
+{"_id": "9911547", "title": "", "text": "Angiopoietin-like protein 3 supports the activityof hematopoietic stem cells in the bone marrowniche.The physiologic roles of angiopoietin-likeproteins (Angptls) in the hematopoietic systemremain unknown. Here we show thathematopoietic stem cells (HSCs) in Angptl3-nullmice are decreased in number and quiescence.HSCs transplanted into Angptl3-null recipientmice exhibited impaired repopulation. Bonemarrow sinusoidal endothelial cells express highlevels of Angptl3 and are adjacent to HSCs.Importantly, bone marrow stromal cells orendothelium deficient in Angptl3 have asignificantly decreased ability to support theexpansion of repopulating HSCs. Angptl3represses the expression of the transcriptionfactor Ikaros, whose unregulated overexpressiondiminishes the repopulation activity of HSCs.Angptl3, as an extrinsic factor, thus supports thestemness of HSCs in the bone marrow niche.", "metadata": {}}
+{"_id": "9929089", "title": "", "text": "Subsequent chemotherapy reverses acquiredtyrosine kinase inhibitor resistance and restoresresponse to tyrosine kinase inhibitor in advancednon-small-cell lung cancerBACKGROUND Patientswith advanced or metastatic non-small cell lungcancer (NSCLC) can develop acquired resistanceto epidermal growth factor receptor tyrosinekinase inhibitors (TKIs) erlotinib and gefitinib.Here, we report the successful treatment withalternating chemotherapy and TKIs of two casesof advanced NSCLC who developed resistance toTKI. CASE PRESENTATION Two patients withadvanced or metastatic NSCLC were treated withpalliative chemotherapy followed byerlotinib/gefitinib. When TKI therapy failed, twocycles of chemotherapy were provided, whichwere followed by re-challenge with erlotinib orgefitinib. CONCLUSION NSCLC patients withacquired TKI resistance should be managedaggressively whenever possible. Subsequentchemotherapy and target treatment is one of thereasonable choices for those with an initial", "metadata": {}}
+{"_id": "9955779", "title": "", "text": "Epigenetic Therapy Ties MYC Depletion toReversing Immune Evasion and Treating LungCancerCombining DNA-demethylating agents(DNA methyltransferase inhibitors [DNMTis])with histone deacetylase inhibitors (HDACis)holds promise for enhancing cancer immunetherapy. Herein, pharmacologic and isoformspecificity of HDACis are investigated to guidetheir addition to a DNMTi, thus devising a new,low-dose, sequential regimen that imparts arobust anti-tumor effect for non-small-cell lungcancer (NSCLC). Using in-vitro-treated NSCLCcell lines, we elucidate an interferon α/β-basedtranscriptional program with accompanyingupregulation of antigen presentation machinery,mediated in part through double-stranded RNA(dsRNA) induction. This is accompanied bysuppression of MYC signaling and an increase inthe T cell chemoattractant CCL5. Use of thiscombination treatment schema in mouse modelsof NSCLC reverses tumor immune evasion andmodulates T cell exhaustion state towards", "metadata": {}}
+{"_id": "9956893", "title": "", "text": "The Role of PPARγ in Advanced Glycation EndProducts-Induced Inflammatory Response inHuman ChondrocytesOBJECTIVE Advances madein the past ten years highlight the notion thatperoxisome proliferator-activated receptorsgamma (PPARγ) has protective properties in thepathophysiology of osteoarthritis (OA). The aimof this study was to define the roles of PPARγ inAGEs-induced inflammatory response in humanchondrocytes. METHODS Primary humanchondrocytes were stimulated with AGEs in thepresence or absence of neutralizing antibodyagainst RAGE (anti-RAGE), MAPK specificinhibitors and PPARγ agonist pioglitazone. Theexpression of IL-1, MMP-13, TNF-α, PPARγ,nuclear NF-κB p65 and cytosol IκBα wasdetermined by western blotting and real-timePCR. RESULTS AGEs could enhance theexpression of IL-1, TNF-α, and MMP-13, but thelevel of PPARγ was decreased in a time- anddose-dependent manner, which was inhibited byanti-RAGE, SB203580 (P38 MAPK specific", "metadata": {}}
+{"_id": "9967265", "title": "", "text": "Surgical versus medical treatment withcyclooxygenase inhibitors for symptomaticpatent ductus arteriosus in preterminfants.BACKGROUND Patent ductus arteriosus(PDA) with significant left to right shunt inpreterm infants increases morbidity andmortality. Early closure of the ductus arteriosusmay be achieved pharmacologically usingcyclooxygenase inhibitors or by surgery. Theefficacy of both treatment modalities is wellestablished. However, the preferred initialtreatment of a symptomatic PDA in a preterminfant, surgical ligation or treatment withindomethacin, has not been well established.OBJECTIVES To compare the effect of surgicalligation of PDA vs. medical treatment withcyclooxygenase inhibitors (using indomethacin,ibuprofen, or mefenamic acid), each used as theinitial treatment, on neonatal mortality inpreterm infants with a symptomatic PDA.SEARCH STRATEGY The standard search strategyof the Cochrane Neonatal Review Group was", "metadata": {}}
+{"_id": "9973014", "title": "", "text": "The Effect of Collinearity on Parameter Estimatesin Nonlinear Mixed Effect ModelsPurpose. Todemonstrate how correlations among predictorvariables in a population pharmacokinetic modelaffect the ability to discern which covariatesshould enter into the structural pharmacokineticmodel. Methods. Monte Carlo simulation wasused to generate multiple-doseconcentration-time data similar to that seen in aPhase III clinical trial. The drugs'pharmacokinetics were dependent on twocovariates. Five data sets were simulated withincreasing correlation between the twocovariates. All data sets were analyzed usingNONMEM both with and without inclusion of thecovariates in the structural pharmacokineticmodel. Summary measures for ill-conditioningand sensitivity analysis were used to examinehow increasing correlation among covariatesaffects the accuracy and precision of theparameter estimates. Results. When covariateswere included in the structural pharmacokinetic", "metadata": {}}
+{"_id": "9976969", "title": "", "text": "An analysis of age and gender influences on therelative risk for suicide and psychotropic drugself-poisoning.Psychiatric illness is a significantrisk factor for both attempted and completedsuicide and psychotropic medications account for80% of all drug overdoses involving prescriptionmedications. One challenge facing clinicians is tobalance the benefit of treatment against the riskof drug overdose. The aim of the present studywas to compare the age and gender distributionof patients prescribed psychotropic drugs withpatients attempting and completing suicide withthese drugs. Data were obtained from theAustralian census and studies of generalpractitioner prescribing, patients who committedsuicide or presented with self-poisoning within adefined geographic area. The characteristics ofthese populations were compared to calculateodds ratios for attempting or completing suicidewith psychotropic drugs, before and aftercorrection for rates of prescription, in differentage and gender groups. The odds ratios (ORs)", "metadata": {}}
+{"_id": "9977329", "title": "", "text": "Cell death and immune privilege.The hostresponse to pathogens involves complexinflammatory responses and immune reactions.While these are central to host defense and vitalto clearing infections, they are oftenaccompanied by injury to surrounding tissue.Most organ systems can tolerate these responseswithout permanent consequences. However,there are sites that limit the spread ofinflammation because it can threaten organfunction. The most prominent examples of theseare the eye, brain, and reproductive organs(testis, ovary), where even minor bouts ofinflammation can have long-term consequencesfor the survival of the organism. In these organsimmune responses either do not proceed, orproceed in a manner different from other areas;thus, they are called \"immunologically privileged.\" Here a functioning immune response can be theculprit that leads to disease.", "metadata": {}}
+{"_id": "9988425", "title": "", "text": "Niche-Independent Symmetrical Self-Renewal ofa Mammalian Tissue Stem CellPluripotent mouseembryonic stem (ES) cells multiply in simplemonoculture by symmetrical divisions. In vivo,however, stem cells are generally thought todepend on specialised cellularmicroenvironments and to undergopredominantly asymmetric divisions. Ex vivoexpansion of pure populations of tissue stemcells has proven elusive. Neural progenitor cellsare propagated in combination withdifferentiating progeny in floating clusters calledneurospheres. The proportion of stem cells inneurospheres is low, however, and they cannotbe directly observed or interrogated. Here wedemonstrate that the complex neurosphereenvironment is dispensable for stem cellmaintenance, and that the combination offibroblast growth factor 2 (FGF-2) and epidermalgrowth factor (EGF) is sufficient for derivationand continuous expansion by symmetricaldivision of pure cultures of neural stem (NS)", "metadata": {}}
+{"_id": "9993008", "title": "", "text": "A Bivalent Chromatin Structure Marks KeyDevelopmental Genes in Embryonic StemCellsThe most highly conserved noncodingelements (HCNEs) in mammalian genomescluster within regions enriched for genesencoding developmentally importanttranscription factors (TFs). This suggests thatHCNE-rich regions may contain key regulatorycontrols involved in development. We exploredthis by examining histone methylation in mouseembryonic stem (ES) cells across 56 largeHCNE-rich loci. We identified a specificmodification pattern, termed \"bivalent domains,\"consisting of large regions of H3 lysine 27methylation harboring smaller regions of H3lysine 4 methylation. Bivalent domains tend tocoincide with TF genes expressed at low levels.We propose that bivalent domains silencedevelopmental genes in ES cells while keepingthem poised for activation. We also foundstriking correspondences between genomesequence and histone methylation in ES cells,", "metadata": {}}
+{"_id": "9997636", "title": "", "text": "Ovarian Surface Epithelium in Patients withSevere Ovarian Infertility: A Potential Source ofCells Expressing Markers ofPluripotent/Multipotent Stem CellsThe aim of thisstudy was to confirm the presence of stem cellsin the ovarian surface epithelium of patients withpremature ovarian failure and no mature folliclesand oocytes. In these patients, small round cellsof unknown origin expressing SOX-2 marker ofpluripotency were observed among the epithelialcells just after the ovarian surface epitheliumscraping. These cells were an integral part of theovarian surface epithelium. When the scrapedcells were cultured in a medium with addedfollicular fluid to provide some ovarian niche,primitive oocyte-like cells and typicalround-shaped cell clusters positively stained onalkaline phosphatase, and markers ofpluripotency, such as SOX-2 and SSEA-4, weredeveloped. These markers were expressed earlyand also later in the culture. Single oocyte-likecells expressed genes OCT4A, SOX-2, NANOG,", "metadata": {}}
+{"_id": "10009203", "title": "", "text": "Structural Homeostasis: CompensatoryAdjustments of Dendritic Arbor Geometry inResponse to Variations of Synaptic InputAs thenervous system develops, there is an inherentvariability in the connections formed betweendifferentiating neurons. Despite this variability,neural circuits form that are functional andremarkably robust. One way in which neuronsdeal with variability in their inputs is throughcompensatory, homeostatic changes in theirelectrical properties. Here, we show that neuronsalso make compensatory adjustments to theirstructure. We analysed the development ofdendrites on an identified central neuron (aCC)in the late Drosophila embryo at the stage whenit receives its first connections and first becomeselectrically active. At the same time, we chartedthe distribution of presynaptic sites on thedeveloping postsynaptic arbor. Geneticmanipulations of the presynaptic partnersdemonstrate that the postsynaptic dendriticarbor adjusts its growth to compensate for", "metadata": {}}
+{"_id": "10010651", "title": "", "text": "Nutrition and physical activity guidelines forcancer survivors.Cancer survivors are oftenhighly motivated to seek information about foodchoices, physical activity, and dietarysupplements to improve their treatmentoutcomes, quality of life, and overall survival. Toaddress these concerns, the American CancerSociety (ACS) convened a group of experts innutrition, physical activity, and cancersurvivorship to evaluate the scientific evidenceand best clinical practices related to optimalnutrition and physical activity after the diagnosisof cancer. This report summarizes their findingsand is intended to present health care providerswith the best possible information with which tohelp cancer survivors and their families makeinformed choices related to nutrition and physicalactivity. The report discusses nutrition andphysical activity guidelines during the continuumof cancer care, briefly highlighting importantissues during cancer treatment and for patientswith advanced cancer, but focusing largely on", "metadata": {}}
+{"_id": "10012166", "title": "", "text": "The role of protein clearance mechanisms inorganismal ageing and age-related diseases.Theability to maintain a functional proteome, orproteostasis, declines during the ageing process.Damaged and misfolded proteins accumulatewith age, impairing cell function and tissuehomeostasis. The accumulation of damagedproteins contributes to multiple age-relateddiseases such as Alzheimer's, Parkinson's orHuntington's disease. Damaged proteins aredegraded by the ubiquitin-proteasome system orthrough autophagy-lysosome, key componentsof the proteostasis network. Modulation of eitherproteasome activity or autophagic-lysosomalpotential extends lifespan and protectsorganisms from symptoms associated withproteostasis disorders, suggesting that proteinclearance mechanisms are directly linked toageing and age-associated diseases.", "metadata": {}}
+{"_id": "10015292", "title": "", "text": "A distinctive DNA damage response in humanhematopoietic stem cells reveals anapoptosis-independent role for p53 inself-renewal.Highly regenerative tissues such asblood must possess effective DNA damageresponses (DDR) that balance long-termregeneration with protection fromleukemogenesis. Hematopoietic stem cells(HSCs) sustain life-long blood production, yettheir response to DNA damage remains largelyunexplored. We report that human HSCs exhibitdelayed DNA double-strand break rejoining,persistent gammaH2AX foci, and enhanced p53-and ASPP1-dependent apoptosis aftergamma-radiation compared to progenitors. p53inactivation or Bcl-2 overexpression reducedradiation-induced apoptosis and preserved invivo repopulating HSC function. Despite similarprotection from irradiation-induced apoptosis,only Bcl-2-overexpressing HSCs showed higherself-renewal capacity, establishing that intactp53 positively regulates self-renewal", "metadata": {}}
+{"_id": "10017612", "title": "", "text": "Behavioral characterization of neuropeptide Yknockout mice.An extensive behavioralcharacterization was conducted with mice lackingthe gene for neuropeptide Y (NPY) includingresponse to 24 and 48 h fast and challenge withsmall molecule antagonists of NPY receptorsimplicated in mediating the feeding effects ofNPY (i.e., Y1 and Y5). In addition, wildtype (WT)and NPY knockout (KO) mice were tested inlocomotor monitors, elevated plus maze,inhibitory avoidance, acoustic startle, prepulseinhibition, and hot plate assays. One of themajor findings was that the NPY KO mice have areduced food intake relative to WT controls inresponse to fasting. Also, based on data from thebehavioral models, the NPY KO mice may havean anxiogenic-like phenotype, and appear to behypoalgesic in the hot plate paradigm. The datafrom these studies provide further evidence ofinvolvement of NPY in energy balance, anxiety,and possibly nociception.", "metadata": {}}
+{"_id": "10024681", "title": "", "text": "Epigenetic-induced repression of microRNA-205is associated with MED1 activation and a poorerprognosis in localized prostatecancerDeregulation of microRNA (miRNA)expression can have a critical role incarcinogenesis. Here we show in prostate cancerthat miRNA-205 (miR-205) transcription iscommonly repressed and the MIR-205 locus ishypermethylated. LOC642587, the MIR-205 hostgene of unknown function, is also concordantlyinactivated. We show that miR-205 targetsmediator 1 (MED1, also called TRAP220 andPPARBP) for transcriptional silencing in normalprostate cells, leading to reduction in MED1mRNA levels, and in total and activephospho-MED1 protein. Overexpression ofmiR-205 in prostate cancer cells negativelyaffects cell viability, consistent with a tumorsuppressor function. We found thathypermethylation of the MIR-205 locus wasstrongly related with a decrease in miR-205expression and an increase in MED1 expression", "metadata": {}}
+{"_id": "10029891", "title": "", "text": "Th2 cytokine response in Major DepressiveDisorder patients before treatmentIn MajorDepressive Disorder (MDD), the neuroendocrineand immune systems interactions are impaired.We investigated the pro/anti-inflammatoryTh1/Th2 cytokine balance in MDD patients and innon-depressed control group. The MDD subjectsshowed higher levels of cortisol and TNF-alpha,increased CD3+CD8+ and NK percentages,diminished B cell counts and no significantvariations in CD3+CD4+ lymphocyte. Moreover,higher levels of IL-4 and IL-13 (Th2) andsignificantly lower measurements of IL-2 andIFN-gamma (Th1) cytokines were also observedin the MDD group. Overall, we propose that allthese changes could be related to the elevatedcortisol levels seen in the MDD patients. Furtherstudies are necessary to explore these findingsand its implication in future therapeutic approachof MDD patients.", "metadata": {}}
+{"_id": "10029970", "title": "", "text": "CDD: conserved domains and proteinthree-dimensional structureCDD, the ConservedDomain Database, is part of NCBI's Entrez queryand retrieval system and is also accessible via http://www.ncbi.nlm.nih.gov/Structure/cdd/cdd.shtml. CDD provides annotation of proteinsequences with the location of conserved domainfootprints and functional sites inferred fromthese footprints. Pre-computed annotation isavailable via Entrez, and interactive searchservices accept single protein or nucleotidequeries, as well as batch submissions of proteinquery sequences, utilizing RPS-BLAST to rapidlyidentify putative matches. CDD incorporatesseveral protein domain and full-length proteinmodel collections, and maintains an activecuration effort that aims at providing fine grainedclassifications for major and well-characterizedprotein domain families, as supported byavailable protein three-dimensional (3D)structure and the published literature. To thisdate, the majority of protein 3D structures are", "metadata": {}}
+{"_id": "10039688", "title": "", "text": "Extensive diversity of Ig-superfamily proteins inthe immune system of insects.The extensivesomatic diversification of immune receptors is ahallmark of higher vertebrates. However,whether molecular diversity contributes toimmune protection in invertebrates is unknown.We present evidence that Drosophilaimmune-competent cells have the potential toexpress more than 18,000 isoforms of theimmunoglobulin (Ig)-superfamily receptor Downsyndrome cell adhesion molecule (Dscam).Secreted protein isoforms of Dscam weredetected in the hemolymph, andhemocyte-specific loss of Dscam impaired theefficiency of phagocytic uptake of bacteria,possibly due to reduced bacterial binding.Importantly, the molecular diversity of Dscamtranscripts generated through a mechanism ofalternative splicing is highly conserved acrossmajor insect orders, suggesting an unsuspectedmolecular complexity of the innate immunesystem of insects.", "metadata": {}}
+{"_id": "10068634", "title": "", "text": "Preparing the outbreak assistance laboratorynetwork in the Netherlands for the detection ofthe influenza virus A(H1N1)variant.BACKGROUND Late April 2009, humaninfection with variant influenza virus A(H1N1)vemerged in the Northern Americas posing athreat that this virus may become the nextpandemic influenza virus. OBJECTIVES Toprepare laboratories for surge capacity formolecular diagnosis of patients suspected forA(H1N1)v infection in the Netherlands. STUDYDESIGN A panel of 10 blinded specimenscontaining seasonal A(H1N1) or A(H3N2), orA/Netherlands/602/2009(H1N1)v influenza virus,or negative control was distributed to theoutbreak assistance laboratories (OAL) togetherwith influenza virus A (M-gene), swine influenzavirus A (NP-gene) and influenza virus A(H1N1)v(H1v-gene) specific primers and probes andprotocol (CDC Atlanta, USA). Laboratories wereasked to implement and test this protocol.RESULTS All OAL were able to detect A(H1N1)v", "metadata": {}}
+{"_id": "10071552", "title": "", "text": "Averting Obesity and Type 2 Diabetes in Indiathrough Sugar-Sweetened Beverage Taxation:An Economic-Epidemiologic ModelingStudyBACKGROUND Taxing sugar-sweetenedbeverages (SSBs) has been proposed inhigh-income countries to reduce obesity andtype 2 diabetes. We sought to estimate thepotential health effects of such a fiscal strategyin the middle-income country of India, wherethere is heterogeneity in SSB consumption,patterns of substitution between SSBs and otherbeverages after tax increases, and vastdifferences in chronic disease risk within thepopulation. METHODS AND FINDINGS Usingconsumption and price variations data from anationally representative survey of 100,855Indian households, we first calculated howchanges in SSB price alter per capitaconsumption of SSBs and substitution with otherbeverages. We then incorporated SSB salestrends, body mass index (BMI), and diabetesincidence data stratified by age, sex, income,", "metadata": {}}
+{"_id": "10071590", "title": "", "text": "Acute myopericarditis after multiple vaccinationsin an adolescent: case report and review of theliterature.We report a case of postvaccinationacute myopericarditis in an adolescent. Thepatient presented with acute chest pain, diffuseST-segment elevation, and elevated cardiacenzyme levels. Cardiac MRI was consistent withacute myocarditis. He recovered within a fewdays with nonsteroidal antiinflammatorytreatment and remains clinically stable, withimprovement of MRI findings at the 10-weekfollow-up. Postvaccination cases ofmyopericarditis reported in the pediatricliterature are also reviewed.", "metadata": {}}
+{"_id": "10072941", "title": "", "text": "Cardiovascular protection with antihypertensivedrugs in dialysis patients: systematic review andmeta-analysis.Epidemiological studiesdemonstrate that a lower blood pressure anddecline in blood pressure over months or yearsare associated with higher mortality in dialysispatients. In contrast, randomized, controlledtrials lack power to establish benefits ofantihypertensive therapy. Patients on long-termdialysis participating in randomized, controlledtrials and receiving antihypertensive drugtherapy were the subject of this meta-analysis.Outcomes assessed were the hazard ratio ofcardiovascular events and all-cause mortality intreated group compared with controls. Among1202 patients who we identified in 5 studies, theoverall benefit of antihypertensive therapycompared with the control or placebo group hada combined hazard ratio for cardiovascularevents of 0.69 (95% CI: 0.56 to 0.84) using afixed-effects model and 0.62 (95% CI: 0.45 to0.86) using a random-effects model. In a", "metadata": {}}
+{"_id": "10074251", "title": "", "text": "Protoplasmic astrocytes in CA1 stratum radiatumoccupy separate anatomicaldomains.Protoplasmic astrocytes are increasinglythought to interact extensively with neuronalelements in the brain and to influence theiractivity. Recent reports have also begun tosuggest that physiologically, and perhapsfunctionally, diverse forms of these cells may bepresent in the CNS. Our current understanding ofastrocyte form and distribution is basedpredominantly on studies that used theastrocytic marker glial fibrillary acidic protein(GFAP) and on studies using metal-impregnationtechniques. The prevalent opinion, based onstudies using these methods, is that astrocyticprocesses overlap extensively and primarilyshare the underlying neuropil. However, both ofthese techniques have serious shortcomings forvisualizing the interactions among thesestructurally complex cells. In the present study,intracellular injection combined withimmunohistochemistry for GFAP show that GFAP", "metadata": {}}
+{"_id": "10078024", "title": "", "text": "Leptin-receptor-expressing mesenchymalstromal cells represent the main source of boneformed by adult bone marrow.Studies of theidentity and physiological function ofmesenchymal stromal cells (MSCs) have beenhampered by a lack of markers that permit bothprospective identification and fate mapping invivo. We found that Leptin Receptor (LepR) is amarker that highly enriches bone marrow MSCs.Approximately 0.3% of bone marrow cells wereLepR(+) , 10% of which were CFU-Fs, accountingfor 94% of bone marrow CFU-Fs. LepR(+) cellsformed bone, cartilage, and adipocytes in cultureand upon transplantation in vivo. LepR(+) cellswere Scf-GFP(+), Cxcl12-DsRed(high), andNestin-GFP(low), markers which also highlyenriched CFU-Fs, but negative for Nestin-CreERand NG2-CreER, markers which were unlikely tobe found in CFU-Fs. Fate-mapping showed thatLepR(+) cells arose postnatally and gave rise tomost bone and adipocytes formed in adult bonemarrow, including bone regenerated after", "metadata": {}}
+{"_id": "10086360", "title": "", "text": "High-resolution sperm typing of meioticrecombination in the mouse MHC Ebetagene.Meiotic crossovers detected by pedigreeanalysis in the mouse MHC cluster into hotspots.To explore the properties of hotspots, wesubjected the class II E(beta) gene tohigh-resolution sperm crossover analysis. Weconfirm the presence of a highly localizedhotspot 1.0-1.6 kb wide in the second intron ofE(beta) and show that it is flanked by DNA whichis almost completely recombinationally inert.Mice heterozygous for haplotype s and anotherMHC haplotype show major haplotype-dependantvariation in crossover rate but always the samehotspot, even in crosses including the highlydiverged p haplotype. Crossovers in reciprocalorientations occur at similar rates but showdifferent distributions across the hotspot, withthe position of centre points in the twoorientations shifted on average by 400 bp. Thisasymmetry results in crossover products showingbiased gene conversion in favour of hotspot", "metadata": {}}
+{"_id": "10128893", "title": "", "text": "Long-term survival of beta thalassemia majorpatients treated with hematopoietic stem celltransplantation compared with survival withconventional treatment.Allogeneic hematopoieticstem cell transplantation (HSCT) in thalassemiaremains a challenge. We reported a single-centrecase-control study of a large cohort of 516children and adult patients treated with HSCT orblood transfusion support and iron chelationtherapy; 258 patients (median age 12, range1-45) underwent sibling (67%) or unrelated(33%) HSCT; 97 patients were adults (age ≥ 16years). The median follow-up after HSCT was 11years (range 1-30). The conditioning regimenwas busulfan (80.6%) or treosulfan-based(19.4%). A cohort of 258 age-sex matchedconventionally treated (CT) patients wasrandomly selected. In transplanted patients the30-year overall survival (OS) andthalassemia-free survival (TFS) were 82.6 ±2.7% and 77.8 ± 2.9%, compared to the OS of85.3 ± 2.7% in CT patients (P = NS); The", "metadata": {}}
+{"_id": "10145528", "title": "", "text": "Global analysis of ATM polymorphism revealssignificant functional constraint.ATM, the genethat is mutated in ataxia-telangiectasia, isassociated with cerebellar degeneration,abnormal proliferation of small blood vessels,and cancer. These clinically importantmanifestations have stimulated interest indefining the sequence variation in the ATM gene.Therefore, we undertook a comprehensivesurvey of sequence variation in ATM in diversehuman populations. The protein-encoding exonsof the gene (9,168 bp) and the adjacent intronand untranslated sequences (14,661 bp) wereanalyzed in 93 individuals from seven majorhuman populations. In addition, the codingsequence was analyzed in one chimpanzee, onegorilla, one orangutan, and one Old Worldmonkey. In human ATM, 88 variant sites werediscovered by denaturing high-performanceliquid chromatography, which is 96%-100%sensitive for detection of DNA sequencevariation. ATM was compared to 14 other", "metadata": {}}
+{"_id": "10162553", "title": "", "text": "Ablation and regeneration of tolerance-inducingmedullary thymic epithelial cells aftercyclosporine, cyclophosphamide, anddexamethasone treatment.Immunosuppressivedrugs and cytotoxic chemotherapy agents aredesigned to kill or suppress autoreactive,alloaggressive, or hyperinflammatory T cells, ordisseminated malignancies. However, they alsocause severe immunological side effects rangingfrom interrupted thymopoiesis and generalimmunodeficiency to, paradoxically,autoimmunity. Consistent with the cross-talkbetween thymocytes and stromal cells, we nowshow that these common therapeutic agentshave major effects on murine thymic epithelialcells (TEC), crucially required to rebuildimmunity posttreatment. We show that theimmunosuppressant cyclosporine A, which hasbeen linked to a thymus-dependent autoimmunesyndrome in some patients, causes extensiveloss of autoimmune regulator (Aire(+))tolerance-inducing MHC class II(high) medullary", "metadata": {}}
+{"_id": "10165258", "title": "", "text": "GATA-3 regulates hematopoietic stem cellmaintenance and cell-cycle entry.Maintaininghematopoietic stem cell (HSC) quiescence is acritical property for the life-long generation ofblood cells. Approximately 75% of cells in ahighly enriched long-term repopulating HSC(LT-HSC) pool(Lin(-)Sca1(+)c-Kit(hi)CD150(+)CD48(-)) arequiescent, with only a small percentage of theLT-HSCs in cycle. Transcription factor GATA-3 isknown to be vital for the development of T cellsat multiple stages in the thymus and for Th2differentiation in the peripheral organs. Althoughit is well documented that GATA-3 is expressedin HSCs, a role for GATA-3 in any prethymicprogenitor cell has not been established. In thepresent study, we show that Gata3-null mutantmice generate fewer LT-HSCs and that fewerGata3-null LT-HSCs are in cycle. Furthermore,Gata3 mutant hematopoietic progenitor cells failto be recruited into an increased cycling stateafter 5-fluorouracil-induced myelosuppression.", "metadata": {}}
+{"_id": "10165723", "title": "", "text": "CpG island methylator phenotype predictsprogression of malignant melanoma.PURPOSEThe CpG island methylator phenotype (CIMP)may be associated with development ofmalignancy through coordinated inactivation oftumor suppressor and tumor-related genes(TRG) and methylation of multiple noncoding,methylated-in-tumor (MINT) loci. Theseepigenetic changes create a distinct CIMP patternthat has been linked to recurrence and survivalin gastrointestinal cancers. Because epigeneticinactivation of TRGs also has been shown inmalignant melanoma, we hypothesized theexistence of a clinically significant CIMP incutaneous melanoma progression.EXPERIMENTAL DESIGN The methylation statusof the CpG island promoter region of TRGsrelated to melanoma pathophysiology (WIF1,TFPI2, RASSF1A, RARbeta2, SOCS1, and GATA4)and a panel of MINT loci (MINT1, MINT2, MINT3,MINT12, MINT17, MINT25, and MINT31) inprimary and metastatic tumors of different", "metadata": {}}
+{"_id": "10169908", "title": "", "text": "SLC1A5 mediates glutamine transport requiredfor lung cancer cell growth and survival.PURPOSEWe have previously identified solute-linkedcarrier family A1 member 5 (SLC1A5) as anoverexpressed protein in a shotgun proteomicanalysis of stage I non-small cell lung cancer(NSCLC) when compared with matched controls.We hypothesized that overexpression of SLC1A5occurs to meet the metabolic demand for lungcancer cell growth and survival. EXPERIMENTALDESIGN To test our hypothesis, we first analyzedthe protein expression of SLC1A5 in archival lungcancer tissues by immunohistochemistry andimmunoblotting (N = 98) and in cell lines (N =36). To examine SLC1A5 involvement in aminoacid transportation, we conducted kineticanalysis of l-glutamine (Gln) uptake in lungcancer cell lines in the presence and absence of apharmacologic inhibitor of SLC1A5,gamma-l-Glutamyl-p-Nitroanilide (GPNA).Finally, we examined the effect of Glndeprivation and uptake inhibition on cell growth,", "metadata": {}}
+{"_id": "10189634", "title": "", "text": "Eic1 links Mis18 with the CCAN/Mis6/Ctf19complex to promote CENP-A assemblyCENP-Achromatin forms the foundation for kinetochoreassembly. Replication-independent incorporationof CENP-A at centromeres depends on itschaperone HJURP(Scm3), and Mis18 invertebrates and fission yeast. The recruitment ofMis18 and HJURP(Scm3) to centromeres is cellcycle regulated. Vertebrate Mis18 associates withMis18BP1(KNL2), which is critical for therecruitment of Mis18 and HJURP(Scm3). Weidentify two novel fission yeast Mis18-interactingproteins (Eic1 and Eic2), components of theMis18 complex. Eic1 is essential to maintainCnp1(CENP-A) at centromeres and is crucial forkinetochore integrity; Eic2 is dispensable. Eic1also associates with Fta7(CENP-Q/Okp1),Cnl2(Nkp2) and Mal2(CENP-O/Mcm21),components of the constitutive CCAN/Mis6/Ctf19complex. No Mis18BP1(KNL2) orthologue hasbeen identified in fission yeast, consequently itremains unknown how the key Cnp1(CENP-A)", "metadata": {}}
+{"_id": "10190462", "title": "", "text": "INTRANASAL INSULIN IMPROVES COGNITIONAND MODULATES β-AMYLOID IN EARLYADBackground: Reduced brain insulin signalingand low CSF-to-plasma insulin ratios have beenobserved in patients with Alzheimer disease(AD). Furthermore, intracerebroventricular or IVinsulin administration improve memory, alterevoked potentials, and modulateneurotransmitters, possibly by augmenting lowbrain levels. After intranasal administration,insulin-like peptides follow extracellularpathways to the brain within 15 minutes.Objective: We tested the hypothesis that dailyintranasal insulin treatment would facilitatecognition in patients with early AD or itsprodrome, amnestic mild cognitive impairment(MCI). The proportion of verbal informationretained after a delay period was the plannedprimary outcome measure. Secondary outcomemeasures included attention, caregiver rating offunctional status, and plasma levels of insulin,glucose, β-amyloid, and cortisol. Methods:", "metadata": {}}
+{"_id": "10190778", "title": "", "text": "Maternal alloantigens promote the developmentof tolerogenic fetal regulatory T cells in utero.Asthe immune system develops, T cells areselected or regulated to become tolerant of selfantigens and reactive against foreign antigens.In mice, the induction of such tolerance isthought to be attributable to the deletion ofself-reactive cells. Here, we show that thehuman fetal immune system takes advantage ofan additional mechanism: the generation ofregulatory T cells (Tregs) that suppress fetalimmune responses. We find that substantialnumbers of maternal cells cross the placenta toreside in fetal lymph nodes, inducing thedevelopment of CD4+CD25highFoxP3+ Tregsthat suppress fetal antimaternal immunity andpersist at least until early adulthood. Thesefindings reveal a form of antigen-specifictolerance in humans, induced in utero andprobably active in regulating immune responsesafter birth.", "metadata": {}}
+{"_id": "10207180", "title": "", "text": "β-site amyloid precursor protein-cleavingenzyme 1(BACE1) inhibitor treatment inducesAβ5-X peptides through alternative amyloidprecursor protein cleavageINTRODUCTION Theβ-secretase enzyme, β-site amyloid precursorprotein-cleaving enzyme 1 (BACE1), cleavesamyloid precursor protein (APP) in the first stepin β-amyloid (Aβ) peptide production. Thus,BACE1 is a key target for candidatedisease-modifying treatment of Alzheimer'sdisease. In a previous exploratory Aβ biomarkerstudy, we found that BACE1 inhibitor treatmentresulted in decreased levels of Aβ1-34 togetherwith increased Aβ5-40, suggesting that these Aβspecies may be novel pharmacodynamicbiomarkers in clinical trials. We have nowexamined whether the same holds true inhumans. METHODS In an investigator-blind,placebo-controlled and randomized study,healthy subjects (n =18) were randomlyassigned to receive a single dose of 30 mg ofLY2811376 (n =6), 90 mg of LY2811376 (n =6),", "metadata": {}}
+{"_id": "10209731", "title": "", "text": "Cardiovascular diseases in Chinese, Malays, andIndians in Singapore. I. Differences inmortality.STUDY OBJECTIVE The aim of thestudy was to analyse differences in mortalityfrom the main cardiovascular diseases(ischaemic heart disease, hypertensive disease,and cerebrovascular disease) among Chinese,Malays, and Indians in Singapore. DESIGN Thestudy was a survey using national deathregistration data in Singapore for the five years1980 to 1984. The underlying cause of death,coded according to the ninth revision of theInternational Classification of Diseases, wastaken for the analyses. SETTING The study wasconfined to the independent island state ofSingapore, population 2.53 million (Chinese76.5%, Malays 14.8%, Indians 6.4%, Others2.3%). Death registration is thought to becomplete. SUBJECTS All registered deaths in theage range 30-69 years during the study periodwere analysed by ethnic group. MEASUREMENTAND MAIN RESULTS Indians had higher mortality", "metadata": {}}
+{"_id": "10212612", "title": "", "text": "Protein localization in electron micrographs usingfluorescence nanoscopyA complete portrait of acell requires a detailed description of itsmolecular topography: proteins must be linkedto particular organelles. Immunocytochemicalelectron microscopy can reveal locations ofproteins with nanometer resolution but is limitedby the quality of fixation, the paucity ofantibodies and the inaccessibility of antigens.Here we describe correlative fluorescenceelectron microscopy for the nanoscopiclocalization of proteins in electron micrographs.We tagged proteins with the fluorescent proteinsCitrine or tdEos and expressed them inCaenorhabditis elegans, fixed the worms andembedded them in plastic. We imaged thetagged proteins from ultrathin sections usingstimulated emission depletion (STED)microscopy or photoactivated localizationmicroscopy (PALM). Fluorescence correlated withorganelles imaged in electron micrographs fromthe same sections. We used these methods to", "metadata": {}}
+{"_id": "10218447", "title": "", "text": "The flavonoid component isorhamnetin in vitroinhibits proliferation and induces apoptosis inEca-109 cells.Isorhamnetin is one member offlavonoid components which has been used inthe treatment of heart disease. Recently the invitro anti-cancer effect of isorhamnetin onhuman esophageal squamous carcinoma cell lineEca-109 was investigated in our lab. WhenEca-109 cells were in vitro exposed to the gradeddoses of isorhamnetin (0-80 microg/ml) for 48 h,respectively, isorhamnetin exhibited cytostaticeffect on the treated cells, with an IC(50) of40+/-0.08 microg/ml as estimated by MTTassay. Inhibition on proliferation by isorhamnetinwas detected by trypan blue exclusion assay,clone formation test, immunocytochemical assayof PCNA and (3)H-thymidine uptake analysis.Cell cycle distribution was measured by FCM. Itwas found that the viability of Eca-109 cells wassignificantly hampered by isorhamnetin.Compared with the negative control group, thetreated group which was exposed to", "metadata": {}}
+{"_id": "10247282", "title": "", "text": "Arachidonic Acid in the Diabetic Rat KidneyIn therat isolated perfused kidney, arachidonic acidelicits cyclooxygenase-dependentvasoconstriction through activation ofPGH2/TxA2 receptors; responses are enhancedin kidneys from diabetic rats. This studyexamined the roles ofcyclooxygenase-1/cyclooxygenase-2 in theenhanced renal vasoconstrictor effect ofarachidonic acid in streptozotocin-diabetic rats.Release of 20-HETE was also determined, as thiseicosanoid has been reported to elicitcyclooxygenase-dependent vasoconstriction. Weconfirmed that vasoconstrictor responses toarachidonic acid were enhanced in the diabeticrat kidney associated with a 2-fold-greaterincrease in the release of 6-ketoPGF1alpha,which was used as an index of cyclooxygenaseactivity. One and three micrograms ofarachidonic acid increased perfusion pressure by85+/-37 and 186+/-6 mm Hg, respectively, indiabetic rat kidneys compared with 3+/-1 and", "metadata": {}}
+{"_id": "10247314", "title": "", "text": "Two sequence motifs from HIF-1alpha bind tothe DNA-binding site of p53.There is evidencethat hypoxia-inducible factor-1alpha(HIF-1alpha) interacts with the tumor suppressorp53. To characterize the putative interaction, wemapped the binding of the core domain of p53(p53c) to an array of immobilizedHIF-1alpha-derived peptides and found twopeptide-sequence motifs that bound to p53c withmicromolar affinity in solution. One sequencewas adjacent to and the other coincided with thetwo proline residues of the oxygen-dependentdegradation domain (P402 and P564) that act asswitches for the oxygen-dependent regulation ofHIF-1alpha. The binding affinity was independentof the hydroxylation state of P564. We foundfrom NMR spectroscopy that these sequencemotifs bind to the DNA-binding site of p53c.Because the two sequences are homologous andseparated by 120 residues, and one is in alargely unstructured transactivation domain, wespeculate that each sequence motif in", "metadata": {}}
+{"_id": "10273147", "title": "", "text": "A functionally characterized test set of humaninduced pluripotent stem cellsHuman inducedpluripotent stem cells (iPSCs) present excitingopportunities for studying development and forin vitro disease modeling. However, reportedvariability in the behavior of iPSCs has calledtheir utility into question. We established a testset of 16 iPSC lines from seven individuals ofvarying age, sex and health status, andextensively characterized the lines with respectto pluripotency and the ability to terminallydifferentiate. Under standardized procedures intwo independent laboratories, 13 of the iPSClines gave rise to functional motor neurons witha range of efficiencies similar to that of humanembryonic stem cells (ESCs). Although threeiPSC lines were resistant to neuraldifferentiation, early neuralization rescued theirperformance. Therefore, all 16 iPSC lines passeda stringent test of differentiation capacity despitevariations in karyotype and in the expression ofearly pluripotency markers and transgenes. This", "metadata": {}}
+{"_id": "10279084", "title": "", "text": "Differential regulation of MAP kinase activationby a novel splice variant of human MAP kinasephosphatase-2.MAP kinase phosphatase-2(MKP-2) is a member of the family of dualspecificity phosphatases that functions toinactivate the ERK and JNK MAP kinase signallingpathways. Here, we identify a novel humanMKP-2 variant (MKP-2-S) lacking the MAP kinasebinding site but retaining the phosphatasecatalytic domain. Endogenous MKP-2-Stranscripts and proteins were found in PC3prostate and MDA-MB-231 breast cancer cellsand also human prostate biopsies. Cellulartransfection of MKP-2-S gave rise to a nuclearprotein of 33kDa which displayed phosphataseactivity comparable to the formerly describedlong form of MKP-2 (MKP-2-L). Due to its lack ofa kinase interacting motif (KIM), MKP-2-S did notbind to JNK or ERK; MKP-2-L bound ERK and to alesser extent JNK. Protein turnover of adenoviralexpressed MKP-2-S was accelerated relative toMKP-2-L, with a greater susceptibility to", "metadata": {}}
+{"_id": "10284593", "title": "", "text": "Myeloperoxidase acts as a profibrotic mediator ofatrial fibrillationObservational clinical and ex vivostudies have established a strong associationbetween atrial fibrillation and inflammation.However, whether inflammation is the cause orthe consequence of atrial fibrillation and whichspecific inflammatory mediators may increasethe atria's susceptibility to fibrillation remainelusive. Here we provide experimental andclinical evidence for the mechanistic involvementof myeloperoxidase (MPO), a heme enzymeabundantly expressed by neutrophils, in thepathophysiology of atrial fibrillation.MPO-deficient mice pretreated with angiotensinII (AngII) to provoke leukocyte activationshowed lower atrial tissue abundance of the MPOproduct 3-chlorotyrosine, reduced activity ofmatrix metalloproteinases and blunted atrialfibrosis as compared to wild-type mice. Uponright atrial electrophysiological stimulation,MPO-deficient mice were protected from atrialfibrillation, which was reversed when MPO was", "metadata": {}}
+{"_id": "10300000", "title": "", "text": "Knowledge and use of secondary contraceptionamong patients requesting termination ofpregnancy.The results of a survey of 769patients attending the St. James's UniversityFertility Control Clinic, England, for abortionservices showed that patients seeing generalpractitioners were less knowledgeable than thoseattending specialist clinics. There was ademonstrated need for counseling on pill andcondom use and protection against sexuallytransmitted diseases. Knowledge of postcoitalmethods was also found to be lacking. Thesurvey was conducted between April 1, 1991,and January 31, 1992. Respondents includedminorities such as Afro-Caribbean (8%) andAsian (9%). 307 of the cases were using a lesseffective form of contraception at the time ofconception, usually a change from the pill tocondoms. Of the 171 people reporting failure ofcontraception, 93 noted a split or leakingcondom; 13, a condom falling off duringintercourse; 32, inconsistent use of condoms;l", "metadata": {}}
+{"_id": "10300888", "title": "", "text": "Domestication and Divergence of Saccharomycescerevisiae Beer YeastsWhereas domestication oflivestock, pets, and crops is well documented, itis still unclear to what extent microbesassociated with the production of food have alsoundergone human selection and where theplethora of industrial strains originates from.Here, we present the genomes and phenomes of157 industrial Saccharomyces cerevisiae yeasts.Our analyses reveal that today's industrial yeastscan be divided into five sublineages that aregenetically and phenotypically separated fromwild strains and originate from only a fewancestors through complex patterns ofdomestication and local divergence. Large-scalephenotyping and genome analysis further showstrong industry-specific selection for stresstolerance, sugar utilization, and flavorproduction, while the sexual cycle and otherphenotypes related to survival in nature showdecay, particularly in beer yeasts. Together,these results shed light on the origins,", "metadata": {}}
+{"_id": "10314816", "title": "", "text": "The ascendancy of Amblyomma americanum asa vector of pathogens affecting humans in theUnited States.Until the 1990s, Amblyommaamericanum was regarded primarily as anuisance species, but a tick of minor importanceas a vector of zoonotic pathogens affectinghumans. With the recent discoveries of Ehrlichiachaffeensis, Ehrlichia ewingii, and \"Borrelialonestari,\" the public health relevance of lonestar ticks is no longer in question. During thenext 25 years, the number of cases of humandisease caused by A. americanum-associatedpathogens will probably increase. Based oncurrent trajectories and historic precedents, theincrease will be primarily driven by biological andenvironmental factors that alter the geographicdistribution and intensity of transmission ofzoonotic pathogens. Sociologic and demographicchanges that influence the likelihood of highlysusceptible humans coming into contact withinfected lone star ticks, in addition to advancesin diagnostic capabilities and national", "metadata": {}}
+{"_id": "10326242", "title": "", "text": "Biallelic mutations in PALB2 cause Fanconianemia subtype FA-N and predispose tochildhood cancerPALB2 was recently identified asa nuclear binding partner of BRCA2. BiallelicBRCA2 mutations cause Fanconi anemia subtypeFA-D1 and predispose to childhood malignancies.We identified pathogenic mutations in PALB2(also known as FANCN) in seven families affectedwith Fanconi anemia and cancer in earlychildhood, demonstrating that biallelic PALB2mutations cause a new subtype of Fanconianemia, FA-N, and, similar to biallelic BRCA2mutations, confer a high risk of childhood cancer.", "metadata": {}}
+{"_id": "10335603", "title": "", "text": "Long tandem arrays of complex repeat units inChironomus telomeres.A cloned 340-bp DNAfragment excised by EcoRI from the Chironomuspallividittatus genome has been localized to thetelomeres by in situ hybridization as well as toconnectives between telomeres. No hybridizationwas observed in other regions of thechromosomes. Another cloned EcoRI fragment,525 bp long has also been studied. Thisrepresents a partial duplication of the 340-bpsequence. Genomic blot hybridizationexperiments show that the 340-bp sequence is arepresentative monomeric unit of tandemlyrepeated arrays which account for 1.2% of theChironomus genome, on average 300 kb pertelomere. The repeat unit contains two types ofsubrepeats each present twice per repeat unit.Northern blot hybridization experiments showthat the telomere-associated sequences aretranscribed into a discrete RNA speciesapproximately 20 kb in size. The evolution of thistelomere-associated DNA is discussed.", "metadata": {}}
+{"_id": "10342807", "title": "", "text": "Localization of Na+ channel isoforms at theatrioventricular junction and atrioventricularnode in the rat.BACKGROUND The electricalactivity of the atrioventricular node (AVN) isfunctionally heterogeneous, but how this relatesto distinct cell types and the 3-dimensionalstructure of the AVN is unknown. To addressthis, we have studied the expression of Na(V)1.5and other Na+ channel isoforms in the AVN.METHODS AND RESULTS The rat AVN wasidentified by Masson's trichrome stainingtogether with immunolabeling of markerproteins: connexin40, connexin43, desmoplakin,atrial natriuretic peptide, andhyperpolarization-activated and cyclicnucleotide-gated channel 4. Na+ channelexpression was investigated withimmunohistochemistry with isoform-specific Na+channel antibodies. Na(V)1.1 was distributed in asimilar manner to Na(V)1.5. Na(V)1.2 was notdetected. Na(V)1.3 labeling was present in nervefibers and cell bodies (but not myocytes) and", "metadata": {}}
+{"_id": "10354110", "title": "", "text": "Follicular B cell trafficking within the spleenactively restricts humoral immuneresponses.Follicular (FO) and marginal zone (MZ)B cells are maintained in distinct locations withinthe spleen, but the genetic basis for thisseparation is still enigmatic. We now report thatB cell sequestration requires lineage-specificregulation of migratory receptors by thetranscription factor Klf2. Moreover, usinggene-targeted mice we show that altered splenicB cell migration confers a significant in vivogain-of-function phenotype to FO B cells,including the ability to quickly respond toMZ-associated antigens and pathogens in a Tcell-dependent manner. This work demonstratesthat in wild-type animals, naive FO B cells areactively removed from the MZ, thus restrictingtheir capacity to respond to blood-bornepathogens.", "metadata": {}}
+{"_id": "10359591", "title": "", "text": "Interleukin-2 and inflammation induce distincttranscriptional programs that promote thedifferentiation of effector cytolytic Tcells.Interleukin(IL)-2 and inflammation regulateeffector and memory cytolytic T-lymphocyte(CTL) generation during infection. Wedemonstrate a complex interplay between IL-2and inflammatory signals during CTLdifferentiation. IL-2 stimulation induced thetranscription factor eomesodermin (Eomes),upregulated perforin (Prf1) transcription, andrepressed re-expression of memory CTL markersBcl6 and IL-7Ralpha. Binding of Eomes andSTAT5 to Prf1 cis-regulatory regions correlatedwith transcriptional initiation (increasedrecruitment of RNA polymerase II to the Prf1promoter). Inflammation (CpG, IL-12) enhancedexpression of IL-2Ralpha and the transcriptionfactor T-bet, but countered late Eomes andperforin induction while preventing IL-7Ralpharepression by IL-2. After infection of mice withlymphocytic choriomeningitis virus,", "metadata": {}}
+{"_id": "10365749", "title": "", "text": "Neighbourhood risk factors for tuberculosis inHong Kong.BACKGROUND Tuberculosis (TB) hasbeen reported to be associated with poverty,especially in developing countries. Hong Kong isone of the few industrialised areas with a highincidence of TB where previous reports on theeffect of poverty at neighbourhood level havebeen conflicting. OBJECTIVE To examine thespatial distribution of TB and its association withneighbourhood risk factors. METHOD A total of17 294 TB cases notified from 2005 to 2007 weremapped down to the District CouncilConstituency Area (DCCA) level, and wereindirectly standardised by age and sex using2006 census population data. The standardisedTB ratio was correlated with neighbourhood riskfactors classified by family, ethnicity, economicand environmental domains. RESULTS Theindirect age- and sex-standardised ratiodemonstrated a spatially varied pattern, and wassignificantly associated with all neighbourhoodfactors on univariate analysis. Only marital", "metadata": {}}
+{"_id": "10365787", "title": "", "text": "Genomic stability and tumour suppression by theAPC/C cofactor Cdh1The anaphase promotingcomplex or cyclosome (APC/C) is a ubiquitinprotein ligase that, together with Cdc20 or Cdh1,targets cell-cycle proteins for degradation.APC/C–Cdh1 specifically promotes proteindegradation in late mitosis and G1. Mutantembryos lacking Cdh1 die at E9.5–E10.5 due todefects in the endoreduplication of trophoblastcells and placental malfunction. This lethality isprevented when Cdh1 is expressed in theplacenta. Cdh1-deficient cells proliferateinefficiently and accumulate numeric andstructural chromosomal aberrations, indicatingthat Cdh1 contributes to the maintenance ofgenomic stability. Cdh1 heterozygous animalsshow increased susceptibility to spontaneoustumours, suggesting that Cdh1 functions as ahaploinsufficient tumour suppressor. Theseheterozygous mice also show several defects inbehaviour associated with increased proliferationof stem cells in the nervous system. These", "metadata": {}}
+{"_id": "10374686", "title": "", "text": "Developing primary palliative care.Although 65%of people with cancer want to die at home, onlyabout 30% are successful in doing so.1,2 Agovernment committed to choice for patientsmust improve this figure.3 Developing palliativecare services in primary care is essential forrealising the expectations of dying people. Suchservices could also offer important opportunitiesfor extending supportive humane care at anearlier stage, and to people not only with cancerbut with chronic obstructive pulmonary disease,motor neurone disease, and cardiac failure, forexample, who also often have palliative careneeds. Primary care professionals have thepotential and ability to provide end of life care formost patients, given adequate training,resources, and, when needed, specialistadvice.4,5 They share common values withpalliative care specialists—holistic, patientcentred care, delivered in the context of familiesand friends.6 However, until recently, apart fromMacmillan general practitioners and nurse", "metadata": {}}
+{"_id": "10408324", "title": "", "text": "The effects of self-administering emergencycontraception.BACKGROUND Emergencypostcoital contraception prevents pregnancy, butit must be prescribed by a doctor and takenwithin 72 hours of intercourse. It has beenproposed that emergency contraception be madeavailable without a prescription. We undertook astudy to learn how women might behave if givena supply of emergency contraceptive pills to keepat home. METHODS We assigned 553 women tobe given a replaceable supply of hormonalemergency contraceptive pills to take home (thetreatment group) and 530 women to useemergency contraception obtained by visiting adoctor (the control group). The frequency of useof emergency contraception, the use of othercontraceptives, and the incidence of unwantedpregnancy were determined in both groups ofwomen one year later. RESULTS The results for549 women in the treatment group and 522women in the control group were available foranalysis. Three hundred seventy-nine of the", "metadata": {}}
+{"_id": "10423989", "title": "", "text": "A coactivator of pre-mRNA splicing.The nuclearmatrix antigen recognized by the monoclonalantibody (mAb) B1C8 is a novel serine (S) andarginine (R)-rich protein associated with splicingcomplexes and is named here SRm160(SR-related matrix protein of 160 kD). SRm160contains multiple SR repeats, but unlike proteinsof the SR family of splicing factors, lacks an RNArecognition motif. SRm160 and a related proteinSRm300 (the 300-kD nuclear matrix antigenrecognized by mAb B4A11) form a complex thatis required for the splicing of specific pre-mRNAs.The SRm160/300 complex associates withsplicing complexes and promotes splicingthrough interactions with SR family proteins.Binding of SRm160/300 to pre-mRNA is normallyalso dependent on U1 snRNP and is stabilized byU2 snRNP. Thus, SRm160/300 forms multipleinteractions with components bound directly toimportant sites within pre-mRNA. The resultssuggest that a complex of the nuclear matrixproteins SRm160 and SRm300 functions as a", "metadata": {}}
+{"_id": "10430148", "title": "", "text": "Comparison of pioglitazone vs glimepiride onprogression of coronary atherosclerosis inpatients with type 2 diabetes: the PERISCOPErandomized controlled trial.CONTEXT Noantidiabetic regimen has demonstrated theability to reduce progression of coronaryatherosclerosis. Commonly used oralglucose-lowering agents include sulfonylureas,which are insulin secretagogues, andthiazolidinediones, which are insulin sensitizers.OBJECTIVE To compare the effects of an insulinsensitizer, pioglitazone, with an insulinsecretagogue, glimepiride, on the progression ofcoronary atherosclerosis in patients with type 2diabetes. DESIGN, SETTING, AND PARTICIPANTSDouble-blind, randomized, multicenter trial at 97academic and community hospitals in North andSouth America (enrollment August 2003-March2006) in 543 patients with coronary disease andtype 2 diabetes. INTERVENTIONS A total of 543patients underwent coronary intravascularultrasonography and were randomized to receive", "metadata": {}}
+{"_id": "10443642", "title": "", "text": "Staphylococcus aureus RNAIII coordinatelyrepresses the synthesis of virulence factors andthe transcription regulator Rot by an antisensemechanism.RNAIII is the intracellular effector ofthe quorum-sensing system in Staphylococcusaureus. It is one of the largest regulatory RNAs(514 nucleotides long) that are known to controlthe expression of a large number of virulencegenes. Here, we show that the 3' domain ofRNAIII coordinately represses at thepost-transcriptional level, the expression ofmRNAs that encode a class of virulence factorsthat act early in the infection process. Wedemonstrate that the 3' domain acts primarily asan antisense RNA and rapidly anneals to thesemRNAs, forming long RNA duplexes. Theinteraction between RNAIII and the mRNAsresults in repression of translation initiation andtriggers endoribonuclease III hydrolysis. Theseprocesses are followed by rapid depletion of themRNA pool. In addition, we show that RNAIIIand its 3' domain mediate translational", "metadata": {}}
+{"_id": "10450300", "title": "", "text": "Human Cytomegalovirus Latency-AssociatedProteins Elicit Immune-Suppressive IL-10Producing CD4+ T CellsHuman cytomegalovirus(HCMV) is a widely prevalent human herpesvirus,which, after primary infection, persists in thehost for life. In healthy individuals, the virus iswell controlled by the HCMV-specific T cellresponse. A key feature of this persistence, inthe face of a normally robust host immuneresponse, is the establishment of viral latency. Incontrast to lytic infection, which is characterisedby extensive viral gene expression and virusproduction, long-term latency in cells of themyeloid lineage is characterised by highlyrestricted expression of viral genes, includingUL138 and LUNA. Here we report that bothUL138 and LUNA-specific T cells were detectabledirectly ex vivo in healthy HCMV seropositivesubjects and that this response is principallyCD4\u0000 T cell mediated. These UL138-specificCD4\u0000 T cells are able to mediate MHC class IIrestricted cytotoxicity and, importantly, show", "metadata": {}}
+{"_id": "10450725", "title": "", "text": "Pamidronate induced anti-proliferative,apoptotic, and anti-migratory effects inhepatocellular carcinoma.BACKGROUND/AIMSThe small GTPase of Ras and Rho families arewidely involved in human tumorgenesis andmetastasis. It has recently been reported thatpamidronate inhibits the mevalonate pathway,which is required for the prenylation of the smallGTPase. We demonstrated a possible beneficialuse of pamidronate in the treatment ofhepatocellular carcinoma (HCC). METHODS Theeffect of pamidronate on cell proliferation wasanalyzed with five hepatoma cell lines using MTTassay. Apoptosis was evaluated by staining withDAPI and a histon ELISA assay. A cell migrationassay was performed using the Modified BoydenChamber. To analyze anti-proliferation effect ofpamidronate in vivo, tumor volumes weremonitored with the intraperitoneal injection ofpamidronate after subcutaneous inoculation ofPLC/PRF/5 cells into nude mice. RESULTSPamidronate inhibited cell growth for all", "metadata": {}}
+{"_id": "10463997", "title": "", "text": "Defective regulation of adipose tissue autophagyin obesityObjectives: Autophagy is a highlyregulated process that has an important role inthe control of a wide range of cellular functions,such as organelle recycling, nutrient availabilityand tissue differentiation. A recent study hasshown an increased autophagic activity in theadipose tissue of obese subjects, and a role forautophagy in obesity-associated insulinresistance was proposed. Body mass reduction isthe most efficient approach to tackle insulinresistance in over-weight subjects; however, theimpact of weight loss in adipose tissueautophagy is unknown. Subjects:Adipose tissueautophagy was evaluated in mice and humans.Results:First, a mouse model of diet-inducedobesity and diabetes was maintained on a15-day, 40% caloric restriction. At baseline,markers of autophagy were increased in obesemice as compared with lean controls. Uponcaloric restriction, autophagy increased in thelean mice, whereas it decreased in the obese", "metadata": {}}
+{"_id": "10474873", "title": "", "text": "Recovery of visual response of injured adult ratoptic nerves treated withtransglutaminase.Failure of axons of the centralnervous system in adult mammals to regeneratespontaneously after injury is attributed in part toinhibitory molecules associated witholigodendrocytes. Regeneration of centralnervous system axons in fish is correlated withthe presence of a transglutaminase. This enzymedimerizes interleukin-2, and the product iscytotoxic to oligodendrocytes in vitro. Applicationof this nerve-derived transglutaminase to ratoptic nerves, in which the injury had caused theloss of visual evoked potential response to light,promoted the recovery of that response within 6weeks after injury. Transmission electronmicroscopy analysis revealed the concomitantappearance of axons in the distal stump of theoptic nerve.", "metadata": {}}
+{"_id": "10482574", "title": "", "text": "Cell survival during complete nutrient deprivationdepends on lipid droplet-fueled β-oxidation offatty acids.Cells exposed to stress of differentorigins synthesize triacylglycerols and generatelipid droplets (LD), but the physiologicalrelevance of this response is uncertain. Usingcomplete nutrient deprivation of cells in cultureas a simple model of stress, we have addressedwhether LD biogenesis has a protective role incells committed to die. Complete nutrientdeprivation induced the biogenesis of LD inhuman LN18 glioblastoma and HeLa cells andalso in CHO and rat primary astrocytes. In all celltypes, death was associated with LD depletionand was accelerated by blocking LD biogenesisafter pharmacological inhibition of Group IVAphospholipase A2 (cPLA2α) or down-regulation ofceramide kinase. Nutrient deprivation alsoinduced β-oxidation of fatty acids that wassensitive to cPLA2α inhibition, and cell survival inthese conditions became strictly dependent onfatty acid catabolism. These results show that,", "metadata": {}}
+{"_id": "10485142", "title": "", "text": "Molecular and cytogenetic changes involved inthe immortalization of nasopharyngeal epithelialcells by telomerase.Nasopharyngeal carcinoma(NPC) is a common disease in Hong Kong andsouthern provinces of China. EBV infection isbelieved to play a critical role in the developmentof NPC. Previous studies on the transformationmechanism of EBV genes were mostly performedin either NPC or nonnasopharyngeal epithelialcells which may not be representative ofpremalignant nasopharyngeal epithelial cells.Establishment of a representative cell systemwould greatly facilitate the elucidation of the roleof EBV infection in the development of NPC.Using telomerase alone, we were able toestablish an immortalized nasopharyngealepithelial cell line from primary nonmalignantnasopharyngeal biopsies. Thetelomerase-immortalized nasopharyngealepithelial cells are largely diploid in karyotype.Interestingly, this newly immortalizednasopharyngeal epithelial cell line, referred as", "metadata": {}}
+{"_id": "10486817", "title": "", "text": "Cellular nucleic acid binding protein suppressestumor cell metastasis and induces tumor celldeath by downregulating heterogeneousribonucleoprotein K in fibrosarcomacells.BACKGROUND Cellular nucleic acid bindingprotein (CNBP) has been implicated in vertebratecraniofacial development and in myotonicdystrophy type 2 (DM2) and sporadic inclusionbody myositis (sIBM) human diseases bycontrolling cell proliferation and survival tomediate neural crest expansion. CNBP has beenfound to bind single-stranded nucleic acid andpromote rearrangements of nucleic acidsecondary structure in an ATP-independentmanner, acting as a nucleic acid chaperone.METHODS A variety of methods were used,including cell viability assays, wound-scratchassays, chemotaxis assays, invasion assays,circular dichroic (CD) spectroscopy, NMRspectroscopy, chromatin immunoprecipitation,expression and purification of recombinanthuman CNBP, electrophoretic mobility shift assay", "metadata": {}}
+{"_id": "10491220", "title": "", "text": "The DHR96 nuclear receptor regulates xenobioticresponses in Drosophila.Exposure to xenobioticssuch as plant toxins, pollutants, or prescriptiondrugs triggers a defense response, inducinggenes that encode key detoxification enzymes.Although xenobiotic responses have been studiedin vertebrates, little effort has been made toexploit a simple genetic system forcharacterizing the molecular basis of thiscoordinated transcriptional response. We showhere that approximately 1000 transcripts aresignificantly affected by phenobarbital treatmentin Drosophila. We also demonstrate that theDrosophila ortholog of the human SXR and CARxenobiotic receptors, DHR96, plays a role in thisresponse. A DHR96 null mutant displaysincreased sensitivity to the sedative effects ofphenobarbital and the pesticide DDT as well asdefects in the expression of manyphenobarbital-regulated genes. Metabolic andstress-response genes are also controlled byDHR96, implicating its role in coordinating", "metadata": {}}
+{"_id": "10494012", "title": "", "text": "A primate virus generates transformed humancells by fusionAmodel that explains both theorigin and sporadic nature of cancer argues thatcancer cells are a chance result of events thatcause genomic and epigenetic variability. Theprevailing view is that these events aremutations that affect chromosome segregationor stability. However, genomic and epigeneticvariability is also triggered by cell fusion, whichis often caused by viruses. Yet, cells fused byviruses are considered harmless because theydie. We provide evidence that a primate virususes both viral and exosomal proteins involved incell fusion to produce transformed proliferatinghuman cells. Although normal cells indeed fail toproliferate after fusion, expression of anoncogene or a mutated tumor suppressor p53 injust one of the fusion partners is sufficient toproduce heterogeneous progeny. We also showthat this virus can produce viable oncogenicallytransformed cells by fusing cells that areotherwise destined to die. Therefore, we argue", "metadata": {}}
+{"_id": "10504681", "title": "", "text": "TAA1-Mediated Auxin Biosynthesis Is Essentialfor Hormone Crosstalk and PlantDevelopmentPlants have evolved a tremendousability to respond to environmental changes byadapting their growth and development. Theinteraction between hormonal anddevelopmental signals is a critical mechanism inthe generation of this enormous plasticity. Agood example is the response to the hormoneethylene that depends on tissue type,developmental stage, and environmentalconditions. By characterizing the Arabidopsiswei8 mutant, we have found that a small familyof genes mediates tissue-specific responses toethylene. Biochemical studies revealed that WEI8encodes a long-anticipated tryptophanaminotransferase, TAA1, in the essential, yetgenetically uncharacterized, indole-3-pyruvicacid (IPA) branch of the auxin biosyntheticpathway. Analysis of TAA1 and its paraloguesrevealed a link between local auxin production,tissue-specific ethylene effects, and organ", "metadata": {}}
+{"_id": "10509344", "title": "", "text": "A research agenda for public health workforcedevelopment.In the past decades, public healthresearch has focused on categorical rather thancross-cutting or systems issues. Little researchhas been carried out on the infrastructurerequired to support public health programs. Thisarticle describes the results of an interactiveprocess to develop a research agenda for publichealth workforce development to inform all thosewith stakes in the public health system. Thisresearch is defined as a multidisciplinary field ofinquiry, both basic and applied, that examinesthe workforce in terms of costs, quality,accessibility, delivery, organization, financing,and outcomes of public health services toincrease knowledge and understanding of therelationships among workforce and structure,processes, and effects of public health services.A logic model and five priority research areasresulted from meetings of expert panels during2000 to 2003. Innovative public and privatepartnerships will be required to advance", "metadata": {}}
+{"_id": "10518721", "title": "", "text": "Parallel processing in the mammalian retinaOureyes send different 'images' of the outside worldto the brain — an image of contours (linedrawing), a colour image (watercolour painting)or an image of moving objects (movie). This iscommonly referred to as parallel processing, andstarts as early as the first synapse of the retina,the cone pedicle. Here, the molecularcomposition of the transmitter receptors of thepostsynaptic neurons defines which images aretransferred to the inner retina. Within the secondsynaptic layer — the inner plexiform layer —circuits that involve complex inhibitory andexcitatory interactions represent filters thatselect 'what the eye tells the brain'.", "metadata": {}}
+{"_id": "10526279", "title": "", "text": "Oxymetholone Therapy of Fanconi AnemiaSuppresses Osteopontin Transcription andInduces Hematopoietic Stem CellCyclingAndrogens are widely used for treatingFanconi anemia (FA) and other human bonemarrow failure syndromes, but their mode ofaction remains incompletely understood. AgedFancd2(-/-) mice were used to assess thetherapeutic efficacy of oxymetholone (OXM) andits mechanism of action. Eighteen-month-oldFancd2(-/-) mice recapitulated key human FAphenotypes, including reduced bone marrowcellularity, red cell macrocytosis, and peripheralpancytopenia. As in humans, chronic OXMtreatment significantly improved thesehematological parameters and stimulated theproliferation of hematopoietic stem andprogenitor cells. RNA-Seq analysis implicateddownregulation of osteopontin as an importantpotential mechanism for the drug's action.Consistent with the increased stem cellproliferation, competitive repopulation assays", "metadata": {}}
+{"_id": "10530014", "title": "", "text": "A point mutation in KINDLIN3 ablates activationof three integrin subfamilies inhumansMonogenic deficiency diseases provideunique opportunities to define the contributionsof individual molecules to human physiology andto identify pathologies arising from theirdysfunction. Here we describe a deficiencydisease in two human siblings that presentedwith severe bleeding, frequent infections andosteopetrosis at an early age. These symptomsare consistent with but more severe than thosereported for people with leukocyte adhesiondeficiency III (LAD-III). Mechanistically, thesesymptoms arose from an inability to activate theintegrins expressed on hematopoietic cells,including platelets and leukocytes. Immortalizedlymphocyte cell lines isolated from the twoindividuals showed integrin activation defects.Several proteins previously implicated in integrinactivation, including Ras-associated protein-1(RAP1) and calcium and diacylglycerol-regulatedguanine nucleotide exchange factor-1", "metadata": {}}
+{"_id": "10534299", "title": "", "text": "Fasting Activation of AgRP Neurons RequiresNMDA Receptors and Involves Spinogenesis andIncreased Excitatory ToneAgRP neuron activitydrives feeding and weight gain whereas that ofnearby POMC neurons does the opposite.However, the role of excitatory glutamatergicinput in controlling these neurons is unknown. Toaddress this question, we generated mice lackingNMDA receptors (NMDARs) on either AgRP orPOMC neurons. Deletion of NMDARs from AgRPneurons markedly reduced weight, body fat andfood intake whereas deletion from POMC neuronshad no effect. Activation of AgRP neurons byfasting, as assessed by c-Fos, Agrp and NpymRNA expression, AMPA receptor-mediatedEPSCs, depolarization and firing rates, requiredNMDARs. Furthermore, AgRP but not POMCneurons have dendritic spines and increasedglutamatergic input onto AgRP neurons causedby fasting was paralleled by an increase inspines, suggesting fasting inducedsynaptogenesis and spinogenesis. Thus", "metadata": {}}
+{"_id": "10536636", "title": "", "text": "Prevalence and Causes of Blindness and LowVision in Southern SudanBackground Blindnessand low vision are thought to be common insouthern Sudan. However, the magnitude andgeographical distribution are largely unknown.We aimed to estimate the prevalence ofblindness and low vision, identify the maincauses of blindness and low vision, and estimatetargets for blindness prevention programs inMankien payam (district), southern Sudan.", "metadata": {}}
+{"_id": "10538985", "title": "", "text": "Origin of nitrite and nitrate in nasal and exhaledbreath condensate and relation to nitric oxideformation.BACKGROUND Raised concentrationsof nitrate and nitrite have been found in exhaledbreath condensate (EBC) in airway disease, andit has been postulated that this reflects increasednitric oxide (NO) metabolism. However, thechemical and anatomical origin of nitrate andnitrite in the airways has not yet been sufficientlystudied. METHODS The fraction of exhaled NO atan exhalation flow rate of 50 ml/s (FE(NO)) andnitrite and nitrate in EBC, nasal condensate, andsaliva were measured in 17 tracheostomised and15 non-tracheostomised subjects, all of whomwere non-smokers without respiratory disease.Tracheal and oral samples were taken from thetracheostomised subjects and nasal (duringvelum closure) and oral samples from thenon-tracheostomised subjects. Measurementswere performed before and after sodium nitrateingestion (10 mg/kg) and use of antibacterialmouthwash (chlorhexidine 0.2%). RESULTS In", "metadata": {}}
+{"_id": "10542877", "title": "", "text": "AZD9150, a next-generation antisenseoligonucleotide inhibitor of STAT3 with earlyevidence of clinical activity in lymphoma andlung cancerNext-generation sequencingtechnologies have greatly expanded ourunderstanding of cancer genetics. Antisensetechnology is an attractive platform with thepotential to translate these advances intoimproved cancer therapeutics, because antisenseoligonucleotide (ASO) inhibitors can be designedon the basis of gene sequence information alone.Recent human clinical data have demonstratedthe potent activity of systemically administeredASOs targeted to genes expressed in the liver.We describe the preclinical activity and initialclinical evaluation of a class of ASOs containingconstrained ethyl modifications for targeting thegene encoding the transcription factor STAT3, anotoriously difficult protein to inhibittherapeutically. Systemic delivery of theunformulated ASO, AZD9150, decreased STAT3expression in a broad range of preclinical cancer", "metadata": {}}
+{"_id": "10546779", "title": "", "text": "Evidence of a pluripotent human embryonic stemcell line derived from a cloned blastocyst.Somaticcell nuclear transfer (SCNT) technology hasrecently been used to generate animals with acommon genetic composition. In this study, wereport the derivation of a pluripotent embryonicstem (ES) cell line (SCNT-hES-1) from a clonedhuman blastocyst. The SCNT-hES-1 cellsdisplayed typical ES cell morphology and cellsurface markers and were capable ofdifferentiating into embryoid bodies in vitro andof forming teratomas in vivo containing cellderivatives from all three embryonic germ layersin severe combined immunodeficient mice. Aftercontinuous proliferation for more than 70passages, SCNT-hES-1 cells maintained normalkaryotypes and were genetically identical to thesomatic nuclear donor cells. Although we cannotcompletely exclude the possibility that the cellshad a parthenogenetic origin, imprintinganalyses support a SCNT origin of the derivedhuman ES cells.", "metadata": {}}
+{"_id": "10548391", "title": "", "text": "Ultrarapid drug metabolism: PCR-baseddetection of CYP2D6 gene duplication.Theenzyme debrisoquine 4-hydroxylase (CYP2D6),which metabolizes many widely used drugs, ishighly polymorphic. The activity of the enzymeranges between subjects from ultrafast to acomplete absence. Therefore, metabolic capacityvaries, producing intersubject differences intherapeutic efficacy and side effects at standardrecommended doses. Up to 7% of Caucasiansmay demonstrate ultrarapid drug metabolism(UM) because of inherited alleles withmultiplicate functional CYP2D6 genes, causing anincreased amount of enzyme to be expressed.Identification of UM subjects is of potentialclinical importance for adjustment of doses indrug therapy, as well as to avoidmisidentification of noncompliance. In our study,we tested recently designed PCR assays for thedetection of the UM genotype. We found a 3.5%prevalence of UMs carrying duplicate activeCYP2D6 genes in a population consisting of 202", "metadata": {}}
+{"_id": "10555591", "title": "", "text": "The Actions of Synaptically Released Zinc atHippocampal Mossy Fiber SynapsesZn2+ ispresent at high concentrations in the synapticvesicles of hippocampal mossy fibers. We haveused Zn2+ chelators and the mocha mutantmouse to address the physiological role of Zn2+in this pathway. Zn2+ is not involved in theunique presynaptic plasticities observed atmossy fiber synapses but is coreleased withglutamate from these synapses, bothspontaneously and with electrical stimulation,where it exerts a strong modulatory effect on theNMDA receptors. Zn2+ tonically occupies thehigh-affinity binding site of NMDA receptors atmossy fiber synapses, whereas the lower affinityvoltage-dependent Zn2+ binding site is occupiedduring action potential driven-release. Weconclude that Zn2+ is a modulatoryneurotransmitter released from mossy fibersynapses and plays an important role in shapingthe NMDA receptor response at these synapses.", "metadata": {}}
+{"_id": "10557471", "title": "", "text": "Association between folate intake from differentfood sources in Norway and homocysteine statusin a dietary intervention among young maleadults.The aim of the present investigation wasto study the effect of a dietary intervention whichcombined nutrition information with increasedavailability of vegetables, fruits and wholegrainbread. The effect of the intervention wasdetermined by changes in the intake ofvegetables, fruits, wholegrain bread andestimated nutrients. Furthermore, the studyinvestigated whether changes in relativecontribution from different food sources of folatewere related to changes in the concentration ofplasma total homocysteine (p-tHcy). The5-month intervention study included 376 malerecruits from the Norwegian National Guard,Vaernes (intervention group) and 105 malerecruits from the Norwegian National Guard,Heggelia (control group). The study resulted inan increase in the total consumption ofvegetables, fruits, berries and juice (P < 0.001)", "metadata": {}}
+{"_id": "10559501", "title": "", "text": "Beta interferon controls West Nile virus infectionand pathogenesis in mice.Studies with micelacking the common plasma membrane receptorfor type I interferon (IFN-αβR(-)(/)(-)) haverevealed that IFN signaling restricts tropism,dissemination, and lethality after infection withWest Nile virus (WNV) or several otherpathogenic viruses. However, the specificfunctions of individual IFN subtypes remainuncertain. Here, using IFN-β(-)(/)(-) mice, wedefined the antiviral and immunomodulatoryfunction of this IFN subtype in restricting viralinfection. IFN-β(-)(/)(-) mice were morevulnerable to WNV infection than wild-type mice,succumbing more quickly and with greateroverall mortality, although the phenotype wasless severe than that of IFN-αβR(-)(/)(-) mice.The increased susceptibility of IFN-β(-)(/)(-)mice was accompanied by enhanced viralreplication in different tissues. Consistent with adirect role for IFN-β in control of WNVreplication, viral titers in ex vivo cultures of", "metadata": {}}
+{"_id": "10562341", "title": "", "text": "Frontrunners of T cell activation: Initial, localizedCa2+ signals mediated by NAADP and the type 1ryanodine receptorThe activation of T cells is thefundamental on switch for the adaptive immunesystem. Ca2+ signaling is essential for T cellactivation and starts as initial, short-lived,localized Ca2+ signals. The second messengernicotinic acid adenine dinucleotide phosphate(NAADP) forms rapidly upon T cell activation andstimulates early Ca2+ signaling. We developed ahigh-resolution imaging technique using multiplefluorescent Ca2+ indicator dyes to characterizethese early signaling events and investigate thechannels involved in NAADP-dependent Ca2+signals. In the first seconds of activation of eitherprimary murine T cells or human Jurkat cells withbeads coated with an antibody against CD3, wedetected Ca2+ signals with diameters close tothe limit of detection and that were close to theactivation site at the plasma membrane. InJurkat cells in which the ryanodine receptor(RyR) was knocked down or in primary T cells", "metadata": {}}
+{"_id": "10574949", "title": "", "text": "A missense LAMB2 mutation causes congenitalnephrotic syndrome by impairing lamininsecretion.Laminin β2 is a component oflaminin-521, which is an important constituent ofthe glomerular basement membrane (GBM). Nullmutations in laminin β2 (LAMB2) cause Piersonsyndrome, a severe congenital nephroticsyndrome with ocular and neurologic defects. Incontrast, patients with LAMB2 missensemutations, such as R246Q, can have less severeextrarenal defects but still exhibit congenitalnephrotic syndrome. To investigate how suchmissense mutations in LAMB2 cause proteinuria,we generated three transgenic lines of mice inwhich R246Q-mutant rat laminin β2 replaced thewild-type mouse laminin β2 in the GBM. Thesetransgenic mice developed much less severeproteinuria than their nontransgenicLamb2-deficient littermates; the level ofproteinuria correlated inversely withR246Q-LAMB2 expression. At the onset ofproteinuria, expression and localization of", "metadata": {}}
+{"_id": "10576136", "title": "", "text": "Interleukin-33 prevents apoptosis and improvessurvival after experimental myocardial infarctionthrough ST2 signaling.BACKGROUND ST2 is aninterleukin (IL)-1 receptor family member withmembrane-bound (ST2L) and soluble (sST2)isoforms, and sST2 is a biomarker for pooroutcome in patients with myocardial infarction(MI). IL-33, the recently discovered ligand forST2, activates nuclear factor kappaB and thusmay regulate apoptotic cell death. We tested thehypothesis that IL-33 is cardioprotective after MIthrough ST2 signaling. METHODS AND RESULTSIL-33 protected cultured cardiomyocytes fromhypoxia-induced apoptosis, and thiscardioprotection was partially inhibited by sST2.IL-33 induced expression of the antiapoptoticfactors XIAP, cIAP1, and survivin. To define thecardioprotective role of IL-33 in vivo, weperformed a blinded and randomized study ofischemia/reperfusion in rats. IL-33 reducedcardiomyocyte apoptosis, suppressed caspase-3activity, and increased expression of IAP family", "metadata": {}}
+{"_id": "10577574", "title": "", "text": "The impact of open versus closed format ICUadmission practices on the outcome of high risksurgical patients: a cohort analysisBACKGROUNDIn the year 2000, the organizational structure ofthe ICU in the Zaandam Medical Centre (ZMC)changed from an open to a closed format ICU.The objective of this study was to evaluate theeffect of this organizational change on outcomein high risk surgical patients. METHODS Themedical records of all consecutive high risksurgical patients admitted to the ICU from 1996to 1998 (open format) and from 2003 to 2005(closed format), were reviewed. High-riskpatients were defined according to theIdentification of Risk in Surgical patients (IRIS)score. Parameters studied were: mortality,morbidity, ICU length of stay (LOS) and hospitalLOS. RESULTS Mortality of ICU patients was25.7% in the open format group and 15.8% inthe closed format group (p = 0.01). Morbiditydecreased from 48.6% to 46.1% (p = 0.6). Theaverage length of hospital stay was 17 days in", "metadata": {}}
+{"_id": "10582939", "title": "", "text": "Induction therapy with autologous mesenchymalstem cells in living-related kidney transplants: arandomized controlled trial.CONTEXTAntibody-based induction therapy pluscalcineurin inhibitors (CNIs) reduce acuterejection rates in kidney recipients; however,opportunistic infections and toxic CNI effectsremain challenging. Reportedly, mesenchymalstem cells (MSCs) have successfully treatedgraft-vs-host disease. OBJECTIVE To assessautologous MSCs as replacement of antibodyinduction for patients with end-stage renaldisease who undergo ABO-compatible,cross-match-negative kidney transplants from aliving-related donor. DESIGN, SETTING, ANDPATIENTS One hundred fifty-nine patients wereenrolled in this single-site, prospective,open-label, randomized study from February2008-May 2009, when recruitment wascompleted. INTERVENTION Patients wereinoculated with marrow-derived autologous MSC(1-2 x 10(6)/kg) at kidney reperfusion and two", "metadata": {}}
+{"_id": "10605189", "title": "", "text": "Cerebral cortex assembly: generating andreprogramming projection neuron diversityThemammalian cerebral cortex is responsible for thehighest levels of associative, cognitive and motorfunctions. In the central nervous system (CNS)the cortex stands as a prime example of extremeneuronal diversity, broadly classified intoexcitatory projection neurons (PNs) andinhibitory interneurons (INs). We review hererecent progress made in understanding thestrategies and mechanisms that shape PNdiversity during embryogenesis, and discuss howPN classes may be maintained, postnatally, forthe life of the organism. In addition, we considerthe intriguing possibility that PNs may beamenable to directed reprogramming of theirclass-specific features to allow enhanced corticalplasticity in the adult.", "metadata": {}}
+{"_id": "10607877", "title": "", "text": "Mechanical modulation of receptor-ligandinteractions at cell-cell interfaces.Cell surfacereceptors have been extensively studied becausethey initiate and regulate signal transductioncascades leading to a variety of functionalcellular outcomes. An important class of immunereceptors (e.g., T-cell antigen receptors) whoseligands are anchored to the surfaces of othercells remain poorly understood. The mechanismby which ligand binding initiates receptorphosphorylation, a process termed \"receptortriggering\", remains controversial. Recently,direct measurements of the (two-dimensional)receptor-ligand complex lifetimes at cell-cellinterface were found to be smaller than(three-dimensional) lifetimes in solution but theunderlying mechanism is unknown. At thecell-cell interface, the receptor-ligand complexspans a short intermembrane distance (15 nm)compared to long surface molecules (LSMs)whose ectodomains span >40 nm and theseLSMs include phosphatases (e.g., CD45) that", "metadata": {}}
+{"_id": "10608397", "title": "", "text": "High-performance neuroprosthetic control by anindividual with tetraplegia.BACKGROUNDParalysis or amputation of an arm results in theloss of the ability to orient the hand and grasp,manipulate, and carry objects, functions that areessential for activities of daily living.Brain-machine interfaces could provide a solutionto restoring many of these lost functions. Wetherefore tested whether an individual withtetraplegia could rapidly achieve neurologicalcontrol of a high-performance prosthetic limbusing this type of an interface. METHODS Weimplanted two 96-channel intracorticalmicroelectrodes in the motor cortex of a52-year-old individual with tetraplegia.Brain-machine-interface training was done for 13weeks with the goal of controlling ananthropomorphic prosthetic limb with sevendegrees of freedom (three-dimensionaltranslation, three-dimensional orientation,one-dimensional grasping). The participant'sability to control the prosthetic limb was", "metadata": {}}
+{"_id": "10608822", "title": "", "text": "Phase locking and multiple oscillating attractorsfor the coupled mammalian clock and cellcycle.Daily synchronous rhythms of cell divisionat the tissue or organism level are observed inmany species and suggest that the circadianclock and cell cycle oscillators are coupled. Formammals, despite known mechanisticinteractions, the effect of such coupling on clockand cell cycle progression, and hence itsbiological relevance, is not understood. Inparticular, we do not know how the temporalorganization of cell division at the single-celllevel produces this daily rhythm at the tissuelevel. Here we use multispectral imaging ofsingle live cells, computational methods, andmathematical modeling to address this questionin proliferating mouse fibroblasts. We show thatin unsynchronized cells the cell cycle andcircadian clock robustly phase lock each other ina 1:1 fashion so that in an expanding cellpopulation the two oscillators oscillate in asynchronized way with a common frequency.", "metadata": {}}
+{"_id": "10617916", "title": "", "text": "Moderate effect of artemisinin-basedcombination therapy on transmission ofPlasmodium falciparum.Background.Artemisinin-based combination therapy (ACT)reduces microscopically confirmedgametocytemia and mosquito infection.However, molecular techniques have recentlyrevealed high prevalences of submicroscopicgametocytemia. Our objective here was todetermine the effect ofsulfadoxine-pyrimethamine (SP) monotherapyand treatment with SP plus amodiaquine (AQ),SP plus artesunate (AS), andartemether-lumefantrine (AL; Coartem) onsubmicroscopic gametocytemia andinfectiousness. Methods. Kenyan children(n=528) 6 months-10 years of age wererandomized to 4 treatment arms.Gametocytemia was determined by bothmicroscopy and Pfs25 RNA-based quantitativenucleic acid sequence-based amplification (Pfs25QT-NASBA). Transmission was determined by", "metadata": {}}
+{"_id": "10624000", "title": "", "text": "Lip movements entrain the observers’low-frequency brain oscillations to facilitatespeech intelligibilityDuring continuous speech, lipmovements provide visual temporal signals thatfacilitate speech processing. Here, using MEG wedirectly investigated how these visual signalsinteract with rhythmic brain activity inparticipants listening to and seeing the speaker.First, we investigated coherence betweenoscillatory brain activity and speaker's lipmovements and demonstrated significantentrainment in visual cortex. We then usedpartial coherence to remove contributions of thecoherent auditory speech signal from thelip-brain coherence. Comparing thissynchronization between different attentionconditions revealed that attending visual speechenhances the coherence between activity invisual cortex and the speaker's lips. Further, weidentified a significant partial coherence betweenleft motor cortex and lip movements and thispartial coherence directly predicted", "metadata": {}}
+{"_id": "10627801", "title": "", "text": "Loss of DExD/H box RNA helicase LGP2 manifestsdisparate antiviral responses.The DExD/H boxRNA helicase retinoic acid-inducible gene I(RIG-I) and the melanomadifferentiation-associated gene 5 (MDA5) are keyintracellular receptors that recognize virusinfection to produce type I IFN. A third helicasegene, Lgp2, is homologous to Rig-I and Mda5 butlacks a caspase activation and recruitmentdomain. We generated Lgp2-deficient mice andreport that the loss of this gene greatlysensitizes cells to cytosolicpolyinosinic/polycytidylic acid-mediated inductionof type I IFN. However, negative feedbackinhibition of IFN-beta transcription was found tobe normal in the absence of LGP2, indicating thatLGP2 is not the primary negative regulator oftype I IFN production. Our data further indicatethat Lgp2-/- mice exhibited resistance to lethalvesicular stomatitis virus infection, a virus whosereplicative RNA intermediates are recognizedspecifically by RIG-I rather than by MDA5 to", "metadata": {}}
+{"_id": "10628767", "title": "", "text": "Three-dimensional, single-molecule fluorescenceimaging beyond the diffraction limit by using adouble-helix point spread function.Wedemonstrate single-molecule fluorescenceimaging beyond the optical diffraction limit in 3dimensions with a wide-field microscope thatexhibits a double-helix point spread function(DH-PSF). The DH-PSF design features high anduniform Fisher information and has 2 dominantlobes in the image plane whose angularorientation rotates with the axial (z) position ofthe emitter. Single fluorescent molecules in athick polymer sample are localized in single500-ms acquisitions with 10- to 20-nm precisionover a large depth of field (2 microm) by findingthe center of the 2 DH-PSF lobes. By using aphotoactivatable fluorophore, repeated imagingof sparse subsets with a DH-PSF microscopeprovides superresolution imaging of highconcentrations of molecules in all 3 dimensions.The combination of optical PSF design and digitalpostprocessing with photoactivatable", "metadata": {}}
+{"_id": "10641162", "title": "", "text": "A unique cell division machinery in theArchaea.In contrast to the cell divisionmachineries of bacteria, euryarchaea, andeukaryotes, no division components have beenidentified in the second main archaeal phylum,Crenarchaeota. Here, we demonstrate that athree-gene operon, cdv, in the crenarchaeonSulfolobus acidocaldarius, forms part of a uniquecell division machinery. The operon is induced atthe onset of genome segregation and division,and the Cdv proteins then polymerize betweensegregating nucleoids and persist throughout celldivision, forming a successively smaller structureduring constriction. The cdv operon isdramatically down-regulated after UV irradiation,indicating division inhibition in response to DNAdamage, reminiscent of eukaryotic checkpointsystems. The cdv genes exhibit a complementaryphylogenetic range relative to FtsZ-basedarchaeal division systems such that, in mostarchaeal lineages, either one or the other systemis present. Two of the Cdv proteins, CdvB and", "metadata": {}}
+{"_id": "10641715", "title": "", "text": "Modelling and rescuing neurodevelopmentaldefect of Down syndrome using inducedpluripotent stem cells from monozygotic twinsdiscordant for trisomy 21Down syndrome(trisomy 21) is the most common viablechromosomal disorder with intellectualimpairment and several other developmentalabnormalities. Here, we report the generationand characterization of induced pluripotent stemcells (iPSCs) derived from monozygotic twinsdiscordant for trisomy 21 in order to eliminatethe effects of the variability of genomicbackground. The alterations observed by geneticanalysis at the iPSC level and at firstapproximation in early development illustrate thedevelopmental disease transcriptional signatureof Down syndrome. Moreover, we observed anabnormal neural differentiation of Downsyndrome iPSCs in vivo when formed teratoma inNOD-SCID mice, and in vitro when differentiatedinto neuroprogenitors and neurons. Thesedefects were associated with changes in the", "metadata": {}}
+{"_id": "10648422", "title": "", "text": "Programmed death-1–induced interleukin-10production by monocytes impairs CD4+ T cellactivation during HIV infectionViral replicationand microbial translocation from the gut to theblood during HIV infection lead to hyperimmuneactivation, which contributes to the decline inCD4+ T cell numbers during HIV infection.Programmed death-1 (PD-1) and interleukin-10(IL-10) are both upregulated during HIVinfection. Blocking interactions between PD-1and programmed death ligand-1 (PD-L1) andbetween IL-10 and IL-10 receptor (IL-10R)results in viral clearance and improves T cellfunction in animal models of chronic viralinfections. Here we show that high amounts ofmicrobial products and inflammatory cytokines inthe plasma of HIV-infected subjects lead toupregulation of PD-1 expression on monocytesthat correlates with high plasma concentrationsof IL-10. Triggering of PD-1 expressed onmonocytes by PD-L1 expressed on various celltypes induced IL-10 production and led to", "metadata": {}}
+{"_id": "10650521", "title": "", "text": "A general role for splicing enhancers in exondefinition.Exonic splicing enhancers (ESEs)facilitate exon definition by assisting in therecruitment of splicing factors to the adjacentintron. Here we demonstrate that suboptimal 5'and 3' splice sites are activated independently byESEs when they are located on different exons.However, when they are situated within a singleexon, the same weak 5' and 3' splice sites areactivated simultaneously by a single ESE. Thesefindings demonstrate that a single ESE promotesthe recognition of both exon/intron junctionswithin the same step during exon definition. Ourresults suggest that ESEs recruit amulticomponent complex that minimally containscomponents of the splicing machinery requiredfor 5' and 3' splice site selection.", "metadata": {}}
+{"_id": "10660080", "title": "", "text": "SecDFyajC is not required for the maintenance ofthe proton motive force.SecDFyajC of Escherichiacoli is required for efficient export of proteins invivo. However, the functional role of SecDFyajCin protein translocation is unclear. We evaluatedthe postulated function of SecDFyajC in themaintenance of the proton motive force. Aspreviously reported, inner membrane vesicles(IMVs) lacking SecDFyajC are defective in thegeneration of a stable proton motive force whenenergized with succinate. This phenomenon is,however, not observed when NADH is used as anelectron donor. Moreover, the proton motiveforce generated in SecDFyajC-depleted vesiclesstimulated translocation to the same extent asseen with IMVs containing SecDFyajC. Furtheranalysis demonstrates that the reduced protonmotive force with succinate in IMVs lackingSecDFyajC is due to a lower amount of theenzyme succinate dehydrogenase. Theexpression of this enzyme complex is repressedby growth on glucose media, the condition used", "metadata": {}}
+{"_id": "10666475", "title": "", "text": "The serine protease inhibitor SerpinA3Nattenuates neuropathic pain by inhibiting Tcell-derived leukocyte elastaseNeuropathic painis a major, intractable clinical problem and itspathophysiology is not well understood. Althoughrecent gene expression profiling studies haveenabled the identification of novel targets forpain therapy, classical study designs provideunclear results owing to the differentialexpression of hundreds of genes across shamand nerve-injured groups, which can be difficultto validate, particularly with respect to thespecificity of pain modulation. To circumventthis, we used two outbred lines of rats, which aregenetically similar except for being geneticallysegregated as a result of selective breeding fordifferences in neuropathic pain hypersensitivity.SerpinA3N, a serine protease inhibitor, wasupregulated in the dorsal root ganglia (DRG)after nerve injury, which was further validatedfor its mouse homolog. Mice lacking SerpinA3Ndeveloped more neuropathic mechanical", "metadata": {}}
+{"_id": "10669582", "title": "", "text": "Tissue Transglutaminase Is an Integrin-BindingAdhesion Coreceptor for FibronectinThe proteincross-linking enzyme tissue transglutaminasebinds in vitro with high affinity to fibronectin viaits 42-kD gelatin-binding domain. Here we reportthat cell surface transglutaminase mediatesadhesion and spreading of cells on the 42-kDfibronectin fragment, which lacksintegrin-binding motifs. Overexpression of tissuetransglutaminase increases its amount on thecell surface, enhances adhesion and spreadingon fibronectin and its 42-kD fragment, enlargesfocal adhesions, and amplifiesadhesion-dependent phosphorylation of focaladhesion kinase. These effects are specific fortissue transglutaminase and are not shared byits functional homologue, a catalytic subunit offactor XIII. Adhesive function of tissuetransglutaminase does not require itscross-linking activity but depends on its stablenoncovalent association with integrins.Transglutaminase interacts directly with multiple", "metadata": {}}
+{"_id": "10669939", "title": "", "text": "Imaging the expression of transfected genes invivo.Imaging the expression of successful genetransduction has been demonstrated in vivo forthe first time by using an appropriatecombination of \"marker gene\" and \"markersubstrate\" in an experimental animal model. Theherpes simplex virus 1 thymidine kinase(HSV1-tk) gene was selected as an example of amarker gene, and the recombinant STKretrovirus containing HSV1-tk was used totransduce RG2 glioma cells in vitro and in vivo.RG2TK+ cell lines expressing the HSV1-tk geneand three potential marker substrates for theHSV1-TK enzyme were evaluated. Radiolabeled5-iodo-2'-fluoro-2'deoxy-1-beta-D-arabinofuranosyluracil (FIAU) was shown to be a substantiallybetter marker substrate for the HSV1-TK enzymethan 5-iodo-2'-deoxyuridine or ganciclovir. Themagnitude of FIAU accumulation in differentRG2TK+ clones corresponded to their sensitivityto ganciclovir and to the level of HSV1-tk mRNAexpression. Imaging the expression of HSV1-tk", "metadata": {}}
+{"_id": "10670430", "title": "", "text": "Engulfment of apoptotic cells: signals for a goodmealThe clearance of apoptotic cells byphagocytes is an integral component of normallife, and defects in this process can havesignificant implications for self tolerance andautoimmunity. Recent studies have provided newinsights into the engulfment process, includinghow phagocytes seek apoptotic cells, how theyrecognize and ingest these targets and how theymaintain cellular homeostasis after the 'meal'.Several new factors that regulate engulfmenthave been identified, whereas the roles of someof the older players require revision. This Reviewfocuses on these recent developments andattempts to highlight some of the importantquestions in this field.", "metadata": {}}
+{"_id": "10675756", "title": "", "text": "Related IgA1 and IgG producing cells in bloodand diseased mucosa in ulcerativecolitis.BACKGROUND Ulcerative colitis (UC) is achronic inflammatory bowel disease in which thecolonic mucosa is infiltrated with plasma cellsproducing IgG autoantibodies. It is not knownwhether this represents a local mucosal responsewhich has switched to IgG or a peripheralresponse which may have been initiated byperipheral antigen which homed to the colonicmucosa. The clonal distribution of IgG secretingcells and isotype switched variants in UC is notknown. AIMS To investigate the clonaldistribution of mucosal IgG in UC and to searchfor related IgG and IgA secreting cells in normaland diseased mucosa and blood in UC. Toinvestigate characteristics which maydiscriminate between the mucosal and peripheralrepertoire in the normal mucosa and in UC.PATIENTS Blood and normal and diseasedmucosa from two patients with UC were studied.METHODS Immunoglobulin gene analysis and", "metadata": {}}
+{"_id": "10692412", "title": "", "text": "Geovisual analytics to enhance spatial scanstatistic interpretation: an analysis of U.S.cervical cancer mortalityBACKGROUNDKulldorff's spatial scan statistic and its softwareimplementation - SaTScan - are widely used fordetecting and evaluating geographic clusters.However, two issues make using the method andinterpreting its results non-trivial: (1) themethod lacks cartographic support forunderstanding the clusters in geographic contextand (2) results from the method are sensitive toparameter choices related to cluster scaling(abbreviated as scaling parameters), but thesystem provides no direct support for makingthese choices. We employ both established andnovel geovisual analytics methods to addressthese issues and to enhance the interpretation ofSaTScan results. We demonstrate our geovisualanalytics approach in a case study analysis ofcervical cancer mortality in the U.S.   RESULTSWe address the first issue by providing aninteractive visual interface to support the", "metadata": {}}
+{"_id": "10692948", "title": "", "text": "Neurological development of 5-year-old childrenreceiving a low-saturated fat, low-cholesteroldiet since infancy: A randomized controlledtrial.CONTEXT Early childhood introduction ofnutritional habits aimed at atherosclerosisprevention is compatible with normal growth, butits effect on neurological development isunknown. OBJECTIVE To analyze how parentalcounseling aimed at keeping children's diets lowin saturated fat and cholesterol influencesneurodevelopment during the first 5 years of life.DESIGN Randomized controlled trial conductedbetween February 1990 and November 1996.SETTING Outpatient clinic of a universitydepartment in Turku, Finland. PARTICIPANTS Atotal of 1062 seven-month-old infants and theirparents, recruited at well-baby clinics between1990 and 1992. At age 5 years, 496 children stillliving in the city of Turku were available toparticipate in neurodevelopmental testing.INTERVENTION Participants were randomlyassigned to receive individualized counseling", "metadata": {}}
+{"_id": "10697096", "title": "", "text": "Vasodilator responses of coronary resistancearteries of exercise-trained pigs.BACKGROUNDThe purpose of this study was to test thehypothesis that vasodilator responses of porcinecoronary resistance arteries are increased byexercise training. METHODS AND RESULTSYucatan miniature swine were randomly dividedinto groups of exercise-trained (ET) andsedentary (SED) control pigs. ET pigs wereplaced on a progressive treadmill trainingprogram lasting 16 to 20 weeks, and SED pigsremained inactive during the same time period.Coronary resistance arteries 64 to 157 micronsin diameter were isolated for in vitro evaluationof relaxation responses to theendothelium-independent dilators sodiumnitroprusside (1 x 10(-10) to 1 x 10(-4) mol/L)and adenosine (1 x 10(-10) to 1 x 10(-5) mol/L)and to bradykinin (1 x 10(-13) to 3 x 10(-7)mol/L), an endothelium-dependent agent.Relaxation responses to adenosine and sodiumnitroprusside were not altered by exercise", "metadata": {}}
+{"_id": "10698739", "title": "", "text": "Modulation of mitochondrial function andmorphology by interaction of Omi/HtrA2 with themitochondrial fusion factor OPA1.Loss ofOmi/HtrA2 function leads to nerve cell loss inmouse models and has been linked toneurodegeneration in Parkinson's andHuntington's disease. Omi/HtrA2 is a serineprotease released as a pro-apoptotic factor fromthe mitochondrial intermembrane space into thecytosol. Under physiological conditions,Omi/HtrA2 is thought to be involved in protectionagainst cellular stress, but the cytological andmolecular mechanisms are not clear. Omi/HtrA2deficiency caused an accumulation of reactiveoxygen species and reduced mitochondrialmembrane potential. In Omi/HtrA2 knockoutmouse embryonic fibroblasts, as well as inOmi/HtrA2 silenced human HeLa cells andDrosophila S2R+ cells, we found elongatedmitochondria by live cell imaging. Electronmicroscopy confirmed the mitochondrialmorphology alterations and showed abnormal", "metadata": {}}
+{"_id": "10699587", "title": "", "text": "Four prognostic groups predict long-termsurvival from prostate cancer followingradiotherapy alone on Radiation TherapyOncology Group clinical trials.PURPOSE Gleasonscore (GS), T stage, and pathologic lymph nodestatus have been described as majorindependent predictors of death due to prostatecancer in men treated with external beamradiotherapy (XRT). In this analysis we combinethese three factors to define prognosticsubgroups that correlate with disease-specificsurvival (DSS) death from prostate cancer.METHODS AND MATERIALS Men entered on oneof four Radiation Therapy Oncology Group(RTOG) Phase III randomized trials between1975 and 1992, for clinically localized prostatecancer (CAP) (n = 1557), were selected for thisanalysis. Patients were included if: 1) they wereevaluable, and eligible for the trial; 2) theyreceived no hormonal therapy with their initialtreatment; and 3) follow-up was available. Forthis study a DSS event was declared if: 1) death", "metadata": {}}
+{"_id": "10703001", "title": "", "text": "The pathogenesis of bleomycin-inducedpulmonary fibrosis in mice.Administration of 0.5mg bleomycin to mice twice weekly for 4 weeksinduced pulmonary fibrosis. The initial site ofinjury was the intima of pulmonary arteries andveins where endothelial cells became edematousand were separated from the underlyingbasement membrane by large blebs. Theselesions occurred after 2 weeks and wereassociated with infiltration of perivascular spacesby lymphocytes and plasma cells. Capillaryendothelial blebbing and interstitial edema wereobserved after 4 weeks, when multifocal necrosisof type 1 alveolar epithelial cells wasaccompanied by fibrinous exudation into thealveoli. The process of repair was characterizedby proliferation and metaplasia of type 2epithelial cells, fibroblastic organization ofalveolar fibrin and fibrosis of the interstitiumwithin 8 to 12 weeks. The consistent induction ofchanges similar to those of diffuse pulmonaryfibrosis or fibrosing alveolitis in man suggests", "metadata": {}}
+{"_id": "10704438", "title": "", "text": "The DNA damage response during mitosis.Cellsare equipped with a cell-intrinsic signalingnetwork called the DNA damage response (DDR).This signaling network recognizes DNA lesionsand initiates various downstream pathways tocoordinate a cell cycle arrest with the repair ofthe damaged DNA. Alternatively, the DDR canmediate clearance of affected cells that arebeyond repair through apoptosis or senescence.The DDR can be activated in response to DNAdamage throughout the cell cycle, although theextent of DDR signaling is different in each cellcycle phase. Especially in response to DNAdouble strand breaks, only a very marginalresponse was observed during mitosis. Early onit was recognized that cells which are irradiatedduring mitosis continued division withoutrepairing broken chromosomes. Although theseinitial observations indicated diminished DNArepair and lack of an acute DNA damage-inducedcell cycle arrest, insight into the mechanisticre-wiring of DDR signaling during mitosis was", "metadata": {}}
+{"_id": "10743131", "title": "", "text": "Model-based GeostatisticsGeostatistics isconcerned with estimation and predictionproblems for spatially continuous phenomena,using data obtained at a limited number ofspatial locations. Model-based geostatisticsrefers to the application of general statisticalprinciples of modelling and inference togeostatisatical problems. This volume is the firstbook-length treatment of model-basedgeostatistics.", "metadata": {}}
+{"_id": "10749308", "title": "", "text": "Placebo-Controlled Trials and Active-ControlTrials in the Evaluation of New Treatments. Part1: Ethical and Scientific IssuesPlacebo-controlledtrials are used extensively in the development ofnew pharmaceuticals. They are sometimeschallenged as unethical in settings in whichpatients could be treated with an existingtherapy (1-7). The issues of when placebocontrols are ethically acceptable and when theyare scientifically necessary are important andworthy of discussion. The Ethics of PlaceboControls The Declaration of Helsinki TheDeclaration of Helsinki (8) is an internationaldocument that describes ethical principles forclinical investigation. Those who contend thatplacebo controls are unethical whenever knowneffective therapy exists for a condition usuallycite the following sentence in the Declaration assupport for that position: In any medical study,every patientincluding those of a control group, ifanyshould be assured of the best provendiagnostic and therapeutic method. We believe", "metadata": {}}
+{"_id": "10761515", "title": "", "text": "Breath-methane in patients with cancer of thelarge bowel.In 30 patients with cancer of thelarge bowel, 24 (80%) had detectable levels ofmethane in their breath, compared with 25(39%) of 64 patients with non-malignantlarge-bowel disease and 83 (40%) of 208subjects without large-bowel disease. Thesefindings suggest that there may be a differencein anaerobic intestinal flora between patientswith cancer of the large bowel and those withoutthe disease. This difference may antedate thedevelopment of the tumour or, alternatively,result from the tumour.", "metadata": {}}
+{"_id": "10765888", "title": "", "text": "Immune cells contribute to the maintenance ofneurogenesis and spatial learning abilities inadulthoodNeurogenesis is known to take place inthe adult brain. This work identifies Tlymphocytes and microglia as being important tothe maintenance of hippocampal neurogenesisand spatial learning abilities in adulthood.Hippocampal neurogenesis induced by anenriched environment was associated with therecruitment of T cells and the activation ofmicroglia. In immune-deficient mice,hippocampal neurogenesis was markedlyimpaired and could not be enhanced byenvironmental enrichment, but was restored andboosted by T cells recognizing a specific CNSantigen. CNS-specific T cells were also found tobe required for spatial learning and memory andfor the expression of brain-derived neurotrophicfactor in the dentate gyrus, implying that acommon immune-associated mechanismunderlies different aspects of hippocampalplasticity and cell renewal in the adult brain.", "metadata": {}}
+{"_id": "10766688", "title": "", "text": "Sperm cross-over activity in regions of thehuman genome showing extreme breakdown ofmarker association.Population diversity datahave recently provided profound, albeitinferential, insights into meiotic recombinationacross the human genome, revealing alandscape dominated by thousands of cross-overhotspots. However, very few of these putativehotspots have been directly analyzed forcross-over activity. We now describe a search forvery active hotspots, by using extremebreakdown of marker association as a guide forhigh-resolution sperm cross-over analysis. Thisstrategy has led to the isolation of the mostactive cross-over hotspots yet described. Theirmorphology, sequence attributes, and cross-overprocesses are very similar to those seen at lessactive hotspots, but their activity in sperm ispoorly predicted from population diversityinformation. Several of these hotspots showedevidence for biased gene conversionaccompanying cross-over, in some cases", "metadata": {}}
+{"_id": "10786948", "title": "", "text": "An efficient nonviral method to generateintegration-free human-induced pluripotent stemcells from cord blood and peripheral bloodcells.The generation of induced pluripotent stemcells (iPSCs) provides the opportunity to usepatient-specific somatic cells, which are avaluable source for disease modeling and drugdiscovery. To promote research involving thesecells, it is important to make iPSCs from easilyaccessible and less invasive tissues, like blood.We have recently reported the efficientgeneration of human iPSCs from adult fibroblastsusing a combination of plasmids encodingOCT3/4, SOX2, KLF4, L-MYC, LIN28, and shRNAfor TP53. We herein report a modified protocolenabling efficient iPSC induction from CD34+cord blood cells and from peripheral bloodisolated from healthy donors using these plasmidvectors. The original plasmid mixture couldinduce iPSCs; however, the efficiency was low.The addition of EBNA1, an essential factor forepisomal amplification of the vectors, by an extra", "metadata": {}}
+{"_id": "10790846", "title": "", "text": "A rapamycin-sensitive signaling pathwaycontributes to long-term synaptic plasticity in thehippocampus.Many forms of long-lastingbehavioral and synaptic plasticity require thesynthesis of new proteins. For example,long-term potentiation (LTP) that endures formore than an hour requires both transcriptionand translation. The signal-transductionmechanisms that couple synaptic events toprotein translational machinery duringlong-lasting synaptic plasticity, however, are notwell understood. One signaling pathway that isstimulated by growth factors and results in thetranslation of specific mRNAs includes therapamycin-sensitive kinase mammalian target ofrapamycin (mTOR, also known as FRAP andRAFT-1). Several components of thistranslational signaling pathway, including mTOR,eukaryotic initiation factor-4E-binding proteins 1and 2, and eukaryotic initiation factor-4E, arepresent in the rat hippocampus as shown byWestern blot analysis, and these proteins are", "metadata": {}}
+{"_id": "10795063", "title": "", "text": "The FASEB Journal express article10.1096/fj.00-0815fje. Published online June 27,2001. Essential role for cholesterol in synapticplasticity and neuronal degenerationSPECIFICAIMSOur previous studies implied the relationbetween lipid metabolism and amyloid betaprotein (Aβ) as ‘a missing link in Alzheimer’spuzzle’ [FASEB J., vol. 12, p. 1097 (1998)]. Inthe present study, we evaluated the role ofcholesterol in synaptic plasticity and neuronaldegeneration by a combination of adult rathippocampal slice technology, a well-establishedprocedure for limited cholesterol efflux, lipidmetabolic labeling, extracellular recording of CA1field excitatory postsynaptic potentials (fEPSPs),and immunofluorescence. PRINCIPALFINDINGS1. Increased cholesterol efflux impairsshort- and long-term synaptic plasticitySynapticplasticity is a fundamental feature of the centralnervous system (CNS) that allows synapses to‘remember’ previous activity and express plasticchanges to fine-tune current synaptic action. In", "metadata": {}}
+{"_id": "10795340", "title": "", "text": "Functional inhibition of osteoblastic cells in an invivo mouse model of myeloidleukemia.Pancytopenia is a major cause ofmorbidity in acute myeloid leukemia (AML), yetits cause is unclear. Normal osteoblastic cellshave been shown to support hematopoiesis. Todefine the effects of leukemia on osteoblasticcells, we used an immunocompetent murinemodel of AML. Leukemic mice had inhibition ofosteoblastic cells, with decreased serum levels ofthe bone formation marker osteocalcin.Osteoprogenitor cells and endosteal-liningosteopontin(+) cells were reduced, andosteocalcin mRNA in CD45(-) marrow cells wasdiminished. This resulted in severe loss ofmineralized bone. Osteoclasts were onlytransiently increased without significantincreases in bone resorption, and their inhibitiononly partially rescued leukemia-induced boneloss. In vitro data suggested that aleukemia-derived secreted factor inhibitedosteoblastic cells. Because the chemokine CCL-3", "metadata": {}}
+{"_id": "10812605", "title": "", "text": "Fibroblast heterogeneity in the cancerwoundFibroblasts regulate the structure andfunction of healthy tissues, participate transientlyin tissue repair after acute inflammation, andassume an aberrant stimulatory role duringchronic inflammatory states including cancer.Such cancer-associated fibroblasts (CAFs)modulate the tumor microenvironment andinfluence the behavior of neoplastic cells in eithera tumor-promoting or tumor-inhibiting manner.These pleiotropic functions highlight the inherentplasticity of fibroblasts and may provide newavenues to understand and therapeuticallyintervene in malignancies. We discuss theemerging themes of CAF biology in the context oftumorigenesis and therapy.", "metadata": {}}
+{"_id": "10827901", "title": "", "text": "Cohort profile: the China Health and RetirementLongitudinal Study (CHARLS).The China Healthand Retirement Longitudinal Study (CHARLS) is anationally representative longitudinal survey ofpersons in China 45 years of age or older andtheir spouses, including assessments of social,economic, and health circumstances ofcommunity-residents. CHARLS examines healthand economic adjustments to rapid ageing of thepopulation in China. The national baseline surveyfor the study was conducted between June 2011and March 2012 and involved 17 708respondents. CHARLS respondents are followedevery 2 years, using a face-to-facecomputer-assisted personal interview (CAPI).Physical measurements are made at every2-year follow-up, and blood sample collection isdone once in every two follow-up periods. A pilotsurvey for CHARLS was conducted in twoprovinces of China in 2008, on 2685 individuals,who were resurveyed in 2012. To ensure theadoption of best practices and international", "metadata": {}}
+{"_id": "10831818", "title": "", "text": "Central role of Th2/Tc2 lymphocytes in pattern IImultiple sclerosis lesionsOBJECTIVE Multiplesclerosis (MS) is a disease of the central nervoussystem with marked heterogeneity in severalaspects including pathological processes. Basedon infiltrating immune cells, deposition ofhumoral factors and loss of oligodendrocytesand/or myelin proteins, four lesion patterns havebeen described. Pattern II is characterized byantibody and complement deposition in additionto T-cell infiltration. MS is considered aT-cell-mediated disease, but until now the studyof pathogenic T cells has encountered majorchallenges, most importantly the limited accessof brain-infiltrating T cells. Our objective was toidentify, isolate, and characterizebrain-infiltrating clonally expanded T cells inpattern II MS lesions. METHODS We usednext-generation sequencing to identify clonallyexpanded T cells in demyelinating pattern IIbrain autopsy lesions, subsequently isolatedthese as T-cell clones from autologous", "metadata": {}}
+{"_id": "10846815", "title": "", "text": "Coordinated oscillations in cortical actin andCa2+ correlate with cycles of vesiclesecretionThe actin cortex both facilitates andhinders the exocytosis of secretory granules.How cells consolidate these two opposing roleswas not well understood. Here we show thatantigen activation of mast cells inducesoscillations in Ca(2+) and PtdIns(4,5)P(2) lipidlevels that in turn drive cyclic recruitment ofN-WASP and cortical actin level oscillations.Experimental and computational analysis arguesthat vesicle fusion correlates with the observedactin and Ca(2+) level oscillations. A vesiclesecretion cycle starts with the capture of vesiclesby actin when cortical F-actin levels are high,followed by vesicle passage through the cortexwhen F-actin levels are low, and vesicle fusionwith the plasma membrane when Ca(2+) levelssubsequently increase. Thus, cells employoscillating levels of Ca(2+), PtdIns(4,5)P(2) andcortical F-actin to increase secretion efficiency,explaining how the actin cortex can function as a", "metadata": {}}
+{"_id": "10852047", "title": "", "text": "WK175, a novel antitumor agent, decreases theintracellular nicotinamide adenine dinucleotideconcentration and induces the apoptotic cascadein human leukemia cells.We recently developed aclass of novel antitumor agents that elicit apotent growth-inhibitory response in many tumorcells cultured in vitro. WK175, a member of thisclass, was chosen as a model compound thatshowed strong in vitro efficacy. WK175 interfereswith the intracellular steady-state level ofNAD(+), resulting in a decreased cellular NAD(+)concentration. We found that WK175 inducesapoptotic cell death without any DNA-damagingeffect. The apoptotic death signaling pathwayinitiated by WK175 was examined in detail:mitochondrial membrane potential, cytochrome crelease, caspase 3 activation, caspase 3 andpoly(ADP-ribose) polymerase cleavage, and theappearance of a sub-G(1) cell cycle populationwere determined in time course studies in THP-1(a human monocytic leukemia cell line) cells. Wefound activation of this cascade after 24 h of", "metadata": {}}
+{"_id": "10854174", "title": "", "text": "Husbands' involvement in delivery careutilization in rural Bangladesh: A qualitativestudyBACKGROUND A primary cause of highmaternal mortality in Bangladesh is lack ofaccess to professional delivery care. Examiningthe role of the family, particularly the husband,during pregnancy and childbirth is important tounderstanding women's access to and utilizationof professional maternal health services that canprevent maternal mortality. This qualitativestudy examines husbands' involvement duringchildbirth and professional delivery careutilization in a rural sub-district of Netrokonadistrict, Bangladesh. METHODS Using purposivesampling, ten households utilizing a skilledattendant during the birth of the youngest childwere selected and matched with ten householdsutilizing an untrained traditional birth attendant,or dhatri. Households were selected based on aset of inclusion criteria, such as approximatehousehold income, ethnicity, and distance to thenearest hospital. Twenty semi-structured", "metadata": {}}
+{"_id": "10874408", "title": "", "text": "Mapping Meiotic Single-Strand DNA Reveals aNew Landscape of DNA Double-Strand Breaks inSaccharomyces cerevisiaeDNA double-strandbreaks (DSBs), which are formed by the Spo11protein, initiate meiotic recombination. PreviousDSB-mapping studies have used rad50S orsae2Δ mutants, which are defective in breakprocessing, to accumulate Spo11-linked DSBs,and report large (≥ 50 kb) “DSB-hot” regionsthat are separated by “DSB-cold” domains ofsimilar size. Substantial recombination occurs insome DSB-cold regions, suggesting that DSBpatterns are not normal in rad50S or sae2Δmutants. We therefore developed a novelmethod to map genome-wide, single-strand DNA(ssDNA)–associated DSBs that accumulate inprocessing-capable, repair-defective dmc1Δ anddmc1Δ rad51Δ mutants. DSBs were observed atknown hot spots, but also in most previouslyidentified “DSB-cold” regions, including nearcentromeres and telomeres. Althoughapproximately 40% of the genome is DSB-cold in", "metadata": {}}
+{"_id": "10883736", "title": "", "text": "Alterations in liver ATP homeostasis in humannonalcoholic steatohepatitis: a pilotstudy.CONTEXT The mechanisms that driveprogression from fatty liver to steatohepatitisand cirrhosis are unknown. In animal models,obese mice with fatty livers are vulnerable toliver adenosine triphosphate (ATP) depletion andnecrosis, suggesting that altered hepatic energyhomeostasis may be involved. OBJECTIVE Todetermine if patients with fatty liver diseaseexhibit impaired recovery from hepatic ATPdepletion. DESIGN Laboratory analysis of liverATP stores monitored by nuclear magneticresonance spectroscopy before and aftertransient hepatic ATP depletion was induced byfructose injection. The study was conductedbetween July 15 and August 30, 1998. SETTINGUniversity hospital. PATIENTS Eight consecutiveadults with biopsy-proven nonalcoholicsteatohepatitis and 7 healthy age- andsex-matched controls. MAIN OUTCOME MEASURELevel of ATP 1 hour after fructose infusion in", "metadata": {}}
+{"_id": "10889845", "title": "", "text": "Blockade of class IB phosphoinositide-3 kinaseameliorates obesity-induced inflammation andinsulin resistance.Obesity and insulin resistance,the key features of metabolic syndrome, areclosely associated with a state of chronic,low-grade inflammation characterized byabnormal macrophage infiltration into adiposetissues. Although it has been reported thatchemokines promote leukocyte migration byactivating class IB phosphoinositide-3 kinase(PI3Kγ) in inflammatory states, little is knownabout the role of PI3Kγ in obesity-inducedmacrophage infiltration into tissues, systemicinflammation, and the development of insulinresistance. In the present study, we used murinemodels of both diet-induced and geneticallyinduced obesity to examine the role of PI3Kγ inthe accumulation of tissue macrophages and thedevelopment of obesity-induced insulinresistance. Mice lacking p110γ (Pik3cg(-/-)), thecatalytic subunit of PI3Kγ, exhibited improvedsystemic insulin sensitivity with enhanced insulin", "metadata": {}}
+{"_id": "10893238", "title": "", "text": "Identifying common impairments in frail anddependent older people: validation of the COPEassessment for non-specialised health workers inlow resource primary health caresettingsBACKGROUND Frail and dependent olderpeople in resource-poor settings are poorlyserved by health systems that lack outreachcapacity. The COPE (Caring for Older PEople)multidimensional assessment tool is designed tohelp community health workers (CHWs) identifyclinically significant impairments and deliverevidence-based interventions   METHODS Olderpeople (n = 150) identified by CHWs as frail ordependent, were assessed at home by the CHWusing the structured COPE assessment tool,generating information on impairments innutrition, mobility, vision, hearing, continence,cognition, mood and behaviour. The older peoplewere reassessed by local physicians who reacheda clinical judgment regarding the presence orabsence of the same impairments based uponclinical examination guided by the EASY-Care", "metadata": {}}
+{"_id": "10906636", "title": "", "text": "The carboxyl terminus of humancytomegalovirus-encoded 7 transmembranereceptor US28 camouflages agonism bymediating constitutive endocytosis.US28 is oneof four 7 transmembrane (7TM) chemokinereceptors encoded by human cytomegalovirusand has been shown to both signal andendocytose in a ligand-independent,constitutively active manner. Here we show thatthe constitutive activity and constitutiveendocytosis properties of US28 are separableentities in this viral chemokine receptor. Wegenerated chimeric and mutant US28 proteinsthat were altered in either their constitutiveendocytic (US28 Delta 300, US28 Delta 317,US28-NK1-ctail, and US28-ORF74-ctail) orsignaling properties (US28R129A). By using thisseries of mutants, we show that the cytoplasmictail domain of US28 per se regulates receptorendocytosis, independent of the signaling abilityof the core domain of US28. The constitutiveendocytic property of the US28 c-tail was", "metadata": {}}
+{"_id": "10931595", "title": "", "text": "Geometry, epistasis, and developmentalpatterning.Developmental signaling networks arecomposed of dozens of components whoseinteractions are very difficult to quantify in anembryo. Geometric reasoning enumerates adiscrete hierarchy of phenotypic models with afew composite variables whose parameters maybe defined by in vivo data. Vulval development inthe nematode Caenorhabditis elegans is a classicmodel for the integration of two signalingpathways; induction by EGF and lateral signalingthrough Notch. Existing data for the relativeprobabilities of the three possible terminal celltypes in diverse genetic backgrounds as well astimed ablation of the inductive signal favor onegeometric model and suffice to fit most of itsparameters. The model is fully dynamic andencompasses both signaling and commitment. Itthen predicts the correlated cell fate probabilitiesfor a cross between any twobackgrounds/conditions. The two signalingpathways are combined additively, without", "metadata": {}}
+{"_id": "10937190", "title": "", "text": "Table of ContentsThe morphogenesis of the C.elegans embryo is largely controlled by thedevelopment of the epidermis, also known as thehypodermis, a single epithelial layer thatsurrounds the animal. Morphogenesis of theepidermis involves cell-cell interactions withinternal tissues, such as the developing nervoussystem and musculature. Genetic analysis ofmutants with aberrant epidermal morphologyhas defined multiple steps in epidermalmorphogenesis. In the wild type, epidermal cellsare generated on the dorsal side of the embryoamong the progeny of four early embryonicblastomeres. Specification of epidermal fate isregulated by a hierarchy of transcription factors.After specification, dorsal epidermal cellsrearrange, a process known as dorsalintercalation. Most epidermal cells fuse togenerate multinucleate syncytia. The dorsallylocated epidermal sheet undergoes epiboly toenclose the rest of the embryo in a processknown as ventral enclosure; this movement", "metadata": {}}
+{"_id": "10944947", "title": "", "text": "High-throughput sequencing reveals extensivevariation in human-specific L1 content inindividual human genomes.Usinghigh-throughput sequencing, we devised atechnique to determine the insertion sites ofvirtually all members of the human-specific L1retrotransposon family in any human genome.Using diagnostic nucleotides, we were able tolocate the approximately 800 L1Hs copiescorresponding specifically to the pre-Ta, Ta-0,and Ta-1 L1Hs subfamilies, with over 90% ofsequenced reads corresponding tohuman-specific elements. We find that any twoindividual genomes differ at an average of 285sites with respect to L1 insertion presence orabsence. In total, we assayed 25 individuals, 15of which are unrelated, at 1139 sites, including772 shared with the reference genome and 367nonreference L1 insertions. We show that L1Hsprofiles recapitulate genetic ancestry, anddetermine the chromosomal distribution of theseelements. Using these data, we estimate that the", "metadata": {}}
+{"_id": "10958594", "title": "", "text": "Nationwide trends in incidence, treatment andsurvival of colorectal cancer patients withsynchronous metastasesThe aim of this studywas to determine trends in incidence, treatmentand survival of colorectal cancer (CRC) patientswith synchronous metastases (Stage IV) in theNetherlands. This nationwide population-basedstudy included 160,278 patients diagnosed withCRC between 1996 and 2011. We evaluatedchanges in stage distribution, location ofsynchronous metastases and treatment in fourconsecutive periods, using Chi square tests fortrend. Median survival in months wasdetermined, using Kaplan–Meier analysis. Theproportion of Stage IV CRC patients (n = 33,421)increased from 19 % (1996–1999) to 23 %(2008–2011, p < 0.001). This waspredominantly due to a major increase in theincidence of lung metastases (1.7–5.0 % of allCRC patients). During the study period, theprimary tumor was resected less often in StageIV patients (65–46 %) and the use of systemic", "metadata": {}}
+{"_id": "10976596", "title": "", "text": "The curious case of the tumour virus: 50 years ofBurkitt's lymphomaBurkitt's lymphoma (BL) wasfirst described 50 years ago, and the first humantumour virus Epstein–Barr virus (EBV) wasdiscovered in BL tumours soon after. Since then,the role of EBV in the development of BL hasbecome more and more enigmatic. Only recentlyhave we finally begun to understand, at thecellular and molecular levels, the complex andinteresting interaction of EBV with B cells thatcreates a predisposition for the development ofBL. Here, we discuss the intertwined histories ofEBV and BL and their relationship to thecofactors in BL pathogenesis: malaria and theMYC translocation.", "metadata": {}}
+{"_id": "10982689", "title": "", "text": "Nanotoxicology: An Emerging Discipline Evolvingfrom Studies of Ultrafine ParticlesAlthoughhumans have been exposed to airbornenanosized particles (NSPs; < 100 nm)throughout their evolutionary stages, suchexposure has increased dramatically over thelast century due to anthropogenic sources. Therapidly developing field of nanotechnology islikely to become yet another source throughinhalation, ingestion, skin uptake, and injectionof engineered nanomaterials. Information aboutsafety and potential hazards is urgently needed.Results of older biokinetic studies with NSPs andnewer epidemiologic and toxicologic studies withairborne ultrafine particles can be viewed as thebasis for the expanding field of nanotoxicology,which can be defined as safety evaluation ofengineered nanostructures and nanodevices.Collectively, some emerging concepts ofnanotoxicology can be identified from the resultsof these studies. When inhaled, specific sizes ofNSPs are efficiently deposited by diffusional", "metadata": {}}
+{"_id": "10984005", "title": "", "text": "ADHD medications and risk of seriouscardiovascular events in young and middle-agedadults.CONTEXT More than 1.5 million US adultsuse stimulants and other medications labeled fortreatment of attention-deficit/hyperactivitydisorder (ADHD). These agents can increaseheart rate and blood pressure, raising concernsabout their cardiovascular safety. OBJECTIVE Toexamine whether current use of medicationsprescribed primarily to treat ADHD is associatedwith increased risk of serious cardiovascularevents in young and middle-aged adults.DESIGN, SETTING, AND PARTICIPANTSRetrospective, population-based cohort studyusing electronic health care records from 4 studysites (OptumInsight Epidemiology, TennesseeMedicaid, Kaiser Permanente California, and theHMO Research Network), starting in 1986 at 1site and ending in 2005 at all sites, withadditional covariate assessment using 2007survey data. Participants were adults aged 25through 64 years with dispensed prescriptions", "metadata": {}}
+{"_id": "10991183", "title": "", "text": "The Rho GEFs LARG and GEF-H1 regulate themechanical response to force on integrinsHowindividual cells respond to mechanical forces is ofconsiderable interest to biologists as force affectsmany aspects of cell behaviour. The applicationof force on integrins triggers cytoskeletalrearrangements and growth of the associatedadhesion complex, resulting in increased cellularstiffness, also known as reinforcement. AlthoughRhoA has been shown to play a role duringreinforcement, the molecular mechanisms thatregulate its activity are unknown. By combiningbiochemical and biophysical approaches, weidentified two guanine nucleotide exchangefactors (GEFs), LARG and GEF-H1, as keymolecules that regulate the cellular adaptation toforce. We show that stimulation of integrins withtensional force triggers activation of these twoGEFs and their recruitment to adhesioncomplexes. Surprisingly, activation of LARG andGEF-H1 involves distinct signalling pathways.Our results reveal that LARG is activated by the", "metadata": {}}
+{"_id": "10993232", "title": "", "text": "Cell death from antibiotics without theinvolvement of reactive oxygen species.Recentobservations have suggested that classicantibiotics kill bacteria by stimulating theformation of reactive oxygen species (ROS). Iftrue, this notion might guide new strategies toimprove antibiotic efficacy. In this study, themodel was directly tested. Contrary to thehypothesis, antibiotic treatment did notaccelerate the formation of hydrogen peroxide inEscherichia coli and did not elevate intracellularfree iron, an essential reactant for the productionof lethal damage. Lethality persisted in theabsence of oxygen, and DNA repair mutantswere not hypersensitive, undermining the ideathat toxicity arose from oxidative DNA lesions.We conclude that these antibiotic exposures didnot produce ROS and that lethality more likelyresulted from the direct inhibition of cell-wallassembly, protein synthesis, and DNAreplication.", "metadata": {}}
+{"_id": "11011905", "title": "", "text": "Pioneer Transcription Factors Target Partial DNAMotifs on Nucleosomes to InitiateReprogrammingPioneer transcription factors(TFs) access silent chromatin and initiatecell-fate changes, using diverse types of DNAbinding domains (DBDs). FoxA, the paradigmpioneer TF, has a winged helix DBD thatresembles linker histone and thereby binds itstarget sites on nucleosomes and in compactedchromatin. Herein, we compare the nucleosomeand chromatin targeting activities of Oct4 (POUDBD), Sox2 (HMG box DBD), Klf4 (zinc fingerDBD), and c-Myc (bHLH DBD), which togetherreprogram somatic cells to pluripotency. PurifiedOct4, Sox2, and Klf4 proteins can bindnucleosomes in vitro, and in vivo theypreferentially target silent sites enriched fornucleosomes. Pioneer activity relates simply tothe ability of a given DBD to target partial motifsdisplayed on the nucleosome surface. Suchpartial motif recognition can occur by coordinatebinding between factors. Our findings provide", "metadata": {}}
+{"_id": "11016410", "title": "", "text": "Experimental Evolution of an RNA Virus in WildBirds: Evidence for Host-Dependent Impacts onPopulation Structure and CompetitiveFitnessWithin hosts, RNA viruses formpopulations that are genetically andphenotypically complex. Heterogeneity in RNAvirus genomes arises due to error-pronereplication and is reduced by stochastic andselective mechanisms that are incompletelyunderstood. Defining how natural selectionshapes RNA virus populations is critical becauseit can inform treatment paradigms and enhancecontrol efforts. We allowed West Nile virus(WNV) to replicate in wild-caught Americancrows, house sparrows and American robins toassess how natural selection shapes RNA viruspopulations in ecologically relevant hosts thatdiffer in susceptibility to virus-induced mortality.After five sequential passages in each birdspecies, we examined the phenotype andpopulation diversity of WNV through fitnesscompetition assays and next generation", "metadata": {}}
+{"_id": "11016788", "title": "", "text": "sasCIF: an extension of core CrystallographicInformation File for SASData acquisitionpackages developed at different small anglescattering facilities use different formats both forraw and processed data storage. To facilitate thedata exchange between laboratories, aconsensus in the small angle scatteringcommunity has been reached on an ASCII formatfor one-dimensional data which includes aself-describing header containing relevantinformation about the sample and instrumentalconditions followed by raw or reduced data in atabular form. This format called sasCIF wasimplemented as an extension of core CIF(Crystallographic Information File) dictionary.", "metadata": {}}
+{"_id": "11020556", "title": "", "text": "Migratory dendritic cells transfer antigen to alymph node-resident dendritic cell population forefficient CTL priming.Skin dendritic cells (DCs)are thought to act as key initiators of local T cellimmunity. Here we show that after skin infectionwith herpes simplex virus (HSV), cytotoxic Tlymphocyte (CTL) activation required MHC classI-restricted presentation by nonmigratoryCD8(+) DCs rather than skin-derived DCs.Despite a lack of direct presentation bymigratory DCs, blocking their egress frominfected skin substantially inhibited classI-restricted presentation and HSV-specific CTLresponses. These results support the argumentfor initial transport of antigen by migrating DCs,followed by its transfer to the lymphoid-residentDCs for presentation and CTL priming. Given thatrelatively robust CTL responses were seen withsmall numbers of skin-emigrant DCs, we proposethat this inter-DC antigen transfer functions toamplify presentation across a larger network oflymphoid-resident DCs for efficient T cell", "metadata": {}}
+{"_id": "11020675", "title": "", "text": "Thrombopoietin-induced Polyploidization of BoneMarrow Megakaryocytes Is Due to a UniqueRegulatory Mechanism in LateMitosisMegakaryocytes undergo a uniquedifferentiation program, becoming polyploidthrough repeated cycles of DNA synthesiswithout concomitant cell division. However, themechanism underlying this polyploidizationremains totally unknown. It has been postulatedthat polyploidization is due to a skipping ofmitosis after each round of DNA replication. Wecarried out immunohistochemical studies onmouse bone marrow megakaryocytes duringthrombopoietin- induced polyploidization andfound that during this process megakaryocytesindeed enter mitosis and progress throughnormal prophase, prometaphase, metaphase,and up to anaphase A, but not to anaphase B,telophase, or cytokinesis. It was clearly observedthat multiple spindle poles were formed as thepolyploid megakaryocytes entered mitosis; thenuclear membrane broke down during prophase;", "metadata": {}}
+{"_id": "11026600", "title": "", "text": "Unifying Viral Genetics and HumanTransportation Data to Predict the GlobalTransmission Dynamics of Human InfluenzaH3N2Information on global human movementpatterns is central to spatial epidemiologicalmodels used to predict the behavior of influenzaand other infectious diseases. Yet it remainsdifficult to test which modes of dispersal drivepathogen spread at various geographic scalesusing standard epidemiological data alone.Evolutionary analyses of pathogen genomesequences increasingly provide insights into thespatial dynamics of influenza viruses, but to datethey have largely neglected the wealth ofinformation on human mobility, mainly becauseno statistical framework exists within which viralgene sequences and empirical data on hostmovement can be combined. Here, we addressthis problem by applying a phylogeographicapproach to elucidate the global spread ofhuman influenza subtype H3N2 and assess itsability to predict the spatial spread of human", "metadata": {}}
+{"_id": "11041152", "title": "", "text": "Microtubule sliding activity of a kinesin-8promotes spindle assembly and spindle lengthcontrolMolecular motors play critical roles in theformation of mitotic spindles, either throughcontrolling the stability of individualmicrotubules, or by crosslinking and slidingmicrotubule arrays. Kinesin-8 motors are bestknown for their regulatory roles in controllingmicrotubule dynamics. They containmicrotubule-destabilizing activities, and restrictspindle length in a wide variety of cell types andorganisms. Here, we report an antiparallelmicrotubule-sliding activity of the budding yeastkinesin-8, Kip3. The in vivo importance of thissliding activity was established through theidentification of complementary Kip3 mutantsthat separate the sliding activity andmicrotubule-destabilizing activity. In conjunctionwith Cin8, a kinesin-5 family member, the slidingactivity of Kip3 promotes bipolar spindleassembly and the maintenance of genomestability. We propose a slide-disassemble model", "metadata": {}}
+{"_id": "11043831", "title": "", "text": "A Pharmacological Map of the PI3-K FamilyDefines a Role for p110α in InsulinSignalingPhosphoinositide 3-kinases (PI3-Ks) arean important emerging class of drug targets, butthe unique roles of PI3-K isoforms remain poorlydefined. We describe here an approach topharmacologically interrogate the PI3-K family. Achemically diverse panel of PI3-K inhibitors wassynthesized, and their target selectivity wasbiochemically enumerated, revealing cryptichomologies across targets and chemotypes.Crystal structures of three inhibitors bound top110gamma identify a conformationally mobileregion that is uniquely exploited by selectivecompounds. This chemical array was then usedto define the PI3-K isoforms required for insulinsignaling. We find that p110alpha is the primaryinsulin-responsive PI3-K in cultured cells,whereas p110beta is dispensable but sets aphenotypic threshold for p110alpha activity.Compounds targeting p110alpha block the acuteeffects of insulin treatment in vivo, whereas a", "metadata": {}}
+{"_id": "11048759", "title": "", "text": "Identification of Epstein-Barr virus nuclearantigen 1 protein domains that directinteractions at a distance between DNA-boundproteins.The EBNA1 protein of Epstein-Barr virus(EBV) binds to and activates DNA replicationfrom the EBV latent origin of replication, oriP, viaa direct interaction with the two noncontiguoussubelements of oriP. The EBNA1 moleculesbound to the oriP subelements interact efficientlywith each other by a DNA looping mechanism.We have previously mapped a region of EBNA1(termed the looping region) that is required tomediate the interaction of the EBNA1 moleculesbound to the oriP subelements. We nowdemonstrate that two fragments of this region ofEBNA1, which consist largely of an eight aminoacid repeat, can mediate homotypic interactionswhen transferred to another DNA-bindingprotein. Protein interactions mediated by theEBNA1 looping region appear to be dependent onDNA binding since these interactions weredetected between DNA-bound forms of the", "metadata": {}}
+{"_id": "11071351", "title": "", "text": "Primary prevention of hypertension: clinical andpublic health advisory from The National HighBlood Pressure Education Program.The NationalHigh Blood Pressure Education ProgramCoordinating Committee published its firststatement on the primary prevention ofhypertension in 1993. This article updates the1993 report, using new and further evidencefrom the scientific literature. Currentrecommendations for primary prevention ofhypertension involve a population-basedapproach and an intensive targeted strategyfocused on individuals at high risk forhypertension. These 2 strategies arecomplementary and emphasize 6 approacheswith proven efficacy for prevention ofhypertension: engage in moderate physicalactivity; maintain normal body weight; limitalcohol consumption; reduce sodium intake;maintain adequate intake of potassium; andconsume a diet rich in fruits, vegetables, andlow-fat dairy products and reduced in saturated", "metadata": {}}
+{"_id": "11083121", "title": "", "text": "Formins: intermediates in signal-transductioncascades that affect cytoskeletalreorganization.The control of cell growth andpolarity depends on a dynamic actin cytoskeletonthat has the ability to reorganize in response todevelopmental and environmental stimuli. Inanimals and fungi, formins are just one of thefour major classes of poly-L-proline-containing(PLP) proteins that form part of thesignal-transduction cascade that leads torearrangement of the actin cytoskeleton.Analysis of the Arabidopsis genome sequenceindicates that, unlike animals and fungi, forminsare the only class of conserved profilin-bindingPLP proteins in plants. Moreover, plant forminsshow significant structural differences comparedwith their animal and fungal counterparts, raisingthe possibility that plant formins are subject tonovel mechanisms of control or perform uniqueroles in plants.", "metadata": {}}
+{"_id": "11090688", "title": "", "text": "Genetic variability in GLP-1 receptor isassociated with inter-individual differences inweight lowering potential of liraglutide in obesewomen with PCOS: a pilot studyThe weightlowering potential of glucagon-like peptide 1(GLP-1) receptor agonists (RAs) isinter-individually different and clinicallyunpredictable. The potential role of geneticvariability of GLP-1R on body weight response toGLP-1 RAs in obese women with polycystic ovarysyndrome (PCOS) has not yet been evaluated.Fifty-seven obese women with PCOS (aged 30.7± 7.0, BMI 38.6 ± 5.3 kg/m2) were assigned toliraglutide 1.2 mg QD s.c. for 12 weeks andclassified as strong responders regarding weightloss if they lost 5 % or more of their initial bodyweight. They were genotyped for commonGLP-1R single nucleotide polymorphisms (SNPs)rs6923761 and rs10305420. Changes ofmeasures of obesity were measured before andat the end of the treatment. Twenty out of 57subjects were strong responders and lost 7.38 ±", "metadata": {}}
+{"_id": "11109043", "title": "", "text": "Cost-effectiveness of aromatase inhibitorco-treatment for controlled ovarianstimulation.BACKGROUND To compare theclinical results and the cost-effectiveness ofusing the aromatase inhibitor, letrozole, inconjunction with FSH and FSH alone forcontrolled ovarian stimulation (COS) in patientsundergoing intrauterine insemination (IUI) for avariety of indications. METHODS Four hundredand thirty-two consecutive patients whounderwent 872 IUI cycles were included. Thestudy population was composed of two groups.Group I included 308 patients who underwent589 IUI cycles with letrozole and FSH for thefollowing indications: anovulation (143 cycles),male factor infertility (147 cycles), unexplainedinfertility (250 cycles), endometriosis (18 cycles)and combined indications (31 cycles). Group IIincluded 124 patients who underwent 283 IUIcycles who received FSH only for the followingindications: ovarian factor infertility (82 cycles),male factor infertility (66 cycles), unexplained", "metadata": {}}
+{"_id": "11117498", "title": "", "text": "The cost effectiveness of stereotacticradiosurgery versus surgical resection in thetreatment of solitary metastatic braintumors.Solitary metastatic brain tumors are themost common intracranial neoplasmsencountered by neurosurgeons. Surgicalresection of brain metastasis with whole brainradiotherapy (WBR) significantly increasessurvival in comparison with WBR alone.Stereotactic radiosurgery (SR) seems to provideresults that are similar to those of surgicalresection. To analyze the economic efficiency ofthese different treatments, we compared theresults of surgical resection and SR as reportedin the medical literature between 1974 and1994. We included studies in which: 1) at least75% of patients received WBR; 2) study dateswere in the computed tomography era (after1975); 3) operative morbidity, mortality, andmedian survival were reported; 4) study dateswere not included in a more recent update orreview; 5) tumor histologies were reported; and", "metadata": {}}
+{"_id": "11117679", "title": "", "text": "Trans-ancestry mutational landscape ofhepatocellular carcinoma genomesDiverseepidemiological factors are associated withhepatocellular carcinoma (HCC) prevalence indifferent populations. However, the globallandscape of the genetic changes in HCCgenomes underpinning different epidemiologicaland ancestral backgrounds still remainsuncharted. Here a collection of data from 503liver cancer genomes from different populationsuncovered 30 candidate driver genes and 11 corepathway modules. Furthermore, a collaborationof two large-scale cancer genome projectscomparatively analyzed the trans-ancestrysubstitution signatures in 608 liver cancer casesand identified unique mutational signatures thatpredominantly contribute to Asian cases. Thiswork elucidates previously unexploredancestry-associated mutational processes in HCCdevelopment. A combination of hotspot TERTpromoter mutation, TERT focal amplification andviral genome integration occurs in more than", "metadata": {}}
+{"_id": "11141995", "title": "", "text": "Organization of the mitotic chromosome.Mitoticchromosomes are among the most recognizablestructures in the cell, yet for over a century theirinternal organization remains largely unsolved.We applied chromosome conformation capturemethods, 5C and Hi-C, across the cell cycle andrevealed two distinct three-dimensional foldingstates of the human genome. We show that thehighly compartmentalized and cell type-specificorganization described previously fornonsynchronous cells is restricted to interphase.In metaphase, we identified a homogenousfolding state that is locus-independent, commonto all chromosomes, and consistent among celltypes, suggesting a general principle ofmetaphase chromosome organization. Usingpolymer simulations, we found that metaphaseHi-C data are inconsistent with classichierarchical models and are instead bestdescribed by a linearly organized longitudinallycompressed array of consecutive chromatinloops.", "metadata": {}}
+{"_id": "11156883", "title": "", "text": "Compensatory anti-inflammatory responsesyndrome.The concept of 'Compensatoryanti-inflammatory response syndrome' (CARS)was proposed in 1997 by Roger Bone(1941-1997) to qualify the consequences of thecounter-regulatory mechanisms initiated to limitthe overzealous inflammatory process in patientswith infectious (sepsis) or non-infectioussystemic inflammatory response syndrome(SIRS). One major consequence of CARS is themodification of the immune status that couldfavour the enhanced susceptibility of intensivecare patients to nosocomial infections. Indeed,most animal 'two-hit' models illustrate anenhanced sensitivity to infection after a firstinsult. However, this observation is highlydependent on the experimental procedure.Numerous functions of circulating leukocytes arealtered in sepsis and SIRS patients, as well as inanimal models of sepsis or SIRS. However, this israther a reprogramming of circulatingleukocytes, since there is not a global defect of", "metadata": {}}
+{"_id": "11172205", "title": "", "text": "Quantum dots spectrally distinguish multiplespecies within the tumor milieu in vivoA solidtumor is an organ composed of cancer and hostcells embedded in an extracellular matrix andnourished by blood vessels. A prerequisite tounderstanding tumor pathophysiology is theability to distinguish and monitor eachcomponent in dynamic studies. Standardfluorophores hamper simultaneous intravitalimaging of these components. Here, we usedmultiphoton microscopy techniques andtransgenic mice that expressed green fluorescentprotein, and combined them with the use ofquantum dot preparations. We show that thesefluorescent semiconductor nanocrystals can becustomized to concurrently image anddifferentiate tumor vessels from both theperivascular cells and the matrix. Moreover, weused them to measure the ability of particles ofdifferent sizes to access the tumor. Finally, wesuccessfully monitored the recruitment ofquantum dot–labeled bone marrow–derived", "metadata": {}}
+{"_id": "11181416", "title": "", "text": "Arginase I: a limiting factor for nitric oxide andpolyamine synthesis by activatedmacrophages?Because arginase hydrolyzesarginine to produce ornithine and urea, it has thepotential to regulate nitric oxide (NO) andpolyamine synthesis. We tested whetherexpression of the cytosolic isoform of arginase(arginase I) was limiting for NO or polyamineproduction by activated RAW 264.7 macrophagecells. RAW 264.7 cells, stably transfected tooverexpress arginase I or beta-galactosidase,were treated with interferon-gamma to inducetype 2 NO synthase or with lipopolysaccharide or8-bromo-cAMP (8-BrcAMP) to induce ornithinedecarboxylase. Overexpression of arginase I hadno effect on NO synthesis. In contrast, cellsoverexpressing arginase I produced twice asmuch putrescine after activation than did cellsexpressing beta-galactosidase. Cellsoverexpressing arginase I also produced morespermidine after treatment with 8-BrcAMP thandid cells expressing beta-galactosidase. Thus", "metadata": {}}
+{"_id": "11195653", "title": "", "text": "Opposing Effects of PKCθ and WASp onSymmetry Breaking and Relocation of theImmunological SynapseThe immunologicalsynapse (IS) is a junction between the T cell andantigen-presenting cell and is composed ofsupramolecular activation clusters (SMACs). Nostudies have been published on naive T cell ISdynamics. Here, we find that IS formation duringantigen recognition comprises cycles of stable ISformation and autonomous naive T cellmigration. The migration phase is driven byPKCtheta, which is localized to theF-actin-dependent peripheral (p)SMAC.PKCtheta(-/-) T cells formed hyperstable IS invitro and in vivo and, like WT cells, displayed fastoscillations in the distal SMAC, but they showedreduced slow oscillations in pSMAC integrity. ISreformation is driven by the Wiscott AldrichSyndrome protein (WASp). WASp(-/-) T cellsdisplayed normal IS formation but were unableto reform IS after migration unless PKCtheta wasinhibited. Thus, opposing effects of PKCtheta and", "metadata": {}}
+{"_id": "11200685", "title": "", "text": "Integrins regulate microtubule nucleating activityof centrosome through mitogen-activated proteinkinase/extracellular signal-regulated kinasekinase/extracellular signal-regulated kinase(MEK/ERK) signaling.Microtubule nucleation is anessential step in the formation of the microtubulecytoskeleton. We recently showed that androgenand Src promote microtubule nucleation andγ-tubulin accumulation at the centrosome. Here,we explore the mechanisms by which androgenand Src regulate these processes and askwhether integrins play a role. We perturbintegrin function by a tyrosine-to-alaninesubstitution in membrane-proximal NPIY motif inthe integrin β1 tail and show that this mutantsubstantially decreases microtubule nucleationand γ-tubulin accumulation at the centrosome.Because androgen stimulation promotes theinteraction of the androgen receptor with Src,resulting in PI3K/AKT and MEK/ERK signaling, weasked whether these pathways are inhibited bythe mutant integrin and whether they regulate", "metadata": {}}
+{"_id": "11201004", "title": "", "text": "Consumption of added sugars from liquid but notsolid sources predicts impaired glucosehomeostasis and insulin resistance among youthat risk of obesity.Little is known aboutlongitudinal associations between added sugarconsumption (solid and liquid sources) andglucose-insulin homeostasis among youth.Caucasian children (8-10 y) with at least oneobese biological parent were recruited in theQUébec Adipose and Lifestyle InvesTigation inYouth (QUALITY) cohort (n = 630) andfollowed-up 2 y later (n = 564). Added sugarswere assessed by 3 24-h dietary recalls atbaseline. Two-year changes were examined inmultivariate linear regression models, adjustingfor baseline level, age, sex, Tanner stage, energyintake, fat mass (dual-energy X-rayabsorptiometry), and physical activity (7 daccelerometer). Added sugar intake in eitherliquid or solid sources was not related to changesin adiposity measures (fat mass, body massindex, or waist circumference). However, a", "metadata": {}}
+{"_id": "11230569", "title": "", "text": "Towards an improved investment approach foran effective response to HIV/AIDS.Substantialchanges are needed to achieve a more targetedand strategic approach to investment in theresponse to the HIV/AIDS epidemic that will yieldlong-term dividends. Until now, advocacy forresources has been done on the basis of acommodity approach that encouraged scaling upof numerous strategies in parallel, irrespective oftheir relative effects. We propose a strategicinvestment framework that is intended tosupport better management of national andinternational HIV/AIDS responses than existswith the present system. Our frameworkincorporates major efficiency gains throughcommunity mobilisation, synergies betweenprogramme elements, and benefits of theextension of antiretroviral therapy for preventionof HIV transmission. It proposes three categoriesof investment, consisting of six basicprogrammatic activities, interventions thatcreate an enabling environment to achieve", "metadata": {}}
+{"_id": "11233339", "title": "", "text": "Pivotal Roles of T-Helper 17-Related Cytokines,IL-17, IL-22, and IL-23, in InflammatoryDiseasesT-helper 17 (Th17) cells arecharacterized by producing interleukin-17 (IL-17,also called IL-17A), IL-17F, IL-21, and IL-22 andpotentially TNF- α and IL-6 upon certainstimulation. IL-23, which promotes Th17 celldevelopment, as well as IL-17 and IL-22produced by the Th17 cells plays essential rolesin various inflammatory diseases, such asexperimental autoimmune encephalomyelitis,rheumatoid arthritis, colitis, and ConcanavalinA-induced hepatitis. In this review, wesummarize the characteristics of the functionalrole of Th17 cells, with particular focus on theTh17 cell-related cytokines such as IL-17, IL-22,and IL-23, in mouse models and humaninflammatory diseases.", "metadata": {}}
+{"_id": "11238784", "title": "", "text": "LXRS and FXR: the yin and yang of cholesteroland fat metabolism.Liver X receptors (LXRs) andfarnesoid X receptor (FXR) are nuclear receptorsthat function as intracellular sensors for sterolsand bile acids, respectively. In response to theirligands, these receptors induce transcriptionalresponses that maintain a balanced, finely tunedregulation of cholesterol and bile acidmetabolism. LXRs also permit the efficientstorage of carbohydrate- and fat-derived energy,whereas FXR activation results in an overalldecrease in triglyceride levels and modulation ofglucose metabolism. The elegant, dual interplaybetween these two receptor systems suggeststhat they coevolved to constitute a highlysensitive and efficient system for themaintenance of total body fat and cholesterolhomeostasis. Emerging evidence suggests thatthe tissue-specific action of these receptors isalso crucial for the proper function of thecardiovascular, immune, reproductive, endocrinepancreas, renal, and central nervous systems.", "metadata": {}}
+{"_id": "11238951", "title": "", "text": "Kaposi's sarcoma-associated herpesvirus/humanherpesvirus type 8-positive solid lymphomas: atissue-based variant of primary effusionlymphoma.Kaposi's sarcoma-associatedherpesvirus (KSHV), also termed humanherpesvirus type 8, is consistently identified inKaposi's sarcoma, primary effusion lymphoma(PEL), and multicentric Castleman's disease.Here we report four cases of KSHV-bearing solidlymphomas that occurred in AIDS patients(cases 1 to 3) and in a human immunodeficiencyvirus (HIV)-seronegative person (case 4). Thepatients presented extranodal masses in theabdomen (cases 1, 3, and 4) or skin (case 2),and nodal involvement, together with Kaposi'ssarcoma (case 3). The gastrointestinal tract wasinvolved in two patients (cases 1 and 3). Thepatients did not develop a lymphomatouseffusion. KSHV was detected in the tumor cells ofall cases by immunohistochemistry and bypolymerase chain reaction. Epstein-Barr viruswas detected in two of the HIV-related cases. All", "metadata": {}}
+{"_id": "11244195", "title": "", "text": "STAR: ultrafast universal RNA-seqaligner.MOTIVATION Accurate alignment ofhigh-throughput RNA-seq data is a challengingand yet unsolved problem because of thenon-contiguous transcript structure, relativelyshort read lengths and constantly increasingthroughput of the sequencing technologies.Currently available RNA-seq aligners suffer fromhigh mapping error rates, low mapping speed,read length limitation and mapping biases.RESULTS To align our large (>80 billon reads)ENCODE Transcriptome RNA-seq dataset, wedeveloped the Spliced Transcripts Alignment to aReference (STAR) software based on a previouslyundescribed RNA-seq alignment algorithm thatuses sequential maximum mappable seed searchin uncompressed suffix arrays followed by seedclustering and stitching procedure. STARoutperforms other aligners by a factor of >50 inmapping speed, aligning to the human genome550 million 2 × 76 bp paired-end reads per houron a modest 12-core server, while at the same", "metadata": {}}
+{"_id": "11246427", "title": "", "text": "Effect of alendronate on risk of fracture inwomen with low bone density but withoutvertebral fractures: results from the FractureIntervention Trial.CONTEXT Alendronate sodiumreduces fracture risk in postmenopausal womenwho have vertebral fractures, but its effects onfracture risk have not been studied for womenwithout vertebral fractures. OBJECTIVE To testthe hypothesis that 4 years of alendronate woulddecrease the risk of clinical and vertebralfractures in women who have low bone mineraldensity (BMD) but no vertebral fractures.DESIGN Randomized, blinded, placebo-controlledtrial. SETTING Eleven community-based clinicalresearch centers. SUBJECTS Women aged 54 to81 years with a femoral neck BMD of 0.68 g/cm2or less (Hologic Inc, Waltham, Mass) but novertebral fracture; 4432 were randomized toalendronate or placebo and 4272 (96%)completed outcome measurements at the finalvisit (an average of 4.2 years later).INTERVENTION All participants reporting calcium", "metadata": {}}
+{"_id": "11250124", "title": "", "text": "AP-1/sigma1B-adaptin mediates endosomalsynaptic vesicle recycling, learning andmemory.Synaptic vesicle recycling involvesAP-2/clathrin-mediated endocytosis, but it is notknown whether the endosomal pathway is alsorequired. Mice deficient in the tissue-specificAP-1-sigma1B complex have impaired synapticvesicle recycling in hippocampal synapses. Theubiquitously expressed AP-1-sigma1A complexmediates protein sorting between the trans-Golginetwork and early endosomes. Vertebratesexpress three sigma1 subunit isoforms: A, B andC. The expressions of sigma1A and sigma1B arehighest in the brain. Synaptic vesicle reformationin cultured neurons from sigma1B-deficient miceis reduced upon stimulation, and largeendosomal intermediates accumulate. Thesigma1B-deficient mice have reduced motorcoordination and severely impaired long-termspatial memory. These data reveal a molecularmechanism for a severe humanX-chromosome-linked mental retardation.", "metadata": {}}
+{"_id": "11253758", "title": "", "text": "Update of the FANTOM web resource: highresolution transcriptome of diverse cell types inmammalsUpon the first publication of the fifthiteration of the Functional Annotation ofMammalian Genomes collaborative project,FANTOM5, we gathered a series of primary dataand database systems into the FANTOM webresource (http://fantom.gsc.riken.jp) to facilitateresearchers to explore transcriptional regulationand cellular states. In the course of thecollaboration, primary data and analysis resultshave been expanded, and functionalities of thedatabase systems enhanced. We believe that ourdata and web systems are invaluable resources,and we think the scientific community will benefitfor this recent update to deepen theirunderstanding of mammalian cellularorganization. We introduce the contents ofFANTOM5 here, report recent updates in the webresource and provide future perspectives.", "metadata": {}}
+{"_id": "11254040", "title": "", "text": "Adverse Events Associated With the Treatment ofMultidrug-Resistant Tuberculosis: A SystematicReview and Meta-analysis.Multidrug-resistanttuberculosis (MDR-TB) is a growing public healthproblem. Due to long duration of therapy andconcurrent use of multiple second-line drugs,adverse drug events (ADEs) are regarded as themost important clinical consideration in patientsundergoing anti-MDR-TB treatment. To evaluatethe frequency and type of treatment-relatedADEs owing to MDR-TB therapy. The CochraneLibrary, MEDLINE, and EMBASE were searchedfrom inception through October 1, 2012, withadditional manual search of International Journalof Tuberculosis and Lung Disease. Studies withavailable ADEs were selected if MDR-TB patientswere treated with regimen including second-linedrugs. Pooled estimations of incidence for eachspecific type of ADEs were calculated with 95%confidence intervals using random-effects model.Of the 5346 patients included, 2602 (57.3%)experienced at least 1 kind of ADE. The 3 most", "metadata": {}}
+{"_id": "11254556", "title": "", "text": "Presynaptically Localized Cyclic GMP-DependentProtein Kinase 1 Is a Key Determinant of SpinalSynaptic Potentiation and PainHypersensitivitySynaptic long-term potentiation(LTP) at spinal neurons directly communicatingpain-specific inputs from the periphery to thebrain has been proposed to serve as a trigger forpain hypersensitivity in pathological states.Previous studies have functionally implicated theNMDA receptor-NO pathway and the downstreamsecond messenger, cGMP, in these processes.Because cGMP can broadly influence diverseion-channels, kinases, and phosphodiesterases,pre- as well as post-synaptically, the preciseidentity of cGMP targets mediating spinal LTP,their mechanisms of action, and their locus in thespinal circuitry are still unclear. Here, we foundthat Protein Kinase G1 (PKG-I) localizedpresynaptically in nociceptor terminals plays anessential role in the expression of spinal LTP.Using the Cre-lox P system, we generatednociceptor-specific knockout mice lacking PKG-I", "metadata": {}}
+{"_id": "11255504", "title": "", "text": "A Sleeping Beauty mutagenesis screen reveals atumor suppressor role for Ncoa2/Src-2 in livercancer.The Sleeping Beauty (SB) transposonmutagenesis system is a powerful tool thatfacilitates the discovery of mutations thataccelerate tumorigenesis. In this study, wesought to identify mutations that cooperate withMYC, one of the most commonly dysregulatedgenes in human malignancy. We performed aforward genetic screen with a mouse model ofMYC-induced liver cancer using SB-mediatedmutagenesis. We sequenced insertions in 63 livertumor nodules and identified at least 16genes/loci that contribute to accelerated tumordevelopment. RNAi-mediated knockdown in aliver progenitor cell line further validate three ofthese genes, Ncoa2/Src-2, Zfx, and Dtnb, astumor suppressors in liver cancer. Moreover,deletion of Ncoa2/Src-2 in mice predisposes todiethylnitrosamine-induced liver tumorigenesis.These findings reveal genes and pathways thatfunctionally restrain MYC-mediated liver", "metadata": {}}
+{"_id": "11256632", "title": "", "text": "Protein-Protein Interaction Inhibition(2P2I)-Oriented Chemical Library Accelerates HitDiscovery.Protein-protein interactions (PPIs)represent an enormous source of opportunity fortherapeutic intervention. We and others haverecently pinpointed key rules that will help inidentifying the next generation of innovativedrugs to tackle this challenging class of targetswithin the next decade. We used these rules todesign an oriented chemical librarycorresponding to a set of diverse \"PPI-like\"modulators with cores identified as privilegedstructures in therapeutics. In this work, wepurchased the resulting 1664 structurally diversecompounds and evaluated them on a series ofrepresentative protein-protein interfaces withdistinct \"druggability\" potential usinghomogeneous time-resolved fluorescence (HTRF)technology. For certain PPI classes, analysis ofthe hit rates revealed up to 100 enrichmentfactors compared with nonoriented chemicallibraries. This observation correlates with the", "metadata": {}}
+{"_id": "11271123", "title": "", "text": "Molecular characterization of endometrial cancer:a correlative study assessing microsatelliteinstability, MLH1 hypermethylation, DNAmismatch repair protein expression, and PTEN,PIK3CA, KRAS, and BRAF mutationanalysis.Endometrial cancer is associated withnumeric and structural chromosomalabnormalities, microsatellite instability (MSI),and alterations that activate oncogenes andinactivate tumor suppressor genes. The aim ofthis study was to characterize a set ofendometrial cancers using multiple moleculargenetic and immunohistochemical techniques.Ninety-six cases were examined for genomicalterations by MSI, MLH1 promoterhypermethylation, p53 and mismatch repairprotein expression (MLH1, MSH2, MSH6, PMS2),and PTEN, PIK3CA, KRAS, and BRAF mutationanalysis. At least 1 alteration was identified in 48of 87 (55%) specimens tested for PTEN, makingit the most common abnormality in this study. APIK3CA alteration was observed in 16 (17%)", "metadata": {}}
+{"_id": "11280569", "title": "", "text": "Identification of indole-3-carboxylic acid asmediator of priming against Plectosphaerellacucumerina.Plant resistance against thenecrotrophic pathogen Plectosphaerellacucumerina is mediated by a combination ofseveral hormonal-controlled signalling pathways.The priming agent β-aminobutyric acid (BABA) isable to induce effective resistance against thispathogen by stimulating callose-rich cell walldepositions. In the present research it isdemonstrated that BABA-Induced Resistance(BABA-IR) against P. cucumerina in Arabidopsishas additional components such as the inductionof defences mediated by indolic derivatives.Chromatographic approach for the detection andcharacterization of metabolites enhanced byBABA compared with water-treated plants onlywhen the challenge is present has beendeveloped. The metabolites matching this criteriaare considered to be primed by BABA. Theanalytic procedure is based on the combinationof liquid chromatography (LC) with a triple", "metadata": {}}
+{"_id": "11288846", "title": "", "text": "Evaluation of networks of randomizedtrials.Randomized trials may be designed andinterpreted as single experiments or they may beseen in the context of other similar or relevantevidence. The amount and complexity ofavailable randomized evidence vary for differenttopics. Systematic reviews may be useful inidentifying gaps in the existing randomizedevidence, pointing to discrepancies betweentrials, and planning future trials. A new,promising, but also very much debated extensionof systematic reviews, mixed treatmentcomparison (MTC) meta-analysis, has becomeincreasingly popular recently. MTC meta-analysismay have value in interpreting the availablerandomized evidence from networks of trials andcan rank many different treatments, goingbeyond focusing on simplepairwise-comparisons. Nevertheless, theevaluation of networks also presents specialchallenges and caveats. In this article, we reviewthe statistical methodology for MTC", "metadata": {}}
+{"_id": "11289247", "title": "", "text": "Metabolic regulation by the mitochondrialphosphatase PTPMT1 is required forhematopoietic stem cell differentiation.Theregulation and coordination of mitochondrialmetabolism with hematopoietic stem cell (HSC)self-renewal and differentiation is not fullyunderstood. Here we report that depletion ofPTPMT1, a PTEN-like mitochondrial phosphatase,in inducible or hematopoietic-cell-specificknockout mice resulted in hematopoietic failuredue to changes in the cell cycle and a block inthe differentiation of HSCs. Surprisingly, the HSCpool was increased by \u000040-fold in PTPMT1knockout mice. Reintroduction of wild-typePTPMT1, but not catalytically deficient PTPMT1 ortruncated PTPMT1 lacking mitochondriallocalization, restored differentiation capabilitiesof PTPMT1 knockout HSCs. Further analysesdemonstrated that PTPMT1 deficiency alteredmitochondrial metabolism and thatphosphatidylinositol phosphate substrates ofPTPMT1 directly enhanced fatty-acid-induced", "metadata": {}}
+{"_id": "11291348", "title": "", "text": "GSK-3-mediated phosphorylation enhancesMaf-transforming activity.The Maf oncoproteinsare b-Zip transcription factors of the AP-1superfamily. They are involved in developmental,metabolic, and tumorigenic processes. Mafproteins are overexpressed in about 50% ofhuman multiple myelomas. Here, we show thatMaf-transforming activity is controlled byGSK-3-dependent phosphorylation and thatphosphorylation by GSK-3 can increase theoncogenic activity of a protein. Using microarrayanalysis, we identify a gene-expressionsubprogram regulated by GSK-3-mediated Mafphosphorylation involved in extracellular matrixremodeling and relevant to cancer progression.We also demonstrate that GSK-3 triggers MafAsequential phosphorylation on residues S61, T57,T53, and S49, inducing its ubiquitination anddegradation. Paradoxically, this phosphorylationincreases MafA-transcriptional activity throughthe recruitment of the coactivator P/CAF. Wefurther demonstrate that P/CAF protects MafA", "metadata": {}}
+{"_id": "11328820", "title": "", "text": "NETs are a source of citrullinated autoantigensand stimulate inflammatory responses inrheumatoid arthritis.The early events leading tothe development of rheumatoid arthritis (RA)remain unclear, but formation of autoantibodiesto citrullinated protein antigens (ACPAs) isconsidered a key pathogenic event. Neutrophilsisolated from patients with various autoimmunediseases display enhanced neutrophilextracellular trap (NET) formation, aphenomenon that exposes autoantigens in thecontext of immunostimulatory molecules. Weinvestigated whether aberrant NETosis occurs inRA, determined its triggers, and examined itsdeleterious inflammatory consequences.Enhanced NETosis was observed in circulatingand RA synovial fluid neutrophils compared toneutrophils from healthy controls and frompatients with osteoarthritis (OA). Further, nettingneutrophils infiltrated RA synovial tissue,rheumatoid nodules, and skin. NETosiscorrelated with ACPA presence and levels and", "metadata": {}}
+{"_id": "11335781", "title": "", "text": "Is autoimmunity the Achilles' heel of cancerimmunotherapy?The emergence ofimmuno-oncology as the first broadly successfulstrategy for metastatic cancer will requireclinicians to integrate this new pillar of medicinewith chemotherapy, radiation, and targetedsmall-molecule compounds. Of equal importanceis gaining an understanding of the limitationsand toxicities of immunotherapy.Immunotherapy was initially perceived to be arelatively less toxic approach to cancer treatmentthan other available therapies—and surely it is,when compared to those. However, as the use ofimmunotherapy becomes more common,especially as first- and second-line treatments,immunotoxicity and autoimmunity are emergingas the Achilles' heel of immunotherapy. In thisPerspective, we discuss evidence that theoccurrence of immunotoxicity bodes well for thepatient, and describe mechanisms that might berelated to the induction of autoimmunity. Wethen explore approaches to limit immunotoxicity,", "metadata": {}}
+{"_id": "11335860", "title": "", "text": "Trophoblast differentiation defect in humanembryonic stem cells lacking PIG-A andGPI-anchored cell-surface proteins.Pluripotenthuman embryonic stem (hES) cells candifferentiate into various cell types derived fromthe three embryonic germ layers andextraembryonic tissues such as trophoblasts. Themechanisms governing lineage choices of hEScells are largely unknown. Here, we report thatwe established two independent hES cell cloneslacking a group of cell surface molecules,glycosyl-phosphatidyl-inositol-anchored proteins(GPI-APs). The GPI-AP deficiency in these twohES clones is due to the deficiency in the geneexpression of PIG-A (phosphatidyl-inositol-glycanclass A), which is required for the first step ofGPI synthesis. GPI-AP-deficient hES cells werecapable of forming embryoid bodies and initiatingcell differentiation into the three embryonic germlayers. However, GPI-AP-deficient hES cellsfailed to form trophoblasts after differentiationinduction by embryoid body formation or by", "metadata": {}}
+{"_id": "11336632", "title": "", "text": "CRISPR Interference Limits Horizontal GeneTransfer in Staphylococci by TargetingDNAHorizontal gene transfer (HGT) in bacteriaand archaea occurs through phage transduction,transformation, or conjugation, and the latter isparticularly important for the spread of antibioticresistance. Clustered, regularly interspaced,short palindromic repeat (CRISPR) loci confersequence-directed immunity against phages. Aclinical isolate of Staphylococcus epidermidisharbors a CRISPR spacer that matches thenickase gene present in nearly all staphylococcalconjugative plasmids. Here we show that CRISPRinterference prevents conjugation and plasmidtransformation in S. epidermidis. Insertion of aself-splicing intron into nickase blocksinterference despite the reconstitution of thetarget sequence in the spliced mRNA, whichindicates that the interference machinery targetsDNA directly. We conclude that CRISPR locicounteract multiple routes of HGT and can limitthe spread of antibiotic resistance in pathogenic", "metadata": {}}
+{"_id": "11344428", "title": "", "text": "Development of leukemia in donor cells afterallogeneic stem cell transplantation--a survey ofthe European Group for Blood and MarrowTransplantation (EBMT).Leukemia in donor cells(donor cell leukemia; DCL) has been reported asa rare but severe complication of allogeneic stemcell transplantation (SCT). However, theincidence, potential pathogenetic factors,therapeutic options and outcome of patientssuffering from DCL and the leukemia risk of theirdonors are not well defined. A questionnairesurvey was carried out within European Bloodand Marrow Transplantation Group (EBMT)centers. Ninety-one EBMT centers participated inthis survey, covering 10489 allogeneic SCTbetween 12/1982 and 09/2003. Fourteen casesof DCL, most with a myeloid phenotype (7 casesof acute myeloid leukemia, 3 each of acutelymphocytic leukemia and 1 case of chronicmyeloid leukemia) were identified.Demonstration of donor cell origin includedmolecular analysis of chimerism in most cases.", "metadata": {}}
+{"_id": "11349166", "title": "", "text": "Lack of evidence of transfusion transmission ofCreutzfeldt-Jakob disease in a US surveillancestudy.BACKGROUND Since 2004, severalreported transfusion transmissions of variantCreutzfeldt-Jakob disease (vCJD) in the UnitedKingdom have reawakened concerns about thepossible risk of similar transmissions ofnonvariant or classic forms of CJD. STUDYDESIGN AND METHODS Patients with a CJDdiagnosis and a history of donating blood werereported to the study coordinator. Throughreview of blood distribution and hospital records,the recipients of blood components from thesedonors were identified. We then determined eachrecipient's vital status and, if deceased, thecause(s) of death identified by matching therecipient's personal identifiers with the Centersfor Disease Control and Prevention's NationalDeath Index database. We conducted suchsearches after recipients were enrolled in thisstudy and annually thereafter for those whoremained alive. RESULTS The study included a", "metadata": {}}
+{"_id": "11359243", "title": "", "text": "Large-scale hypomethylated blocks associatedwith Epstein-Barr virus-induced B-cellimmortalization.Altered DNA methylation occursubiquitously in human cancer from the earliestmeasurable stages. A cogent approach tounderstanding the mechanism and timing ofaltered DNA methylation is to analyze it in thecontext of carcinogenesis by a defined agent.Epstein-Barr virus (EBV) is a human oncogenicherpesvirus associated with lymphoma andnasopharyngeal carcinoma, but also usedcommonly in the laboratory to immortalizehuman B-cells in culture. Here we haveperformed whole-genome bisulfite sequencing ofnormal B-cells, activated B-cells, andEBV-immortalized B-cells from the same threeindividuals, in order to identify the impact oftransformation on the methylome. Surprisingly,large-scale hypomethylated blocks comprisingtwo-thirds of the genome were induced by EBVimmortalization but not by B-cell activation perse. These regions largely corresponded to", "metadata": {}}
+{"_id": "11360430", "title": "", "text": "Stem cell self-renewal specified by JAK-STATactivation in response to a support cell cue.Stemcells generate many differentiated, short-livedcell types, such as blood, skin, and sperm,throughout adult life. Stem cells maintain along-term capacity to divide, producing daughtercells that either self-renew or initiatedifferentiation. Although the surroundingmicroenvironment or \"niche\" influences stem cellfate decisions, few signals that emanate from theniche to specify stem cell self-renewal have beenidentified. Here we demonstrate that the apicalhub cells in the Drosophila testis act as a cellularniche that supports stem cell self-renewal. Hubcells express the ligand Unpaired (Upd), whichactivates the Janus kinase-signal transducer andactivator of transcription (JAK-STAT) pathway inadjacent germ cells to specify self-renewal andcontinual maintenance of the germ line stem cellpopulation.", "metadata": {}}
+{"_id": "11360768", "title": "", "text": "Effects of interventions in pregnancy on maternalweight and obstetric outcomes: meta-analysis ofrandomised evidenceOBJECTIVE To evaluate theeffects of dietary and lifestyle interventions inpregnancy on maternal and fetal weight and toquantify the effects of these interventions onobstetric outcomes. DESIGN Systematic reviewand meta-analysis. DATA SOURCES Majordatabases from inception to January 2012without language restrictions. STUDY SELECTIONRandomised controlled trials that evaluated anydietary or lifestyle interventions with potential toinfluence maternal weight during pregnancy andoutcomes of pregnancy. DATA SYNTHESISResults summarised as relative risks fordichotomous data and mean differences forcontinuous data. RESULTS We identified 44relevant randomised controlled trials (7278women) evaluating three categories ofinterventions: diet, physical activity, and a mixedapproach. Overall, there was 1.42 kg reduction(95% confidence interval 0.95 to 1.89 kg) in", "metadata": {}}
+{"_id": "11369420", "title": "", "text": "Tetraspanin 3 Is Required for the Developmentand Propagation of Acute MyelogenousLeukemia.Acute Myelogenous Leukemia (AML) isan aggressive cancer that strikes both adults andchildren and is frequently resistant to therapy.Thus, identifying signals needed for AMLpropagation is a critical step toward developingnew approaches for treating this disease. Here,we show that Tetraspanin 3 is a target of theRNA binding protein Musashi 2, which plays akey role in AML. We generated Tspan3 knockoutmice that were born without overt defects.However, Tspan3 deletion impaired leukemiastem cell self-renewal and disease propagationand markedly improved survival in mousemodels of AML. Additionally, Tspan3 inhibitionblocked growth of AML patient samples,suggesting that Tspan3 is also important inhuman disease. As part of the mechanism, weshow that Tspan3 deficiency disabled responsesto CXCL12/SDF-1 and led to defects in AMLlocalization within the niche. These identify", "metadata": {}}
+{"_id": "11390393", "title": "", "text": "Reorganization of enhancer patterns in transitionfrom naive to primed pluripotency.Naive andprimed pluripotency is characterized by distinctsignaling requirements, transcriptomes, anddevelopmental properties, but both cellularstates share key transcriptional regulators: Oct4,Sox2, and Nanog. Here, we demonstrate thattransition between these two pluripotent states isassociated with widespread Oct4 relocalization,mirrored by global rearrangement of enhancerchromatin landscapes. Our genomic andbiochemical analyses identified candidatemediators of primed state-specific Oct4 binding,including Otx2 and Zic2/3. Even whendifferentiation cues are blocked, premature Otx2overexpression is sufficient to exit the naivestate, induce transcription of a substantial subsetof primed pluripotency-associated genes, andredirect Oct4 to previously inaccessible enhancersites. However, the ability of Otx2 to engage newenhancer regions is determined by its levels,cis-encoded properties of the sites, and the", "metadata": {}}
+{"_id": "11401602", "title": "", "text": "Topoisomerase II plays an essential role as aswivelase in the late stage of SV40 chromosomereplication in vitro.The effects of topoisomerasesI and II on the replication of SV40 DNA wereexamined using an in vitro replication system ofpurified proteins that constitutes themonopolymerase system. In the presence of thetwo topoisomerases, two distinct nascent DNAswere formed. One product arising from thereplication of the leading template strand wasapproximately half the size of the template DNA,whereas the other product derived from thelagging template strand consisted of short DNAs.These products were synthesized from bothSV40 naked DNA and SV40 chromosomes. Forthe replication of SV40 naked DNA, eithertopoisomerase I or II maintained replication forkmovement and supported complete leadingstrand synthesis. When SV40 chromosomes werereplicated with the same proteins, reactionscontaining only topoisomerase I producedshorter leading strands. However, mature size", "metadata": {}}
+{"_id": "11411060", "title": "", "text": "Bromodomain Proteins Contribute toMaintenance of Bloodstream Form Stage Identityin the African TrypanosomeTrypanosoma brucei,the causative agent of African sleeping sickness,is transmitted to its mammalian host by thetsetse. In the fly, the parasite's surface iscovered with invariant procyclin, while in themammal it resides extracellularly in itsbloodstream form (BF) and is densely coveredwith highly immunogenic Variant SurfaceGlycoprotein (VSG). In the BF, the parasitevaries this highly immunogenic surface VSGusing a repertoire of ~2500 distinct VSG genes.Recent reports in mammalian systems point to arole for histone acetyl-lysine recognizingbromodomain proteins in the maintenance ofstem cell fate, leading us to hypothesize thatbromodomain proteins may maintain the BF cellfate in trypanosomes. Using small-moleculeinhibitors and genetic mutants for individualbromodomain proteins, we performed RNA-seqexperiments that revealed changes in the", "metadata": {}}
+{"_id": "11414664", "title": "", "text": "Timing requirements for insulin/IGF-1 signalingin C. elegans.The insulin/IGF-1 (where IGF-1 isinsulin-like growth factor-1) signaling pathwayinfluences longevity, reproduction, and diapausein many organisms. Because of the fundamentalimportance of this system in animal physiology,we asked when during the animal's life it isrequired to regulate these different processes.We find that in Caenorhabditis elegans, thepathway acts during adulthood, to relativelyadvanced ages, to influence aging. In contrast, itregulates diapause during development. Inaddition, the pathway controls longevity andreproduction independently of one another.Together our findings show that life-spanregulation can be dissociated temporally fromphenotypes that might seem to decrease thequality of life.", "metadata": {}}
+{"_id": "11415809", "title": "", "text": "Predominance of Type 1 Innate Lymphoid Cells inthe Rectal Mucosa of Patients With Non-CeliacWheat Sensitivity: Reversal After a Wheat-FreeDietOBJECTIVES Non-celiac wheat sensitivity(NCWS) is defined as a reaction to ingestedwheat after exclusion of celiac disease and wheatallergy. As its pathogenesis is incompletelyunderstood, we evaluated the inflammatoryresponse in the rectal mucosa of patients withwell-defined NCWS. METHODS The prospectivestudy included 22 patients with irritable bowelsyndrome (IBS)-like clinical presentation,diagnosed with NCWS by double-blindplacebo-controlled challenge. Eight IBS patientsnot improving on wheat-free diet were used ascontrols. Two weeks after oral challenge wasperformed with 80 grams of wheat daily, cellswere isolated from rectal biopsies and thoroughlycharacterized by fluorescence-activated cellsorting analysis for intracellular cytokines andsurface markers. RESULTS Rectal biopsies fromwheat-challenged NCWS patients showed that a", "metadata": {}}
+{"_id": "11419230", "title": "", "text": "Folding and Self-Assembly of the TatATranslocation Pore Based on a Charge ZipperMechanismWe propose a concept for the foldingand self-assembly of the pore-forming TatAcomplex from the Twin-arginine translocase andof other membrane proteins based onelectrostatic \"charge zippers. \" Each subunit ofTatA consists of a transmembrane segment, anamphiphilic helix (APH), and a C-terminaldensely charged region (DCR). The sequence ofcharges in the DCR is complementary to thecharge pattern on the APH, suggesting that theprotein can be \"zipped up\" by a ladder of sevensalt bridges. The length of the resulting hairpinmatches the lipid bilayer thickness, hence atransmembrane pore could self-assemble viaintra- and intermolecular salt bridges. The stericfeasibility was rationalized by moleculardynamics simulations, and experimentalevidence was obtained by monitoring themonomer-oligomer equilibrium of specific chargemutants. Similar \"charge zippers\" are proposed", "metadata": {}}
+{"_id": "11420613", "title": "", "text": "Molecular mechanisms of ribosomal protein genecoregulation.The 137 ribosomal protein genes(RPGs) of Saccharomyces provide a model forgene coregulation. We examined the positionaland functional organization of their regulators(Rap1 [repressor activator protein 1], Fhl1, Ifh1,Sfp1, and Hmo1), the transcription machinery(TFIIB, TFIID, and RNA polymerase II), andchromatin at near-base-pair resolution usingChIP-exo, as RPGs are coordinatelyreprogrammed. Where Hmo1 is enriched, Fhl1,Ifh1, Sfp1, and Hmo1 cross-linked broadly topromoter DNA in an RPG-specific manner anddemarcated by general minor groove widening.Importantly, Hmo1 extended 20-50 base pairs(bp) downstream from Fhl1. Upon RPGrepression, Fhl1 remained in place. Hmo1dissociated, which was coupled to an upstreamshift of the +1 nucleosome, as reflected by theHmo1 extension and core promoter region. Fhl1and Hmo1 may create two regulatable andpositionally distinct barriers, against which", "metadata": {}}
+{"_id": "11428884", "title": "", "text": "Lipoatrophy and severe metabolic disturbance inmice with fat-specific deletion of PPARγ.Adiposetissue is an important metabolic organ, thedysfunction of which is associated with thedevelopment of obesity, diabetes mellitus, andcardiovascular disease. The nuclear receptorperoxisome proliferator-activated receptorgamma (PPARγ) is considered the masterregulator of adipocyte differentiation andfunction. Although its cell-autonomous role inadipogenesis has been clearly demonstrated incell culture, previous fat-specific knockouts ofthe murine PPARγ gene did not demonstrate adramatic phenotype in vivo. Here, usingAdipoq-Cre mice to drive adipose-specificrecombination, we report a unique fat-specificPPARγ knockout (PPARγ FKO) mouse model withalmost no visible brown and white adipose tissueat age 3 mo. As a consequence, PPARγ FKO micehad hugely enlarged pancreatic islets, massivefatty livers, and dramatically elevated levels ofblood glucose and serum insulin accompanied by", "metadata": {}}
+{"_id": "11441172", "title": "", "text": "Fluconazole prophylaxis: can we eliminateinvasive Candida infections in the neonatalICU?PURPOSE OF REVIEW Owing to the highmortality, risk of neurodevelopmentalimpairment and end-organ involvement withfungal infections in the neonate, prevention ofinvasive Candida infections in extremely preterminfants should be a priority for each neonatalICU. RECENT FINDINGS Even with prompt orempiric treatment, mortality andneurodevelopmental impairment is high (57%) ininfants <1000 g. Multiple studies have beenperformed with fluconazole prophylaxis,including a recent multicenter randomizedcontrolled trial. All of the studies havedemonstrated efficacy and safety with noincrease or emergence of fungal resistance.Analysis of these studies demonstrates thatfluconazole prophylaxis decreased the incidenceof invasive Candida infections in high-risk infants<1000 g by 91% (P = 0.0004) and all infants<1500 g by 85% (P < 0.0001). The mortality", "metadata": {}}
+{"_id": "11457219", "title": "", "text": "Fumarase deficiency in dichorionic diamniotictwins.Fumarase deficiency is a rare autosomalrecessive inborn error of metabolism of theKrebs Tricarboxylic Acid cycle. A heavyneurological disease burden is imparted byfumarase deficiency, commonly manifesting asmicrocephaly, dystonia, global developmentaldelay, seizures, and lethality in the infantileperiod. Heterozygous carriers also carry anincreased risk of developing hereditaryleiomyomatosis and renal cell carcinoma. Wedescribe a non-consanguineous family in whom adichorionic diamniotic twin pregnancy resulted intwin boys with fumarase deficiency proven at thebiochemical, enzymatic, and molecular levels.Their clinical phenotype included hepaticinvolvement. A novel mutation in the fumaratehydratase gene was identified in this family.", "metadata": {}}
+{"_id": "11459139", "title": "", "text": "Angiopoietin-2 is increased in sepsis andinversely associated with nitric oxide-dependentmicrovascular reactivityINTRODUCTIONAngiopoietin-2 (ang-2), an angiogenic peptidereleased by endothelial cell Weibel-Palade bodies(WPBs), increases endothelial activation andvascular permeability. Ang-2 is raised in severesepsis but the mechanisms underlying this arenot known. Nitric oxide (NO) inhibits WPBexocytosis, and bioavailability of endothelial NOis decreased in sepsis. We hypothesized thatendothelial NO bioavailability would be inverselycorrelated with ang-2 concentrations in sepsis.METHODS Plasma ang-2, vascular endothelialgrowth factor (VEGF) and endothelial-activecytokines were assessed in 83 patients with earlysepsis and 41 hospital controls, and related toreactive hyperaemia-peripheral arterialtonometry, RH-PAT, a measure of endothelial NObioavailability. RESULTS Plasma Ang-2 waselevated in sepsis (median [interquartile range(IQR)], ng/ml: severe sepsis 12.4 [8.5-33.4],", "metadata": {}}
+{"_id": "11469078", "title": "", "text": "Ecologic versus individual-level sources of bias inecologic estimates of contextual health effects.Anumber of authors have attempted to defendecologic (aggregate) studies by claiming that thegoal of those studies is estimation of ecologic(contextual or group-level) effects rather thanindividual-level effects. Critics of these attemptspoint out that ecologic effect estimates areinevitably used as estimates of individual effects,despite disclaimers. A more subtle problem isthat ecologic variation in the distribution ofindividual effects can bias ecologic estimates ofcontextual effects. The conditions leading to thisbias are plausible and perhaps even common instudies of ecosocial factors and health outcomesbecause social context is not randomized acrosstypical analysis units (administrative regions). Bydefinition, ecologic data contain only marginalobservations on the joint distribution ofindividually defined confounders and outcomes,and so identify neither contextual norindividual-level effects. While ecologic studies", "metadata": {}}
+{"_id": "11475379", "title": "", "text": "Left–right asymmetry in the vertebrate embryo:from early information to higher-levelintegrationAlthough vertebrates seem to beessentially bilaterally symmetrical on theexterior, there are numerous interior left–rightasymmetries in the disposition and placement ofinternal organs. These asymmetries areestablished during embryogenesis by complexepigenetic and genetic cascades. Recent studiesin a range of model organisms have madeimportant progress in understanding how thislaterality information is generated and conveyedto large regions of the embryo. Bothcommonalities and divergences are emerging inthe mechanisms that different vertebrates use inleft–right axis specification. Recent evidence alsoprovides intriguing links between theestablishment of left–right asymmetries and thesymmetrical elongation of the anterior–posterioraxis.", "metadata": {}}
+{"_id": "11481946", "title": "", "text": "Obesity, type 2 diabetes, and cancer: the insulinand IGF connection.Epidemiological studiessuggest a positive association between obesityand type 2 diabetes mellitus (T2D) with the riskof cancer and cancer-related mortality. Insulinresistance, hyperinsulinemia, increased levels ofIGF, elevated levels of steroid and peptidehormones, and inflammatory markers appear toplay a role in the connection between thesedifferent diseases. Medications, such asmetformin and exogenous insulin, used to treatT2D may affect the risk of cancer andcancer-related mortality. Newer therapiestargeting the insulin and IGF1 systems are beingdeveloped for use in cancer therapy.", "metadata": {}}
+{"_id": "11484808", "title": "", "text": "Non-coding RNAs: Functions and applications inendocrine-related cancer.A significant fraction ofthe human genome is transcribed as non-codingRNAs (ncRNAs). This non-coding transcriptomehas challenged the notion of the central dogmaand its involvement in transcriptional andpost-transcriptional regulation of geneexpression is well established. Interestingly,several ncRNAs are dysregulated in cancer andcurrent non-coding transcriptome research aimsto use our increasing knowledge of these ncRNAsfor the development of cancer biomarkers andanti-cancer drugs. In endocrine-related cancers,for which survival rates can be relatively low,there is a need for such advancements. In thisreview, we aimed to summarize the roles andclinical implications of recently discoveredncRNAs, including long ncRNAs, PIWI-interactingRNAs, tRNA- and Y RNA-derived ncRNAs, andsmall nucleolar RNAs, in endocrine-relatedcancers affecting both sexes. We focus on recentstudies highlighting discoveries in ncRNA biology", "metadata": {}}
+{"_id": "11498670", "title": "", "text": "NMR structural and kinetic characterization of ahomeodomain diffusing and hopping onnonspecific DNA.Nonspecific protein-DNAinteractions are inherently dynamic and involveboth diffusion of the protein along the DNA andhopping of the protein from one DNA molecule orsegment to another. Understanding how generegulatory proteins interact nonspecifically withDNA in terms of both structure and dynamics ischallenging because the experimentalobservables are an ensemble average of manyrapidly exchanging states. By using a variety ofNMR spectroscopic techniques, includingrelaxation analysis, paramagnetic relaxationenhancement, and residual dipolar couplings, wehave characterized structural and kinetic aspectsof the interaction of the HoxD9 homeodomainwith a nonspecific, 24-bp DNA duplex in asystem in which the protein is not constrained toany particular site. The data reveal that HoxD9binds to nonspecific DNA with the same bindingmode and orientation as that observed in the", "metadata": {}}
+{"_id": "11527199", "title": "", "text": "MHC Haplotype Matching for UnrelatedHematopoietic CellTransplantationBackground  Current criteria forthe selection of unrelated donors forhematopoietic cell transplantation (HCT) includematching for the alleles of each human leukocyteantigen (HLA) locus within the majorhistocompatibility complex (MHC).Graft-versus-host disease (GVHD), however,remains a significant and potentiallylife-threatening complication even afterHLA-identical unrelated HCT. The MHC harborsmore than 400 genes, but the total number oftransplantation antigens is unknown. Genes thatinfluence transplantation outcome could beidentified by using linkage disequilibrium(LD)-mapping approaches, if the extended MHChaplotypes of the unrelated donor and recipientcould be defined.", "metadata": {}}
+{"_id": "11527822", "title": "", "text": "The SIR2/3/4 complex and SIR2 alone promotelongevity in Saccharomyces cerevisiae by twodifferent mechanisms. Genes Dev 13The SIRgenes are determinants of life span in yeastmother cells. Here we show that life spanregulation by the Sir proteins is independent oftheir role in nonhomologous end joining. Theshort life span of a sir3 or sir4 mutant is due tothe simultaneous expression of a and alphamating-type information, which indirectly causesan increase in rDNA recombination and likelyincreases the production of extrachromosomalrDNA circles. The short life span of a sir2 mutantalso reveals a direct failure to repressrecombination generated by the Fob1p-mediatedreplication block in the rDNA. Sir2p is a limitingcomponent in promoting yeast longevity, andincreasing the gene dosage extends the life spanin wild-type cells. A possible role of theconserved SIR2 in mammalian aging isdiscussed.", "metadata": {}}
+{"_id": "11532028", "title": "", "text": "Meta-analysis identifies common variantsassociated with body mass index in EastAsiansMultiple genetic loci associated withobesity or body mass index (BMI) have beenidentified through genome-wide associationstudies conducted predominantly in populationsof European ancestry. We performed ameta-analysis of associations between BMI andapproximately 2.4 million SNPs in 27,715 eastAsians, which was followed by in silico and denovo replication studies in 37,691 and 17,642additional east Asians, respectively. We identifiedten BMI-associated loci at genome-widesignificance (P < 5.0 × 10(-8)), including sevenpreviously identified loci (FTO, SEC16B, MC4R,GIPR-QPCTL, ADCY3-DNAJC27, BDNF andMAP2K5) and three novel loci in or near theCDKAL1, PCSK1 and GP2 genes. Three additionalloci nearly reached the genome-wide significancethreshold, including two previously identified lociin the GNPDA2 and TFAP2B genes and a newlyidentified signal near PAX6, all of which were", "metadata": {}}
+{"_id": "11532659", "title": "", "text": "Phosphorylation of histone H3(T118) altersnucleosome dynamics andremodelingNucleosomes, the fundamental unitsof chromatin structure, are regulators andbarriers to transcription, replication and repair.Post-translational modifications (PTMs) of thehistone proteins within nucleosomes regulatethese DNA processes. Histone H3(T118) is a siteof phosphorylation [H3(T118ph)] and isimplicated in regulation of transcription and DNArepair. We prepared H3(T118ph) by expressedprotein ligation and determined its influence onnucleosome dynamics. We find H3(T118ph)reduces DNA-histone binding by 2  kcal/mol,increases nucleosome mobility by 28-fold andincreases DNA accessibility near the dyad regionby 6-fold. Moreover, H3(T118ph) increases therate of hMSH2-hMSH6 nucleosome disassemblyand enables nucleosome disassembly by theSWI/SNF chromatin remodeler. These studiessuggest that H3(T118ph) directly enhances andmay reprogram chromatin remodeling reactions.", "metadata": {}}
+{"_id": "11535539", "title": "", "text": "Mechanosignaling through YAP and TAZ drivesfibroblast activation and fibrosis.Pathologicalfibrosis is driven by a feedback loop in which thefibrotic extracellular matrix is both a cause andconsequence of fibroblast activation. However,the molecular mechanisms underlying thisprocess remain poorly understood. Here weidentify yes-associated protein (YAP) (homologof drosophila Yki) and transcriptional coactivatorwith PDZ-binding motif (TAZ) (also known asWwtr1), transcriptional effectors of the Hippopathway, as key matrix stiffness-regulatedcoordinators of fibroblast activation and matrixsynthesis. YAP and TAZ are prominentlyexpressed in fibrotic but not healthy lung tissue,with particularly pronounced nuclear expressionof TAZ in spindle-shaped fibroblastic cells. Inculture, both YAP and TAZ accumulate in thenuclei of fibroblasts grown on pathologically stiffmatrices but not physiologically compliantmatrices. Knockdown of YAP and TAZ together invitro attenuates key fibroblast functions,", "metadata": {}}
+{"_id": "11557602", "title": "", "text": "Control of cellular cholesterol efflux by thenuclear oxysterol receptor LXR alpha.LXR alphais a nuclear receptor that has previously beenshown to regulate the metabolic conversion ofcholesterol to bile acids. Here we define a role forthis transcription factor in the control of cellularcholesterol efflux. We demonstrate that retroviralexpression of LXR alpha in NIH 3T3 fibroblasts orRAW264.7 macrophages and/or treatment ofthese cells with oxysterol ligands of LXR resultsin 7- to 30-fold induction of the mRNA encodingthe putative cholesterol/phospholipid transporterATP-binding cassette (ABC)A1. In contrast,induction of ABCA1 mRNA in response tooxysterols is attenuated in cells thatconstitutively express dominant-negative formsof LXR alpha or LXR beta that lack the AF2transcriptional activation domain. We furtherdemonstrate that expression of LXR alpha in NIH3T3 fibroblasts and/or treatment of these cellswith oxysterols is sufficient to stimulatecholesterol efflux to extracellular apolipoprotein", "metadata": {}}
+{"_id": "11565780", "title": "", "text": "Circadian regulation of intracellular G-proteinsignalling mediates intercellular synchrony andrhythmicity in the suprachiasmaticnucleusSynchronous oscillations of thousands ofcellular clocks in the suprachiasmatic nucleus(SCN), the circadian centre, are coordinated byprecisely timed cell-cell communication, theprinciple of which is largely unknown. Here weshow that the amount of RGS16 (regulator of Gprotein signalling 16), a protein known toinactivate Gαi, increases at a selective circadiantime to allow time-dependent activation ofintracellular cyclic AMP signalling in the SCN.Gene ablation of Rgs16 leads to the loss ofcircadian production of cAMP and as a resultlengthens circadian period of behaviouralrhythm. The temporally precise regulation of thecAMP signal by clock-controlled RGS16 is neededfor the dorsomedial SCN to maintain a normalphase-relationship to the ventrolateral SCN.Thus, RGS16-dependent temporal regulation ofintracellular G protein signalling coordinates the", "metadata": {}}
+{"_id": "11568270", "title": "", "text": "MDC1 collaborates with TopBP1 in DNAreplication checkpoint controlHuman TopBP1 is amajor player in the control of the DNA replicationcheckpoint. In this study, we identified MDC1, akey checkpoint protein involved in the cellularresponse to DNA double-strand breaks, as aTopBP1-associated protein. The specificTopBP1-MDC1 interaction is mediated by the fifthBRCT domain of TopBP1 and the Ser-Asp-Thr(SDT) repeats of MDC1. In addition, wedemonstrated that TopBP1 accumulation atstalled replication forks is promoted by theH2AX/MDC1 signaling cascade. Moreover, MDC1is important for ATR-dependent Chk1 activationin response to replication stress. Collectively, ourdata suggest that MDC1 facilitates severalimportant steps in both cellular DNA damageresponse and the DNA replication checkpoint.", "metadata": {}}
+{"_id": "11569583", "title": "", "text": "Deregulated DNA polymerase β strengthensionizing radiation-induced nucleotidic andchromosomal instabilitiesDNA polymerase β (Polβ) is an error-prone enzyme which has beenfound to be overexpressed in several humantumors. By using a couple of recombinant CHOcells differing only from the exogenousexpression of Pol β, we showed here that cellsoverexpressing Pol β are much more sensitive toIR treatments by increasing apoptosis. We alsofound that the surviving cells displayed anhypermutator phenotype which could beexplained by different pathways involving Pol β,such as (i) an increased capacity to incorporateinto DNA the mutagenic dGTP analog,8-oxo-dGTP, one of the most abundantpurine-derived nucleotides exposed toγ-irradiation, (ii) the induction of IR-induced DNAbreaks and (iii) accumulation of chromosomeaberrations induced by radiation. Alteration ofPol β expression in irradiated cells thus appearsto strengthen both cell death and genetic", "metadata": {}}
+{"_id": "11578459", "title": "", "text": "Chromosome 7 gain and DNA hypermethylationat the HOXA10 locus are associated withexpression of a stem cell related HOX-signaturein glioblastomaBACKGROUND HOX genes are afamily of developmental genes that areexpressed neither in the developing forebrain norin the normal brain. Aberrant expression of aHOX-gene dominated stem-cell signature inglioblastoma has been linked with increasedresistance to chemo-radiotherapy and sustainedproliferation of glioma initiating cells. Here wedescribe the epigenetic and genetic alterationsand their interactions associated with theexpression of this signature in glioblastoma.RESULTS We observe prominenthypermethylation of the HOXA locus 7p15.2 inglioblastoma in contrast to non-tumoral brain.Hypermethylation is associated with a gain ofchromosome 7, a hallmark of glioblastoma, andmay compensate for tumor-driven enhancedgene dosage as a rescue mechanism bypreventing undue gene expression. We identify", "metadata": {}}
+{"_id": "11581157", "title": "", "text": "Probing the phenomenon of trained immunity ininvertebrates during a transgenerational study,using brine shrimp Artemia as a modelsystemThe invertebrate's innate immune systemwas reported to show some form of adaptivefeatures, termed trained immunity. However, thememory characteristics of innate immune systemand the mechanisms behind such phenomenaremain unclear. Using the invertebrate modelArtemia, we verified the possibility orimpossibility of trained immunity, examining thepresence or absence of enduring memory againsthomologous and heterologous antigens (Vibriospp.) during a transgenerational study. We alsodetermined the mechanisms behind suchphenomenon. Our results showed the occurrenceof memory and partial discrimination in Artemia'simmune system, as manifested by increasedresistance, for three successive generations, ofthe progenies of Vibrio-exposed ancestorstowards a homologous bacterial strain, ratherthan to a heterologous strain. This increased", "metadata": {}}
+{"_id": "11603066", "title": "", "text": "Using Structural Information to Change thePhosphotransfer Specificity of a Two-ComponentChemotaxis Signalling ComplexTwo-componentsignal transduction pathways comprisinghistidine protein kinases (HPKs) and theirresponse regulators (RRs) are widely used tocontrol bacterial responses to environmentalchallenges. Some bacteria have over 150different two-component pathways, and thespecificity of the phosphotransfer reactionswithin these systems is tightly controlled toprevent unwanted crosstalk. One of the bestunderstood two-component signalling pathwaysis the chemotaxis pathway. Here, we present the1.40 A crystal structure of thehistidine-containing phosphotransfer domain ofthe chemotaxis HPK, CheA(3), in complex withits cognate RR, CheY(6). A methionine finger onCheY(6) that nestles in a hydrophobic pocket inCheA(3) was shown to be important for theinteraction and was found to only occur in thecognate RRs of CheA(3), CheY(6), and CheB(2).", "metadata": {}}
+{"_id": "11614737", "title": "", "text": "Combination varenicline and bupropion SR fortobacco-dependence treatment in cigarettesmokers: a randomized trial.IMPORTANCECombining pharmacotherapies fortobacco-dependence treatment may increasesmoking abstinence. OBJECTIVE To determineefficacy and safety of varenicline and bupropionsustained-release (SR; combination therapy)compared with varenicline (monotherapy) incigarette smokers. DESIGN, SETTING, ANDPARTICIPANTS Randomized, blinded,placebo-controlled multicenter clinical trial with a12-week treatment period and follow-up throughweek 52 conducted between October 2009 andApril 2013 at 3 midwestern clinical researchsites. Five hundred six adult (≥18 years)cigarette smokers were randomly assigned and315 (62%) completed the study.INTERVENTIONS Twelve weeks of vareniclineand bupropion SR or varenicline and placebo.MAIN OUTCOMES AND MEASURES Primaryoutcome was abstinence rates at week 12,", "metadata": {}}
+{"_id": "11615242", "title": "", "text": "Effect of a C/EBP gene replacement onmitochondrial biogenesis in fatcells.CCAAT/enhancer-binding proteins,C/EBPalpha and C/EBPbeta, are required for fatcell differentiation and maturation. Previousstudies showed that replacement of C/EBPalphawith C/EBPbeta, generating the beta/beta allelesin the mouse genome, prevents lipidaccumulation in white adipose tissue (WAT). Inthis study, beta/beta mice lived longer and hadhigher energy expenditure than their controllittermates due to increased WAT energyoxidation. The WAT of beta/beta mice wasenriched with metabolically active, thermogenicmitochondria known for energy burning. Thebeta/beta allele exerted its effect through theelevated expression of the G protein alphastimulatory subunit (Galphas) in WAT. Galphas,when overexpressed in fat-laden 3T3-L1 cells,stimulated mitochondrial biogenesis similar tothat seen in the WAT of beta/beta mice, andeffectively diminished the stored lipid pool.", "metadata": {}}
+{"_id": "11615422", "title": "", "text": "Variable breakpoints target PAX5 in patients withdicentric chromosomes: a model for the basis ofunbalanced translocations in cancer.The searchfor target genes involved in unbalanced acquiredchromosomal abnormalities has been largelyunsuccessful, because the breakpoints of theserearrangements are too variable. Here, we usethe example of dicentric chromosomes in B cellprecursor acute lymphoblastic leukemia to showthat, despite this heterogeneity, single genes aretargeted through a variety of mechanisms. FISHshowed that, although they were heterogeneous,breakpoints on 9p resulted in the partial orcomplete deletion of PAX5. Molecular copynumber counting further delineated thebreakpoints and facilitated cloning withlong-distance inverse PCR. This approachidentified 5 fusion gene partners with PAX5:LOC392027 (7p12.1), SLCO1B3 (12p12), ASXL1(20q11.1), KIF3B (20q11.21), and C20orf112(20q11.1). In each predicted fusion protein, theDNA-binding paired domain of PAX5 was present.", "metadata": {}}
+{"_id": "11616424", "title": "", "text": "Copyright \u0000 1996, American Society forMicrobiology Endotoxin-Induced Enhancement ofGlucose Influx intoHypoglycemia is among themost injurious metabolic disorders caused byendotoxemia. In experimental endotoxemia withlipopolysaccharide (LPS) in animals, a markedglucose consumption is observed inmacrophage-rich organs. However, the directeffect of LPS on the uptake of glucose bymacrophages has not been fully understood, andthe present study was undertaken to shed lighton this point. The consumption and uptake ofglucose, as measured with2-deoxy-D-[3H]glucose, by murine peritonealexudate macrophages in culture wereaccelerated two- to threefold by stimulation with3 ng of LPS per ml. The rate of glucose uptakereached a plateau after 20 min of stimulationand remained at the maximum as long as LPSwas present. Northern (RNA) blot analysis withcDNA probes for five known isoforms of glucosetransporter (GLUT) revealed that the expression", "metadata": {}}
+{"_id": "11624482", "title": "", "text": "Factors associated with American Board ofMedical Specialties member board certificationamong US medical school graduates.CONTEXTCertification by an American Board of MedicalSpecialties (ABMS) member board is emergingas a measure of physician quality. OBJECTIVE Toidentify demographic and educational factorsassociated with ABMS member board certificationof US medical school graduates. DESIGN,SETTING, AND PARTICIPANTS Retrospectivestudy of a national cohort of 1997-2000 USmedical school graduates, grouped by specialtychoice at graduation and followed up throughMarch 2, 2009. In separate multivariable logisticregression models for each specialty category,factors associated with ABMS member boardcertification were identified. MAIN OUTCOMEMEASURE ABMS member board certification.RESULTS Of 42,440 graduates in the studysample, 37,054 (87.3%) were board certified.Graduates in all specialty categories withfirst-attempt passing scores in the highest tertile", "metadata": {}}
+{"_id": "11630388", "title": "", "text": "Body-mass index and mortality in Korean menand women.BACKGROUND Obesity is associatedwith diverse health risks, but the role of bodyweight as a risk factor for death remainscontroversial. METHODS We examined theassociation between body weight and the risk ofdeath in a 12-year prospective cohort study of1,213,829 Koreans between the ages of 30 and95 years. We examined 82,372 deaths from anycause and 48,731 deaths from specific diseases(including 29,123 from cancer, 16,426 fromatherosclerotic cardiovascular disease, and 3362from respiratory disease) in relation to thebody-mass index (BMI) (the weight in kilogramsdivided by the square of the height in meters).RESULTS In both sexes, the average baselineBMI was 23.2, and the rate of death from anycause had a J-shaped association with the BMI,regardless of cigarette-smoking history. The riskof death from any cause was lowest amongpatients with a BMI of 23.0 to 24.9. In allgroups, the risk of death from respiratory causes", "metadata": {}}
+{"_id": "11659421", "title": "", "text": "Human iPSC-based modeling of late-onsetdisease via progerin-inducedaging.Reprogramming somatic cells to inducedpluripotent stem cells (iPSCs) resets theiridentity back to an embryonic age and, thus,presents a significant hurdle for modelinglate-onset disorders. In this study, we describe astrategy for inducing aging-related features inhuman iPSC-derived lineages and apply it to themodeling of Parkinson's disease (PD). Ourapproach involves expression of progerin, atruncated form of lamin A associated withpremature aging. We found that expression ofprogerin in iPSC-derived fibroblasts and neuronsinduces multiple aging-related markers andcharacteristics, including dopamine-specificphenotypes such as neuromelanin accumulation.Induced aging in PD iPSC-derived dopamineneurons revealed disease phenotypes thatrequire both aging and genetic susceptibility,such as pronounced dendrite degeneration,progressive loss of tyrosine hydroxylase (TH)", "metadata": {}}
+{"_id": "11661377", "title": "", "text": "SNAREs — engines for membrane fusionSincethe discovery of SNARE proteins in the late1980s, SNAREs have been recognized as keycomponents of protein complexes that drivemembrane fusion. Despite considerablesequence divergence among SNARE proteins,their mechanism seems to be conserved and isadaptable for fusion reactions as diverse as thoseinvolved in cell growth, membrane repair,cytokinesis and synaptic transmission. Afascinating picture of these robust nanomachinesis emerging.", "metadata": {}}
+{"_id": "11666252", "title": "", "text": "Maintaining the norm: T-cell homeostasisThepersistence of naive and memory T cells has longbeen of interest to immunologists, but thefactors that influence the survival andhomeostasis of these subsets have remainedobscure. In recent years, it has become evidentthat the homeostasis of both naive and memoryT-cell pools is highly dynamic and tightlyregulated by internal stimuli, including cytokinesand self-peptide–MHC ligands for the T-cellreceptor. These homeostatic mechanisms mighthave a vital influence on the capacity of theT-cell pool to respond to both foreign andself-antigens.", "metadata": {}}
+{"_id": "11674288", "title": "", "text": "Cell type of origin influences the molecular andfunctional properties of mouse inducedpluripotent stem cellsInduced pluripotent stemcells (iPSCs) have been derived from varioussomatic cell populations through ectopicexpression of defined factors. It remains unclearwhether iPSCs generated from different celltypes are molecularly and functionally similar.Here we show that iPSCs obtained from mousefibroblasts, hematopoietic and myogenic cellsexhibit distinct transcriptional and epigeneticpatterns. Moreover, we demonstrate that cellularorigin influences the in vitro differentiationpotentials of iPSCs into embryoid bodies anddifferent hematopoietic cell types. Notably,continuous passaging of iPSCs largely attenuatesthese differences. Our results suggest thatearly-passage iPSCs retain a transient epigeneticmemory of their somatic cells of origin, whichmanifests as differential gene expression andaltered differentiation capacity. Theseobservations may influence ongoing attempts to", "metadata": {}}
+{"_id": "11674596", "title": "", "text": "Spatiotemporal control of mitosis by theconserved spindle matrix protein MegatorAputative spindle matrix has been hypothesized tomediate chromosome motion, but its existenceand functionality remain controversial. In thisreport, we show that Megator (Mtor), theDrosophila melanogaster counterpart of thehuman nuclear pore complex proteintranslocated promoter region (Tpr), and thespindle assembly checkpoint (SAC) protein Mad2form a conserved complex that localizes to anuclear derived spindle matrix in living cells.Fluorescence recovery after photobleachingexperiments supports that Mtor is retainedaround spindle microtubules, where it showsdistinct dynamic properties. Mtor/Tpr promotesthe recruitment of Mad2 and Mps1 but not Mad1to unattached kinetochores (KTs), mediatingnormal mitotic duration and SAC response. Atanaphase, Mtor plays a role in spindleelongation, thereby affecting normalchromosome movement. We propose that", "metadata": {}}
+{"_id": "11705328", "title": "", "text": "Randomized trial of folic acid supplementationand serum homocysteine levels.BACKGROUNDLowering serum homocysteine levels with folicacid is expected to reduce mortality fromischemic heart disease. Homocysteine reductionis known to be maximal at a folic acid dosage of1 mg/d, but the effect of lower doses (relevant tofood fortification) is unclear. METHODS Werandomized 151 patients with ischemic heartdisease to 1 of 5 dosages of folic acid (0.2, 0.4,0.6, 0.8, and 1.0 mg/d) or placebo. Fasting bloodsamples for serum homocysteine and serumfolate analysis were taken initially, after 3months of supplementation, and 3 months afterfolic acid use was discontinued. RESULTS Medianserum homocysteine level decreased withincreasing folic acid dosage, to a maximum at0.8 mg of folic acid per day, when thehomocysteine reduction (placebo adjusted) was2.7 micromol/L (23%), similar to the knowneffect of folic acid dosages of 1 mg/d and above.The higher a person's initial serum homocysteine", "metadata": {}}
+{"_id": "11710511", "title": "", "text": "Adherens junctions in Drosophila retinalmorphogenesis.Adherens junctions and theircore molecular components, classic cadherins,make major contributions to animalmorphogenesis. Although the significance ofcadherins in development is generally accepted,the mechanisms regulating adherens junctionfunction during morphogenesis remain a subjectof intense research. Adherens junctions areinvolved in the organization of simple cellularpatterns, and more complex cell shape changesand cell movements that depend on the dynamicmodulation of adherens junctions.", "metadata": {}}
+{"_id": "11716783", "title": "", "text": "Multiple roles of vascular endothelial growthfactor (VEGF) in skeletal development, growth,and repair.Publisher Summary This chapterdiscusses the developmental roles of vascularendothelial growth factor (VEGF) in skeletalmorphogenesis, speculates on the futuredirections of research in this area, and describessome of the challenges in the field. VEGFregulates osteoclastic differentiation, migration,and activity. VEGF is, therefore, a keycoordinator of the entire process. VEGF isnecessary for osteoclastic activity both at thestage when the primary ossification center isestablished and later during bone growth. Anumber of studies have led to the identificationof VEGF as a critical factor for the survival ofchondrocytes. Several factors with importantroles in regulating bone formation also inducethe expression of VEGF by osteoblasts.Prostaglandins E1 and E2, BMP-4, BMP-6, BMP-7,FGF-2, TGF-β, endothelin-1, IGF-1, and vitaminD3 can all induce VEGF expression in osteoblasts", "metadata": {}}
+{"_id": "11718220", "title": "", "text": "Effectiveness of thigh-length graduatedcompression stockings to reduce the risk of deepvein thrombosis after stroke (CLOTS trial 1): amulticentre, randomised controlledtrialBACKGROUND Deep vein thrombosis (DVT)and pulmonary embolism are common afterstroke. In small trials of patients undergoingsurgery, graduated compression stockings (GCS)reduce the risk of DVT. National stroke guidelinesextrapolating from these trials recommend theiruse in patients with stroke despite insufficientevidence. We assessed the effectiveness ofthigh-length GCS to reduce DVT after stroke.METHODS In this outcome-blinded, randomisedcontrolled trial, 2518 patients who were admittedto hospital within 1 week of an acute stroke andwho were immobile were enrolled from 64centres in the UK, Italy, and Australia. Patientswere allocated via a central randomisationsystem to routine care plus thigh-length GCS(n=1256) or to routine care plus avoidance ofGCS (n=1262). A technician who was blinded to", "metadata": {}}
+{"_id": "11721286", "title": "", "text": "Streptococcus pneumoniae early response genesto human lung epithelial cellsBACKGROUNDStreptococcus pneumoniae infection starts fromcolonization of the host respiratory tract whereinteraction with host respiratory tract epithelialcells occurs. To investigate pneumococcal genesthat are involved in the early stage of interactionwith host epithelial cells, transcriptionalresponses of an encapsulated pathogenicpneumococcal strain TIGR4 upon exposure tohuman lung epithelial cells A549 for 0.5 h and 1h time periods were investigated by using TIGR(JCVI) microarray technology. Gene expressionchanges were validated by quantitative real-timePCR (qRT-PCR) analysis. FINDINGS We observeddifferent transcriptional profiles at two incubationtime periods in which most gene expressionswere down-regulated at 0.5 h but up-regulatedat 1 h. Many genes associated withribonucleotide biosynthesis were down-regulatedat both time points, whereas the genesassociated with cell envelope, energy", "metadata": {}}
+{"_id": "11721676", "title": "", "text": "Proteomic identification of a novel isoform ofcollapsin response mediator protein-2 in spinalnerves peripheral to dorsal root ganglia.Primaryafferent fibers are originated frompseudounipolar sensory cells in dorsal rootganglia (DRG) and transmit external stimulireceived in the skin to the spinal cord. Here weundertook a proteomic approach to uncover thepolarity of primary afferent fibers. Lumbar spinalnerve segments, peripheral and central to DRG,were dissected from 5-wk-old Wistar rats and thelysates were subjected to large-sized 2-DE at pH5-6. Among approximately 800 protein spotsdetected in the central and peripheral fractions,one of the unique spots in the peripheral fractionwith MW of 60 kDa and pI of 5.6 was identifiedas an isoform of collapsin response mediatorprotein-2 (CRMP-2) by MALDI-TOF MS andWestern blots with anti-CRMP-2 antibodies thatrecognize 1-17 and 486-528 residues. Since thisnovel spot was detected only in the peripheralfraction, but not in the central fraction, DRG, and", "metadata": {}}
+{"_id": "11728637", "title": "", "text": "Empirical statistical estimates for sequencesimilarity searchesThe FASTA package ofsequence comparison programs has beenmodified to provide accurate statistical estimatesfor local sequence similarity scores with gaps.These estimates are derived using the extremevalue distribution from the mean and variance ofthe local similarity scores of unrelated sequencesafter the scores have been corrected for theexpected effect of library sequence length. Thisapproach allows accurate estimates to becalculated for both FASTA and Smith-Watermansimilarity scores for protein/protein, DNA/DNA,and protein/translated-DNA comparisons. Theaccuracy of the statistical estimates issummarized for 54 protein families using FASTAand Smith-Waterman scores. Probabilityestimates calculated from the distribution ofsimilarity scores are generally conservative, asare probabilities calculated using theAltschul-Gish lambda, kappa, and etaparameters. The performance of several", "metadata": {}}
+{"_id": "11738716", "title": "", "text": "Steroid hormone signalling links reproduction tolifespan in dietary-restricted Caenorhabditiselegans.Dietary restriction (DR) increaseshealthspan and longevity in many species,including primates, but it is often accompaniedby impaired reproductive function. Whethersignals associated with the reproductive systemcontribute to or are required for DR effects onlifespan has not been established. Here we showthat expression of the cytochrome P450DAF-9/CYP450 and production of the steroidhormone Δ(7)-dafachronic acid (DA) areincreased in C. elegans subjected to DR. DAsignalling through the non-canonical nuclearhormone receptor NHR-8/NHR and thenutrient-responsive kinase let-363/mTOR isessential for DR-mediated longevity. Steroidsignalling also affects germline plasticity inresponse to nutrient deprivation and this isrequired to achieve lifespan extension. Thesedata demonstrate that steroid signalling linksgermline physiology to lifespan when nutrients", "metadata": {}}
+{"_id": "11742219", "title": "", "text": "Regulation and effects of hypothalamic galanin:relation to dietary fat, alcohol ingestion,circulating lipids and energy homeostasis.Galanin(GAL) is known to stimulate feeding behavior.This peptide has different properties andfunctions from other feeding stimulants, e.g.,neuropeptide Y and agouti-related protein.Hypothalamic GAL is relatively unresponsive tofood deprivation and to changes incorticosterone, glucose utilization, dietarycarbohydrate and leptin. This indicates that thispeptide is not essential under conditions whenfood is scarce or low-energy, high-carbohydratediets are being consumed. In contrast, recentevidence suggests that GAL in theparaventricular nucleus (PVN) functions in closerelation to dietary fat and alcohol. In particular,it mediates functions that allow animals to adaptto conditions of positive energy balance involvingexcess consumption of these nutrients. Thispeptide in the PVN is stimulated by a high-fatdiet and also by alcohol. It is stimulated by an", "metadata": {}}
+{"_id": "11748341", "title": "", "text": "Evidence-based interventions for improvement ofmaternal and child nutrition: what can be doneand at what cost?Maternal undernutritioncontributes to 800,000 neonatal deaths annuallythrough small for gestational age births;stunting, wasting, and micronutrient deficienciesare estimated to underlie nearly 3·1 million childdeaths annually. Progress has been made withmany interventions implemented at scale andthe evidence for effectiveness of nutritioninterventions and delivery strategies has grownsince The Lancet Series on Maternal and ChildUndernutrition in 2008. We did a comprehensiveupdate of interventions to address undernutritionand micronutrient deficiencies in women andchildren and used standard methods to assessemerging new evidence for delivery platforms.We modelled the effect on lives saved and cost ofthese interventions in the 34 countries that have90% of the world's children with stunted growth.We also examined the effect of various deliveryplatforms and delivery options using community", "metadata": {}}
+{"_id": "11771811", "title": "", "text": "FGF regulates TGF-β signaling andendothelial-to-mesenchymal transition viacontrol of let-7 miRNA expression.Maintenance ofnormal endothelial function is critical to variousaspects of blood vessel function, but itsregulation is poorly understood. In this study, weshow that disruption of baseline fibroblast growthfactor (FGF) signaling to the endothelium leadsto a dramatic reduction in let-7 miRNA levelsthat, in turn, increases expression oftransforming growth factor (TGF)-β ligands andreceptors and activation of TGF-β signaling,leading to endothelial-to-mesenchymal transition(Endo-MT). We also find that Endo-MT is animportant driver of neointima formation in amurine transplant arteriopathy model and inrejection of human transplant lesions. Thedecline in endothelial FGF signaling input is dueto the appearance of an FGF resistance state thatis characterized by inflammation-dependentreduction in expression and activation of keycomponents of the FGF signaling cascade. These", "metadata": {}}
+{"_id": "11774598", "title": "", "text": "Nuclear Receptors, RXR, and the BigBangIsolation of genes encoding the receptorsfor steroids, retinoids, vitamin D, and thyroidhormone and their structural and functionalanalysis revealed an evolutionarily conservedtemplate for nuclear hormone receptors. Thisdiscovery sparked identification of numerousgenes encoding related proteins, termed orphanreceptors. Characterization of these orphanreceptors and, in particular, of the retinoid Xreceptor (RXR) positioned nuclear receptors atthe epicenter of the \"Big Bang\" of molecularendocrinology. This Review provides a personalperspective on nuclear receptors and explorestheir integrated and coordinated signalingnetworks that are essential for multicellular life,highlighting the RXR heterodimer and itsassociated ligands and transcriptionalmechanism.", "metadata": {}}
+{"_id": "11784947", "title": "", "text": "A genome-wide short hairpin RNA screening ofjurkat T-cells for human proteins contributing toproductive HIV-1 replication.Short interferingRNAs (siRNAs) have been used to inhibit HIV-1replication. The durable inhibition of HIV-1replication by RNA interference has beenimpeded, however, by a high mutation rate whenviral sequences are targeted and by cytotoxicitywhen cellular genes are knocked down. Toidentify cellular proteins that contribute to HIV-1replication that can be chronically silencedwithout significant cytotoxicity, we employed ashRNA library that targets 54,509 humantranscripts. We used this library to select acomprehensive population of Jurkat T-cell clones,each expressing a single discrete shRNA. TheJurkat clones were then infected with HIV-1.Clones that survived viral infection representmoieties silenced for a human mRNA needed forvirus replication, but whose chronic knockdowndid not cause cytotoxicity. Overall, 252 individualJurkat mRNAs were identified. Twenty-two of", "metadata": {}}
+{"_id": "11822354", "title": "", "text": "UNR facilitates the interaction of MLE with thelncRNA roX2 during Drosophila dosagecompensation.Dosage compensation is aregulatory process that balances the expressionof X-chromosomal genes between males (XY)and females (XX). In Drosophila, this requiresnon-coding RNAs and RNA-binding proteins(RBPs) whose specific functions remain elusive.Here we show that the Drosophila RBP UNRpromotes the targeting of the activatingmale-specific-lethal complex to theX-chromosome by facilitating the interaction oftwo crucial subunits: the RNA helicase MLE andthe long non-coding RNA roX2.", "metadata": {}}
+{"_id": "11831598", "title": "", "text": "BMP/SMAD1 signaling sets a threshold for theleft/right pathway in lateral plate mesoderm andlimits availability of SMAD4.Bistability indevelopmental pathways refers to the generationof binary outputs from graded or noisy inputs.Signaling thresholds are critical for bistability.Specification of the left/right (LR) axis invertebrate embryos involves bistable expressionof transforming growth factor beta (TGFbeta)member NODAL in the left lateral platemesoderm (LPM) controlled by feed-forward andfeedback loops. Here we provide evidence thatbone morphogenetic protein (BMP)/SMAD1signaling sets a repressive threshold in the LPMessential for the integrity of LR signaling.Conditional deletion of Smad1 in the LPM led toprecocious and bilateral pathway activation.NODAL expression from both the left and rightsides of the node contributed to bilateralactivation, indicating sensitivity of mutant LPM tonoisy input from the LR system. In vitro, BMPsignaling inhibited NODAL pathway activation", "metadata": {}}
+{"_id": "11837657", "title": "", "text": "Human Macrophages Infected with a HighBurden of ESAT-6-Expressing M. tuberculosisUndergo Caspase-1- and CathepsinB-Independent NecrosisMycobacteriumtuberculosis (Mtb) infects lung macrophages,which instead of killing the pathogen can bemanipulated by the bacilli, creating anenvironment suitable for intracellular replicationand spread to adjacent cells. The role of host celldeath during Mtb infection is debated becausethe bacilli have been shown to be bothanti-apoptotic, keeping the host cell alive toavoid the antimicrobial effects of apoptosis, andpro-necrotic, killing the host macrophage toallow infection of neighboring cells. Sincemycobacteria activate the NLRP3 inflammasomein macrophages, we investigated whether Mtbcould induce one of the recently describedinflammasome-linked cell death modespyroptosis and pyronecrosis. These are mediatedthrough caspase-1 and cathepsin-B, respectively.Human monocyte-derived macrophages were", "metadata": {}}
+{"_id": "11840194", "title": "", "text": "Differentiation of Human Induced-PluripotentStem Cells into Smooth-Muscle Cells: Two NovelProtocolsConventional protocols fordifferentiating human induced-pluripotent stemcells (hiPSCs) into smooth-muscle cells (SMCs)can be inefficient and generally fail to yield cellswith a specific SMC phenotype (i.e., contractileor synthetic SMCs). Here, we present two novelhiPSC-SMC differentiation protocols that yieldSMCs with predominantly contractile or syntheticphenotypes. Flow cytometry analyses ofsmooth-muscle actin (SMA) expression indicatedthat ~45% of the cells obtained with eachprotocol assumed an SMC phenotype, and thatthe populations could be purified to ~95% viametabolic selection. Assessments of cellularmRNA and/or protein levels indicated that SMA,myosin heavy chain II, collagen 1, calponin,transgelin, connexin 43, and vimentin expressionin the SMCs obtained via the Contractile SMCprotocol and in SMCs differentiated via atraditional protocol were similar, while SMCs", "metadata": {}}
+{"_id": "11844791", "title": "", "text": "Conserved Histone Variant H2A.Z ProtectsEuchromatin from the Ectopic Spread of SilentHeterochromatinBoundary elements hinder thespread of heterochromatin, yet these sites do notfully account for the preservation of adjacenteuchromatin. Histone variant H2A.Z (Htz1 inyeast) replaces conventional H2A in manynucleosomes. Microarray analysis revealed thatHTZ1-activated genes cluster near telomeres.The reduced expression of most of these genesin htz1Delta cells was reversed by the deletion ofSIR2 (sir2Delta) suggesting that H2A.Zantagonizes telomeric silencing. OtherHtz1-activated genes flank the silent HMRmating-type locus. Their requirement for Htz1can be bypassed by sir2Delta or by a deletionencompassing the silencing nucleation sites inHMR. In htz1Delta cells, Sir2 and Sir3 spreadinto flanking euchromatic regions, producingchanges in histone H4 acetylation and H34-methylation indicative of ectopicheterochromatin formation. Htz1 is enriched in", "metadata": {}}
+{"_id": "11844826", "title": "", "text": "COMMD proteins, a novel family of structural andfunctional homologs of MURR1.MURR1 is amultifunctional protein that inhibits nuclearfactor kappaB (NF-kappaB), a transcriptionfactor with pleiotropic functions affecting innateand adaptive immunity, apoptosis, cell cycleregulation, and oncogenesis. Here we report thediscovery of a new family of proteins withhomology to MURR1. These proteins formmultimeric complexes and were identified in abiochemical screen for MURR1-associatedfactors. The family is defined by the presence ofa conserved and unique motif termed the COMM(copper metabolism gene MURR1) domain, whichfunctions as an interface for protein-proteininteractions. Like MURR1, several of thesefactors also associate with and inhibitNF-kappaB. The proteins designated as COMMDor COMM domain containing 1-10 are extensivelyconserved in multicellular eukaryotic organismsand define a novel family of structural andfunctional homologs of MURR1. The prototype of", "metadata": {}}
+{"_id": "11861374", "title": "", "text": "Occurrence of chromosome 9 and p53 alterationsin multifocal dysplasia and carcinoma in situ ofhuman urinary bladderTo define the geneticchanges of flat urothelial lesions, carcinoma insitu (CIS) and moderate dysplasias (DII) wereinvestigated for alterations in the twochromosomal regions most frequently involved inbladder cancer. Overall, 33 CIS and 16 DII from21 patients were used to microdissecturothelium. Dual color fluorescence in situhybridization (FISH) using gene locus probes of9q22 (FACC), 9p21 (CDK), 17p13 (p53), andrelated centromeric probes was applied oninterphase nuclei. In parallel, preamplified DNAof these samples was used for loss ofheterozygosity (LOH) analyses with eightmicrosatellite markers on chromosomes 9p, 9qand 17p, and for sequencing of exons 5-9 of p53.Data indicated nearly identical deletionfrequencies for chromosomes 9 and 17 for CIS(chromosome 9, 86%; p53, 84%). DII showed alower deletion rate in comparison with CIS", "metadata": {}}
+{"_id": "11862753", "title": "", "text": "Fresh meat and further processing characteristicsof ham muscles from finishing pigs fedractopamine hydrochloride.Ractopaminehydrochloride (RAC) has consistently led to anadvantage in carcass cutting yields of finishingpigs and remains a common feed additive in USfinishing pig diets. Less is known about the effectof RAC on further processing characteristics.Some researchers have reported advantages inultimate pH of the LM in pigs fed RAC. If agreater ultimate pH was also observed in hams,the increased pH could affect further processingcharacteristics and lead to better proteininteraction and improved textural properties. Theobjective of this experiment was to determine ifRAC-fed pigs yielded hams with a greaterultimate pH, and if so, whether or not thatadvantage improves textural properties andwater retention of further processed hams. Twohundred hams from barrows and gilts fed RAC orcontrol diets were selected based on HCW. Hamswere fabricated into 5 separate pieces to", "metadata": {}}
+{"_id": "11868606", "title": "", "text": "Translocated LPS Might Cause EndotoxinTolerance in Circulating Monocytes of CysticFibrosis PatientsCystic Fibrosis (CF) is aninherited pleiotropic disease that results fromabnormalities in the gene codes of a chloridechannel. The lungs of CF patients are chronicallyinfected by several pathogens but bacteraemiahave rarely been reported in this pathology.Besides that, circulating monocytes in CFpatients exhibit a patent Endotoxin Tolerance(ET) state since they show a significant reductionof the inflammatory response to bacterialstimulus. Despite a previous description of thisphenomenon, the direct cause of ET in CFpatients remains unknown. In this study we haveresearched the possible role ofmicrobial/endotoxin translocation from alocalized infection to the bloodstream as apotential cause of ET induction in CF patients.Plasma analysis of fourteen CF patients revealedhigh levels of LPS compared to healthyvolunteers and patients who suffer from Chronic", "metadata": {}}
+{"_id": "11880289", "title": "", "text": "Effect of mammographic screening from age 40years on breast cancer mortality in the UK Agetrial at 17 years' follow-up: a randomisedcontrolled trial.BACKGROUND Age-specificeffects of mammographic screening, and thetiming of such effects, are a matter of debate.The results of the UK Age trial, which comparedthe effect of invitation to annual mammographicscreening from age 40 years withcommencement of screening at age 50 years onbreast cancer mortality, have been reported at10 years of follow-up and showed no significantdifference in mortality between the trial groups.Here, we report the results of the UK Age trialafter 17 years of follow-up. METHODS Womenaged 39-41 from 23 UK NHS Breast ScreeningProgramme units years were randomly assignedby individual randomisation (1:2) to either anintervention group offered annual screening bymammography up to and including the calendaryear of their 48th birthday or to a control groupreceiving usual medical care (invited for", "metadata": {}}
+{"_id": "11884292", "title": "", "text": "Concordance, disease progression, andheritability of coeliac disease in Italiantwins.BACKGROUND AND AIMS We adopted thetwin method to disentangle the genetic andenvironmental components of susceptibility tocoeliac disease (CD). We estimated diseaseconcordance rate by zygosity and HLAgenotypes, discordance times, progression ratesto disease, and heritability. METHODS Wecrosslinked the Italian Twin Registry with themembership lists of the Italian Coeliac DiseaseAssociation and recruited 23 monozygotic (MZ)and 50 dizygotic (DZ) twin pairs with at least oneaffected member. Zygosity was assigned by DNAfingerprinting, and HLA-DQ and DR alleles weregenotyped. Disease status was ascertained byantiendomysial, anti-human tissuetransglutaminase antibodies, and bowel biopsy.RESULTS Concordance was significantly higher inMZ (83.3% probandwise, 71.4% pairwise) thanin DZ (16.7% probandwise, 9.1% pairwise)pairs. Concordance was not affected by sex or", "metadata": {}}
+{"_id": "11884867", "title": "", "text": "A literature review of the safety of medical bodyarea network devices in magnetic resonanceimagingElectro-magnetic fields and wirelesstechnology are part of modern life. The use ofMagnetic Resonance Imaging (MRI) machines forclarification of internal human structures andfunction in healthcare is increasing. The rapiddevelopment of wireless devices, theirminiaturization and their application as clinicaltools creates an expanding intersection zone.Although safety standards for devices in MRImachines have been previously published, it isnot clear that newer wireless technologies,including devices used in Medical Body AreaNetworks (MBAN) have been rigorously tested ordisclosed. We undertook a review of the clinicalscientific literature and the United States Foodand Drug Administration adverse eventsdatabase to discover whether this is a significantissue. There are currently no published studiesspecifically addressing the safety of wirelessdevices potentially used in MBAN in MRI", "metadata": {}}
+{"_id": "11886686", "title": "", "text": "Synaptic glutamate release by ventromedialhypothalamic neurons is part of theneurocircuitry that prevents hypoglycemia.Theimportance of neuropeptides in thehypothalamus has been experimentallyestablished. Due to difficulties in assessingfunction in vivo, the roles of the fast-actingneurotransmitters glutamate and GABA arelargely unknown. Synaptic vesicular transporters(VGLUTs for glutamate and VGAT for GABA) arerequired for vesicular uptake and, consequently,synaptic release of neurotransmitters.Ventromedial hypothalamic (VMH) neurons arepredominantly glutamatergic and expressVGLUT2. To evaluate the role of glutamaterelease from VMH neurons, we generated micelacking VGLUT2 selectively in SF1 neurons (amajor subset of VMH neurons). These mice havehypoglycemia during fasting secondary toimpaired fasting-induced increases in theglucose-raising pancreatic hormone glucagonand impaired induction in liver of mRNAs", "metadata": {}}
+{"_id": "11887584", "title": "", "text": "c-Src and cooperating partners in humancancer.The proto-oncogene c-src is rarelymutated in human cancers, and whenoverexpressed in normal cells is non- or weaklyoncogenic. These observations have raiseddoubts about the involvement of c-src in theetiology of human tumors. However, recentstudies have shown that c-Src, a non-receptortyrosine kinase, exhibits elevated protein levelsand activity in numerous types of humancancers. Furthermore, it has been found to be acritical component of multiple signaling pathwaysthat regulate proliferation, survival, metastasis,and angiogenesis. Because of its important rolein these oncogenic processes, it represents atherapeutic target ripe for exploitation.", "metadata": {}}
+{"_id": "11899391", "title": "", "text": "Type 1 diabetes-associated IL2RA variationlowers IL-2 signaling and contributes todiminished CD4+CD25+ regulatory T cellfunction.Numerous reports have demonstratedthat CD4(+)CD25(+) regulatory T cells (Tregs)from individuals with a range of humanautoimmune diseases, including type 1 diabetes,are deficient in their ability to control autologousproinflammatory responses when compared withnondiseased, control individuals. Tregdysfunction could be a primary, causal event ormay result from perturbations in the immunesystem during disease development.Polymorphisms in genes associated with Tregfunction, such as IL2RA, confer a higher risk ofautoimmune disease. Although this suggests aprimary role for defective Tregs in autoimmunity,a link between IL2RA gene polymorphisms andTreg function has not been examined. Weaddressed this by examining the impact of anIL2RA haplotype associated with type 1 diabeteson Treg fitness and suppressive function. Studies", "metadata": {}}
+{"_id": "11900630", "title": "", "text": "Hematopoietic stem cells and otherhematopoietic cells show broad resistance tochemotherapeutic agents in vivo whenoverexpressing bcl-2.Objective.Chemotherapeutic agents function by inducingapoptosis and their effectiveness depends on thebalance of pro- and anti-apoptotic proteins incells. Due to the complicated interactions of themany proteins involved, it has been difficult todetermine in tumors whether overexpression ofsingle genes is prognostic for increasedresistance. Therefore, we studied the influence ofbcl-2 overexpression on resistance tochemotherapeutics in a transgenic mousesystem. This allowed us to study a wide varietyof cells, including important but rare populationssuch as hematopoietic stem cells (HSC).Methods.H2K-bcl-2 transgenic and wild-type (WT) micewere treated with several agents(5-fluoruracil,cyclophosphamide, and busulfan) to determinethe contribution of increased amounts of bcl-2 tothe response to these chemotherapeutics in vivo.", "metadata": {}}
+{"_id": "11902109", "title": "", "text": "Direct sensing of systemic and nutritional signalsby hematopoietic progenitors in DrosophilaTheDrosophila lymph gland is a haematopoieticorgan in which progenitor cells, which are mostakin to the common myeloid progenitor inmammals, proliferate and differentiate into threetypes of mature cell--plasmatocytes, crystal cellsand lamellocytes--the functions of which arereminiscent of mammalian myeloid cells. Duringthe first and early second instars of larvaldevelopment, the lymph gland contains onlyprogenitors, whereas in the third instar, a medialregion of the primary lobe of the lymph glandcalled the medullary zone contains theseprogenitors, and maturing blood cells are foundjuxtaposed in a peripheral region designated thecortical zone. A third group of cells referred to asthe posterior signalling centre functions as ahaematopoietic niche. Similarly to mammalianmyeloid cells, Drosophila blood cells respond tomultiple stresses including hypoxia, infection andoxidative stress. However, how systemic signals", "metadata": {}}
+{"_id": "11903247", "title": "", "text": "Regulation of autophagy by cytoplasmicp53Multiple cellular stressors, includingactivation of the tumour suppressor p53, canstimulate autophagy. Here we show thatdeletion, depletion or inhibition of p53 can induceautophagy in human, mouse and nematode cellssubjected to knockout, knockdown orpharmacological inhibition of p53. Enhancedautophagy improved the survival of p53-deficientcancer cells under conditions of hypoxia andnutrient depletion, allowing them to maintainhigh ATP levels. Inhibition of p53 led toautophagy in enucleated cells, and cytoplasmic,not nuclear, p53 was able to repress theenhanced autophagy of p53−/− cells. Manydifferent inducers of autophagy (for example,starvation, rapamycin and toxins affecting theendoplasmic reticulum) stimulatedproteasome-mediated degradation of p53through a pathway relying on the E3 ubiquitinligase HDM2. Inhibition of p53 degradationprevented the activation of autophagy in several", "metadata": {}}
+{"_id": "11913139", "title": "", "text": "The Neurobiology of Sleep: Genetics, cellularphysiology and subcortical networksToappreciate the neural underpinnings of sleep, itis important to view this universal mammalianbehaviour at multiple levels of its biologicalorganization. Molecularly, the circadian rhythmof sleep involves interlocking positive- andnegative-feedback mechanisms of circadiangenes and their protein products in cells of thesuprachiasmatic nucleus that are entrained toambient conditions by light. Circadianinformation is integrated with information onhomeostatic sleep need in nuclei of the anteriorhypothalamus. These nuclei interact with arousalsystems in the posterior hypothalamus, basalforebrain and brainstem to control sleep onset.During sleep, an ultradian oscillator in themesopontine junction controls the regularalternation of rapid eye movement (REM) andnon-REM sleep. Sleep cycles are accompanied byneuromodulatory influences on forebrainstructures that influence behaviour,", "metadata": {}}
+{"_id": "11915280", "title": "", "text": "Suppression of intestinal neoplasia by deletion ofDnmt3bAberrant gene silencing accompanied byDNA methylation is associated with neoplasticprogression in many tumors that also showglobal loss of DNA methylation. Using conditionalinactivation of de novo methyltransferaseDnmt3b in Apc(Min/+) mice, we demonstratethat the loss of Dnmt3b has no impact onmicroadenoma formation, which is consideredthe earliest stage of intestinal tumor formation.Nevertheless, we observed a significant decreasein the formation of macroscopic colonicadenomas. Interestingly, many large adenomasshowed regions with Dnmt3b inactivation,indicating that Dnmt3b is required for initialoutgrowth of macroscopic adenomas but is notrequired for their maintenance. These resultssupport a role for Dnmt3b in the transition stagebetween microadenoma formation andmacroscopic colonic tumor growth and furthersuggest that Dnmt3b, and by extension de novomethylation, is not required for maintaining", "metadata": {}}
+{"_id": "11921405", "title": "", "text": "Epithelium-intrinsic NAIP/NLRC4 inflammasomedrives infected enterocyte expulsion to restrictSalmonella replication in the intestinalmucosa.The gut mucosal epithelium separatesthe host from the microbiota, butenteropathogens such as SalmonellaTyphimurium (S.Tm) can invade and breach thisbarrier. Defenses against such acute insultsremain incompletely understood. Using a murinemodel of Salmonella enterocolitis, we analyzedmechanisms limiting pathogen loads in theepithelium during early infection. Although theepithelium-invading S.Tm replicate initially, thisintraepithelial replicative niche is restricted byexpulsion of infected enterocytes into the lumen.This mechanism is compromised ifinflammasome components (NAIP1-6, NLRC4,caspase-1/-11) are deleted, or ablatedspecifically in the epithelium, resulting in\u0000100-fold higher intraepithelial loads andaccelerated lymph node colonization.Interestingly, the cytokines downstream of", "metadata": {}}
+{"_id": "11922370", "title": "", "text": "GEMC1 is a TopBP1 interacting protein requiredfor chromosomal DNA replicationMany of thefactors required for chromosomal DNA replicationhave been identified in unicellular eukaryotes.However, DNA replication is poorly understood inmulticellular organisms. Here, we report theidentification of GEMC1 (geminin coiled-coilcontaining protein 1), a novel vertebrate proteinrequired for chromosomal DNA replication.GEMC1 is highly conserved in vertebrates and ispreferentially expressed in proliferating cells.Using Xenopus laevis egg extract we show thatXenopus GEMC1 (xGEMC1) binds to thecheckpoint and replication factor TopBP1, whichpromotes binding of xGEMC1 to chromatin duringpre-replication complex (pre-RC) formation. Wedemonstrate that xGEMC1 interacts directly withreplication factors such as Cdc45 and the kinaseCdk2-CyclinE, through which it is heavilyphosphorylated. Phosphorylated xGEMC1stimulates initiation of DNA replication, whereasdepletion of xGEMC1 prevents the onset of DNA", "metadata": {}}
+{"_id": "11933721", "title": "", "text": "Does an arthroscopic suture bridge techniquemaintain repair integrity?: a serial evaluation byultrasonography.UNLABELLED Biomechanicalstudies suggest a suture bridge techniqueenhances rotator cuff tendon footprint contactarea, holding strength, and mean contactpressure. Based on these studies, we askedwhether (1) the suture bridge technique wouldprovide a high rate of cuff integrity after surgery,(2) the status of the repaired cuff would changewith time, (3) preoperative factors could predictpostoperative cuff integrity, and (4) patients withretears had less favorable pain, functionalscores, range of motion (ROM), and musclestrength compared with those with intact repairs.We prospectively followed 78 patients witharthroscopic repairs in whom we used the suturebridge technique. The integrity of the rotator cuffrepair was determined using ultrasonographicevaluation at 4.5 and 12 months after surgery.Ultrasonography revealed intact cuffs in 91% at4.5 months postoperatively, all of which were", "metadata": {}}
+{"_id": "11935250", "title": "", "text": "Widespread and tissue specific age-related DNAmethylation changes in mice.Aberrantmethylation of promoter CpG islands in cancer isassociated with silencing of tumor-suppressorgenes, and age-dependent hypermethylation innormal appearing mucosa may be a risk factorfor human colon cancer. It is not known whetherthis age-related DNA methylation phenomenon isspecific to human tissues. We performedcomprehensive DNA methylation profiling ofpromoter regions in aging mouse intestine usingmethylated CpG island amplification incombination with microarray analysis. Bycomparing C57BL/6 mice at 3-mo-old versus35-mo-old for 3627 detectable autosomal genes,we found 774 (21%) that showed increasedmethylation and 466 (13%) that showeddecreased methylation. We used pyrosequencingto quantitatively validate the microarray dataand confirmed linear age-related methylationchanges for all 12 genomic regions examined.We then examined 11 changed genomic loci for", "metadata": {}}
+{"_id": "11936877", "title": "", "text": "Environmental and economic costs of soil erosionand conservation benefits.Soil erosion is a majorenvironmental threat to the sustainability andproductive capacity of agriculture. During thelast 40 years, nearly one-third of the world'sarable land has been lost by erosion andcontinues to be lost at a rate of more than 10million hectares per year. With the addition of aquarter of a million people each day, the worldpopulation's food demand is increasing at a timewhen per capita food productivity is beginning todecline.", "metadata": {}}
+{"_id": "11939159", "title": "", "text": "Association between influenza vaccination andcardiovascular outcomes in high-risk patients: ameta-analysis.IMPORTANCE Amongnontraditional cardiovascular risk factors, recentinfluenzalike infection is associated with fatal andnonfatal atherothrombotic events. OBJECTIVESTo determine if influenza vaccination isassociated with prevention of cardiovascularevents. DATA SOURCES AND STUDY SELECTIONA systematic review and meta-analysis ofMEDLINE (1946-August 2013), EMBASE(1947-August 2013), and the Cochrane LibraryCentral Register of Controlled Trials(inception-August 2013) for randomized clinicaltrials (RCTs) comparing influenza vaccine vsplacebo or control in patients at high risk ofcardiovascular disease, reporting cardiovascularoutcomes either as efficacy or safety events.DATA EXTRACTION AND SYNTHESIS Twoinvestigators extracted data independently ontrial design, baseline characteristics, outcomes,and safety events from published manuscripts", "metadata": {}}
+{"_id": "11943989", "title": "", "text": "Baby hands that move to the rhythm oflanguage: hearing babies acquiring signlanguages babble silently on the handsThe \"ba,ba, ba\" sound universal to babies' babblingaround 7 months captures scientific attentionbecause it provides insights into the mechanismsunderlying language acquisition and vestiges ofits evolutionary origins. Yet the prevailingmystery is what is the biological basis ofbabbling, with one hypothesis being that it is anon-linguistic motoric activity driven largely bythe baby's emerging control over the mouth andjaw, and another being that it is a linguisticactivity reflecting the babies' early sensitivity tospecific phonetic-syllabic patterns. Two groups ofhearing babies were studied over time (ages 6,10, and 12 months), equal in all developmentalrespects except for the modality of languageinput (mouth versus hand): three hearing babiesacquiring spoken language (group 1:\"speech-exposed\") and a rare group of threehearing babies acquiring sign language only, not", "metadata": {}}
+{"_id": "11951999", "title": "", "text": "The Ten-Eleven Translocation-2 (TET2) gene inhematopoiesis and hematopoieticdiseasesTen-Eleven Translocation-2 (TET2)inactivation through loss-of-function mutation,deletion and IDH1/2 (Isocitrate Dehydrogenase 1and 2) gene mutation is a common event inmyeloid and lymphoid malignancies. TET2 genemutations similar to those observed in myeloidand lymphoid malignancies also accumulate withage in otherwise healthy subjects with clonalhematopoiesis. TET2 is one of the three proteinsof the TET (Ten-Eleven Translocation) family,which are evolutionarily conserved dioxygenasesthat catalyze the conversion of5-methyl-cytosine (5-mC) to5-hydroxymethyl-cytosine (5-hmC) and promoteDNA demethylation. TET dioxygenases require2-oxoglutarate, oxygen and Fe(II) for theiractivity, which is enhanced in the presence ofascorbic acid. TET2 is the most expressed TETgene in the hematopoietic tissue, especially inhematopoietic stem cells. In addition to their", "metadata": {}}
+{"_id": "11953232", "title": "", "text": "Impaired Awareness of Hypoglycemia in aPopulation-Based Sample of Children andAdolescents With Type 1 DiabetesOBJECTIVE Todetermine the prevalence and clinicalassociations of impaired awareness ofhypoglycemia in a population-based sample ofchildren and adolescents with type 1 diabetes.RESEARCH DESIGN AND METHODS A validatedquestionnaire was administered to 656 patientswith type 1 diabetes over a 6-month period todetermine hypoglycemia awareness status. Caseascertainment was 79% of the clinic population.The rate of severe hypoglycemia was determinedby data collected prospectively in the precedingyear. RESULTS Impaired awareness ofhypoglycemia was present in 29% of patients.Patients with impaired awareness ofhypoglycemia had an earlier onset of diabetes (P< 0.001), were younger (P < 0.001), and hadlower mean levels of A1C since diabetes onset (P= 0.006) and at their last visit (P = 0.001). Theoverall rate of severe hypoglycemia was 24.5", "metadata": {}}
+{"_id": "11968641", "title": "", "text": "Enhancing circadian clock function in cancer cellsinhibits tumor growthBACKGROUND Circadianclocks control cell cycle factors, and circadiandisruption promotes cancer. To address whetherenhancing circadian rhythmicity in tumor cellsaffects cell cycle progression and reducesproliferation, we compared growth and cell cycleevents of B16 melanoma cells and tumors witheither a functional or dysfunctional clock.RESULTS We found that clock genes weresuppressed in B16 cells and tumors, buttreatments inducing circadian rhythmicity, suchas dexamethasone, forskolin and heat shock,triggered rhythmic clock and cell cycle geneexpression, which resulted in fewer cells in Sphase and more in G1 phase. Accordingly, B16proliferation in vitro and tumor growth in vivowas slowed down. Similar effects were observedin human colon carcinoma HCT-116 cells.Notably, the effects of dexamethasone were notdue to an increase in apoptosis nor to anenhancement of immune cell recruitment to the", "metadata": {}}
+{"_id": "11983390", "title": "", "text": "Distinct functions ofnucleotide-binding/hydrolysis sites in the fourAAA modules of cytoplasmic dynein.Cytoplasmicdynein is a microtubule-based motor protein thatis responsible for most intracellular retrogradetransports along microtubule filaments. Themotor domain of dynein contains six tandemlylinked AAA (ATPases associated with diversecellular activities) modules, with the first fourcontaining predictednucleotide-binding/hydrolysis sites (P1-P4). Todissect the functions of these multiplenucleotide-binding/hydrolysis sites, weexpressed and purified Dictyostelium dyneinmotor domains in which mutations wereintroduced to block nucleotide binding at each ofthe four AAA modules, and then examined theirdetailed biochemical properties. The P1 mutantwas trapped in a strong-binding state even in thepresence of ATP and lost its motile activity. TheP3 mutant also showed a high affinity formicrotubules in the presence of ATP and lost", "metadata": {}}
+{"_id": "11992632", "title": "", "text": "Over-expression of RCAN1 causes Downsyndrome-like hippocampal deficits that alterlearning and memory.People with Downsyndrome (DS) exhibit abnormal brain structure.Alterations affecting neurotransmission andsignalling pathways that govern brain functionare also evident. A large number of genes aresimultaneously expressed at abnormal levels inDS; therefore, it is a challenge to determinewhich gene(s) contribute to specificabnormalities, and then identify the keymolecular pathways involved. We generatedRCAN1-TG mice to study the consequences ofRCAN1 over-expression and investigate thecontribution of RCAN1 to the brain phenotype ofDS. RCAN1-TG mice exhibit structural brainabnormalities in those areas affected in DS. Thevolume and number of neurons within thehippocampus is reduced and this correlates witha defect in adult neurogenesis. The density ofdendritic spines on RCAN1-TG hippocampalpyramidal neurons is also reduced. Deficits in", "metadata": {}}
+{"_id": "12009265", "title": "", "text": "Vitamins E and C in the prevention of prostateand total cancer in men: the Physicians' HealthStudy II randomized controlled trial.CONTEXTMany individuals take vitamins in the hopes ofpreventing chronic diseases such as cancer, andvitamins E and C are among the most commonindividual supplements. A large-scalerandomized trial suggested that vitamin E mayreduce risk of prostate cancer; however, fewtrials have been powered to address thisrelationship. No previous trial in men at usualrisk has examined vitamin C alone in theprevention of cancer. OBJECTIVE To evaluatewhether long-term vitamin E or Csupplementation decreases risk of prostate andtotal cancer events among men. DESIGN,SETTING, AND PARTICIPANTS The Physicians'Health Study II is a randomized, double-blind,placebo-controlled factorial trial of vitamins Eand C that began in 1997 and continued until itsscheduled completion on August 31, 2007. Atotal of 14,641 male physicians in the United", "metadata": {}}
+{"_id": "12014458", "title": "", "text": "Micromanagers of gene expression: thepotentially widespread influence of metazoanmicroRNAsWe propose that the microRNA milieu,unique to each cell type, productively dampensthe expression of thousands of mRNAs andprovides important context for the evolution ofall metazoan mRNA sequences. For genes thatshould not be expressed in a particular cell type,protein output is lowered to inconsequentiallevels. For other genes, dosage is adjusted in amanner that allows for customized expression indifferent cell types while achieving a moreuniform level within each cell type. In theseways, the microRNAs add an extensive layer ofgene control that integrates with transcriptionaland other regulatory processes to expand thecomplexity of metazoan gene expression.", "metadata": {}}
+{"_id": "12030318", "title": "", "text": "The Kinase Regulator Mob1 Acts as a PatterningProtein for Stentor MorphogenesisMorphogenesisand pattern formation are vital processes in anyorganism, whether unicellular or multicellular.But in contrast to the developmental biology ofplants and animals, the principles ofmorphogenesis and pattern formation in singlecells remain largely unknown. Although all cellsdevelop patterns, they are most obvious inciliates; hence, we have turned to a classicalunicellular model system, the giant ciliateStentor coeruleus. Here we show that the RNAinterference (RNAi) machinery is conserved inStentor. Using RNAi, we identify the kinasecoactivator Mob1--with conserved functions incell division and morphogenesis from plants tohumans-as an asymmetrically localizedpatterning protein required for global patterningduring development and regeneration in Stentor.Our studies reopen the door for Stentor as amodel regeneration system.", "metadata": {}}
+{"_id": "12030680", "title": "", "text": "Measurement and clinical monitoring of humanlymphocyte clonality by massively parallel VDJpyrosequencing.The complex repertoire ofimmune receptors generated by B and T cellsenables recognition of diverse threats to the hostorganism. In this work, we show that massivelyparallel DNA sequencing of rearranged immunereceptor loci can provide direct detection andtracking of immune diversity and expandedclonal lymphocyte populations in physiologicaland pathological contexts. DNA was isolatedfrom blood and tissue samples, a series ofredundant primers was used to amplify diverseDNA rearrangements, and the resulting mixturesof barcoded amplicons were sequenced usinglong-read ultra deep sequencing. Individual DNAmolecules were then characterized on the basisof DNA segments that had been joined to make afunctional (or nonfunctional) immune effector.Current experimental designs can accommodateup to 150 samples in a single sequence run, withthe depth of sequencing sufficient to identify", "metadata": {}}
+{"_id": "12030735", "title": "", "text": "Can we apply the National Cholesterol EducationProgram Adult Treatment Panel definition of themetabolic syndrome to Asians?OBJECTIVELimited information is available about themetabolic syndrome in Asians. Furthermore, thedefinition of central obesity using waistcircumference may not be appropriate for Asians.The objectives of this study were to determinethe optimal waist circumference for diagnosingcentral obesity in Asians and to estimate theprevalence of the metabolic syndrome in anAsian population. RESEARCH DESIGN ANDMETHODS We used data from the 1998Singapore National Health Survey, across-sectional survey involving 4,723 men andwomen of Chinese, Malay, and Asian-Indianethnicity aged 18-69 years. Receiver operatingcharacteristic analysis suggested that waistcircumference >80 cm in women and >90 cm inmen was a more appropriate definition of centralobesity in this population. The prevalence of themetabolic syndrome was then determined using", "metadata": {}}
+{"_id": "12039953", "title": "", "text": "Serotonin and fluoxetine levels in plasma andplatelets after fluoxetine treatment in depressivepatients.Depression is a mood disordercharacterized by complex alterations ofneurotransmitters such as serotonin,norepinephrine, and dopamine. In particular,there is substantial evidence of abnormalities inserotonin neurotransmission. Peripheralparameters of serotoninergic transmission, suchas the 5-hydroxytryptamine content of plasmaand platelets, have been used to identifybiochemical alterations related to depression. Inrecent years, these parameters have also beenused to examine the mechanism of action ofantidepressive drugs such as the selectiveserotonin reuptake inhibitors. This studyinvestigated the interaction between the plasmaand platelet levels of fluoxetine and serotoninafter fluoxetine administration to depressedpatients. Twelve patients affected by majordepression (according to the DSM-IV criteria)received a single oral dose of fluoxetine in the", "metadata": {}}
+{"_id": "12040627", "title": "", "text": "The histone acetyltransferase MOF is a keyregulator of the embryonic stem cell coretranscriptional network.Pluripotent embryonicstem cells (ESCs) maintain self-renewal and thepotential for rapid response to differentiationcues. Both ESC features are subject to epigeneticregulation. Here we show that the histoneacetyltransferase Mof plays an essential role inthe maintenance of ESC self-renewal andpluripotency. ESCs with Mof deletion losecharacteristic morphology, alkaline phosphatase(AP) staining, and differentiation potential. Theyalso have aberrant expression of the coretranscription factors Nanog, Oct4, and Sox2.Importantly, the phenotypes of Mof null ESCscan be partially suppressed by Nanogoverexpression, supporting the idea that Moffunctions as an upstream regulator of Nanog inESCs. Genome-wide ChIP-sequencing andtranscriptome analyses further demonstrate thatMof is an integral component of the ESC coretranscriptional network and that Mof primes", "metadata": {}}
+{"_id": "12058271", "title": "", "text": "Role of the CXCR4/SDF-1 chemokine axis incirculating neutrophil homeostasis.The bonemarrow is the primary site for neutrophilproduction and release into the circulation.Because the CXC chemokine receptor-4/stromalderived factor-1 (CXCR4/SDF-1) axis plays acentral role in the interactions of hematopoieticstem cells, lymphocytes, and developingneutrophils in the marrow, we investigatedwhether reciprocal CXCR4-dependentmechanisms might be involved in neutrophilrelease and subsequent return to the marrowfollowing circulation. Neutralizing antibody toCXCR4 reduced marrow retention of infusedneutrophils (45.7% +/- 0.5% to 6.9% +/- 0.5%)and was found to mobilize neutrophils frommarrow (34.4% +/- 4.4%). Neutrophil CXCR4expression and SDF-1-induced calcium fluxdecreased with maturation and activation of thecells, corresponding to the decreased marrowhoming associated with these characteristics invivo. Infusion of the inflammatory mediator and", "metadata": {}}
+{"_id": "12074066", "title": "", "text": "Vitamin D and prevention of colorectalcancer.BACKGROUND Inadequate photosynthesisor oral intake of Vitamin D are associated withhigh incidence rates of colorectal cancer, but thedose-response relationship has not beenadequately studied. METHODS Dose-responsegradients from observational studies of VitaminD intake and serum 25-hydroxyvitamin D wereplotted as trend lines. The point on each lineartrend line corresponding to an odds ratio of 0.50provided the prediagnostic Vitamin D intake or25-hydroxyvitamin D concentration associatedwith 50% lower risk compared to <100IU/dayVitamin D or <13ng/ml serum25-hydroxyvitamin D. Medians of these valueswere determined. RESULTS Overall, individualswith >or=1000IU/day oral Vitamin D (p<0.0001)or >or=33ng/ml (82nmol/l) serum25-hydroxyvitamin D (p<0.01) had 50% lowerincidence of colorectal cancer compared toreference values. CONCLUSIONS Intake of1000IU/day of Vitamin D, half the safe upper", "metadata": {}}
+{"_id": "12086599", "title": "", "text": "Repeat expansion in the budding yeast ribosomalDNA can occur independently of the canonicalhomologous recombination machineryMajoreukaryotic genomic elements, including theribosomal DNA (rDNA), are composed ofrepeated sequences with well-defined copynumbers that must be maintained by regulatedrecombination. Although mechanisms thatinstigate rDNA recombination have beenidentified, none are directional and theytherefore cannot explain precise repeat numbercontrol. Here, we show that yeast lacking histonechaperone Asf1 undergo reproducible rDNArepeat expansions. These expansions do notrequire the replication fork blocking protein Fob1and are therefore independent of known rDNAexpansion mechanisms. We propose theexistence of a regulated rDNA repeat gainpathway that becomes constitutively active inasf1Δ mutants. Cells lacking ASF1 accumulaterDNA repeats with high fidelity in a processivemanner across multiple cell divisions. The", "metadata": {}}
+{"_id": "12086818", "title": "", "text": "cDNA and genomic cloning of lacritin, a novelsecretion enhancing factor from the humanlacrimal gland.Multiple extracellular factors arehypothesized to promote the differentiation ofunstimulated and/or stimulated secretorypathways in exocrine secretory cells, but theidentity of differentiation factors, particularlythose organ-specific, remain largely unknown.Here, we report on the identification of a novelsecreted glycoprotein, lacritin, that enhancesexocrine secretion in overnight cultures oflacrimal acinar cells which otherwise display lossof secretory function. Lacritin mRNA and proteinare highly expressed in human lacrimal gland,moderately in major and minor salivary glandsand slightly in thyroid. No lacritin message orprotein is detected elsewhere among more than50 human tissues examined. Lacritin displayspartial similarity to theglycosaminoglycan-binding region ofbrain-specific neuroglycan C (32 % identity over102 amino acid residues) and to the possibly", "metadata": {}}
+{"_id": "12087063", "title": "", "text": "The structure of informal care: are theredifferences by race?This study investigatedwhether there are race differences in thestructure of informal caregiving networks. Dataon 3,793 functionally impaired persons age 65and over from the 1989 National Long-Term CareSurvey were analyzed. The size of the totalcaregiver network and the unpaid network didnot differ by race, but the likelihood of therebeing a non-immediate family member amongunpaid caregivers was higher among disabledolder blacks. These findings raise questionsabout whether race differences in nursing homeutilization and paid long-term care services,documented in other studies, can be explainedby differences in caregiving arrangements.", "metadata": {}}
+{"_id": "12100854", "title": "", "text": "Proteomic and genomic approaches reveal criticalfunctions of H3K9 methylation andHeterochromatin Protein-1γ in reprogramming topluripotencyReprogramming of somatic cells intoinduced pluripotent stem cells (iPSCs) involves amarked reorganization of chromatin. To identifypost-translational histone modifications thatchange in global abundance during this process,we have applied a quantitativemass-spectrometry-based approach. We foundthat iPSCs, compared with both the startingfibroblasts and a late reprogrammingintermediate (pre-iPSCs), are enriched forhistone modifications associated with activechromatin, and depleted for marks oftranscriptional elongation and a subset ofrepressive modifications includingH3K9me2/me3. Dissecting the contribution ofH3K9 methylation to reprogramming, we showthat the H3K9 methyltransferases Ehmt1, Ehmt2and Setdb1 regulate global H3K9me2/me3 levelsand that their depletion increases iPSC formation", "metadata": {}}
+{"_id": "12100963", "title": "", "text": "Tissue exit: a novel control point in theaccumulation of antigen-specific CD8 T cells inthe influenza a virus-infectedlung.Memory/effector T cells efficiently migrateinto extralymphoid tissues and sites of infection,providing immunosurveillance and a first line ofdefense against invading pathogens. Eventhough it is a potential means to regulate thesize, quality, and duration of a tissue infiltrate, Tcell egress from infected tissues is poorlyunderstood. Using a mouse model of influenza Avirus infection, we found that CD8 effector T cellsegressed from the infected lung in aCCR7-dependent manner. In contrast, followingantigen recognition, effector CD8 T cell egressdecreased and CCR7 function was reduced invivo and in vitro, indicating that the exit of CD8 Tcells from infected tissues is tightly regulated.Our data suggest that the regulation of T cellegress is a mechanism to retain antigen-specificeffectors at the site of infection to promote viralclearance, while decreasing the numbers of", "metadata": {}}
+{"_id": "12102963", "title": "", "text": "The relation between dietary flavonol intake andcoronary heart disease mortality: ameta-analysis of prospective cohortstudiesObjective: To assess the association ofdietary flavonol intake with the subsequent riskof coronary heart disease (CHD) mortality.Design: Meta-analysis of prospective cohortstudies published before September 2001.Studies were identified by MEDLINE and EMBASEsearches and by scanning relevant referencelists. The following information was extractedfrom published reports: size of cohort, meanage, mean duration of follow-up, number of fatalCHD events, mean flavonol intake, main sourcesof flavonol intake, degree of adjustment forpotential confounders, and the relation of CHDmortality to dietary flavonol intake measured atbaseline. Results: Seven prospective cohorts ofmen and women were identified including a totalof 2087 fatal CHD events. Comparison ofindividuals in the top third with those in thebottom third of dietary flavonol intake yielded a", "metadata": {}}
+{"_id": "12122482", "title": "", "text": "MRI in the diagnosis of MS: a prospective studywith comparison of clinical evaluation, evokedpotentials, oligoclonal banding, and CT.Wecompared the diagnostic capabilities of MRI toCT, evoked potentials (EP), and CSF oligoclonalbanding analysis in a prospective evaluation of200 patients with suspected multiple sclerosis(MS). MRI was the best method fordemonstrating dissemination in space. Anabnormal appropriate EP in monosymptomaticdisease was usually supported by MRI and CSFanalysis as being predictive of MS as a clinicaldiagnosis. A normal appropriate EP study wasnot satisfactory because MRI and CSF analysisoften did not support a diagnosis of non-MS.When there is agreement between three of theseparaclinical studies, the diagnosis of MS isprobably unequivocal. For use in researchstudies, laboratory-supported definite MS(LSDMS) could be diagnosed in 85 patients ofthe total 200 (42.5%), in 19/38 (50%) of opticneuritis (ON) patients, and in 24/52 (46%) of", "metadata": {}}
+{"_id": "12130067", "title": "", "text": "Osteoclasts promote the formation ofhematopoietic stem cell niches in the bonemarrowFormation of the hematopoietic stem cell(HSC) niche in bone marrow (BM) is tightlyassociated with endochondral ossification, butlittle is known about the mechanisms involved.We used the oc/oc mouse, a mouse model withimpaired endochondral ossification caused by aloss of osteoclast (OCL) activity, to investigatethe role of osteoblasts (OBLs) and OCLs in theHSC niche formation. The absence of OCLactivity resulted in a defective HSC nicheassociated with an increased proportion ofmesenchymal progenitors but reducedosteoblastic differentiation, leading to impairedHSC homing to the BM. Restoration of OCLactivity reversed the defect in HSC nicheformation. Our data demonstrate that OBLs arerequired for establishing HSC niches and thatosteoblastic development is induced by OCLs.These findings broaden our knowledge of theHSC niche formation, which is critical for", "metadata": {}}
+{"_id": "12130200", "title": "", "text": "A prospective study of plasma homocyst(e)ineand risk of myocardial infarction in USphysicians.OBJECTIVE To assess prospectivelythe risk of coronary heart disease associatedwith elevated plasma levels of homocyst(e)ine.DESIGN Nested case-control study usingprospectively collected blood samples. SETTINGParticipants in the Physicians' Health Study.PARTICIPANTS A total of 14,916 malephysicians, aged 40 to 84 years, with no priormyocardial infarction (MI) or stroke providedplasma samples at baseline and were followed upfor 5 years. Samples from 271 men whosubsequently developed MI were analyzed forhomocyst(e)ine levels together with pairedcontrols, matched by age and smoking. MAINOUTCOME MEASURE Acute MI or death due tocoronary disease. RESULTS Levels ofhomocyst(e)ine were higher in cases than incontrols (11.1 +/- 4.0 [SD] vs 10.5 +/- 2.8nmol/mL; P = .03). The difference wasattributable to an excess of high values among", "metadata": {}}
+{"_id": "12130690", "title": "", "text": "Involvement of transient receptor potentialvanilloid 1 receptors in protease-activatedreceptor-2-induced joint inflammation andnociception.Protease-activated receptor-2(PAR-2) is a G-protein-coupled receptoractivated through proteolytic cleavage. It islocalized on epithelial, endothelial andinflammatory cells, as well as on transientreceptor potential vanilloid 1 (TRPV1)receptor-expressing neurones. It plays animportant role in inflammatory/nociceptiveprocesses. Since there are few reportsconcerning PAR-2 function in joints, the effects ofintraarticular PAR-2 activation on joint pain andinflammation were studied. Secondaryhyperalgesia/allodynia, spontaneous weightdistribution, swelling and inflammatory cytokineproduction were measured and the involvementof TRPV1 ion channels was investigated in ratsand mice. Injection of the PAR-2 receptor agonistSLIGRL-NH(2) into the knee decreased touchsensitivity and weight bearing of the ipsilateral", "metadata": {}}
+{"_id": "12145359", "title": "", "text": "Relationship between reduced forced expiratoryvolume in one second and the risk of lungcancer: a systematic review andmeta-analysis.BACKGROUND Individuals withseverely impaired lung function have anincreased risk of lung cancer. Whether milderreductions in forced expiratory volume in 1second (FEV(1)) also increase the risk of lungcancer is controversial. Moreover, there is littleconsensus on whether men and women havesimilar risks for lung cancer for similar decreasesin FEV(1). METHODS A search was conducted ofPubMed and EMBASE from January 1966 toJanuary 2005 and studies that examined therelationship between FEV1 and lung cancer wereidentified. The search was limited to studies thatwere population based, employed a prospectivedesign, were large in size (> or = 5000participants), and adjusted for cigarette smokingstatus. RESULTS Twenty eight abstracts wereidentified, six of which did not report FEV1 andeight did not adjust for smoking. Included in this", "metadata": {}}
+{"_id": "12149169", "title": "", "text": "Functional Architecture of RNA PolymeraseISynthesis of ribosomal RNA (rRNA) by RNApolymerase (Pol) I is the first step in ribosomebiogenesis and a regulatory switch in eukaryoticcell growth. Here we report the 12 Acryo-electron microscopic structure for thecomplete 14-subunit yeast Pol I, a homologymodel for the core enzyme, and the crystalstructure of the subcomplex A14/43. In theresulting hybrid structure of Pol I, A14/43, theclamp, and the dock domain contribute to aunique surface interacting with promoter-specificinitiation factors. The Pol I-specific subunits A49and A34.5 form a heterodimer near the enzymefunnel that acts as a built-in elongation factorand is related to the Pol II-associated factorTFIIF. In contrast to Pol II, Pol I has a strongintrinsic 3'-RNA cleavage activity, which requiresthe C-terminal domain of subunit A12.2 and,apparently, enables ribosomal RNA proofreadingand 3'-end trimming.", "metadata": {}}
+{"_id": "12152977", "title": "", "text": "SWI/SNF-Brg1 regulates self-renewal andoccupies core pluripotency-related genes inembryonic stem cells.The SWI/SNF-Brg1chromatin remodeling protein plays critical rolesin cell-cycle control and differentiation throughregulation of gene expression. Loss of Brg1 inmice results in early embryonic lethality, andrecent studies have implicated a role for Brg1 insomatic stem cell self-renewal anddifferentiation. However, little is known aboutBrg1 function in preimplantation embryos andembryonic stem (ES) cells. Here we report thatBrg1 is required for ES cell self-renewal andpluripotency. RNA interference-mediatedknockdown of Brg1 in blastocysts causedaberrant expression of Oct4 and Nanog. In EScells, knockdown of Brg1 resulted in phenotypicchanges indicative of differentiation,downregulation of self-renewal and pluripotencygenes (e.g., Oct4, Sox2, Sall4, Rest), andupregulation of differentiation genes. Usinggenome-wide promoter analysis (chromatin", "metadata": {}}
+{"_id": "12156187", "title": "", "text": "Rapid induction of Alternative Lengthening ofTelomeres by depletion of the histone chaperoneASF1The mechanism of activation of thealternative lengthening of telomeres (ALT)pathway of mammalian chromosome-endmaintenance has been unclear. We have nowdiscovered that co-depletion of the histonechaperones ASF1a and ASF1b in human cellsinduced all hallmarks of ALT in both primary andcancer cells. These included the formation ofALT-associated PML (promyelocytic leukemia)bodies (APBs), the presence ofextrachromosomal telomeric DNA species, anelevated frequency of telomeric sister chromatidexchanges (t-SCE) events and intertelomericexchange of an integrated tag. The induction ofALT characteristics in this setting led to thesimultaneous suppression of telomerase. Wedetermined that ALT induction is positivelyregulated by the proteins RAD17 and BLM andnegatively regulated by EXO1 and DNA2. Theinduction of ALT phenotypes as a consequence of", "metadata": {}}
+{"_id": "12172346", "title": "", "text": "Targeting bromodomains: epigenetic readers oflysine acetylationLysine acetylation is a keymechanism that regulates chromatin structure;aberrant acetylation levels have been linked tothe development of several diseases.Acetyl-lysine modifications create docking sitesfor bromodomains, which are small interactionmodules found on diverse proteins, some ofwhich have a key role in theacetylation-dependent assembly oftranscriptional regulator complexes. Thesecomplexes can then initiate transcriptionalprogrammes that result in phenotypic changes.The recent discovery of potent and highly specificinhibitors for the BET (bromodomain andextra-terminal) family of bromodomains hasstimulated intensive research activity in diversetherapeutic areas, particularly in oncology,where BET proteins regulate the expression ofkey oncogenes and anti-apoptotic proteins. Inaddition, targeting BET bromodomains could holdpotential for the treatment of inflammation and", "metadata": {}}
+{"_id": "12197393", "title": "", "text": "Arachidonic acid cytochrome P450 epoxygenasepathway.Cytochrome P450 (CYP) epoxygenasesconvert arachidonic acid to fourepoxyeicosatrienoic acid (EET) regioisomers,5,6-, 8,9-, 11,12-, and 14,15-EET, that functionas autacrine and paracrine mediators. EETsproduce vascular relaxation by activating smoothmuscle large-conductance Ca2+-activated K+channels (BKCa). In addition, they haveanti-inflammatory effects on blood vessels and inthe kidney, promote angiogenesis, and protectischemic myocardium and brain. CYPepoxygenases also convert eicosapentaenoic acidto vasoactive epoxy-derivatives, andendocannabinoids containing 11,12- and14,15-EET are formed. Many EET actions appearto be initiated by EET binding to a membranereceptor that activates ion channels andintracellular signal transduction pathways.However, EETs also are taken up by cells, areincorporated into phospholipids, and bind tocytosolic proteins and nuclear receptors,", "metadata": {}}
+{"_id": "12205576", "title": "", "text": "Physical activity at 36 years: patterns andchildhood predictors in a longitudinalstudy.OBJECTIVE The aim was to describe thesex and socioeconomic differences in patterns ofphysical activity at work and in leisure time ofmen and women aged 36 years, and toinvestigate factors in childhood and adolescencewhich predict high rates of participation in sportsand recreational activities in later life. DESIGNData collected in childhood, adolescence, and at36 years on members of a national prospectivebirth cohort study were used. SETTING Thepopulation sample was resident in England,Scotland, and Wales. SUBJECTS A stratifiedsample of about 3500 men and women wasstudied regularly from birth until 43 years.MEASUREMENTS AND MAIN RESULTS More menthan women reported high rates of sports andrecreational activities, gardening, anddo-it-yourself. In contrast women reportedhigher rates of bicycling and walking. Higherlevels of education were associated with frequent", "metadata": {}}
+{"_id": "12206390", "title": "", "text": "Residual lifetime risk for developing hypertensionin middle-aged women and men: TheFramingham Heart Study.CONTEXT Thelong-term risk for developing hypertension isbest described by the lifetime risk statistic. Thelifetime risk for hypertension and trends in thisrisk over time are unknown. OBJECTIVES Toestimate the residual lifetime risk forhypertension in older US adults and to evaluatetemporal trends in this risk. DESIGN, SETTING,AND PARTICIPANTS Community-basedprospective cohort study of 1298 participantsfrom the Framingham Heart Study who wereaged 55 to 65 years and free of hypertension atbaseline (1976-1998). MAIN OUTCOMEMEASURES Residual lifetime risk (lifetimecumulative incidence not adjusted for competingcauses of mortality) for hypertension, defined asblood pressure of 140/90 mm Hg or greater oruse of antihypertensive medications. RESULTSThe residual lifetime risks for developinghypertension and stage 1 high blood pressure or", "metadata": {}}
+{"_id": "12207167", "title": "", "text": "Adverse effects of excessive consumption ofamino acids.PHENYLALANINE TOXICITY 158Developing the 0. -M ethylphenylalanine Model. .. . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . 160 Use of the a-Methylphenylalanine Model in Brain Protein Synthesis . .. . . . . . . . . . . . . . . . . 161 TYROSINE TOXICITY162 General Nutritional Observations . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . 162 Factors AffectingTissue Concentrations of Tyrosine . ... .. .. .. ....... . . . . . .. . . 163 Probable Cause of TyrosineToxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 ANew Animal Model for Human Tyrosinemia II 165TRYPTOPHAN TOXICITy 165 General NutritionalObservations . .. ....... . ....... . .... . . .. . . . .. . ... .. ..... ......... 165 Factors Affecting TryptophanToxicity . . . .. . . . . . . . .... . ........ 166Tryptophan and Ruminant Interstitial PulmonaryEmphysema and Edema ..... . . . . . . . 167HISTIDINE TOXICITY 168 General Nutritional", "metadata": {}}
+{"_id": "12207340", "title": "", "text": "Mechanism and regulation of DNA end resectionin eukaryotes.The repair of DNA double-strandbreaks (DSBs) by homologous recombination(HR) is initiated by nucleolytic degradation of the5'-terminated strands in a process termed endresection. End resection generates3'-single-stranded DNA tails, substrates forRad51 to catalyze homologous pairing and DNAstrand exchange, and for activation of the DNAdamage checkpoint. The commonly acceptedview is that end resection occurs by a two-stepmechanism. In the first step, Sae2/CtIP activatesthe Mre11-Rad50-Xrs2/Nbs1 (MRX/N) complexto endonucleolytically cleave the 5'-terminatedDNA strands close to break ends, and in thesecond step Exo1 and/or Dna2 nucleases extendthe resected tracts to produce long3'-ssDNA-tailed intermediates. Initiation ofresection commits a cell to repair a DSB by HRbecause long ssDNA overhangs are poorsubstrates for non-homologous end joining(NHEJ). Thus, the initiation of end resection has", "metadata": {}}
+{"_id": "12209494", "title": "", "text": "Multiple-dose activated charcoal in acuteself-poisoning: a randomised controlledtrialBACKGROUND The case-fatality forintentional self-poisoning in the rural developingworld is 10-50-fold higher than that inindustrialised countries, mostly because of theuse of highly toxic pesticides and plants. Wetherefore aimed to assess whether routinetreatment with multiple-dose activated charcoal,to interrupt enterovascular or enterohepaticcirculations, offers benefit compared with nocharcoal in such an environment. METHODS Wedid an open-label, parallel group, randomised,controlled trial of six 50 g doses of activatedcharcoal at 4-h intervals versus no charcoalversus one 50 g dose of activated charcoal inthree Sri Lankan hospitals. 4632 patients wererandomised to receive no charcoal (n=1554),one dose of charcoal (n=1545), or six doses ofcharcoal (n=1533); outcomes were available for4629 patients. 2338 (51%) individuals hadingested pesticides, whereas 1647 (36%) had", "metadata": {}}
+{"_id": "12217662", "title": "", "text": "Post-prenylation-processing enzymes as newtargets in oncogenesisRAS and many otheroncogenic proteins undergo a complex series ofpost-translational modifications that are initiatedby the addition of an isoprenoid lipid through aprocess known as prenylation. Followingprenylation, these proteins usually undergoendoproteolytic processing by the RCE1 proteaseand then carboxyl methylation by a uniquemethyltransferase known as isoprenylcysteinecarboxyl methyltransferase (ICMT). Althoughinhibitors that have been designed to target theprenylation step are now in advanced-stageclinical trials, their utility and efficacy seem to belimited. Recent findings, however, indicate thatthe inhibition of thesepost-prenylation-processing steps — particularlythat of ICMT-catalysed methylation — mightprovide a better approach to the control ofcancer-cell proliferation.", "metadata": {}}
+{"_id": "12224536", "title": "", "text": "Trends in sugar-sweetened beverageconsumption among youth and adults in theUnited States: 1999-2010.BACKGROUNDReducing sugar-sweetened beverage (SSB)consumption is a recommended strategy topromote optimal health. OBJECTIVE Theobjective was to describe trends in SSBconsumption among youth and adults in theUnited States. DESIGN We analyzed energyintake from SSBs among 22,367 youth aged2-19 y and 29,133 adults aged ≥20 y whoparticipated in a 24-h dietary recall as part ofNHANES, a nationally representative sample ofthe US population with a cross-sectional design,between 1999 and 2010. SSBs included soda,fruit drinks, sports and energy drinks, sweetenedcoffee and tea, and other sweetened beverages.Patterns of SSB consumption, including locationof consumption and meal occasion associatedwith consumption, were also examined. RESULTSIn 2009-2010, youth consumed a mean (±SE) of155 ± 7 kcal/d from SSBs, and adults consumed", "metadata": {}}
+{"_id": "12225214", "title": "", "text": "Ubiquitination on nonlysine residues by a viral E3ubiquitin ligase.Ubiquitination controls a broadrange of cellular functions. The last step of theubiquitination pathway is regulated by enzymetype 3 (E3) ubiquitin ligases. E3 enzymes areresponsible for substrate specificity and catalyzethe formation of an isopeptide bond between alysine residue of the substrate (or the N terminusof the substrate) and ubiquitin. MIR1 and MIR2are two E3 ubiquitin ligases encoded by Kaposi'ssarcoma-associated herpesvirus that mediate theubiquitination of major histocompatibilitycomplex class I (MHC I) molecules andsubsequent internalization. Here, we found thatMIR1, but not MIR2, promoted down-regulationof MHC I molecules lacking lysine residues intheir intracytoplasmic domain. In the presence ofMIR1, these MHC I molecules were ubiquitinated,and their association with ubiquitin was sensitiveto beta2-mercaptoethanol, unlike lysine-ubiquitinbonds. This form of ubiquitination required acysteine residue in the intracytoplasmic tail of", "metadata": {}}
+{"_id": "12232678", "title": "", "text": "All dosage compensation is local: Gene-by-generegulation of sex-biased expression on thechicken Z chromosomeRecent reports havesuggested that birds lack a mechanism ofwholesale dosage compensation for the Z sexchromosome. This discovery was ratherunexpected, as all other animals investigatedwith chromosomal mechanisms of sexdetermination have some method to counteractthe effects of gene dosage of the dominant sexchromosome in males and females. Despite thelack of a global mechanism of avian dosagecompensation, the pattern of gene expressiondifference between males and females varies agreat deal for individual Z-linked genes. Thissuggests that some genes may be individuallydosage compensated, and that someless-than-global pattern of dosagecompensation, such as local or temporal, existson the avian Z chromosome. We used globalgene expression profiling in males and femalesfor both somatic and gonadal tissue at several", "metadata": {}}
+{"_id": "12236208", "title": "", "text": "Hormone replacement therapy prevents boneloss in patients with inflammatory boweldisease.Patients with inflammatory boweldisease have an increased prevalence ofosteoporosis, and suffer high rates of spinal boneloss. Hormone replacement therapy (HRT) iseffective in the treatment and prevention ofosteoporosis but has not been studied in patientswith inflammatory bowel disease. A two yearprospective study of HRT in inflammatory boweldisease was performed in 47 postmenopausalwomen aged 44 to 67 years with ulcerativecolitis (25) or Crohn's disease (22). Patients hadradial and spinal bone density measured annuallyby single photon absorptiometry and quantitativecomputed tomography respectively. The mean(95% confidence intervals) annual change inradial bone density was +1.42%/yr (+0.58 to+2.26; P < 0.005) and for spinal bone+2.60%/yr (+1.06 to +4.15; p < 0.005). Therewas no significant correlation between rates ofchange of bone density at the two sites, or", "metadata": {}}
+{"_id": "12240507", "title": "", "text": "Disruption of the 5S RNP–Mdm2 interactionsignificantly improves the erythroid defect in amouse model for Diamond-BlackfananemiaDiamond-Blackfan anemia (DBA) is acongenital erythroid hypoplasia caused byhaploinsufficiency of genes encoding ribosomalproteins (RPs). Perturbed ribosome biogenesis inDBA has been shown to induce a p53-mediatedribosomal stress response. However, themechanisms of p53 activation and its relevancefor the erythroid defect remain elusive. Previousstudies have indicated that activation of p53 iscaused by the inhibition of mouse double minute2 (Mdm2), the main negative regulator of p53,by the 5S ribonucleoprotein particle (RNP).Meanwhile, it is not clear whether thismechanism solely mediates the p53-dependentcomponent found in DBA. To approach thisquestion, we crossed our mouse model forRPS19-deficient DBA with Mdm2C305F knock-inmice that have a disrupted 5S RNP–Mdm2interaction. Upon induction of the Rps19", "metadata": {}}
+{"_id": "12258338", "title": "", "text": "Pharmacist participation on physician rounds andadverse drug events in the intensive careunit.CONTEXT Pharmacist review of medicationorders in the intensive care unit (ICU) has beenshown to prevent errors, and pharmacistconsultation has reduced drug costs. However,whether pharmacist participation in the ICU atthe time of drug prescribing reduces adverseevents has not been studied. OBJECTIVE Tomeasure the effect of pharmacist participation onmedical rounds in the ICU on the rate ofpreventable adverse drug events (ADEs) causedby ordering errors. DESIGN Before-aftercomparison between phase 1 (baseline) andphase 2 (after intervention implemented) andphase 2 comparison with a control unit that didnot receive the intervention. SETTING A medicalICU (study unit) and a coronary care unit(control unit) in a large urban teaching hospital.PATIENTS Seventy-five patients randomlyselected from each of 3 groups: all admissions tothe study unit from February 1, 1993, through", "metadata": {}}
+{"_id": "12265561", "title": "", "text": "Ligand-target interactions: what can we learnfrom NMR?The conformation of the ligand incomplex with a macromolecular target can bestudied by nuclear magnetic resonance (NMR) insolution for both tightly and weakly formingcomplexes. In the weak binding regime (k(off) >10(4) Hz), the structure of the bound ligand isaccessible also for very large complexes (>100kDa), which are not amenable to NMR studies inthe tight binding regime. Here I review thestate-of-the-art NMR methodology used forscreening ligands and for the structuralinvestigation of bound ligand conformations, inboth tight and weak binding regimes. Theadvantages and disadvantages of each approachare critically described. The NMR methodologyused to investigate transiently formingcomplexes has expanded considerably in thepast few years, opening new possibilities for adetailed description of ligand-target interactions.Novel methods for the determination of thebound ligand conformation, in particular", "metadata": {}}
+{"_id": "12271486", "title": "", "text": "MotifMap: integrative genome-wide maps ofregulatory motif sites for modelspeciesBACKGROUND A central challenge ofbiology is to map and understand generegulation on a genome-wide scale. For anygiven genome, only a small fraction of theregulatory elements embedded in the DNAsequence have been characterized, and there isgreat interest in developing computationalmethods to systematically map all theseelements and understand their relationships.Such computational efforts, however, aresignificantly hindered by the overwhelming sizeof non-coding regions and the statisticalvariability and complex spatial organizations ofregulatory elements and interactions.Genome-wide catalogs of regulatory elements forall model species simply do not yet exist.RESULTS The MotifMap system uses databasesof transcription factor binding motifs, refinedgenome alignments, and a comparative genomicstatistical approach to provide comprehensive", "metadata": {}}
+{"_id": "12280462", "title": "", "text": "Inhibition of apical sodium-dependent bile acidtransporter as a novel treatment fordiabetes.Bile acids are recognized as metabolicmodulators. The present study was aimed atevaluating the effects of a potent Asbt inhibitor(264W94), which blocks intestinal absorption ofbile acids, on glucose homeostasis in ZuckerDiabetic Fatty (ZDF) rats. Oral administration of264W94 for two wk increased fecal bile acidconcentrations and elevated non-fasting plasmatotal Glp-1. Treatment of 264W94 significantlydecreased HbA1c and glucose, and prevented thedrop of insulin levels typical of ZDF rats in adose-dependent manner. An oral glucosetolerance test revealed up to two-fold increase inplasma total Glp-1 and three-fold increase ininsulin in 264W94 treated ZDF rats at dosessufficient to achieve glycemic control. TissuemRNA analysis indicated a decrease in farnesoidX receptor (Fxr) activation in small intestines andthe liver but co-administration of a Fxr agonist(GW4064) did not attenuate 264W94 induced", "metadata": {}}
+{"_id": "12315072", "title": "", "text": "Early chromatin unfolding by RUNX1: amolecular explanation for differentialrequirements during specification versusmaintenance of the hematopoietic geneexpression program.At the cellular level,development progresses through successiveregulatory states, each characterized by theirspecific gene expression profile. However, themolecular mechanisms regulating first thepriming and then maintenance of geneexpression within one developmental pathwayare essentially unknown. The hematopoieticsystem represents a powerful experimentalmodel to address these questions and here wehave focused on a regulatory circuit playing acentral role in myelopoiesis: the transcriptionfactor PU.1, its target genecolony-stimulating-factor 1 receptor (Csf1r), andkey upstream regulators such as RUNX1. We findthat during ontogeny, chromatin unfoldingprecedes the establishment of active histonemarks and the formation of stable transcription", "metadata": {}}
+{"_id": "12324049", "title": "", "text": "Whole-genome fingerprint of the DNAmethylome during human B celldifferentiationWe analyzed the DNA methylomeof ten subpopulations spanning the entire B celldifferentiation program by whole-genomebisulfite sequencing and high-densitymicroarrays. We observed that non-CpGmethylation disappeared upon B cellcommitment, whereas CpG methylation changedextensively during B cell maturation, showing anaccumulative pattern and affecting around 30%of all measured CpG sites. Early differentiationstages mainly displayed enhancer demethylation,which was associated with upregulation of key Bcell transcription factors and affected multiplegenes involved in B cell biology. Latedifferentiation stages, in contrast, showedextensive demethylation of heterochromatin andmethylation gain at Polycomb-repressed areas,and genes with apparent functional impact in Bcells were not affected. This signature, which haspreviously been linked to aging and cancer, was", "metadata": {}}
+{"_id": "12337611", "title": "", "text": "LIN28B induces neuroblastoma and enhancesMYCN levels via let-7 suppressionLIN28Bregulates developmental processes bymodulating microRNAs (miRNAs) of the let-7family. A role for LIN28B in cancer has beenproposed but has not been established in vivo.Here, we report that LIN28B showed genomicaberrations and extensive overexpression inhigh-risk neuroblastoma compared to severalother tumor entities and normal tissues. HighLIN28B expression was an independent riskfactor for adverse outcome in neuroblastoma.LIN28B signaled through repression of the let-7miRNAs and consequently resulted in elevatedMYCN protein expression in neuroblastoma cells.LIN28B–let-7–MYCN signaling blockeddifferentiation of normal neuroblasts andneuroblastoma cells. These findings were fullyrecapitulated in a mouse model in which LIN28Bexpression in the sympathetic adrenergic lineageinduced development of neuroblastomas markedby low let-7 miRNA levels and high MYCN protein", "metadata": {}}
+{"_id": "12358173", "title": "", "text": "Platelet-derived endothelial cell growth factorexpression correlates with tumour angiogenesisand prognosis in non-small-cell lungcancer.Angiogenesis is a recently describedprognostic factor in non-small-cell lung cancer.Platelet-derived endothelial cell growth factor(PD-ECGF), shown to be the enzyme thymidinephosphorylase (TP), induces angiogenesis invitro and in vivo. High intracellular levels of theenzyme are associated with increasedchemosensitivity to pyrimidine antimetabolites.PD-ECGF/TP expression was evaluatedimmunohistochemically in surgically resectedspecimens from 107 patients with operablenon-small-cell lung cancer using the P-GF,44Cmonoclonal antibody. High expression ofPD-ECGF/TP was found in 25% of cases and wasassociated with high vascular grade (P = 0.01).Fourteen of 32 (44%) high vascular gradetumours showed a positive reactivity forPD-ECGF/TP vs 13/75 (17%) of low/mediumvascular grade. Positive expression was observed", "metadata": {}}
+{"_id": "12364109", "title": "", "text": "The association between psychological distanceand construal level: evidence from an implicitassociation test.According to construal leveltheory (N. Liberman, Y. Trope, & E. Stephan, inpress; Y. Trope & N. Liberman, 2003), peopleuse a more abstract, high construal level whenjudging, perceiving, and predicting morepsychologically distal targets, and they judgemore abstract targets as being morepsychologically distal. The present researchdemonstrated that associations between moredistance and higher level of construal also existon a pure conceptual level. Eight experimentsused the Implicit Association Test (IAT; A. G.Greenwald, D. E. McGhee, & J. L. K. Schwartz,1998) to demonstrate an association betweenwords related to construal level (low vs. high)and words related to four dimensions of distance(proximal vs. distal): temporal distance, spatialdistance, social distance, and hypotheticality. Inaddition to demonstrating an associationbetween level of construal and psychological", "metadata": {}}
+{"_id": "12370190", "title": "", "text": "A load driver device for engineering modularity inbiological networksThe behavior of gene modulesin complex synthetic circuits is oftenunpredictable. After joining modules to create acircuit, downstream elements (such as bindingsites for a regulatory protein) apply a load toupstream modules that can negatively affectcircuit function. Here we devised a genetic devicenamed a load driver that mitigates the impact ofload on circuit function, and we demonstrate itsbehavior in Saccharomyces cerevisiae. The loaddriver implements the design principle oftimescale separation: inclusion of the loaddriver's fast phosphotransfer processes restoresthe capability of a slower transcriptional circuit torespond to time-varying input signals even in thepresence of substantial load. Without the loaddriver, we observed circuit behavior that sufferedfrom a 76% delay in response time and a 25%decrease in system bandwidth due to load. Withthe addition of a load driver, circuit performancewas almost completely restored. Load drivers will", "metadata": {}}
+{"_id": "12370881", "title": "", "text": "Inflammatory monocyte/macrophage modulationby liposome-entrapped spironolactoneameliorates acute lung injury in mice.AIM Toexamine the therapeutic/preventive potential ofliposome-encapsulated spironolactone (SP;Lipo-SP) for acute lung injury (ALI) and fibrosis.MATERIALS & METHODS Lipo-SP was preparedby the film-ultrasonic method, andphysicochemical and pharmacokineticcharacterized for oral administration (10 and 20mg/kg for SP-loaded liposome; 20 mg/kg for freeSP) in a mouse model bleomycin-induced ALI.RESULTS Lipo-SP enhanced bioavailability of SPwith significant amelioration in lung pathology.Mechanistically, SP-mediated mineralocorticoidreceptor antagonism contributes to inflammatorymonocyte/macrophage modulation via aninhibitory effect on Ly6C(hi)monocytosis-directed M2 polarization of alveolarmacrophages. Moreover, Lipo-SP at lower dose(10 mg/kg) exhibited more improvement in bodyweight gain. CONCLUSION Our data highlight", "metadata": {}}
+{"_id": "12383365", "title": "", "text": "Passive Surveillance for I. scapularis Ticks:Enhanced Analysis for Early Detection ofEmerging Lyme Disease RiskABSTRACT Lymedisease (LD) is emerging in Canada because ofthe northward expansion of the geographic rangeof the tick vector Ixodes scapularis (Say). Earlydetection of emerging areas of LD risk is criticalto public health responses, but the methods todo so on a local scale are lacking. Passive ticksurveillance has operated in Canada since 1990but this method lacks specificity for identifyingareas where tick populations are establishedbecause of dispersion of ticks from establishedLD risk areas by migratory birds. Using data from70 field sites in Quebec visited previously, wedeveloped a logistic regression model forestimating the risk of I. scapularis populationestablishment based on the number of tickssubmitted in passive surveillance and amodel-derived environmental suitability index.Sensitivity-specificity plots were used to selectan optimal threshold value of the linear predictor", "metadata": {}}
+{"_id": "12409683", "title": "", "text": "Reduction of transmission from malaria patientsby artemisinin combination therapies: a pooledanalysis of six randomized trialsBACKGROUNDArtemisinin combination therapies (ACT), whichare increasingly being introduced for treatmentof Plasmodium falciparum malaria, are moreeffective against sexual stage parasites(gametocytes) than previous first-lineantimalarials and therefore have the potential toreduce parasite transmission. The size of thiseffect is estimated in symptomatic P. falciparuminfections. METHODS Data on 3,174 patientswere pooled from six antimalarial trialsconducted in The Gambia and Kenya.Multivariable regression was used to investigatethe role of ACT versus non-artemisininantimalarial treatment, treatment failure,presence of pre-treatment gametocytes andsubmicroscopic gametocytaemia on transmissionto mosquitoes and the area under the curve(AUC) of gametocyte density during the 28 daysof follow up. RESULTS ACT treatment was", "metadata": {}}
+{"_id": "12411274", "title": "", "text": "Skeletal Myogenic Progenitors Originating fromEmbryonic Dorsal Aorta Coexpress Endothelialand Myogenic Markers and Contribute toPostnatal Muscle Growth andRegenerationSkeletal muscle in vertebrates isderived from somites, epithelial structures of theparaxial mesoderm, yet many unrelated reportsdescribe the occasional appearance of myogeniccells from tissues of nonsomite origin, suggestingeither transdifferentiation or the persistence of amultipotent progenitor. Here, we show thatclonable skeletal myogenic cells are present inthe embryonic dorsal aorta of mouse embryos.This finding is based on a detailed clonal analysisof different tissue anlagen at variousdevelopmental stages. In vitro, these myogeniccells show the same morphology as satellite cellsderived from adult skeletal muscle, and expressa number of myogenic and endothelial markers.Surprisingly, the latter are also expressed byadult satellite cells. Furthermore, it is possible toclone myogenic cells from limbs of mutant", "metadata": {}}
+{"_id": "12428137", "title": "", "text": "Mapping of a gene for severe pediatricgastroesophageal reflux to chromosome13q14.CONTEXT Gastroesophageal reflux (GER)has not previously been widely regarded as ahereditary disease. A few reports havesuggested, however, that a genetic componentmay contribute to the incidence of GER,especially in its severe or chronic forms.OBJECTIVE To identify a genetic locus thatcosegregates with a severe pediatric GERphenotype in families with multiple affectedmembers. DESIGN A genome-wide scan offamilies affected by severe pediatric GER usingpolymorphic microsatellite markers spaced at anaverage of 8 centimorgans (cM), followed byhaplotyping and by pairwise and multipointlinkage analyses. SETTING General UScommunity, with research performed in auniversity tertiary care hospital. SUBJECTSAffected and unaffected family members from 5families having multiple individuals affected bysevere pediatric GER, identified through a patient", "metadata": {}}
+{"_id": "12428497", "title": "", "text": "Accelerating Policy Decisions to AdoptHaemophilus influenzae Type b Vaccine: AGlobal, Multivariable AnalysisBACKGROUNDAdoption of new and underutilized vaccines bynational immunization programs is an essentialstep towards reducing child mortality. Policydecisions to adopt new vaccines in high mortalitycountries often lag behind decisions inhigh-income countries. Using the case ofHaemophilus influenzae type b (Hib) vaccine,this paper endeavors to explain these delaysthrough the analysis of country-level economic,epidemiological, programmatic and policy-relatedfactors, as well as the role of the Global Alliancefor Vaccines and Immunisation (GAVI Alliance).METHODS AND FINDINGS Data for 147 countriesfrom 1990 to 2007 were analyzed in acceleratedfailure time models to identify factors that areassociated with the time to decision to adopt Hibvaccine. In multivariable models that control forGross National Income, region, and burden ofHib disease, the receipt of GAVI support speeded", "metadata": {}}
+{"_id": "12428814", "title": "", "text": "Haemolysin coregulated protein is an exportedreceptor and chaperone of type VI secretionsubstrates.Secretion systems requirehigh-fidelity mechanisms to discriminatesubstrates among the vast cytoplasmic pool ofproteins. Factors mediating substrate recognitionby the type VI secretion system (T6SS) ofGram-negative bacteria, a widespread pathwaythat translocates effector proteins into targetbacterial cells, have not been defined. We reportthat haemolysin coregulated protein (Hcp), aring-shaped hexamer secreted by allcharacterized T6SSs, binds specifically tocognate effector molecules. Electron microscopyanalysis of an Hcp-effector complex fromPseudomonas aeruginosa revealed the effectorbound to the inner surface of Hcp. Furtherstudies demonstrated that interaction with theHcp pore is a general requirement for secretionof diverse effectors encompassing severalenzymatic classes. Though previous modelsdepict Hcp as a static conduit, our data indicate it", "metadata": {}}
+{"_id": "12438901", "title": "", "text": "Long-term effects of continuing adjuvanttamoxifen to 10 years versus stopping at 5 yearsafter diagnosis of oestrogen receptor-positivebreast cancer: ATLAS, a randomisedtrialBACKGROUND For women with oestrogenreceptor (ER)-positive early breast cancer,treatment with tamoxifen for 5 yearssubstantially reduces the breast cancer mortalityrate throughout the first 15 years afterdiagnosis. We aimed to assess the further effectsof continuing tamoxifen to 10 years instead ofstopping at 5 years. METHODS In the worldwideAdjuvant Tamoxifen: Longer Against Shorter(ATLAS) trial, 12,894 women with early breastcancer who had completed 5 years of treatmentwith tamoxifen were randomly allocated tocontinue tamoxifen to 10 years or stop at 5 years(open control). Allocation (1:1) was by centralcomputer, using minimisation. After entry(between 1996 and 2005), yearly follow-upforms recorded any recurrence, second cancer,hospital admission, or death. We report effects", "metadata": {}}
+{"_id": "12440953", "title": "", "text": "Roles for MicroRNAs in Conferring Robustness toBiological ProcessesBiological systems use avariety of mechanisms to maintain theirfunctions in the face of environmental andgenetic perturbations. Increasing evidencesuggests that, among their roles asposttranscriptional repressors of geneexpression, microRNAs (miRNAs) help to conferrobustness to biological processes by reinforcingtranscriptional programs and attenuatingaberrant transcripts, and they may in somenetwork contexts help suppress randomfluctuations in transcript copy number. Theseactivities have important consequences fornormal development and physiology, disease,and evolution. Here, we will discuss examplesand principles of miRNAs that contribute torobustness in animal systems.", "metadata": {}}
+{"_id": "12442311", "title": "", "text": "Six-Year Follow-Up of Impact of Co-proxamolWithdrawal in England and Wales on Prescribingand Deaths: Time-Series StudyBACKGROUNDThe analgesic co-proxamol(paracetamol/dextropropoxyphene combination)has been widely involved in fatal poisoning.Concerns about its safety/effectiveness profileand widespread use for suicidal poisoningprompted its withdrawal in the UK in 2005, withpartial withdrawal between 2005 and 2007, andfull withdrawal in 2008. Our objective in thisstudy was to assess the association betweenco-proxamol withdrawal and prescribing anddeaths in England and Wales in 2005-2010compared with 1998-2004, including estimationof possible substitution effects by otheranalgesics. METHODS AND FINDINGS Weobtained prescribing data from the NHS Healthand Social Care Information Centre (England)and Prescribing Services PartneriaethCydwasanaethau GIG Cymru (Wales), andmortality data from the Office for National", "metadata": {}}
+{"_id": "12443371", "title": "", "text": "Apolipoprotein E genotype and concussion incollege athletes.OBJECTIVE To evaluate theassociation between apolipoprotein E (APOE)polymorphisms (E2, C/T Arg158Cys; E4, T/CCys112Arg; and promoter, g-219t) and thehistory of concussion in college athletes. Wehypothesized that carrying 1 or more APOE rare(or minor) allele assessed in this study would beassociated with having a history of 1 or moreconcussions. DESIGN Multicenter cross-sectionalstudy. SETTING University athletic facilities.PARTICIPANTS One hundred ninety-six malefootball (n = 163) and female soccer (n = 33)college athletes volunteered. INTERVENTIONSWritten concussion history questionnaire andsaliva samples for genotyping. MAIN OUTCOMEMEASURES Self-reported history of adocumented concussion and rare APOE genotype(E2, E4, promoter). RESULTS There was asignificant association (Wald χ² = 3.82; P =0.05; odds ratio = 9.8) between carrying allAPOE rare alleles and the history of a previous", "metadata": {}}
+{"_id": "12451492", "title": "", "text": "Plasma soluble corin and N-terminal pro-atrialnatriuretic peptide levels in pregnancy inducedhypertension.OBJECTIVE One of the theoriesinvolved in the pathogenesis of pregnancyinduced hypertension involves salt and waterretention. We aimed to measure the proenzymeconvertase corin, responsible for pro-atrialnatriuretic peptide (ANP) cleavage to active ANP,in plasma of hypertensive pregnant females.STUDY DESIGN Sixty pregnant females sufferingfrom pregnancy induced hypertension in secondand third trimesters of pregnancy werecompared to twenty eight healthy pregnantfemales of the same gestational period.Concomitant urine and plasma samples werecollected for the determination of somebiochemical parameters. Plasma soluble corinand N-terminal (NT) pro-ANP (1-98) values weredetermined in both groups using enzymeimmunoassays. RESULTS Plasma soluble corinmean value was significantly higher in thepatient group compared to the control group.", "metadata": {}}
+{"_id": "12462961", "title": "", "text": "GATA-4 and GATA-6 modulate tissue-specifictranscription of the human gene for P450c17 bydirect interaction with Sp1.Cytochrome P450c17catalyzes steroidogenic 17alpha-hydroxylase and17,20 lyase activities. Expression of the gene forP450c17 is cAMP dependent, tissue specific,developmentally programmed, and varies amongspecies. Binding of Sp1, Sp3, and NF1-C (nuclearfactor 1-C) to the first 227 bp of 5'flanking DNA(-227/LUC) is crucial for basal transcription inhuman NCI-H295A adrenal cells. Humanplacental JEG-3 cells contain Sp1, Sp3, and NF1,but do not express -227/LUC, even whentransfected with a vector expressingsteroidogenic factor 1 (SF-1). Therefore, otherfactors are essential for basal expression ofP450c17. Deoxyribonuclease I footprinting andEMSAs identified a GATA consensus site at-64/-58 and an SF-1 site at -58/-50. RT-PCRidentified GATA-4, GATA-6, and SF-1 inNCI-H295A cells and GATA-2 and GATA-3, butnot GATA-4, GATA-6, or SF-1 in JEG-3 cells.", "metadata": {}}
+{"_id": "12470783", "title": "", "text": "Performance of an abbreviated version of theLubben Social Network Scale among threeEuropean community-dwelling older adultpopulations.PURPOSE There is a need for validand reliable short scales that can be used toassess social networks and social supports and toscreen for social isolation in older persons.DESIGN AND METHODS The present study is across-national and cross-cultural evaluation ofthe performance of an abbreviated version of theLubben Social Network Scale (LSNS-6), whichwas used to screen for social isolation amongcommunity-dwelling older adult populations inthree European countries. Based on the conceptof lack of redundancy of social ties we definedclinical cut-points of the LSNS-6 for identifyingpersons deemed at risk for social isolation.RESULTS Among all three samples, the LSNS-6and two subscales (Family and Friends)demonstrated high levels of internal consistency,stable factor structures, and high correlationswith criterion variables. The proposed clinical", "metadata": {}}
+{"_id": "12471115", "title": "", "text": "The PneuCarriage Project: A Multi-CentreComparative Study to Identify the BestSerotyping Methods for Examining PneumococcalCarriage in Vaccine EvaluationStudiesBACKGROUND The pneumococcus is adiverse pathogen whose primary niche is thenasopharynx. Over 90 different serotypes exist,and nasopharyngeal carriage of multipleserotypes is common. Understandingpneumococcal carriage is essential for evaluatingthe impact of pneumococcal vaccines. Traditionalserotyping methods are cumbersome andinsufficient for detecting multiple serotypecarriage, and there are few data comparing thenew methods that have been developed over thepast decade. We established the PneuCarriageproject, a large, international multi-centre studydedicated to the identification of the bestpneumococcal serotyping methods for carriagestudies. METHODS AND FINDINGS Referencesample sets were distributed to 15 researchgroups for blinded testing. Twenty pneumococcal", "metadata": {}}
+{"_id": "12486491", "title": "", "text": "Ribosome-Mediated Specificity in Hox mRNATranslation and Vertebrate TissuePatterningHistorically, the ribosome has beenviewed as a complex ribozyme with constitutiverather than regulatory capacity in mRNAtranslation. Here we identify mutations of theRibosomal Protein L38 (Rpl38) gene in miceexhibiting surprising tissue-specific patterningdefects, including pronounced homeotictransformations of the axial skeleton. In Rpl38mutant embryos, global protein synthesis isunchanged; however the translation of a selectsubset of Homeobox mRNAs is perturbed. Ourdata reveal that RPL38 facilitates 80S complexformation on these mRNAs as a regulatorycomponent of the ribosome to confertranscript-specific translational control. Wefurther show that Rpl38 expression is markedlyenriched in regions of the embryo whereloss-of-function phenotypes occur. Unexpectedly,a ribosomal protein (RP) expression screenreveals dynamic regulation of individual RPs", "metadata": {}}
+{"_id": "12489130", "title": "", "text": "Growth and invasion of human melanomas inhuman skin grafted to immunodeficient mice.Anorthotopic model of human melanoma wasdeveloped in which malignant cells were injectedinto human skin grafted to nude and SCID mice.Melanoma cells proliferated and invaded thehuman skin grafts with characteristic patterns.Three of six melanomas grew as multiple nodulesand infiltered the grafts without majorarchitectural changes in the dermis, whereas theothers invaded the dermis along collagen fiberswith prominent endothelial vessels. By contrast,melanoma cells inoculated into mouse skin grewas diffusely expanding nodules that did notinvade the murine dermis. In human skin grafts,human melanoma cells were angiogenic forhuman blood vessels, and murine vessels wereonly found at the periphery of grafts. Tumor cellsinvaded the human vessels, and four out ofseven cell lines metastasized to lungs,suggesting that this model is useful to determinein vivo the interactions between normal and", "metadata": {}}
+{"_id": "12489688", "title": "", "text": "Myeloperoxidase: friend and foe.Neutrophilicpolymorphonuclear leukocytes (neutrophils) arehighly specialized for their primary function, thephagocytosis and destruction of microorganisms.When coated with opsonins (generallycomplement and/or antibody), microorganismsbind to specific receptors on the surface of thephagocyte and invagination of the cell membraneoccurs with the incorporation of themicroorganism into an intracellular phagosome.There follows a burst of oxygen consumption,and much, if not all, of the extra oxygenconsumed is converted to highly reactive oxygenspecies. In addition, the cytoplasmic granulesdischarge their contents into the phagosome,and death of the ingested microorganism soonfollows. Among the antimicrobial systems formedin the phagosome is one consisting ofmyeloperoxidase (MPO), released into thephagosome during the degranulation process,hydrogen peroxide (H2O2), formed by therespiratory burst and a halide, particularly", "metadata": {}}
+{"_id": "12513042", "title": "", "text": "Role of microsomal prostaglandin E synthase-1 inthe facilitation of angiogenesis and the healing ofgastric ulcers.The importance of prostaglandinE(2) in various pathophysiological eventsemphasizes the necessity of understanding therole of PGE synthases (PGESs) in vivo. However,there has been no report on the functionalrelevance of microsomal PGES-1 (mPGES-1) tothe physiological healing processes of gastriculcers, or to angiogenesis, which is indispensableto the healing processes. In this report, wetested whether mPGES-1 plays a role in thehealing of gastric ulcers and in the enhancementof angiogenesis using mPGES-1 knockout mice(mPGES-1 KO mice) and their wild-type (WT)counterparts. Gastric ulcers were induced by theserosal application of 100% acetic acid, and theareas of the ulcers were measured thereafter.mPGES-1 together with cyclooxygenase-2 wereinduced in the granulation tissues compared withnormal stomach tissues. The healing of aceticacid-induced ulcers was significantly delayed in", "metadata": {}}
+{"_id": "12513972", "title": "", "text": "Echocardiographic Evidence of Innate Aortopathyin the Human IntracranialAneurysmBACKGROUND Intracranial aneurysm(IA) is significantly more prevalent in patientswith coarctation of the aorta or bicuspid aorticvalve than in the general population, suggestinga common pathophysiology connecting IA andaortopathy. Here, we analyzed echocardiographicaortic root dimension (ARD) in patients with IAto confirm this possibility. METHODS FromJanuary 2008 to December 2010, 260consecutive patients with IA who were admittedto our institution for coil embolization or foracute stroke management and who alsounderwent echocardiography were enrolled. Wehypothesized that patients with large, ruptured,or multiple IAs are more likely to harborco-prevalent aortopathy as measured by ARDcompared to patients with small, isolated,unruptured IAs. Eccentric group was defined aspatients aged <55 years with at least oneruptured aneurysm, an aneurysm ≥7 mm in size,", "metadata": {}}
+{"_id": "12549585", "title": "", "text": "Aortic and large artery compliance in end-stagerenal failure.Pulse wave velocity (PWV) wasmeasured in the aorta, right leg and arm of 90control subjects (CS) and 92 hemodialysispatients (HD) of the same age and mean arterialpressure (MAP). Blood chemistry, including bloodlipids, and echographic dimensions of the aorta,were measured in all subjects. Presence of aorticcalcification was evaluated by abdominal X-rayand echography. Whereas femoral and brachialPWV were only slightly increased in HD (P lessthan 0.05), the aortic PWV was significantlyelevated (1113 +/- 319 cm/sec) in comparisonwith CS (965 +/- 216 cm/sec; P = 0.0016).Aortic diameters were larger in HD, both at theroot of aorta (32.7 +/- 4 vs. 28.2 +/- 2.8 mm; Pless than 0.0001) and aortic bifurcation (16.9+/- 3.1 vs. 14.6 +/- 2.2 mm; P less than0.0001). Although the MAP was similar in HD(109.9 +/- 19.3 mm Hg) and CS (110.2 +/- 17.2mm Hg), the pulse pressure was significantlyincreased in HD patients (76.6 +/- 23.7 vs. 63.9", "metadata": {}}
+{"_id": "12552297", "title": "", "text": "The DNA polymerase λ is required for the repairof non-compatible DNA double strand breaks byNHEJ in mammalian cellsDNA polymeraselambda (polλ) is a recently identified DNApolymerase whose cellular function remainselusive. Here we show, that polλ participates atthe molecular level in a chromosomal context, inthe repair of DNA double strand breaks (DSB) vianon-homologous end joining (NHEJ) inmammalian cells. The expression of acatalytically inactive form of polλ (polλDN)decreases the frequency of NHEJ events inresponse to I-Sce-I-induced DSB whereasinactivated forms of its homologues polβ andpolμ do not. Only events requiring DNA endprocessing before ligation are affected; thisdefect is associated with large deletions arisingin the vicinity of the induced DSB. Furthermore,polλDN-expressing cells exhibit increasedsensitization and genomic instability in responseto ionizing radiation similar to that ofNHEJ-defective cells. Our data support a", "metadata": {}}
+{"_id": "12561083", "title": "", "text": "Angina with \"normal\" coronary arteries: sexdifferences in outcomes.BACKGROUND Severalstudies have demonstrated that women withnonobstructive coronary disease have a high rateof subsequent investigations, rehospitalizationsfor recurrent chest pain, and repeat coronaryangiography. The sex specificity of this finding isunclear. We therefore undertook an evaluation ofsex differences in rehospitalization for acutecoronary syndrome (ACS) or chest pain inpatients with \"angiographically normal\"coronaries. METHODS A retrospective cohortstudy using prospectively collected angiographicand clinical data on all patients in BritishColumbia, Canada, presenting for their firstcardiac catheterization with suspected ischemicheart disease but angiographically normalcoronaries. RESULTS Among 32,856 patients,7.1% of men versus 23.3% of women wereangiographically normal (P < .001). Amongangiographically normal patients, women wereolder and more likely to present with", "metadata": {}}
+{"_id": "12580014", "title": "", "text": "Keratin-dependent regulation of Aire and geneexpression in skin tumor keratinocytesExpressionof the intermediate filament protein keratin 17(K17) is robustly upregulated in inflammatoryskin diseases and in many tumors originating instratified and pseudostratified epithelia. Wereport that autoimmune regulator (Aire), atranscriptional regulator, is inducibly expressedin human and mouse tumor keratinocytes in aK17-dependent manner and is required fortimely onset of Gli2-induced skin tumorigenesisin mice. The induction of Aire mRNA inkeratinocytes depends on a functional interactionbetween K17 and the heterogeneous nuclearribonucleoprotein hnRNP K. Further, K17colocalizes with Aire protein in the nucleus oftumor-prone keratinocytes, and each factor isbound to a specific promoter region featuring anNF-κB consensus sequence in a relevant subsetof K17- and Aire-dependent proinflammatorygenes. These findings provide radically newinsight into keratin intermediate filament and", "metadata": {}}
+{"_id": "12582729", "title": "", "text": "Flow-Dependent Regulation of Kruppel-LikeFactor 2 Is Mediated byMicroRNA-92a.BACKGROUND Upregulated byatheroprotective flow, the transcription factorKrüppel-like factor 2 (KLF2) is crucial formaintaining endothelial function. MicroRNAs(miRNAs) are noncoding small RNAs thatregulate gene expression at theposttranscriptional level. We examined the roleof miRNAs, particularly miR-92a, in theatheroprotective flow-regulated KLF2. METHODSAND RESULTS Dicer knockdown increased thelevel of KLF2 mRNA in human umbilical veinendothelial cells, suggesting that KLF2 isregulated by miRNA. In silico analysis predictedthat miR-92a could bind to the 3' untranslatedregion of KLF2 mRNA. Overexpression ofmiR-92a decreased the expression of KLF2 andthe KLF2-regulated endothelial nitric oxidesynthase and thrombomodulin at mRNA andprotein levels. A complementary finding is thatmiR-92a inhibitor increased the mRNA and", "metadata": {}}
+{"_id": "12584053", "title": "", "text": "Effectiveness of a diabetes education and selfmanagement programme (DESMOND) for peoplewith newly diagnosed type 2 diabetes mellitus:three year follow-up of a cluster randomisedcontrolled trial in primary careOBJECTIVE Tomeasure whether the benefits of a singleeducation and self management structuredprogramme for people with newly diagnosedtype 2 diabetes mellitus are sustained at threeyears. DESIGN Three year follow-up of amulticentre cluster randomised controlled trial inprimary care, with randomisation at practicelevel. SETTING 207 general practices in 13primary care sites in the United Kingdom.PARTICIPANTS 731 of the 824 participantsincluded in the original trial were eligible forfollow-up. Biomedical data were collected on 604(82.6%) and questionnaire data on 513 (70.1%)participants. INTERVENTION A structured groupeducation programme for six hours delivered inthe community by two trained healthcareprofessional educators compared with usual care.", "metadata": {}}
+{"_id": "12588500", "title": "", "text": "Acetylation of Histone H3 Lysine 56 RegulatesReplication-Coupled NucleosomeAssemblyChromatin assembly factor 1 (CAF-1)and Rtt106 participate in the deposition of newlysynthesized histones onto replicating DNA toform nucleosomes. This process is critical for themaintenance of genome stability and inheritanceof functionally specialized chromatin structures inproliferating cells. However, the molecularfunctions of the acetylation of newly synthesizedhistones in this DNA replication-couplednucleosome assembly pathway remainenigmatic. Here we show that histone H3acetylated at lysine 56 (H3K56Ac) isincorporated onto replicating DNA and, byincreasing the binding affinity of CAF-1 andRtt106 for histone H3, H3K56Ac enhances theability of these histone chaperones to assembleDNA into nucleosomes. Genetic analysis indicatesthat H3K56Ac acts in a nonredundant mannerwith the acetylation of the N-terminal residues ofH3 and H4 in nucleosome assembly. These", "metadata": {}}
+{"_id": "12622860", "title": "", "text": "Selective inhibition of Ras-dependent cell growthby farnesylthiosalisylicacid.S-trans,trans-Farnesylthiosalicylic acid(FTS) is a novel farnesylated rigid carboxylic acidderivative. In cell-free systems, it acts as apotent competitive inhibitor (Ki = 2.6 microM) ofthe enzyme prenylated proteinmethyltransferase (PPMTase), which methylatesthe carboxyl-terminal S-prenylcysteine in a largenumber of prenylated proteins including Ras. Insuch systems, FTS inhibits Ras methylation butnot Ras farnesylation. Inhibition of the PPMTaseby FTS in homogenates or membranes of avariety of tissues and cell lines is inferred from ablock in the methylation of exogenously addedsubstrates such asN-acetyl-S-trans,trans-farnesyl-L-cysteine and ofendogenous substrates including smallGTP-binding proteins. FTS can also inhibitmethylation of these proteins in intact cells (e.g.in Rat-1 fibroblasts, Ras-transformed Rat-1, andB16 melanoma cells). Unlike in cell-free systems,", "metadata": {}}
+{"_id": "12631182", "title": "", "text": "NADPH oxidase controls phagosomal pH andantigen cross-presentation in human dendriticcells.The phagocyte NADPH oxidase (NOX2) iscritical for the bactericidal activity of phagocyticcells and plays a major role in innate immunity.We showed recently that NOX2 activity in mousedendritic cells (DCs) prevents acidification ofphagosomes, promoting antigencross-presentation. In order to investigate therole of NOX2 in the regulation of the phagosomalpH in human DCs, we analyzed the production ofreactive oxygen species (ROS) and thephagosomal/endosomal pH in monocyte-derivedDCs and macrophages (M(diameter)s) fromhealthy donors or patients with chronicgranulomatous disease (CGD). As expected, wefound that human M(diameter)s acidify theirphagosomes more efficiently than human DCs.Accordingly, the expression of the vacuolarproton ATPase (V-H(+)-ATPase) was higher inM(diameter)s than in DCs. Phagosomal ROSproduction, however, was also higher in", "metadata": {}}
+{"_id": "12631697", "title": "", "text": "Activation of fast skeletal muscle troponin as apotential therapeutic approach for treatingneuromuscular diseasesLimited neural inputresults in muscle weakness in neuromusculardisease because of a reduction in the density ofmuscle innervation, the rate of neuromuscularjunction activation or the efficiency of synaptictransmission. We developed a small-moleculefast-skeletal-troponin activator, CK-2017357, asa means to increase muscle strength byamplifying the response of muscle when neuralinput is otherwise diminished secondary toneuromuscular disease. Binding selectively to thefast-skeletal-troponin complex, CK-2017357slows the rate of calcium release from troponin Cand sensitizes muscle to calcium. As aconsequence, the force-calcium relationship ofmuscle fibers shifts leftwards, as does theforce-frequency relationship of a nerve-musclepair, so that CK-2017357 increases theproduction of muscle force in situ atsub-maximal nerve stimulation rates. Notably,", "metadata": {}}
+{"_id": "12640810", "title": "", "text": "Cortactin regulates cofilin and N-WASp activitiesto control the stages of invadopodium assemblyand maturationInvadopodia arematrix-degrading membrane protrusions ininvasive carcinoma cells. The mechanismsregulating invadopodium assembly andmaturation are not understood. We havedissected the stages of invadopodium assemblyand maturation and show that invadopodia usecortactin phosphorylation as a master switchduring these processes. In particular, cortactinphosphorylation was found to regulate cofilin andArp2/3 complex-dependent actin polymerization.Cortactin directly binds cofilin and inhibits itssevering activity. Cortactin phosphorylation isrequired to release this inhibition so cofilin cansever actin filaments to create barbed ends atinvadopodia to support Arp2/3-dependent actinpolymerization. After barbed end formation,cortactin is dephosphorylated, which blockscofilin severing activity thereby stabilizinginvadopodia. These findings identify novel", "metadata": {}}
+{"_id": "12641252", "title": "", "text": "Calreticulin exposure dictates theimmunogenicity of cancer celldeathAnthracyclin-treated tumor cells areparticularly effective in eliciting an anticancerimmune response, whereas other DNA-damagingagents such as etoposide and mitomycin C donot induce immunogenic cell death. Here weshow that anthracyclins induce the rapid,preapoptotic translocation of calreticulin (CRT) tothe cell surface. Blockade or knockdown of CRTsuppressed the phagocytosis ofanthracyclin-treated tumor cells by dendritic cellsand abolished their immunogenicity in mice. Theanthracyclin-induced CRT translocation wasmimicked by inhibition of the proteinphosphatase 1/GADD34 complex. Administrationof recombinant CRT or inhibitors of proteinphosphatase 1/GADD34 restored theimmunogenicity of cell death elicited byetoposide and mitomycin C, and enhanced theirantitumor effects in vivo. These data identify CRTas a key feature determining anticancer immune", "metadata": {}}
+{"_id": "12642224", "title": "", "text": "In vivo disruption of Xenopus U3 snRNA affectsribosomal RNA processing.DNA oligonucleotidecomplementary to sequences in the 5' third of U3snRNA were injected into Xenopus oocyte nucleito disrupt endogenous U3 snRNA. The effect ofthis treatment on rRNA processing wasexamined. We found that some toads have asingle rRNA processing pathway, whereas inother toads, two rRNA processing pathways cancoexist in a single oocyte. U3 snRNA disruption intoads with the single rRNA processing pathwaycaused a reduction in 20S and '32S' pre-rRNA. Inaddition, in toads with two rRNA processingpathways, an increase in '36S' pre-rRNA of thesecond pathway is observed. This is the first invivo demonstration that U3 snRNA plays a role inrRNA processing. Cleavage site #3 is at theboundary of ITS 1 and 5.8S and links all of theaffected rRNA intermediates: 20S and '32S' arethe products of site #3 cleavage in the firstpathway and '36S' is the substrate for cleavageat site #3 in the second pathway. We postulate", "metadata": {}}
+{"_id": "12643937", "title": "", "text": "A genome-wide siRNA screen reveals diversecellular processes and pathways that mediategenome stability.Signaling pathways thatrespond to DNA damage are essential for themaintenance of genome stability and are linkedto many diseases, including cancer. Here, agenome-wide siRNA screen was employed toidentify additional genes involved in genomestabilization by monitoring phosphorylation ofthe histone variant H2AX, an early mark of DNAdamage. We identified hundreds of genes whosedownregulation led to elevated levels of H2AXphosphorylation (gammaH2AX) and revealedlinks to cellular complexes and to genes withunclassified functions. We demonstrate awidespread role for mRNA-processing factors inpreventing DNA damage, which in some cases iscaused by aberrant RNA-DNA structures.Furthermore, we connect increased gammaH2AXlevels to the neurological disorderCharcot-Marie-Tooth (CMT) syndrome, and wefind a role for several CMT proteins in the", "metadata": {}}
+{"_id": "12650610", "title": "", "text": "Alphavbeta6-Fyn signaling promotes oral cancerprogression.We have previously shown that theintegrin beta6 is neo-expressed in invasive oralsquamous cell carcinoma (SCC) and is correlatedwith oral tumor progression. However, themechanism by which the integrin beta6promotes oral tumor progression is not wellunderstood. The purpose of the present studywas to determine whether integrin beta6signaling activates Fyn and thus promotes oralsquamous cell carcinoma progression. Weanalyzed the integrin beta6 signaling complexand investigated the function of these signalingmolecules in oral SCC cells. We found that, uponligation of the integrin beta6 with fibronectin,beta6 complexed with Fyn and activated it. Theactivation of Fyn recruited and activated focaladhesion kinase to this complex. This complexwas necessary to activate Shc and to couplebeta6 signaling to the Raf-ERK/MAPK pathway.This pathway transcriptionally activated thematrix metalloproteinase-3 gene and promoted", "metadata": {}}
+{"_id": "12652963", "title": "", "text": "miRNA-dependent gene silencing involvingAgo2-mediated cleavage of a circular antisenseRNA.MicroRNAs (miRNAs) are \u000022 nt non-codingRNAs that typically bind to the 3' UTR of targetmRNAs in the cytoplasm, resulting in mRNAdestabilization and translational repression.Here, we report that miRNAs can also regulategene expression by targeting non-codingantisense transcripts in human cells. Specifically,we show that miR-671 directs cleavage of acircular antisense transcript of the CerebellarDegeneration-Related protein 1 (CDR1) locus inan Ago2-slicer-dependent manner. The resultingdownregulation of circular antisense has aconcomitant decrease in CDR1 mRNA levels,independently of heterochromatin formation.This study provides the first evidence fornon-coding antisense transcripts as functionalmiRNA targets, and a novel regulatorymechanism involving a positive correlationbetween mRNA and antisense circular RNAlevels.", "metadata": {}}
+{"_id": "12658073", "title": "", "text": "Regulation of Serum Amyloid A3 (SAA3) inMouse Colonic Epithelium and Adipose Tissue bythe Intestinal MicrobiotaThe gut microbiota hasbeen proposed as an environmental factor thataffects the development of metabolic andinflammatory diseases in mammals. Recentreports indicate that gut bacteria-derivedlipopolysaccharide (LPS) can initiate obesity andinsulin resistance in mice; however, themolecular interactions responsible for microbialregulation of host metabolism and mediators ofinflammation have not been studied in detail.Hepatic serum amyloid A (SAA) proteins aremarkers and proposed mediators of inflammationthat exhibit increased levels in serum ofinsulin-resistant mice. Adipose tissue-derivedSAA3 displays monocyte chemotactic activity andmay play a role in metabolic inflammationassociated with obesity and insulin resistance. Toinvestigate a potential mechanistic link betweenthe intestinal microbiota and induction ofproinflammatory host factors, we performed", "metadata": {}}
+{"_id": "12662435", "title": "", "text": "Reversing the tide — diagnosis and prevention ofT2DM in populations of African descentAbstract |Populations of African descent are at theforefront of the worldwide epidemic of type 2diabetes mellitus (T2DM). The burden of T2DM isamplified by diagnosis after preventablecomplications of the disease have occurred.Earlier detection would result in a reduction inundiagnosed T2DM, more accurate statistics,more informed resource allocation and betterhealth. An underappreciated factor contributingto undiagnosed T2DM in populations of Africandescent is that screening tests forhyperglycaemia, specifically, fasting plasmaglucose and HbA1c, perform sub\u0000optimally inthese populations. To offset this problem,combining tests or adding glycated albumin (anonfasting marker of glycaemia), might be theway forward. However, differences in diet,exercise, BMI, environment, gene\u0000environmentinteractions and the prevalence of sickle cell traitmean that neither diagnostic tests nor", "metadata": {}}
+{"_id": "12667988", "title": "", "text": "Biofeedback and relaxation in the treatment ofmigraine headaches: comparative effectivenessand physiological correlates.Twenty-sevenmigraine headache patients were divided intothree equal groups which received thermalbiofeedback, frontalis EMG biofeedback, orrelaxation training. Training was given under\"massed\" practice conditions (nine sessions perweek) and consisted of 18 training sessions andsix test-generalisation sessions. Whileimprovements in headaches were observed in allgroups, the best improvements took place in thethermal biofeedback group, which had almostcomplete elimination of migraine attacks by theend of training, and maintained that performanceas long as six months after training. Examinationof the patterns of skin temperature and EMGchanges in the three groups over the course oftraining also points to a relationship betweenskin temperature control and reduction inmigraine headache symptomatology, andsuggests that this relationship is worthy of", "metadata": {}}
+{"_id": "12669325", "title": "", "text": "Fine-scale chromatin interaction maps reveal thecis-regulatory landscape of human lincRNAgenesHigh-throughput methods based onchromosome conformation capture have greatlyadvanced our understanding of thethree-dimensional (3D) organization of genomesbut are limited in resolution by their reliance onrestriction enzymes. Here we describe a methodcalled DNase Hi-C for comprehensively mappingglobal chromatin contacts. DNase Hi-C usesDNase I for chromatin fragmentation, leading togreatly improved efficiency and resolution overthat of Hi-C. Coupling this method withDNA-capture technology provides ahigh-throughput approach for targeted mappingof fine-scale chromatin architecture. We appliedtargeted DNase Hi-C to characterize the 3Dorganization of 998 large intergenic noncodingRNA (lincRNA) promoters in two human celllines. Our results revealed that expression oflincRNAs is tightly controlled by complexmechanisms involving both super-enhancers and", "metadata": {}}
+{"_id": "12670680", "title": "", "text": "BASOPHILS AND THE T HELPER 2 ENVIRONMENTCAN PROMOTE THE DEVELOPMENT OF LUPUSNEPHRITISIn systemic lupus erythematosus(SLE), self-reactive antibodies can target thekidney (lupus nephritis), leading to functionalfailure and possible mortality. We report thatactivation of basophils by autoreactive IgEcauses their homing to lymph nodes, promotingT helper type 2 (T(H)2) cell differentiation andenhancing the production of self-reactiveantibodies that cause lupus-like nephritis in micelacking the Src family protein tyrosine kinase Lyn(Lyn(-/-) mice). Individuals with SLE also haveelevated serum IgE, self-reactive IgEs andactivated basophils that express CD62 ligand(CD62L) and the major histocompatibilitycomplex (MHC) class II molecule humanleukocyte antigen-DR (HLA-DR), parameters thatare associated with increased disease activityand active lupus nephritis. Basophils were alsopresent in the lymph nodes and spleen ofsubjects with SLE. Thus, in Lyn(-/-) mice,", "metadata": {}}
+{"_id": "12672066", "title": "", "text": "Behavioral treatment of obesity in patientsencountered in primary care settings: asystematic review.IMPORTANCE In 2011, theCenters for Medicare & Medicaid Services (CMS)approved intensive behavioral weight losscounseling for approximately 14 face-to-face,10- to 15-minute sessions over 6 months forobese beneficiaries in primary care settings,when delivered by physicians and otherCMS-defined primary care practitioners.OBJECTIVE To conduct a systematic review ofbehavioral counseling for overweight and obesepatients recruited from primary care, asdelivered by primary care practitioners workingalone or with trained interventionists (eg,medical assistants, registered dietitians), or bytrained interventionists working independently.EVIDENCE REVIEW We searched PubMed,CINAHL, and EMBASE for randomized controlledtrials published between January 1980 and June2014 that recruited overweight and obesepatients from primary care; provided behavioral", "metadata": {}}
+{"_id": "12685434", "title": "", "text": "Guanylate binding protein 1 is a novel effector ofEGFR-driven invasion in glioblastomaAlthoughGBP1 (guanylate binding protein 1) was amongthe first interferon-inducible proteins identified,its function is still largely unknown. Epidermalgrowth factor receptor (EGFR) activation byamplification or mutation is one of the mostfrequent genetic lesions in a variety of humantumors. These include glioblastoma multiforme(GBM), which is characterized by independentbut interrelated features of extensive invasioninto normal brain parenchyma, rapid growth,necrosis, and angiogenesis. In this study, weshow that EGFR activation promoted GBP1expression in GBM cell lines through a signalingpathway involving Src and p38mitogen-activated protein kinase. Moreover, weidentified YY1 (Yin Yang 1) as the downstreamtranscriptional regulator regulating EGFR-drivenGBP1 expression. GBP1 was required forEGFR-mediated MMP1 (matrix metalloproteinase1) expression and glioma cell invasion in vitro.", "metadata": {}}
+{"_id": "12691537", "title": "", "text": "ATP binding to PAN or the 26S ATPases causesassociation with the 20S proteasome, gateopening, and translocation of unfoldedproteins.The archaeal ATPase complex PAN, thehomolog of the eukaryotic 26Sproteasome-regulatory ATPases, was shown toassociate transiently with the 20S proteasomeupon binding of ATP or ATPgammaS, but notADP. By electron microscopy (EM), PAN appearsas a two-ring structure, capping the 20S, andresembles two densities in the 19S complex. TheN termini of the archaeal 20S alpha subunitswere found to function as a gate that preventsentry of seven-residue peptides but allows entryof tetrapeptides. Upon association with the 20Sparticle, PAN stimulates gate opening. Althoughdegradation of globular proteins requires ATPhydrolysis, the PAN-20S complex withATPgammaS translocates and degrades unfoldedand denatured proteins. Rabbit 26S proteasomesalso degrade these unfolded proteins upon ATPbinding, without hydrolysis. Thus, although", "metadata": {}}
+{"_id": "12705056", "title": "", "text": "Cytokines and anti-cytokine biologicals inautoimmunity: present and future.The increasingunderstanding of the role of cytokines inautoimmunity, and the observation that tumournecrosis factor alpha (TNFalpha) is central to theinflammatory and destructive process commonto several human autoimmune diseases, has ledto a new generation of therapeutics, theTNFalpha blocking agents. In this article, wereview the current knowledge of the role ofcytokines in autoimmunity as unravelled bystudies both in the laboratory and the clinic. Inaddition, we discuss future prospects of theanti-TNFalpha therapy that may involvecombination therapy with other anti-cytokine oranti-T cell biologicals, or the use of smallchemicals targeting molecules involved inTNFalpha production such as NF-kappaB and p38MAPK. The future developments of anti-TNFalphaand anti-cytokine therapy in general will beinteresting.", "metadata": {}}
+{"_id": "12709184", "title": "", "text": "Vegetarian dietary patterns and mortality inAdventist Health Study 2.IMPORTANCE Someevidence suggests vegetarian dietary patternsmay be associated with reduced mortality, butthe relationship is not well established.OBJECTIVE To evaluate the association betweenvegetarian dietary patterns and mortality.DESIGN Prospective cohort study; mortalityanalysis by Cox proportional hazards regression,controlling for important demographic andlifestyle confounders. SETTING Adventist HealthStudy 2 (AHS-2), a large North American cohort.PARTICIPANTS A total of 96,469 Seventh-dayAdventist men and women recruited between2002 and 2007, from which an analytic sample of73,308 participants remained after exclusions.EXPOSURES Diet was assessed at baseline by aquantitative food frequency questionnaire andcategorized into 5 dietary patterns:nonvegetarian, semi-vegetarian,pesco-vegetarian, lacto-ovo-vegetarian, andvegan. MAIN OUTCOME AND MEASURE The", "metadata": {}}
+{"_id": "12737132", "title": "", "text": "TEAD mediates YAP-dependent gene inductionand growth control.The YAP transcriptioncoactivator has been implicated as an oncogeneand is amplified in human cancers. Recentstudies have established that YAP isphosphorylated and inhibited by the Hippo tumorsuppressor pathway. Here we demonstrate thatthe TEAD family transcription factors areessential in mediating YAP-dependent geneexpression. TEAD is also required forYAP-induced cell growth, oncogenictransformation, and epithelial-mesenchymaltransition. CTGF is identified as a direct YAPtarget gene important for cell growth. Moreover,the functional relationship between YAP andTEAD is conserved in Drosophila Yki (the YAPhomolog) and Scalloped (the TEAD homolog).Our study reveals TEAD as a new component inthe Hippo pathway playing essential roles inmediating biological functions of YAP.", "metadata": {}}
+{"_id": "12742164", "title": "", "text": "Direct isolation of human central nervous systemstem cells.Stem cells, which are clonogenic cellswith self-renewal and multilineage differentiationproperties, have the potential to replace or repairdamaged tissue. We have directly isolatedclonogenic human central nervous system stemcells (hCNS-SC) from fresh human fetal braintissue, using antibodies to cell surface markersand fluorescence-activated cell sorting. ThesehCNS-SC are phenotypically 5F3 (CD133)(+),5E12(+), CD34(-), CD45(-), and CD24(-/lo).Single CD133(+) CD34(-) CD45(-) sorted cellsinitiated neurosphere cultures, and the progenyof clonogenic cells could differentiate into bothneurons and glial cells. Single cells fromneurosphere cultures initiated from CD133(+)CD34(-) CD45(-) cells were again replated assingle cells and were able to reestablishneurosphere cultures, demonstrating theself-renewal potential of this highly enrichedpopulation. Upon transplantation into brains ofimmunodeficient neonatal mice, the", "metadata": {}}
+{"_id": "12762485", "title": "", "text": "p53 mutation in breast cancer. Correlation withcell kinetics and cell of origin.AIM Several studieshave investigated the expression of thecytokeratins (CKs), vimentin, the epithelialgrowth factor receptor (EGFR), the oestrogenreceptor (ER), and the progesterone receptor(PgR), in breast cancer, but no study has directlycompared p53 mutations with these phenotypicand differentiation markers in the same case.The present study was designed to provide someof this information. METHODS The expression ofthe p53 and bcl-2 proteins was evaluated byimmunohistochemistry in relation to phenotypiccharacteristics and cellular kinetic parameters(mitotic index and apoptotic index) in 37 cases ofductal carcinoma in situ (DCIS) and 27 cases ofinfiltrating ductal carcinoma (IDC) of the breast.In addition, p53 gene mutation was examined bypolymerase chain reaction single strandconformation polymorphism analysis (SSCP).RESULTS Thirteen cases (eight DCIS and fiveIDC) showed expression of CK8, CK14, CK18,", "metadata": {}}
+{"_id": "12770738", "title": "", "text": "Cardiorespiratory fitness and body mass index aspredictors of cardiovascular disease mortalityamong men with diabetes.BACKGROUNDQuestions remain as to whether higher levels ofcardiorespiratory fitness, a measure of regularphysical activity, are associated with lower risk ofcardiovascular disease (CVD) mortality inoverweight and obese individuals with diabetes.Our objective was to quantify the independentand joint relations of cardiorespiratory fitness(hereafter, fitness) and body mass index (BMI;calculated as weight in kilograms divided by thesquare of height in meters) with CVD mortality inmen with diabetes. METHODS This study wasconducted using prospective observational datafrom the Aerobics Center Longitudinal Study.Study participants comprised 2316 men with nohistory of stroke or myocardial infarction andwho were diagnosed as having diabetes (mean[SD] age, 50 [10] years); had a medicalexamination, including a maximal exercise testduring 1970 to 1997 with mortality surveillance", "metadata": {}}
+{"_id": "12779444", "title": "", "text": "Effect of screening on cervical cancer mortality inEngland and Wales: analysis of trends with anage period cohort model.The number of womendying from cervical cancer in 1997 was 7% lowerthan in 1996 and has fallen by over 25% since1992.1 Such rapid change must be at least partlydue to cervical screening, although strong cohorteffects have caused large fluctuations in cervicalmortality in the past.2 We modelled mortalitydata, taking into account the effects of age andyear of birth and looking for trends in time withinfour age groups to estimate the beneficial effectsof cervical screening. We obtained mortalitydata, in 5 year age bands, from deathregistrations in England and Wales andcalculated rates using mid-year populationestimates. Mortality since 1993 was adjustedupwards by 4% because of changes inclassification of cause of death.3  We modelledthe data assuming that the age specific mortalityis the product of a smoothly varying age effect,birth cohort effect, and age dependent …", "metadata": {}}
+{"_id": "12785130", "title": "", "text": "The regulation of N-methyl-D-aspartatereceptors by Src kinase.Src family kinases(SFKs) play critical roles in the regulation ofmany cellular functions by growth factors,G-protein-coupled receptors and ligand-gated ionchannels. Recent data have shown that SFKsserve as a convergent point of multiple signalingpathways regulating N-methyl-d-aspartate(NMDA) receptors in the central nervous system.Multiple SFK molecules, such as Src and Fyn,closely associate with their substrate, NMDAreceptors, via indirect and direct bindingmechanisms. The NMDA receptor is associatedwith an SFK signaling complex consisting ofSFKs; the SFK-activating phosphatase, proteintyrosine phosphatase α; and the SFK-inactivatingkinase, C-terminal Src kinase. Early studies havedemonstrated that intramolecular interactionswith the SH2 or SH3 domain lock SFKs in aclosed conformation. Disruption of theinterdomain interactions can induce theactivation of SFKs with multiple signaling", "metadata": {}}
+{"_id": "12787125", "title": "", "text": "The art and design of genetic screens: RNAinterferenceThe remarkable gene knockdowntechnique of RNAi has opened exciting newavenues for genetic screens in model organismsand human cells. Here we describe the currentstate of the art for RNAi screening, and stressthe importance of well-designed assays and ofanalytical approaches for large-scale screeningexperiments, from high-throughput screensusing simplified homogenous assays tomicroscopy and whole-animal experiments. Likeclassical genetic screens in the past, the successof large-scale RNAi surveys depends on a carefuldevelopment of phenotypic assays and theirinterpretation in a relevant biological context.", "metadata": {}}
+{"_id": "12789595", "title": "", "text": "Computer assisted learning in undergraduatemedical education.It is becoming “a truthuniversally acknowledged” that the education ofundergraduate medical students will beenhanced through the use of computer assistedlearning. Access to the wide range of onlineoptions illustrated in the figure must surely makelearning more exciting, effective, and likely to beretained. This assumption is potentially but by nomeans inevitably correct. ### Box 1: Why fundcomputer assisted learning? Computer assistedlearning is inevitable —Individual lecturers anddepartments are already beginning to introducea wide range of computer based applications,sometimes in a haphazard way. Planned andcoordinated development is better thanindiscriminate expansion  It is convenient andflexible —Courses supported by computerassisted learning applications may require fewerface to face lectures and seminars and placefewer geographical and temporal constraints onstaff and students. Students at peripheral", "metadata": {}}
+{"_id": "12794099", "title": "", "text": "Combined Impact of Health Behaviours andMortality in Men and Women: The EPIC-NorfolkProspective Population StudyBACKGROUNDThere is overwhelming evidence that behaviouralfactors influence health, but their combinedimpact on the general population is less welldocumented. We aimed to quantify the potentialcombined impact of four health behaviours onmortality in men and women living in the generalcommunity. METHODS AND FINDINGS Weexamined the prospective relationship betweenlifestyle and mortality in a prospective populationstudy of 20,244 men and women aged 45-79 ywith no known cardiovascular disease or cancerat baseline survey in 1993-1997, living in thegeneral community in the United Kingdom, andfollowed up to 2006. Participants scored onepoint for each health behaviour: currentnon-smoking, not physically inactive, moderatealcohol intake (1-14 units a week) and plasmavitamin C >50 mmol/l indicating fruit andvegetable intake of at least five servings a day,", "metadata": {}}
+{"_id": "12800122", "title": "", "text": "Increased Cell Bond Tension Governs Cell Sortingat the Drosophila Anteroposterior CompartmentBoundarySubdividing proliferating tissues intocompartments is an evolutionarily conservedstrategy of animal development [1-6]. Signalsacross boundaries between compartments canresult in local expression of secreted proteinsorganizing growth and patterning of tissues[1-6]. Sharp and straight interfaces betweencompartments are crucial for stabilizing theposition of such organizers and therefore forprecise implementation of body plans.Maintaining boundaries in proliferating tissuesrequires mechanisms to counteract cellrearrangements caused by cell division;however, the nature of such mechanismsremains unclear. Here we quantitatively analyzedcell morphology and the response to the laserablation of cell bonds in the vicinity of theanteroposterior compartment boundary indeveloping Drosophila wings. We found thatmechanical tension is approximately 2.5-fold", "metadata": {}}
+{"_id": "12801438", "title": "", "text": "Plant products as antimicrobial agents.The use ofand search for drugs and dietary supplementsderived from plants have accelerated in recentyears. Ethnopharmacologists, botanists,microbiologists, and natural-products chemistsare combing the Earth for phytochemicals and\"leads\" which could be developed for treatmentof infectious diseases. While 25 to 50% ofcurrent pharmaceuticals are derived from plants,none are used as antimicrobials. Traditionalhealers have long used plants to prevent or cureinfectious conditions; Western medicine is tryingto duplicate their successes. Plants are rich in awide variety of secondary metabolites, such astannins, terpenoids, alkaloids, and flavonoids,which have been found in vitro to haveantimicrobial properties. This review attempts tosummarize the current status of botanicalscreening efforts, as well as in vivo studies oftheir effectiveness and toxicity. The structureand antimicrobial properties of phytochemicalsare also addressed. Since many of these", "metadata": {}}
+{"_id": "12804937", "title": "", "text": "Nature, Nurture, or Chance: Stochastic GeneExpression and Its ConsequencesGeneexpression is a fundamentally stochastic process,with randomness in transcription and translationleading to cell-to-cell variations in mRNA andprotein levels. This variation appears inorganisms ranging from microbes to metazoans,and its characteristics depend both on thebiophysical parameters governing geneexpression and on gene network structure.Stochastic gene expression has importantconsequences for cellular function, beingbeneficial in some contexts and harmful inothers. These situations include the stressresponse, metabolism, development, the cellcycle, circadian rhythms, and aging.", "metadata": {}}
+{"_id": "12805683", "title": "", "text": "Nuclear Hormone Receptor NHR-49 Controls FatConsumption and Fatty Acid Composition in C.elegansMammalian nuclear hormone receptors(NHRs), such as liver X receptor, farnesoid Xreceptor, and peroxisome proliferator-activatedreceptors (PPARs), precisely control energymetabolism. Consequently, these receptors areimportant targets for the treatment of metabolicdiseases, including diabetes and obesity. Athorough understanding of NHR fat regulatorynetworks has been limited, however, by a lack ofgenetically tractable experimental systems. Herewe show that deletion of the Caenorhabditiselegans NHR gene nhr-49 yielded worms withelevated fat content and shortened life span.Employing a quantitative RT-PCR screen, wefound that nhr-49 influenced the expression of13 genes involved in energy metabolism. Indeed,nhr-49 served as a key regulator of fat usage,modulating pathways that control theconsumption of fat and maintain a normalbalance of fatty acid saturation. We found that", "metadata": {}}
+{"_id": "12810152", "title": "", "text": "Folate and vitamin B6 from diet and supplementsin relation to risk of coronary heart diseaseamong women.CONTEXT Hyperhomocysteinemiais caused by genetic and lifestyle influences,including low intakes of folate and vitamin B6.However, prospective data relating intake ofthese vitamins to risk of coronary heart disease(CHD) are not available. OBJECTIVE To examineintakes of folate and vitamin B6 in relation to theincidence of nonfatal myocardial infarction (MI)and fatal CHD. DESIGN Prospective cohort study.SETTING AND PATIENTS In 1980, a total of80082 women from the Nurses' Health Studywith no previous history of cardiovasculardisease, cancer, hypercholesterolemia, ordiabetes completed a detailed food frequencyquestionnaire from which we derived usualintake of folate and vitamin B6. MAIN OUTCOMEMEASURE Nonfatal MI and fatal CHD confirmedby World Health Organization criteria. RESULTSDuring 14 years of follow-up, we documented658 incident cases of nonfatal MI and 281 cases", "metadata": {}}
+{"_id": "12821938", "title": "", "text": "Control of oocyte meiotic maturation andfertilization.Sexual reproduction depends uponmeiosis for the generation of haploid gametenuclei, which unite after fertilization to form thediploid zygote. The oocytes of most animalspecies arrest during meiotic prophase, andcomplete meiosis in response to intercellularsignaling in a process called meiotic maturation.Oocyte meiotic maturation is defined by thetransition between diakinesis and metaphase ofmeiosis I and is accompanied by nuclearenvelope breakdown, rearrangement of thecortical cytoskeleton, and meiotic spindleassembly. Thus, the meiotic maturation processis essential for meiosis and prepares the oocytefor fertilization. In C. elegans, the processes ofmeiotic maturation, ovulation, and fertilizationare temporally coupled: sperm utilize the majorsperm protein as a hormone to trigger oocytemeiotic maturation, and in turn, the maturingoocyte signals its own ovulation therebyfacilitating fertilization. This chapter highlights", "metadata": {}}
+{"_id": "12824568", "title": "", "text": "From Cell Differentiation to Cell Collectives:Bacillus subtilis Uses Division of Labor toMigrateThe organization of cells, emerging fromcell-cell interactions, can give rise to collectiveproperties. These properties are adaptive whentogether cells can face environmental challengesthat they separately cannot. One particularchallenge that is important for microorganisms ismigration. In this study, we show howflagellum-independent migration is driven by thedivision of labor of two cell types that appearduring Bacillus subtilis sliding motility. Cellcollectives organize themselves into bundles(called \"van Gogh bundles\") of tightly aligned cellchains that form filamentous loops at the colonyedge. We show, by time-course microscopy, thatthese loops migrate by pushing themselves awayfrom the colony. The formation of van Goghbundles depends critically on the synergisticinteraction of surfactin-producing andmatrix-producing cells. We propose thatsurfactin-producing cells reduce the friction", "metadata": {}}
+{"_id": "12827098", "title": "", "text": "Tissue-resident macrophages self-maintainlocally throughout adult life with minimalcontribution from circulating monocytes.Despiteaccumulating evidence suggesting localself-maintenance of tissue macrophages in thesteady state, the dogma remains that tissuemacrophages derive from monocytes. Usingparabiosis and fate-mapping approaches, weconfirmed that monocytes do not showsignificant contribution to tissue macrophages inthe steady state. Similarly, we found that afterdepletion of lung macrophages, the majority ofrepopulation occurred by stochastic cellularproliferation in situ in a macrophagecolony-stimulating factor (M-Csf)- andgranulocyte macrophage (GM)-CSF-dependentmanner but independently of interleukin-4. Wealso found that after bone marrowtransplantation, host macrophages retained thecapacity to expand when the development ofdonor macrophages was compromised.Expansion of host macrophages was functional", "metadata": {}}
+{"_id": "12839939", "title": "", "text": "Registration and real-time visualization oftranscranial magnetic stimulation with 3-D MRimagesThis paper describes a method forregistering and visualizing in real-time theresults of transcranial magnetic stimulations(TMS) in physical space on the correspondinganatomical locations in MR images of the brain.The method proceeds in three main steps. First,the patient scalp is digitized in physical spacewith a magnetic-field digitizer, following aspecific digitization pattern. Second, aregistration process minimizes the mean squaredistance between those points and a segmentedscalp surface extracted from the magneticresonance image. Following this registration, thephysician can follow the change in coil position inreal-time through the visualization interface andadjust the coil position to the desired anatomicallocation. Third, amplitude of motor evokedpotentials can be projected onto the segmentedbrain in order to create functional brain maps.The registration has subpixel accuracy in a study", "metadata": {}}
+{"_id": "12866641", "title": "", "text": "Enzymatic targeting of the stroma ablatesphysical barriers to treatment of pancreaticductal adenocarcinoma.Pancreatic ductaladenocarcinomas (PDAs) are characterized by arobust fibroinflammatory response. We showhere that this desmoplastic reaction generatesinordinately high interstitial fluid pressures(IFPs), exceeding those previously measured ortheorized for solid tumors, and induces vascularcollapse, while presenting substantial barriers toperfusion, diffusion, and convection of smallmolecule therapeutics. We identify hyaluronan,or hyaluronic acid (HA), as the primary matrixdeterminant of these barriers and show thatsystemic administration of an enzymatic agentcan ablate stromal HA from autochthonousmurine PDA, normalize IFP, and re-expand themicrovasculature. In combination with thestandard chemotherapeutic, gemcitabine, thetreatment permanently remodels the tumormicroenvironment and consistently achievesobjective tumor responses, resulting in a near", "metadata": {}}
+{"_id": "12869200", "title": "", "text": "Circulating adiponectin, leptin andadiponectin-leptin ratio and endometrial cancerrisk: Evidence from a meta-analysis ofepidemiologic studies.We performed thismeta-analysis of epidemiologic studies toinvestigate the associations between circulatingadiponectin, leptin and adiponectin-leptin (A/L)ratio and endometrial cancer risk. Relevantmanuscripts were identified by searching PubMedand ISI Web of Science databases as well as bymanual searching the references cited inretrieved manuscripts. Random-effects modelswere used to estimate summary odds ratio(SOR) and 95% confidence intervals (CIs) foraforementioned associations. Fourteenmanuscripts with 13 studies (five nestedcase-control and eight case-control studies)cumulatively involving a total of 1,963endometrial cancer cases and 3,503 noncaseswere included in the analyses. Overall,comparing persons with circulatingconcentrations of adiponectin, leptin and A/L", "metadata": {}}
+{"_id": "12871002", "title": "", "text": "CDE-1 Affects Chromosome Segregation throughUridylation of CSR-1-Bound siRNAsWe havestudied the function of a conservedgermline-specific nucleotidyltransferase protein,CDE-1, in RNAi and chromosome segregation inC. elegans. CDE-1 localizes specifically to mitoticchromosomes in embryos. This localizationrequires the RdRP EGO-1, which physicallyinteracts with CDE-1, and the Argonaute proteinCSR-1. We found that CDE-1 is required for theuridylation of CSR-1 bound siRNAs, and that inthe absence of CDE-1 these siRNAs accumulateto inappropriate levels, accompanied by defectsin both meiotic and mitotic chromosomesegregation. Elevated siRNA levels areassociated with erroneous gene silencing, mostlikely through the inappropriate loading of CSR-1siRNAs into other Argonaute proteins. Wepropose a model in which CDE-1 restricts specificEGO-1-generated siRNAs to the CSR-1 mediated,chromosome associated RNAi pathway, thusseparating it from other endogenous RNAi", "metadata": {}}
+{"_id": "12871281", "title": "", "text": "Localized diacylglycerol drives the polarization ofthe microtubule-organizing center in T cellsThereorientation of the T cell microtubule-organizingcenter (MTOC) toward the antigen-presentingcell enables the directional secretion of cytokinesand lytic factors. By single-cell photoactivation ofthe T cell antigen receptor, we show that MTOCpolarization is driven by localized accumulationof diacylglycerol (DAG). MTOC reorientation wasclosely preceded first by production of DAG andthen by recruitment of the microtubule motorprotein dynein. Blocking DAG production ordisrupting the localization of DAG impaired MTOCrecruitment. Localized DAG accumulation wasalso required for cytotoxic T cell–mediatedkilling. Furthermore, photoactivation of DAGitself was sufficient to induce transientpolarization. Our data identify a DAG-dependentpathway that signals through dynein to controlmicrotubule polarity in T cells.", "metadata": {}}
+{"_id": "12880573", "title": "", "text": "Dual roles of plcA in Listeria monocytogenespathogenesis.The plcA gene of Listeriamonocytogenes encodes a secretedphosphatidylinositol-specific phospholipase C(Pl-PLC). Recent studies have established thattransposon mutations within plcA result inavirulence for mice and pleiotropic effects whenexamined in tissue-culture models of infection.Genetic analysis reveals that many of the effectsof the transposon insertions are due to loss ofreadthrough transcription from plcA into thedownstream gene prfA, which encodes anessential transcription factor of numerous L.monocytogenes virulence genes. Construction ofan in-frame deletion within plcA had no effect onexpression of prfA thus allowing directassignment of a role of the Pl-PLC inpathogenesis. Pl-PLC was shown to play asignificant role in mediating escape of L.monocytogenes from phagosomes of primarymurine macrophages. Interestingly, this defectmanifested itself in vivo in the liver but not in the", "metadata": {}}
+{"_id": "12881593", "title": "", "text": "Fine-tuning in regulation of Clp protein content inBacillus subtilis.Clp-controlled proteolysis inBacillus subtilis seems to play a substantial role,particularly under stress conditions. CalibratedWestern blot analyses were used to estimate theapproximate numbers of heat-inducible Clpmolecules within a single cell. According to thesenumbers, the different Clp ATPases do not seemto compete for the proteolytic subunit ClpP.Coimmunoprecipitation experiments revealed thepredicted specific ClpX-ClpP, ClpC-ClpP, andClpE-ClpP interactions. ClpE and ClpX are rapidlydegraded in wild-type cells during permanentheat stress but remained almost stable in a clpPmutant, suggesting ClpP-dependent degradation.In particular, ClpCP appeared to be involved inthe degradation of the short-lived ClpE ATPase,indicating a negative \"autoregulatory\" circuit forthis particular Clp ATPase at the posttranslationallevel. Analysis of the half-life of stress-inducibleclp mRNAs during exponential growth and heatshock revealed precise regulation of the", "metadata": {}}
+{"_id": "12885341", "title": "", "text": "A C-Type Lectin Collaborates with a CD45Phosphatase Homolog to Facilitate West NileVirus Infection of MosquitoesWest Nile virus(WNV) is the most common arthropod-borneflavivirus in the United States; however, thevector ligand(s) that participate in infection arenot known. We now show that an Aedes aegyptiC-type lectin, mosGCTL-1, is induced by WNV,interacts with WNV in a calcium-dependentmanner, and facilitates infection in vivo and invitro. A mosquito homolog of human CD45 in A.aegypti, designated mosPTP-1, recruitsmosGCTL-1 to enable viral attachment to cellsand to enhance viral entry. In vivo experimentsshow that mosGCTL-1 and mosPTP-1 function aspart of the same pathway and are critical forWNV infection of mosquitoes. A similarphenomenon was also observed in Culexquinquefasciatus, a natural vector of WNV,further demonstrating that these genesparticipate in WNV infection. During themosquito blood-feeding process, WNV infection", "metadata": {}}
+{"_id": "12887068", "title": "", "text": "Use of human embryonic stem cells to modelpediatric gliomas with H3.3K27M histonemutationOver 70% of diffuse intrinsic pediatricgliomas, an aggressive brainstem tumor, harborheterozygous mutations that create a K27Mamino acid substitution (methionine replaceslysine 27) in the tail of histone H3.3. The role ofthe H3.3K27M mutation in tumorigenesis is notfully understood. Here, we use a humanembryonic stem cell system to model this tumor.We show that H3.3K27M expression synergizeswith p53 loss and PDGFRA activation in neuralprogenitor cells derived from human embryonicstem cells, resulting in neoplastic transformation.Genome-wide analyses indicate a resetting of thetransformed precursors to a developmentallymore primitive stem cell state, with evidence ofmajor modifications of histone marks at severalmaster regulator genes. Drug screening assaysidentified a compound targeting the proteinmenin as an inhibitor of tumor cell growth invitro and in mice.", "metadata": {}}
+{"_id": "12892137", "title": "", "text": "Basis for avid homologous DNA strand exchangeby human Rad51 and RPA.Human Rad51(hRad51), a member of a conserved family ofgeneral recombinases, is shown here to have anavid capability to make DNA joints betweenhomologous DNA molecules and promote highlyefficient DNA strand exchange of the pairedmolecules over at least 5.4 kilobase pairs.Furthermore, maximal efficiency of homologousDNA pairing and strand exchange is stronglydependent on the heterotrimeric single-strandedDNA binding factor hRPA and requires conditionsthat lessen interactions of the homologousduplex with the hRad51-single-stranded DNAnucleoprotein filament. The homologous DNApairing and strand exchange system describedshould be valuable for dissecting the actionmechanism of hRad51 and for deciphering itsfunctional interactions with other recombinationfactors.", "metadata": {}}
+{"_id": "12899460", "title": "", "text": "A multiple indicators multiple causes model oflate-life depression in Latin AmericancountriesBACKGROUND The Euro-D depressionscale consists of symptom clusters that may bedifferentially related to demographic andcognitive characteristics in older adults. Thishypothesis needs further investigation and therole of measurement bias on substantiveconclusions remains to be established. METHODThe study sample comprised 10,405community-dwelling older adults from six LatinAmerican countries. We applied a MultipleIndicators Multiple Causes (MIMIC) model for aconcurrent investigation of measurement biasand of the association between Euro-D symptomclusters and background variables. RESULTS Thefactorial validity of Euro-D, with atwo-dimensional structure--affective sufferingand motivation disturbance, was consistentlysupported in all countries. Although completemeasurement invariance could not be assumedacross countries, measurement bias was minor.", "metadata": {}}
+{"_id": "12899612", "title": "", "text": "Microvesicles derived from human umbilical cordmesenchymal stem cells stimulated by hypoxiapromote angiogenesis both in vitro and invivo.Although mesenchymal stem cells (MSCs)have been increasingly trialed to treat a varietyof diseases, the underlying mechanisms remainstill elusive. In this study, human umbilical cord(UC)-derived MSCs were stimulated by hypoxia,and the membrane microvesicles (MVs) in thesupernatants were collected byultracentrifugation, observed under an electronmicroscope, and the origin was identified withthe flow cytometric technique. The resultsshowed that upon hypoxic stimulus, MSCsreleased a large quantity of MVs of ~100 nm indiameter. The MVs were phenotypically similar tothe parent MSCs, except that the majority ofthem were negative for the receptor ofplatelet-derived growth factor. DiI-labeling assayrevealed that MSC-MVs could be internalized intohuman UC endothelial cells (UC-ECs) within 8 hafter they were added into the culture medium.", "metadata": {}}
+{"_id": "12903921", "title": "", "text": "Evaluation of oxidative status anddepression-like responses in Brown Norway ratswith acute myeloid leukemiaIt has been provedthat oxidative stress increases when leukemia isaccompanied by depression. This fact mayindicate the role of oxidative stress in thedevelopment of depression in cancer patients.The aim of this study was to determine whetherthe acute myeloid leukemia of Brown Norwayrats, which is accompanied by oxidative stress,evoked behavioral and receptor changesresembling alterations characteristic of ratmodels of depression. The rats were divided intotwo groups: leukemic rats and healthy control.Leukemia was induced through intraperitonealinjection of 10(7) promyelocytic leukemia cells tothe Brown Norway rats. Depression-like behaviorwas evaluated in the forced swim test at 30 or34 days after leukemic cells injection. The ratswere killed after the evaluation and the spleen,brain cortex and hippocampus were excised. Thered-ox state was assessed in homogenates of", "metadata": {}}
+{"_id": "12909503", "title": "", "text": "Distinct roles for DNA-PK, ATM and ATR in RPAphosphorylation and checkpoint activation inresponse to replication stressDNA damageencountered by DNA replication forks poses risksof genome destabilization, a precursor tocarcinogenesis. Damage checkpoint systemscause cell cycle arrest, promote repair andinduce programed cell death when damage issevere. Checkpoints are critical parts of the DNAdamage response network that act to suppresscancer. DNA damage and perturbation ofreplication machinery causes replication stress,characterized by accumulation of single-strandedDNA bound by replication protein A (RPA), whichtriggers activation of ataxia telangiectasia andRad3 related (ATR) and phosphorylation of theRPA32, subunit of RPA, leading to Chk1activation and arrest. DNA-dependent proteinkinase catalytic subunit (DNA-PKcs) [a kinaserelated to ataxia telangiectasia mutated (ATM)and ATR] has well characterized roles in DNAdouble-strand break repair, but poorly", "metadata": {}}
+{"_id": "12922760", "title": "", "text": "The essential Schizosaccharomyces pombe Pfh1DNA helicase promotes fork movement pastG-quadruplex motifs to prevent DNAdamageBACKGROUND G-quadruplexes (G4s) arestable non-canonical DNA secondary structuresconsisting of stacked arrays of four guanines,each held together by Hoogsteen hydrogenbonds. Sequences with the ability to form thesestructures in vitro, G4 motifs, are foundthroughout bacterial and eukaryotic genomes.The budding yeast Pif1 DNA helicase, as well asseveral bacterial Pif1 family helicases, unwind G4structures robustly in vitro and suppressG4-induced DNA damage in S. cerevisiae in vivo.RESULTS We determined the genomicdistribution and evolutionary conservation of G4motifs in four fission yeast species andinvestigated the relationship between G4 motifsand Pfh1, the sole S. pombe Pif1 family helicase.Using chromatin immunoprecipitation combinedwith deep sequencing, we found that many G4motifs in the S. pombe genome were associated", "metadata": {}}
+{"_id": "12932176", "title": "", "text": "Wnt7a signaling promotes dendritic spine growthand synaptic strength throughCa²\u0000/Calmodulin-dependent protein kinaseII.The balance between excitatory and inhibitorysynapses is crucial for normal brain function. Wntproteins stimulate synapse formation byincreasing synaptic assembly. However, it isunclear whether Wnt signaling differentiallyregulates the formation of excitatory andinhibitory synapses. Here, we demonstrate thatWnt7a preferentially stimulates excitatorysynapse formation and function. In hippocampalneurons, Wnt7a increases the number ofexcitatory synapses, whereas inhibitory synapsesare unaffected. Wnt7a or postsynapticexpression of Dishevelled-1 (Dvl1), a core Wntsignaling component, increases the frequencyand amplitude of miniature excitatorypostsynaptic currents (mEPSCs), but notminiature inhibitory postsynaptic currents(mIPSCs). Wnt7a increases the density andmaturity of dendritic spines, whereas", "metadata": {}}
+{"_id": "12943966", "title": "", "text": "Bitter taste receptors and α-gustducin regulatethe secretion of ghrelin with functional effects onfood intake and gastric emptying.Ghrelin is ahunger hormone with gastroprokinetic propertiesbut the factors controlling ghrelin secretion fromthe stomach are unknown. Bitter taste receptors(T2R) and the gustatory G proteins, α-gustducin(gust) and α-transducin, are expressed in the gutand are involved in the chemosensation ofnutrients. This study aimed to investigatewhether T2R-agonists affect (i) ghrelin releasevia α-gustducin and (ii) food intake and gastricemptying via the release of ghrelin. The mousestomach contains two ghrelin cell populations:cells containing octanoyl and desoctanoylghrelin, which were colocalized with α-gustducinand α-transducin, and cells staining fordesoctanoyl ghrelin. Gavage of T2R-agonistsincreased plasma octanoyl ghrelin levels in WTmice but the effect was partially blunted ingust(-/-) mice. Intragastric administration ofT2R-agonists increased food intake during the", "metadata": {}}
+{"_id": "12948892", "title": "", "text": "Ca2+-permeable AMPA receptors regulategrowth of human glioblastoma via Aktactivation.Evidence has been accumulated thatglioblastoma cells release and exploit glutamatefor proliferation and migration by autocrine orparacrine loops through Ca2+-permeableAMPA-type glutamate receptors. Here, we showthat Ca2+ signaling mediated by AMPA receptorregulates the growth and motility of glioblastomacells via activation of Akt. Ca2+ supplied throughCa2+-permeable AMPA receptor phosphorylatedAkt at Ser-473, thereby facilitating proliferationand mobility. A dominant-negative form of Aktinhibited cell proliferation and migrationaccelerated by overexpression ofCa2+-permeable AMPA receptor. In contrast,introduction of a constitutively active form of Aktrescued tumor cells from apoptosis induced bythe conversion of Ca2+-permeable AMPAreceptor to Ca2+-impermeable receptors by thedelivery of GluR2 cDNA. Therefore, Akt functionsas downstream effectors for Ca2+-signaling", "metadata": {}}
+{"_id": "12956194", "title": "", "text": "The Extracellular Surface of the GLP-1 ReceptorIs a Molecular Trigger for BiasedAgonismLigand-directed signal bias offersopportunities for sculpting molecular events, withthe promise of better, safer therapeutics. Criticalto the exploitation of signal bias is anunderstanding of the molecular events couplingligand binding to intracellular signaling.Activation of class B G protein-coupled receptorsis driven by interaction of the peptide N terminuswith the receptor core. To understand how thisdrives signaling, we have used advancedanalytical methods that enable separation ofeffects on pathway-specific signaling from thosethat modify agonist affinity and mapped thefunctional consequence of receptor modificationonto three-dimensional models of areceptor-ligand complex. This yields molecularinsights into the initiation of receptor activationand the mechanistic basis for biased agonism.Our data reveal that peptide agonists can engagedifferent elements of the receptor extracellular", "metadata": {}}
+{"_id": "12966719", "title": "", "text": "A local macrophage chemokine network sustainsprotective tissue-resident memory CD4 TcellsCD8 tissue-resident memory T (TRM) cellsprovide efficient local control of viral infection,but the role of CD4 TRM is less clear. Here, byusing parabiotic mice, we show that a preexistingpool of CD4 TRM cells in the genital mucosa wasrequired for full protection from a lethal herpessimplex virus 2 (HSV-2) infection. Chemokinessecreted by a local network of macrophagesmaintained vaginal CD4 TRM in memorylymphocyte clusters (MLCs), independently ofcirculating memory T cells. CD4 TRM cells withinthe MLCs were enriched in clones that expandedin response to HSV-2. Our results highlight theneed for vaccine strategies that enableestablishment of TRM cells for protection from asexually transmitted virus and provide insightsas to how such a pool might be established.", "metadata": {}}
+{"_id": "12991445", "title": "", "text": "Influence of smoking and plasma factors onpatency of femoropopliteal veingrafts.OBJECTIVE To determine the effects ofsmoking, plasma lipids, lipoproteins,apolipoproteins, and fibrinogen on the patency ofsaphenous vein femoropopliteal bypass grafts atone year. DESIGN Prospective study of patientswith saphenous vein femoropopliteal bypassgrafts entered into a multicentre trial. SETTINGSurgical wards, outpatient clinics, and homevisits coordinated by two tertiary referral centresin London and Birmingham. PATIENTS 157Patients (mean age 66.6 (SD 8.2) years), 113with patent grafts and 44 with occluded graftsone year after bypass. MAIN OUTCOMEMEASURE Cumulative percentage patency at oneyear. RESULTS Markers for smoking (bloodcarboxyhaemoglobin concentration (p less than0.05) and plasma thiocyanate concentration (pless than 0.01) and plasma concentrations offibrinogen (p less than 0.001) andapolipoproteins AI (p less than 0.04) and (a) (p", "metadata": {}}
+{"_id": "12994780", "title": "", "text": "No effect of dietary fat on short-term weight gainin mice treated with atypical antipsychoticdrugsRationale:Atypical antipsychotic drugs(AAD) induce significant weight gain in femaleC57BL/6J mice. The effect of dietary fat onweight gain and serum lipids in this model isunknown. Objectives: Test the hypothesis thatthe obesigenic effects of these drugs are greaterin the presence of a high-fat diet.Methods:Female C57BL/6J mice were treatedwith atypical antipsychotics for 3 weeks and fedeither a low-fat or high-fat diet (4.6 vs 15.6% fatby wt). Food intake (FI), body weight (BW), bodycomposition, and serum lipids were measuredduring treatment with optimized doses ofolanzapine, quetiapine, and risperidone. Energyintake (EI) and feed efficiency (FE) werecalculated. Group differences in change wereanalyzed via repeated measures analysis ofvariance (ANOVA). Serum lipid concentrations,EI and FE were compared using two-wayANOVA.Results:AAD-treated mice gained", "metadata": {}}
+{"_id": "13000926", "title": "", "text": "The role of free radicals in cold injuries.Coldinjury is a tissue trauma produced by exposureto freezing temperatures and even briefexposure to a severely cold and windyenvironment. Rewarming of frozen tissue isassociated with blood reperfusion and thesimultaneous generation of free oxygen radicals.In this review is discussed the currentunderstanding of the mechanism of action of freeoxygen radicals as related to cold injury duringrewarming. Decreased energy stores duringischaemia lead to the accumulation of adeninenucleotides and liberation of free fatty acids dueto the breakdown of lipid membranes. Onrewarming, free fatty acids are metabolized viacyclo-oxygenase and adenine nucleotides aremetabolized via the xanthine oxidase pathway.These may be the source of free oxygen radicals.Leukocytes may also play a major role in thepathogenesis of cold injury. Oxygen radicalscavengers, such as superoxide dismutase andcatalase, may help to reduce the cold induced", "metadata": {}}
+{"_id": "13001323", "title": "", "text": "SIRT1 deacetylase in SF1 neurons protectsagainst metabolic imbalance.Chronic feeding onhigh-calorie diets causes obesity and type 2diabetes mellitus (T2DM), illnesses that affecthundreds of millions. Thus, understanding thepathways protecting against diet-inducedmetabolic imbalance is of paramount medicalimportance. Here, we show that mice lackingSIRT1 in steroidogenic factor 1 (SF1) neuronsare hypersensitive to dietary obesity owing tomaladaptive energy expenditure. Also, mutantmice have increased susceptibility to developingdietary T2DM due to insulin resistance in skeletalmuscle. Mechanistically, these aberrations arise,in part, from impaired metabolic actions of theneuropeptide orexin-A and the hormone leptin.Conversely, mice overexpressing SIRT1 in SF1neurons are more resistant to diet-inducedobesity and insulin resistance due to increasedenergy expenditure and enhanced skeletalmuscle insulin sensitivity. Our results unveilimportant protective roles of SIRT1 in SF1", "metadata": {}}
+{"_id": "13002003", "title": "", "text": "mTOR supports long-term self-renewal andsuppresses mesoderm and endoderm activitiesof human embryonic stem cells.Despite therecent identification of the transcriptionalregulatory circuitry involving SOX2, NANOG, andOCT-4, the intracellular signaling networks thatcontrol pluripotency of human embryonic stemcells (hESCs) remain largely undefined. Here, wedemonstrate an essential role for theserine/threonine protein kinase mammaliantarget of rapamycin (mTOR) in regulating hESClong-term undifferentiated growth. Inhibition ofmTOR impairs pluripotency, prevents cellproliferation, and enhances mesoderm andendoderm activities in hESCs. At the molecularlevel, mTOR integrates signals from extrinsicpluripotency-supporting factors and repressesthe transcriptional activities of a subset ofdevelopmental and growth-inhibitory genes, asrevealed by genome-wide microarray analyses.Repression of the developmental genes by mTORis necessary for the maintenance of hESC", "metadata": {}}
+{"_id": "13007205", "title": "", "text": "Intrinsic genetic characteristics determinetumor-modifying capacity of fibroblasts: matrixmetalloproteinase-3 5A/5A genotype enhancesbreast cancer cell invasionStromal fibroblasts cancontribute to tumor invasion through the releaseof matrix metalloproteinases (MMPs). Populationstudies have suggested that single nucleotidepolymorphisms (SNPs) in MMP genes influencelevels of expression and may be associated withbreast cancer risk and with disease progression.This study directly examined the impact of MMPSNP genotype on the ability of host fibroblasts topromote tumor cell invasion. Primary breastfibroblasts were isolated from patients with (n =13) or without (n = 19) breast cancer, and theirability to promote breast cancer cell invasion wasmeasured in in vitro invasion assays. Fibroblastinvasion-promoting capacity (IPC) was analyzedin relation to donor type (tumor or non-tumorpatient), MMP-1, MMP-3, and MMP-9 SNPgenotype and MMP activity using independentsamples t test and analysis of variance. All", "metadata": {}}
+{"_id": "13011249", "title": "", "text": "Hallmarks of Cancer: The Next GenerationThehallmarks of cancer comprise six biologicalcapabilities acquired during the multistepdevelopment of human tumors. The hallmarksconstitute an organizing principle for rationalizingthe complexities of neoplastic disease. Theyinclude sustaining proliferative signaling, evadinggrowth suppressors, resisting cell death,enabling replicative immortality, inducingangiogenesis, and activating invasion andmetastasis. Underlying these hallmarks aregenome instability, which generates the geneticdiversity that expedites their acquisition, andinflammation, which fosters multiple hallmarkfunctions. Conceptual progress in the last decadehas added two emerging hallmarks of potentialgenerality to this list-reprogramming of energymetabolism and evading immune destruction. Inaddition to cancer cells, tumors exhibit anotherdimension of complexity: they contain arepertoire of recruited, ostensibly normal cellsthat contribute to the acquisition of hallmark", "metadata": {}}
+{"_id": "13023410", "title": "", "text": "BCR/ABL oncogenic kinase promotes unfaithfulrepair of the reactive oxygen species-dependentDNA double-strand breaks.The oncogenicBCR/ABL tyrosine kinase induces constitutiveDNA damage in Philadelphia chromosome(Ph)-positive leukemia cells. We find thatBCR/ABL-induced reactive oxygen species(ROSs) cause chronic oxidative DNA damageresulting in double-strand breaks (DSBs) in Sand G(2)/M cell cycle phases. These lesions arerepaired by BCR/ABL-stimulated homologousrecombination repair (HRR) and nonhomologousend-joining (NHEJ) mechanisms. A high mutationrate is detected in HRR products inBCR/ABL-positive cells, but not in the normalcounterparts. In addition, large deletions arefound in NHEJ products exclusively in BCR/ABLcells. We propose that the following series ofevents may contribute to genomic instability ofPh-positive leukemias: BCR/ABL --> ROSs -->oxidative DNA damage --> DSBs in proliferatingcells --> unfaithful HRR and NHEJ repair.", "metadata": {}}
+{"_id": "13025574", "title": "", "text": "Cancer risks attributable to low doses of ionizingradiation: assessing what we really know.Highdoses of ionizing radiation clearly producedeleterious consequences in humans, including,but not exclusively, cancer induction. At very lowradiation doses the situation is much less clear,but the risks of low-dose radiation are of societalimportance in relation to issues as varied asscreening tests for cancer, the future of nuclearpower, occupational radiation exposure,frequent-flyer risks, manned space exploration,and radiological terrorism. We review thedifficulties involved in quantifying the risks oflow-dose radiation and address two specificquestions. First, what is the lowest dose of x- orgamma-radiation for which good evidence existsof increased cancer risks in humans? Theepidemiological data suggest that it isapproximately 10-50 mSv for an acute exposureand approximately 50-100 mSv for a protractedexposure. Second, what is the most appropriateway to extrapolate such cancer risk estimates to", "metadata": {}}
+{"_id": "13027590", "title": "", "text": "Laparoscopic uterosacral nerve ablation foralleviating chronic pelvic pain: a randomizedcontrolled trial.CONTEXT Chronic pelvic pain is acommon condition with a major effect onhealth-related quality of life, work productivity,and health care use. Operative interruption ofnerve trunks in the uterosacral ligaments bylaparoscopic uterosacral nerve ablation (LUNA) isa treatment option for patients with chronicpelvic pain. OBJECTIVE To assess theeffectiveness of LUNA in patients with chronicpelvic pain. DESIGN, SETTING, ANDPARTICIPANTS Randomized controlled trial of487 women with chronic pelvic pain lastinglonger than 6 months without or with minimalendometriosis, adhesions, or pelvic inflammatorydisease, who were recruited to the study byconsultant gynecological surgeons from 18 UKhospitals between February 1998 and December2005. Follow-up was conducted byquestionnaires mailed at 3 and 6 months and at1, 2, 3, and 5 years. INTERVENTION Bilateral", "metadata": {}}
+{"_id": "13030852", "title": "", "text": "Identification of bone and liver metastases frombreast cancer by measurement of plasmaalkaline phosphatase isoenzyme activity.Plasmaalkaline phosphatase isoenzyme activities weredetermined in patients with breast cancer todiagnose and monitor bone and liver metastases.Bone alkaline phosphatase activity was increasedin 21 of 50 patients (42%) with radiologicallyconfirmed bone metastases, while total alkalinephosphatase activity was increased in only 10 of50 (20%); liver alkaline phosphatase activitywas raised in 12 of 25 patients (48%) with livermetastases. All patients with liver metastaseshad bone metastases. Bone alkaline phosphataseactivity was significantly higher in patients withsymptomatic bone disease. Isoenzymedetermination provided additional informationthat would have changed patient management infive of 20 patients who were monitored serially.Measurement of alkaline phosphatase isoenzymeactivity, though less sensitive than imagingprocedures, can assist in screening for, and in", "metadata": {}}
+{"_id": "13031967", "title": "", "text": "Recommendations on how to ensure the safetyand effectiveness of biosimilars in Latin America:a point of viewThe use of biotechnology-derivedmedicines has significantly increased in recentdecades. Although biosimilars undergo rigorouscharacterization as well as clinical studies todocument their safety and effectiveness, theyare highly complex molecules and small changesin the purification and production process of abiosimilar can have major implications in itssafety and effectiveness profile. In LatinAmerica, regulatory authorities have begun toestablish well-described and standardizedpathways that permit a biosimilar to gaincommercial licensure. In order to be certain thata biosimilar reaches its potential in ordinaryclinical use, an intensive post-licensingmonitoring system must be established since it isthe only means to ascertain the true similaritybetween the original biologic and its biosimilar.Pharmacovigilance allows national authorities todetermine a drug's performance in the", "metadata": {}}
+{"_id": "13036442", "title": "", "text": "Coordinated regulation of sulfur and phospholipidmetabolism reflects the importance ofmethylation in the growth of yeastA yeast strainlacking Met4p, the primary transcriptionalregulator of the sulfur assimilation pathway,cannot synthesize methionine. This apparentlysimple auxotroph did not grow well in rich mediacontaining excess methionine, forming smallcolonies on yeast extract/peptone/dextroseplates. Faster-growing large colonies wereabundant when overnight cultures were plated,suggesting that spontaneous suppressors of thegrowth defect arise with high frequency. Toidentify the suppressor mutations, we usedgenome-wide single-nucleotide polymorphismand standard genetic analyses. The mostcommon suppressors were loss-of-functionmutations in OPI1, encoding a transcriptionalrepressor of phospholipid metabolism. Using anew system that allows rapid and specificdegradation of Met4p, we could study thedynamic expression of all genes following loss of", "metadata": {}}
+{"_id": "13042119", "title": "", "text": "Glossary of reference terms for alternative testmethods and their validation.This glossary wasdeveloped to provide technical references tosupport work in the field of the alternatives toanimal testing. It was compiled from variousexisting reference documents coming fromdifferent sources and is meant to be a point ofreference on alternatives to animal testing.Giving the ever-increasing number of alternativetest methods and approaches being developedover the last decades, a combination, revision,and harmonization of earlier published collectionsof terms used in the validation of such methodsis required. The need to update previousglossary efforts came from the acknowledgementthat new words have emerged with thedevelopment of new approaches, while othershave become obsolete, and the meaning of someterms has partially changed over time. With thisglossary we intend to provide guidance on issuesrelated to the validation of new or updatedtesting methods consistent with current", "metadata": {}}
+{"_id": "13048272", "title": "", "text": "Combinatorial transcriptional control in bloodstem/progenitor cells: genome-wide analysis often major transcriptionalregulators.Combinatorial transcription factor (TF)interactions control cellular phenotypes and,therefore, underpin stem cell formation,maintenance, and differentiation. Here, wereport the genome-wide binding patterns andcombinatorial interactions for ten key regulatorsof blood stem/progenitor cells (SCL/TAL1, LYL1,LMO2, GATA2, RUNX1, MEIS1, PU.1, ERG, FLI-1,and GFI1B), thus providing the mostcomprehensive TF data set for any adultstem/progenitor cell type to date. Genome-widecomputational analysis of complex bindingpatterns, followed by functional validation,revealed the following: first, a previouslyunrecognized combinatorial interaction betweena heptad of TFs (SCL, LYL1, LMO2, GATA2,RUNX1, ERG, and FLI-1). Second, we implicatedirect protein-protein interactions between fourkey regulators (RUNX1, GATA2, SCL, and ERG)", "metadata": {}}
+{"_id": "13069283", "title": "", "text": "Influence of CYP2D6 Polymorphisms on SerumLevels of Tamoxifen Metabolites in SpanishWomen with Breast CancerBACKGROUNDEstrogen receptor-positive breast cancer tumorsdepend on estrogen signaling for their growthand replication and can be treated byanti-estrogen therapy with tamoxifen.Polymorphisms of the CYP2D6 and CYP2C19genes are associated with an impaired responseto tamoxifen. The study objective was toinvestigate the impact of genetic polymorphismsin CYP2D6 and CYP2C19 on thepharmacokinetics of tamoxifen and itsmetabolites in Spanish women with estrogenreceptor-positive breast cancer who werecandidates for tamoxifen therapy. METHODS Westudied 90 women with estrogenreceptor-positive breast cancer, using theAmpliChip CYP450 test to determine CYP2D6 andCYP2C19 gene variants. Plasma levels oftamoxifen and its metabolites were quantified byhigh-performance liquid chromatography.", "metadata": {}}
+{"_id": "13070316", "title": "", "text": "Role of tumor associated macrophages in tumorangiogenesis and lymphangiogenesisTumorangiogenesis is an essential process forsupplying rapidly growing malignant tissues withessential nutrients and oxygen. An angiogenicswitch allows tumor cells to survive and grow,and provides them access to vasculatureresulting in metastatic disease.Monocyte-derived macrophages recruited andreprogrammed by tumor cells serve as a majorsource of angiogenic factors boosting theangiogenic switch. Tumor endothelium releasesangiopoietin-2 and further facilitates recruitmentof TIE2 receptor expressing monocytes (TEM)into tumor sites. Tumor-associated macrophages(TAM) sense hypoxia in avascular areas oftumors, and react by production of angiogenicfactors such as VEGFA. VEGFA stimulateschemotaxis of endothelial cells (EC) andmacrophages. In some tumors, TAM appeared tobe a major source of MMP9. Elevated expressionof MMP9 by TAM mediates extracellular matrix", "metadata": {}}
+{"_id": "13071728", "title": "", "text": "The HIV Treatment Gap: Estimates of theFinancial Resources Needed versus Available forScale-Up of Antiretroviral Therapy in 97Countries from 2015 to 2020BACKGROUND TheWorld Health Organization (WHO) releasedrevised guidelines in 2015 recommending that allpeople living with HIV, regardless of CD4 count,initiate antiretroviral therapy (ART) upondiagnosis. However, few studies have projectedthe global resources needed for rapid scale-up ofART. Under the Health Policy Project, weconducted modeling analyses for 97 countries toestimate eligibility for and numbers on ART from2015 to 2020, along with the facility-levelfinancial resources required. We compared theestimated financial requirements to estimatedfunding available. METHODS AND FINDINGSCurrent coverage levels and future need fortreatment were based on country-specificepidemiological and demographic data.Simulated annual numbers of individuals ontreatment were derived from three scenarios: (1)", "metadata": {}}
+{"_id": "13072112", "title": "", "text": "Distinction and relationship between elongationrate and processivity of RNA polymerase II invivo.A number of proteins and drugs have beenimplicated in the process of transcriptionalelongation by RNA polymerase (Pol) II, but thefactors that govern the elongation rate(nucleotide additions per min) and processivity(nucleotide additions per initiation event) in vivoare poorly understood. Here, we show that amutation in the Rpb2 subunit of Pol II reducesboth the elongation rate and processivity in vivo.In contrast, none of the putative elongationfactors tested affect the elongation rate,although mutations in the THO complex and inSpt4 significantly reduce processivity. The drugs6-azauracil and mycophenolic acid reduce boththe elongation rate and processivity, and thisprocessivity defect is aggravated by mutations inSpt4, TFIIS, and CTDK-1. Our results suggestthat, in vivo, a reduced rate of Pol II elongationleads to premature dissociation along thechromatin template and that Pol II processivity", "metadata": {}}
+{"_id": "13072113", "title": "", "text": "Neurite sprouting and synapse deterioration inthe aging Caenorhabditis elegans nervoussystem.Caenorhabditis elegans is a powerfulmodel for analysis of the conserved mechanismsthat modulate healthy aging. In the agingnematode nervous system, neuronal deathand/or detectable loss of processes are notreadily apparent, but because dendriterestructuring and loss of synaptic integrity arehypothesized to contribute to human braindecline and dysfunction, we combinedfluorescence microscopy and electron microscopy(EM) to screen at high resolution for nervoussystem changes. We report two majorcomponents of morphological change in theaging C. elegans nervous system: (1)accumulation of novel outgrowths from specificneurons, and (2) physical decline in synapticintegrity. Novel outgrowth phenotypes, includingbranching from the main dendrite or new growthfrom somata, appear at a high frequency insome aging neurons, but not all. Mitochondria", "metadata": {}}
+{"_id": "13083189", "title": "", "text": "Determinants of adolescent physical activity andinactivity patterns.OBJECTIVES Despiterecognition of the important influence ofenvironmental determinants on physical activitypatterns, minimal empirical research has beendone to assess the impact ofenvironmental/contextual determinants ofphysical activity. This article aims to investigateenvironmental and sociodemographicdeterminants of physical activity and inactivitypatterns among subpopulations of USadolescents. We define environmentaldeterminants as modifiable factors in thephysical environment that impose a directinfluence on the opportunity to engage inphysical activity. The present research examinesenvironmental and sociodemographicdeterminants of physical activity and inactivitywith the implication that these findings can pointtoward societal-level intervention strategies forincreasing physical activity and decreasinginactivity among adolescents. STUDY DESIGN", "metadata": {}}
+{"_id": "13097856", "title": "", "text": "Suicide prevention strategies: a systematicreview.CONTEXT In 2002, an estimated 877,000lives were lost worldwide through suicide. Somedeveloped nations have implemented nationalsuicide prevention plans. Although these plansgenerally propose multiple interventions, theireffectiveness is rarely evaluated. OBJECTIVES Toexamine evidence for the effectiveness of specificsuicide-preventive interventions and to makerecommendations for future preventionprograms and research. DATA SOURCES ANDSTUDY SELECTION Relevant publications wereidentified via electronic searches of MEDLINE,the Cochrane Library, and PsychINFO databasesusing multiple search terms related to suicideprevention. Studies, published between 1966and June 2005, included those that evaluatedpreventative interventions in major domains;education and awareness for the general publicand for professionals; screening tools for at-riskindividuals; treatment of psychiatric disorders;restricting access to lethal means; and", "metadata": {}}
+{"_id": "13106686", "title": "", "text": "Oxidative damage of DNA confers resistance tocytosolic nuclease TREX1 degradation andpotentiates STING-dependent immunesensing.Immune sensing of DNA is critical forantiviral immunity but can also triggerautoimmune diseases such as lupuserythematosus (LE). Here we have providedevidence for the involvement of adamage-associated DNA modification in thedetection of cytosolic DNA. The oxidized base8-hydroxyguanosine (8-OHG), a marker ofoxidative damage in DNA, potentiated cytosolicimmune recognition by decreasing itssusceptibility to 3' repair exonuclease 1(TREX1)-mediated degradation. Oxidizativemodifications arose physiologically in pathogenDNA during lysosomal reactive oxygen species(ROS) exposure, as well as in neutrophilextracellular trap (NET) DNA during the oxidativeburst. 8-OHG was also abundant in UV-exposedskin lesions of LE patients and colocalized withtype I interferon (IFN). Injection of oxidized DNA", "metadata": {}}
+{"_id": "13108582", "title": "", "text": "IL-18 induction of osteopontin mediates cardiacfibrosis and diastolic dysfunction inmice.Osteopontin (OPN), a key component of theextracellular matrix, is associated with thefibrotic process during tissue remodeling. OPNand the cytokine interleukin (IL)-18 have beenshown to be overexpressed in an array of humancardiac pathologies. In the present study, wedetermined the role of IL-18 in the regulation ofcardiac OPN expression and the subsequentinterstitial fibrosis and diastolic dysfunction. Wedemonstrated parallel increases in IL-18, OPNexpression, and interstitial fibrosis in murinemodels of left ventricular pressure and volumeoverload. Exogenous recombinant (r)IL-18administered for 2 wk increased cardiac OPNexpression, interstitial fibrosis, and diastolicdysfunction. Stimulation of the T helper (Th)1lymphocyte phenotype with a selective toll-likereceptor (TLR)9 agonist induced cardiac IL-18and OPN expression, which was associated withincreased cardiac fibrillar collagen concentrations", "metadata": {}}
+{"_id": "13116880", "title": "", "text": "Hematopoietic stem cell: self-renewal versusdifferentiation.The mammalian blood system,containing more than 10 distinct mature celltypes, stands on one specific cell type,hematopoietic stem cell (HSC). Within thesystem, only HSCs possess the ability of bothmultipotency and self-renewal. Multipotency isthe ability to differentiate into all functional bloodcells. Self-renewal is the ability to give rise toHSC itself without differentiation. Since matureblood cells (MBCs) are predominantly short-lived,HSCs continuously provide more differentiatedprogenitors while properly maintaining the HSCpool size throughout life by precisely balancingself-renewal and differentiation. Thus,understanding the mechanisms of self-renewaland differentiation of HSC has been a centralissue. In this review, we focus on the hierarchicalstructure of the hematopoietic system, thecurrent understanding of microenvironment andmolecular cues regulating self-renewal anddifferentiation of adult HSCs, and the currently", "metadata": {}}
+{"_id": "13123189", "title": "", "text": "RSEM: accurate transcript quantification fromRNA-Seq data with or without a referencegenomeBACKGROUND RNA-Seq isrevolutionizing the way transcript abundancesare measured. A key challenge in transcriptquantification from RNA-Seq data is the handlingof reads that map to multiple genes or isoforms.This issue is particularly important forquantification with de novo transcriptomeassemblies in the absence of sequencedgenomes, as it is difficult to determine whichtranscripts are isoforms of the same gene. Asecond significant issue is the design of RNA-Seqexperiments, in terms of the number of reads,read length, and whether reads come from oneor both ends of cDNA fragments. RESULTS Wepresent RSEM, an user-friendly software packagefor quantifying gene and isoform abundancesfrom single-end or paired-end RNA-Seq data.RSEM outputs abundance estimates, 95%credibility intervals, and visualization files andcan also simulate RNA-Seq data. In contrast to", "metadata": {}}
+{"_id": "13135544", "title": "", "text": "A synthetic Escherichia coli predator–preyecosystemWe have constructed a syntheticecosystem consisting of two Escherichia colipopulations, which communicate bi-directionallythrough quorum sensing and regulate eachother's gene expression and survival viaengineered gene circuits. Our syntheticecosystem resembles canonical predator-preysystems in terms of logic and dynamics. Thepredator cells kill the prey by inducingexpression of a killer protein in the prey, whilethe prey rescue the predators by elicitingexpression of an antidote protein in the predator.Extinction, coexistence and oscillatory dynamicsof the predator and prey populations are possibledepending on the operating conditions asexperimentally validated by long-term culturingof the system in microchemostats. A simplemathematical model is developed to capturethese system dynamics. Coherent interplaybetween experiments and mathematical analysisenables exploration of the dynamics of", "metadata": {}}
+{"_id": "13162391", "title": "", "text": "Funnel trap for the capture of phlebotomine sandflies (Diptera: Psychodidae) from tree holes.Afunnel trap that fitted over holes leading intohollow trees was used to capture adultphlebotomine sand flies, Lutzomyia shannoniDyar, on Ossabaw Island, Chatham County, Ga.These insects rested in hollow trees during theday and were collected by funnel traps as theyegressed from the tree holes at night. The trap islightweight, durable, inexpensive, waterproof,and selective. Using this trap, greater than 100healthy L. shannoni ++were captured per nightby a single investigator during July and August1988 when adult flies were abundant on theisland.", "metadata": {}}
+{"_id": "13172737", "title": "", "text": "Cystine/glutamate exchange regulatesmetabotropic glutamate receptor presynapticinhibition of excitatory transmission andvulnerability to cocaine seeking.Withdrawal fromchronic cocaine reduces extracellular glutamatelevels in the nucleus accumbens by decreasingcystine/glutamate exchange (xc-). Activating xc-with N-acetylcysteine restores extracellularglutamate and prevents cocaine-induced drugseeking. It was hypothesized that the activationof xc- prevents drug seeking by increasingglutamatergic tone on presynaptic group IImetabotropic glutamate receptors (mGluR2/3)and thereby inhibiting excitatory transmission. Inthe first experiment, the capacity of glutamatederived from xc- to regulate excitatorytransmission via mGluR2/3 was determined.Physiological levels of cystine (100-300 nm)were restored to acute tissue slices from thenucleus accumbens or prefrontal cortex. Cystineincreased glutamate efflux and decreasedminiature EPSC (mEPSC) and spontaneous EPSC", "metadata": {}}
+{"_id": "13179318", "title": "", "text": "Survival analysis: time-dependent effects andtime-varying risk factors.In traditionalKaplan-Meier or Cox regression analysis, usuallya risk factor measured at baseline is related tomortality thereafter. During follow-up, however,things may change: either the effect of a fixedbaseline risk factor may vary over time, resultingin a weakening or strengthening of associationsover time, or the risk factor itself may vary overtime. In this paper, short-term versus long-termeffects (so-called time-dependent effects) of afixed baseline risk factor are addressed. Anexample is presented showing that underweightis a strong risk factor for mortality in dialysispatients, especially in the short run. In contrast,overweight is a risk factor for mortality, which isstronger in the long run than in the short run. Inaddition, the analysis of how time-varying riskfactors (so-called time-dependent risk factors)are related to mortality is demonstrated bypaying attention to the pitfall of adjusting forsequelae. The proper analysis of effects over", "metadata": {}}
+{"_id": "13189693", "title": "", "text": "Control of interneuron dendritic growth throughNRG1/erbB4-mediated kalirin-7disinhibitionNeuregulin 1 (NRG1) is a secretedtrophic factor that activates the postsynapticerbB4 receptor tyrosine kinase. Both NRG1 anderbB4 have been repeatedly associated withschizophrenia, but their downstream targets arenot well characterized. ErbB4 is highly abundantin interneurons, and NRG1-mediated erbB4activation has been shown to modulateinterneuron function, but the role forNRG1-erbB4 signaling in regulating interneurondendritic growth is not well understood. Here weshow that NRG1/erbB4 promote the growth ofdendrites in mature interneurons through kalirin,a major dendritic Rac1-GEF. Recent studies haveshown associations of the KALRN gene withschizophrenia. Our data point to an essential roleof phosphorylation in kalirin-7's C terminus asthe critical site for these effects. As reducedinterneuron dendrite length occurs inschizophrenia, understanding how NRG1-erbB4", "metadata": {}}
+{"_id": "13205096", "title": "", "text": "Use of gene-expression profiling to identifyprognostic subclasses in adult acute myeloidleukemia.BACKGROUND In patients with acutemyeloid leukemia (AML), the presence orabsence of recurrent cytogenetic aberrations isused to identify the appropriate therapy.However, the current classification system doesnot fully reflect the molecular heterogeneity ofthe disease, and treatment stratification isdifficult, especially for patients withintermediate-risk AML with a normal karyotype.METHODS We used complementary-DNAmicroarrays to determine the levels of geneexpression in peripheral-blood samples or bonemarrow samples from 116 adults with AML(including 45 with a normal karyotype). We usedunsupervised hierarchical clustering analysis toidentify molecular subgroups with distinctgene-expression signatures. Using a training setof samples from 59 patients, we applied a novelsupervised learning algorithm to devise agene-expression-based clinical-outcome", "metadata": {}}
+{"_id": "13205803", "title": "", "text": "Perspectives on public health workforceresearch.The Centers for Disease Control andPrevention Office of Workforce and CareerDevelopment is committed to developing acompetent, sustainable, and diverse publichealth workforce through evidence-basedtraining, career and leadership development, andstrategic workforce planning to improvepopulation health outcomes. This article reviewsthe previous efforts in identifying priorities ofpublic health workforce research, which aresummarized as eight major research themes. Weoutline a strategic framework for public healthworkforce research that includes six functionalareas (ie, definition and standards, data,methodology, evaluation, policy, anddissemination and translation). To conceptualizeand prioritize development of an actionablepublic health research agenda, we constructed amatrix of key challenges in workforce analysis bypublic health workforce categories. Extensivereviews were conducted to identify valuable", "metadata": {}}
+{"_id": "13221399", "title": "", "text": "Gene targeting using zinc finger nucleasesTheability to achieve site-specific manipulation of themammalian genome has widespread implicationsfor basic and applied research. Gene targeting isa process in which a DNA molecule introducedinto a cell replaces the correspondingchromosomal segment by homologousrecombination, and thus presents a precise wayto manipulate the genome. In the past, theapplication of gene targeting to mammalian cellshas been limited by its low efficiency. Zinc fingernucleases (ZFNs) show promise in improving theefficiency of gene targeting by introducing DNAdouble-strand breaks in target genes, which thenstimulate the cell's endogenous homologousrecombination machinery. Recent results haveshown that ZFNs can be used to create targetingfrequencies of up to 20% in a humandisease-causing gene. Future work will beneeded to translate these in vitro findings to invivo applications and to determine whether zincfinger nucleases create undesired genomic", "metadata": {}}
+{"_id": "13223806", "title": "", "text": "relative expression results in real-timeReal-timereverse transcription followed by polymerasechain reaction (RT-PCR) is the most suitablemethod for the detection and quantification ofmRNA. It offers high sensitivity, goodreproducibility and a wide quantification range.Today, relative expression is increasingly used,where the expression of a target gene isstandardised by a non-regulated reference gene.Several mathematical algorithms have beendeveloped to compute an expression ratio, basedon real-time PCR efficiency and the crossingpoint deviation of an unknown sample versus acontrol. But all published equations and availablemodels for the calculation of relative expressionratio allow only for the determination of a singletranscription difference between one control andone sample. Therefore a new software tool wasestablished, named REST (relative expressionsoftware tool), which compares two groups, withup to 16 data points in a sample and 16 in acontrol group, for reference and up to four target", "metadata": {}}
+{"_id": "13223957", "title": "", "text": "Pain attacks in non-complicated and complicatedgallstone disease have a characteristic patternand are accompanied by dyspepsia in mostpatients: the results of a prospectivestudy.OBJECTIVE The cardinal indication forsurgical treatment of gallstones is pain attacks.However, following cholecystectomy, 20% ofpatients remain symptomatic. It is unclear towhat extent post-cholecystectomy symptoms canbe ascribed to persistence of preoperativesymptoms or to new pathology. The pain anddigestive pattern in gallstone patients has notbeen defined in a recent setting withultrasonography as the diagnostic method. Theaim of this study was to characterize a painpattern that is typical for gallstone disease andto describe the extent of associated dyspepsia.MATERIAL AND METHODS A total of 220 patientswith symptomatic gallstone disease includingcomplicated disease (acute cholecystitis andcommon bile duct stones) were interviewedusing detailed questionnaires to disclose pain", "metadata": {}}
+{"_id": "13230773", "title": "", "text": "Prevalence and cardiovascular disease correlatesof low cardiorespiratory fitness in adolescentsand adults.CONTEXT Population surveys indicatethat physical activity levels are low in the UnitedStates. One consequence of inactivity, lowcardiorespiratory fitness, is an established riskfactor for cardiovascular disease (CVD) morbidityand mortality, but the prevalence ofcardiorespiratory fitness has not been quantifiedin representative US population samples.OBJECTIVES To describe the prevalence of lowfitness in the US population aged 12 through 49years and to relate low fitness to CVD risk factorsin this population. DESIGN, SETTING, ANDPARTICIPANTS Inception cohort study using datafrom the cross-sectional nationallyrepresentative National Health and NutritionExamination Survey 1999-2002. Participantswere adolescents (aged 12-19 years; n = 3110)and adults (aged 20-49 years; n = 2205) freefrom previously diagnosed CVD who underwentsubmaximal graded exercise treadmill testing to", "metadata": {}}
+{"_id": "13231899", "title": "", "text": "In situ regulation of DC subsets and T cellsmediates tumor regression in mice.Vaccines arelargely ineffective for patients with establishedcancer, as advanced disease requires potent andsustained activation of CD8(+) cytotoxic Tlymphocytes (CTLs) to kill tumor cells and clearthe disease. Recent studies have found thatsubsets of dendritic cells (DCs) specialize inantigen cross-presentation and in the productionof cytokines, which regulate both CTLs and Tregulatory (Treg) cells that shut down effector Tcell responses. Here, we addressed thehypothesis that coordinated regulation of a DCnetwork, and plasmacytoid DCs (pDCs) andCD8(+) DCs in particular, could enhance hostimmunity in mice. We used functionalizedbiomaterials incorporating various combinationsof an inflammatory cytokine, immune dangersignal, and tumor lysates to control theactivation and localization of host DC populationsin situ. The numbers of pDCs and CD8(+) DCs,and the endogenous production of", "metadata": {}}
+{"_id": "13235609", "title": "", "text": "VEGF inhibits tumor cell invasion andmesenchymal transition through a MET/VEGFR2complex.Inhibition of VEGF signaling leads to aproinvasive phenotype in mouse models ofglioblastoma multiforme (GBM) and in a subsetof GBM patients treated with bevacizumab. Here,we demonstrate that vascular endothelial growthfactor (VEGF) directly and negatively regulatestumor cell invasion through enhancedrecruitment of the protein tyrosine phosphatase1B (PTP1B) to a MET/VEGFR2 heterocomplex,thereby suppressing HGF-dependent METphosphorylation and tumor cell migration.Consequently, VEGF blockade restores andincreases MET activity in GBM cells in ahypoxia-independent manner, while inducing aprogram reminiscent ofepithelial-to-mesenchymal transition highlightedby a T-cadherin to N-cadherin switch andenhanced mesenchymal features. Inhibition ofMET in GBM mouse models blocks mesenchymaltransition and invasion provoked by VEGF", "metadata": {}}
+{"_id": "13242763", "title": "", "text": "Interaction between Oct3/4 and Cdx2Determines TrophectodermDifferentiationTrophectoderm (TE), the firstdifferentiated cell lineage of mammalianembryogenesis, forms the placenta, a structureunique to mammalian development. Thedifferentiation of TE is a hallmark event in earlymammalian development, but molecularmechanisms underlying this first differentiationevent remain obscure. Embryonic stem (ES) cellscan be induced to differentiate into the TElineage by forced repression of the POU-familytranscription factor, Oct3/4. We show here thatthis event can be mimicked by overexpression ofCaudal-related homeobox 2 (Cdx2), which issufficient to generate proper trophoblast stem(TS) cells. Cdx2 is dispensable for trophectodermdifferentiation induced by Oct3/4 repression butessential for TS cell self-renewal. Inpreimplantation embryos, Cdx2 is initiallycoexpressed with Oct3/4 and they form acomplex for the reciprocal repression of their", "metadata": {}}
+{"_id": "13244602", "title": "", "text": "SSEA-1 is an enrichment marker fortumor-initiating cells in humanglioblastoma.CD133+ populations of humanglioblastoma multiforme (GBM) cells arereportedly enriched for tumor stem cells (TSCs)or tumor-initiating cells (TICs). Approximately40% of freshly isolated GBM specimens,however, do not contain CD133+ tumor cells,raising the possibility that CD133 may not be auniversal enrichment marker for GBM TSCs/TICs.Here we demonstrate that stage-specificembryonic antigen 1(SSEA-1/LeX)+ GBM cellsfulfill the functional criteria for TSC/TIC, since (1)SSEA-1+ cells are highly tumorigenic in vivo,unlike SSEA-1- cells; (2) SSEA-1+ cells can giverise to both SSEA-1+ and SSEA-1- cells, therebyestablishing a cellular hierarchy; and (3)SSEA-1+ cells have self-renewal andmultilineage differentiation potentials. A distinctsubpopulation of SSEA-1+ cells was present inall but one of the primary GBMs examined (n =24), and most CD133+ tumor cells were also", "metadata": {}}
+{"_id": "13245542", "title": "", "text": "Temporal regulation of topoisomerase IV activityin E. coli.We isolated a mutant allele of dnaX,encoding the tau and gamma subunits of theDNA polymerase III holoenzyme, that causesextreme cell filamentation but does not affecteither cell growth or DNA replication. Thisphenotype results from a defect in daughterchromosome decatenation during rapid growth.In these cells, ParC, one subunit oftopoisomerase IV, no longer associated with thereplication factory, as occurs in wild-type cells,and was instead distributed uniformly on thenucleoid; the distribution of ParE, the othersubunit of topoisomerase IV, was unaffected. Inaddition, the majority of topoisomerase IVactivity in synchronized cell populations wasrestricted to late in the cell cycle, whenreplication was essentially complete. Theseobservations suggest that topoisomerase IVactivity in vivo might be dependent on release ofParC from the replication factory.", "metadata": {}}
+{"_id": "13256155", "title": "", "text": "Molecularly targeted therapy based on tumourmolecular profiling versus conventional therapyfor advanced cancer (SHIVA): a multicentre,open-label, proof-of-concept, randomised,controlled phase 2 trial.BACKGROUNDMolecularly targeted agents have been reportedto have anti-tumour activity for patients whosetumours harbour the matching molecularalteration. These results have led to increasedoff-label use of molecularly targeted agents onthe basis of identified molecular alterations. Weassessed the efficacy of several molecularlytargeted agents marketed in France, which werechosen on the basis of tumour molecular profilingbut used outside their indications, in patientswith advanced cancer for whom standard-of-caretherapy had failed. METHODS The open-label,randomised, controlled phase 2 SHIVA trial wasdone at eight French academic centres. Weincluded adult patients with any kind ofmetastatic solid tumour refractory to standard ofcare, provided they had an Eastern Cooperative", "metadata": {}}
+{"_id": "13277039", "title": "", "text": "CRTC2 (TORC2) contributes to the transcriptionalresponse to fasting in the liver but is notrequired for the maintenance of glucosehomeostasis.The liver contributes to glucosehomeostasis by promoting either storage orproduction of glucose, depending on thephysiological state. The cAMP responseelement-binding protein (CREB) is a principalregulator of genes involved in coordinating thehepatic response to fasting, but its mechanism ofgene activation remains controversial. Wederived CRTC2 (CREB-regulated transcriptioncoactivator 2, previously TORC2)-deficient miceto assess the contribution of this cofactor tohepatic glucose metabolism in vivo. CRTC2mutant hepatocytes showed reduced glucoseproduction in response to glucagon, whichcorrelated with decreased CREB binding toseveral gluconeogenic genes. However, despiteattenuated expression of CREB target genes,including PEPCK, G6Pase, and PGC-1alpha, nohypoglycemia was observed in mutant mice.", "metadata": {}}
+{"_id": "13277118", "title": "", "text": "Ancient Hybridization and an Irish Origin for theModern Polar Bear MatrilineBACKGROUND Polarbears (Ursus maritimus) are among thosespecies most susceptible to the rapidly changingarctic climate, and their survival is of globalconcern. Despite this, little is known about polarbear species history. Future conservationstrategies would significantly benefit from anunderstanding of basic evolutionary information,such as the timing and conditions of their initialdivergence from brown bears (U. arctos) or theirresponse to previous environmental change.RESULTS We used a spatially explicitphylogeographic model to estimate the dynamicsof 242 brown bear and polar bear matrilinessampled throughout the last 120,000 years andacross their present and past geographic ranges.Our results show that the present distribution ofthese matrilines was shaped by a combination ofregional stability and rapid, long-distancedispersal from ice-age refugia. In addition,hybridization between polar bears and brown", "metadata": {}}
+{"_id": "13277623", "title": "", "text": "FBW7 ubiquitin ligase: a tumour suppressor atthe crossroads of cell division, growth anddifferentiationFBW7 (F-box and WD repeatdomain-containing 7) is the substrate recognitioncomponent of an evolutionary conserved SCF(complex of SKP1, CUL1 and F-box protein)-typeubiquitin ligase. SCFFBW7 degrades severalproto-oncogenes that function in cellular growthand division pathways, including MYC, cyclin E,Notch and JUN. FBW7 is also a tumoursuppressor, the regulatory network of which isperturbed in many human malignancies.Numerous cancer-associated mutations in FBW7and its substrates have been identified, and lossof FBW7 function causes chromosomal instabilityand tumorigenesis. This Review focuses onstructural and functional aspects of FBW7 and itsrole in the development of cancer.", "metadata": {}}
+{"_id": "13282296", "title": "", "text": "Hypoglycemic episodes and risk of dementia inolder patients with type 2 diabetesmellitus.CONTEXT Although acute hypoglycemiamay be associated with cognitive impairment inchildren with type 1 diabetes, no studies to datehave evaluated whether hypoglycemia is a riskfactor for dementia in older patients with type 2diabetes. OBJECTIVE To determine ifhypoglycemic episodes severe enough to requirehospitalization are associated with an increasedrisk of dementia in a population of older patientswith type 2 diabetes followed up for 27 years.DESIGN, SETTING, AND PATIENTS A longitudinalcohort study from 1980-2007 of 16,667 patientswith a mean age of 65 years and type 2 diabeteswho are members of an integrated health caredelivery system in northern California. MAINOUTCOME MEASURE Hypoglycemic events from1980-2002 were collected and reviewed usinghospital discharge and emergency departmentdiagnoses. Cohort members with no priordiagnoses of dementia, mild cognitive", "metadata": {}}
+{"_id": "13283919", "title": "", "text": "Defective mast cell effector functions in micelacking the CRACM1 pore subunit ofstore-operated calcium release–activatedcalcium channelsCRACM1 (also called Orai1)constitutes the pore subunit of store-operatedcalcium release–activated calcium channels. Apoint mutation in the gene encoding CRACM1 isassociated with severe combinedimmunodeficiency disease in humans. Here wegenerated CRACM1-deficient mice in whichβ-galactosidase activity 'reported' CRACM1expression. CRACM1-deficient mice were smallerin size. Mast cells derived from CRACM1-deficientmice showed grossly defective degranulation andcytokine secretion, and the allergic reactionselicited in vivo were inhibited inCRACM1-deficient mice. We detected robustCRACM1 expression in skeletal muscles andsome regions of the brain, heart and kidney butnot in the lymphoid regions of thymus andspleen. In contrast, we found CRACM2expression to be much higher in mouse T cells.", "metadata": {}}
+{"_id": "13290521", "title": "", "text": "MicroRNA-7: A miRNA with expanding roles indevelopment and disease.MicroRNAs (miRNAs)are a family of short, non-coding RNA molecules(\u000022nt) involved in post-transcriptional controlof gene expression. They act via base-pairingwith mRNA transcripts that harbour targetsequences, resulting in accelerated mRNA decayand/or translational attenuation. Given miRNAsmediate the expression of molecules involved inmany aspects of normal cell development andfunctioning, it is not surprising that aberrantmiRNA expression is closely associated withmany human diseases. Their pivotal role indriving a range of normal cellular physiology aswell as pathological processes has establishedmiRNAs as potential therapeutics, as well aspotential diagnostic and prognostic tools inhuman health. MicroRNA-7 (miR-7) is a highlyconserved miRNA which displays restrictedspatiotemporal expression during developmentand in maturity. In humans and mice, maturemiR-7 is generated from three different genes,", "metadata": {}}
+{"_id": "13293033", "title": "", "text": "Integration-free induced pluripotent stem cellsmodel genetic and neural developmentalfeatures of down syndrome etiology.Downsyndrome (DS) is the most frequent cause ofhuman congenital mental retardation. Cognitivedeficits in DS result from perturbations of normalcellular processes both during development andin adult tissues, but the mechanisms underlyingDS etiology remain poorly understood. To assessthe ability of induced pluripotent stem cells(iPSCs) to model DS phenotypes, as aprototypical complex human disease, wegenerated bona fide DS and wild-type (WT)nonviral iPSCs by episomal reprogramming. DSiPSCs selectively overexpressed chromosome 21genes, consistent with gene dosage, which wasassociated with deregulation of thousands ofgenes throughout the genome. DS and WT iPSCswere neurally converted at >95% efficiency andhad remarkably similar lineage potency,differentiation kinetics, proliferation, and axonextension at early time points. However, at later", "metadata": {}}
+{"_id": "13296399", "title": "", "text": "In Vivo CRISPR/Cas9 Gene Editing CorrectsRetinal Dystrophy in the S334ter-3 Rat Model ofAutosomal Dominant RetinitisPigmentosaReliable genome editing via ClusteredRegularly Interspaced Short Palindromic Repeat(CRISPR)/Cas9 may provide a means to correctinherited diseases in patients. As proof ofprinciple, we show that CRISPR/Cas9 can beused in vivo to selectively ablate the rhodopsingene carrying the dominant S334ter mutation(Rho(S334)) in rats that model severe autosomaldominant retinitis pigmentosa. A singlesubretinal injection of guide RNA/Cas9 plasmid incombination with electroporation generatedallele-specific disruption of Rho(S334), whichprevented retinal degeneration and improvedvisual function.", "metadata": {}}
+{"_id": "13312471", "title": "", "text": "Vitamin D insufficiency and the blunted PTHresponse in established osteoporosis: the role ofmagnesium deficiencyVitamin D insufficiency iscommon, however within individuals, not allmanifest the biochemical effects of PTH excess.This further extends to patients with establishedosteoporosis. The mechanism underlying theblunted PTH response is unclear but may berelated to magnesium (Mg) deficiency. The aimsof this study were to compare in patients withestablished osteoporosis and differing degrees ofvitamin D and PTH status : (1) the presence ofMg deficiency using the standard Mg loading test(2) evaluate the effects of Mg loading on thecalcium-PTH endocrine axis (3) determine theeffects of oral, short term Mg supplementationon the calcium-PTH endocrine axis and boneturnover. 30 patients (10 women in 3 groups)were evaluated prospectively measuring calcium,PTH, Mg retention (Mg loading test), dietarynutrient intake (calcium, vitamin D, Mg) andbone turnover markers (serum CTX & P1CP).", "metadata": {}}
+{"_id": "13322804", "title": "", "text": "Novel syndromes associated with JC virusinfection of neurons and meningeal cells: nolonger a gray area.PURPOSE OF REVIEW Theavailability of a growing number ofimmunomodulatory medications over the pastfew years has been associated with various JCvirus (JCV)-associated brain syndromes inpatients with autoimmune diseases, includingmultiple sclerosis, Crohn's disease, and psoriasisthat had not been previously recognized aspredisposing factors for progressive multifocalleukoencephalopathy. This review covers thethree novel syndromes discovered in the lastdecade that are caused by JCV infection ofneurons and meningeal cells. RECENT FINDINGSFor more than 30 years, JCV was thought toexclusively infect oligodendrocytes andastrocytes in the white matter of the brain ofimmunosuppressed individuals. We nowrecognize that JCV-infected glial cells arefrequently located at the gray-white matterjunction or exclusively within the gray matter", "metadata": {}}
+{"_id": "13329980", "title": "", "text": "Phosphoinositide 3-kinase signalling pathways intumor progression, invasion andangiogenesis.AIMS AND BACKGROUND The PI3kinase signalling pathway is now accepted asbeing at least as important as the ras-MAPkinase pathway in cell survival and proliferation,and hence its potential role in cancer is of greatinterest. The purpose of this review is briefly toexamine evidence for an involvement of PI3K inhuman cancers, discuss the mechanisms bywhich its activation promotes tumor progression,and consider its utility as a novel target foranticancer therapy. METHODS AND STUDYDESIGN A Medline review of recent literatureconcerning the role of PI3 kinase in tumorprogression--mechanisms of action and clinicalimplications. RESULTS Evidence is presentedthat misregulation of the PI3 kinase pathway is afeature of many common cancers, either by lossof the suppressor protein PTEN, or byconstitutive activation of PI3 kinase isoforms ordownstream elements such as AKT and mTOR.", "metadata": {}}
+{"_id": "13338820", "title": "", "text": "Complementary foods for infant feeding indeveloping countries: their nutrient adequacyand improvementObjective: To assess theenergy and nutrient adequacy of a variety ofcomplementary foods used in parts of Africa,India, Papua New Guinea, the Philippines andThailand. Method: The energy, nutrient andanti-nutrient (dietary fibre and phytic acid)content (per 100 g as eaten, per 100 kcal, andper day) of twenty-three plant-basedcomplementary foods consumed in developingcountries was calculated from food compositionvalues based on chemical analysis for the traceminerals, non-starch polysaccharide and phyticacid, and the literature. Results were comparedwith the estimated nutrient needs (per day; per100 kcal) from complementary foods for infants9–11 months, assuming a breast milk intake ofaverage volume and composition and threecomplementary feedings per day, each of 250 g.Results: Complementary foods should provideapproximately 25–50% of total daily", "metadata": {}}
+{"_id": "13350374", "title": "", "text": "Early aging and age-related pathologies in micedeficient in BMAL1, the core componentof thecircadian clock.Mice deficient in the circadiantranscription factor BMAL1 (brain and muscleARNT-like protein) have impaired circadianbehavior and demonstrate loss of rhythmicity inthe expression of target genes. Here we reportthat Bmal1(-/-) mice have reduced lifespans anddisplay various symptoms of premature agingincluding sarcopenia, cataracts, lesssubcutaneous fat, organ shrinkage, and others.The early aging phenotype correlates withincreased levels of reactive oxygen species insome tissues of the Bmal1(-/- )animals. Thesefindings, together with data onCLOCK/BMAL1-dependent control of stressresponses, may provide a mechanisticexplanation for the early onset of age-relatedpathologies in the absence of BMAL1.", "metadata": {}}
+{"_id": "13368032", "title": "", "text": "A self-inactivating lentiviral vector for SCID-X1gene therapy that does not activate LMO2expression in human T cells.To develop safer andmore effective vectors for gene therapy ofX-linked severe combined immunodeficiency(SCID-X1), we have evaluated newself-inactivating lentiviral vectors based on theHIV virus. The CL20i4-hgamma(c)-Revgenvector contains the entire human commongamma chain (gamma(c)) genomic sequencedriven by the gamma(c) promoter. TheCL20i4-EF1alpha-hgamma(c)OPT vector uses apromoter fragment from the eukaryoticelongation factor alpha (EF1alpha) gene toexpress a codon-optimized human gamma(c)cDNA. Both vectors contain a 400-bp insulatorfragment from the chicken beta-globin locuswithin the self-inactivating long-terminal repeat.Transduction of bone marrow cells using either ofthese vectors restored T, B, and natural killerlymphocyte development and function in amouse SCID-X1 transplantation model.", "metadata": {}}
+{"_id": "13373629", "title": "", "text": "Genetic Variants at Newly Identified Lipid LociAre Associated with Coronary Heart Disease in aChinese Han PopulationBACKGROUND Recentgenome-wide association studies (GWAS) havemapped several novel loci influencing blood lipidlevels in Caucasians. We sought to explorewhether the genetic variants at newly identifiedlipid-associated loci were associated with CHDsusceptibility in a Chinese Han population.METHODOLOGY/PRINCIPAL FINDINGS Weconducted a two-stage case-control study in aChinese Han population. The first-stage,consisting of 1,376 CHD cases and 1,376 sex andage- frequency matched controls, examined 5novel lipid-associated single-nucleotidepolymorphisms (SNPs) identified from GWASamong Caucasians in relation to CHD risk inChinese. We then validated significant SNPs inthe second-stage, consisting of 1,269 cases and2,745 controls. We also tested associationsbetween SNPs within the five novel loci andblood lipid levels in 4,121 controls. We identified", "metadata": {}}
+{"_id": "13380011", "title": "", "text": "Spare respiratory capacity rather than oxidativestress regulates glutamate excitotoxicity afterpartial respiratory inhibition of mitochondrialcomplex I with rotenone.Partial inhibition ofmitochondrial respiratory complex I by rotenonereproduces aspects of Parkinson's disease inrodents. The hypothesis that rotenoneenhancement of neuronal cell death isattributable to oxidative stress was tested in anacute glutamate excitotoxicity model usingprimary cultures of rat cerebellar granuleneurons. As little as 5 nM rotenone increasedmitochondrial superoxide (O2*-) levels andpotentiated glutamate-induced cytoplasmic Ca2+deregulation, the first irreversible stage ofnecrotic cell death. However, the potentcell-permeant O2*- trap manganese tetrakis(N-ethylpyridinium-2yl) porphyrin failed toprevent the effects of the inhibitor. Thebioenergetic consequences of rotenone additionwere quantified by monitoring cell respiration.Glutamate activation of NMDA receptors used the", "metadata": {}}
+{"_id": "13380980", "title": "", "text": "Isolated liver perfusion for non-resectable livertumours: a review.Many treatments have beenproposed for non-resectable primary orsecondary hepatic cancer but the results havegenerally been disappointing. Isolated HepaticPerfusion (IHP) was first attempted four decadesago but it gained acceptance only recently, afterspectacular tumour responses were obtained byisolated limb perfusion with melphalan andtumour necrosis factor (TNF) for melanomas andsarcomas. Surgical isolation of the liver is atechnically demanding operation that allows thesafe administration of high doses ofchemotherapeutics and TNF. Percutaneoustechniques using balloon occlusion catheters aresimpler but result in higher leakage rates fromthe perfusion circuit into the systemic circulation.Several phase I-II trials indicate that IHP canyield high tumour response rates, even whenthere is resistance to systemic chemotherapy.However, no significant advantage in overallsurvival has been demonstrated so far. IHP", "metadata": {}}
+{"_id": "13384318", "title": "", "text": "Combinatorial control of exonrecognition.Pre-mRNA splicing is a fundamentalprocess required for the expression of mostmetazoan genes. It is carried out by thespliceosome, which catalyzes the removal ofnoncoding intronic sequences to assemble exonsinto mature mRNAs prior to export andtranslation. Given the complexity of highereukaryotic genes and the relatively low level ofsplice site conservation, the precision of thesplicing machinery in recognizing and pairingsplice sites is impressive. Introns ranging in sizefrom <100 up to 100,000 bases are removedefficiently. At the same time, a large number ofalternative splicing events are observed betweendifferent cell types, during development, orduring other biological processes. This extensivealternative splicing implies a significant flexibilityof the spliceosome to identify and process exonswithin a given pre-mRNA. To reach thisflexibility, splice site selection in highereukaryotes has evolved to depend on multiple", "metadata": {}}
+{"_id": "13398997", "title": "", "text": "High CTLA-4 expression on Th17 cells results inincreased sensitivity to CTLA-4 coinhibition andresistance to belatacept.The CD28/cytotoxicT-lymphocyte antigen 4 (CTLA-4)blockerbelatacept selectively inhibits alloreactive T cellresponses but is associated with a high incidenceof acute rejection following renaltransplantation,which led us to investigate theetiology of belatacept–resistant graft rejection. Tcells can differentiate into functionally distinctsubsets of memory T cellsthat collectively enableprotection against diverse classes of pathogensand can cross-react with allogeneicantigen andmediate graft rejection. T helper 17(Th17) cellsare a pro-inflammatory CD4+ lineage thatprovides immunity to pathogens and arepathogenic in autoimmune disease. We foundthat T helper 1 (Th1)and Th17 memorycompartments contained a similar frequency ofdivided cells following allogeneic stimulation.Compared to Th1 cells, Th17 memory cellsexpressed significantly higher levels of the", "metadata": {}}
+{"_id": "13400643", "title": "", "text": "A small molecule modulates Jumonji histonedemethylase activity and selectively inhibitscancer growthThe pharmacological inhibition ofgeneral transcriptional regulators has thepotential to block growth through targetingmultiple tumorigenic signalling pathwayssimultaneously. Here, using an innovativecell-based screen, we identify a structurallyunique small molecule (named JIB-04) thatspecifically inhibits the activity of the Jumonjifamily of histone demethylases in vitro, in cancercells, and in tumours in vivo. Unlike knowninhibitors, JIB-04 is not a competitive inhibitor ofα-ketoglutarate. In cancer, but not inpatient-matched normal cells, JIB-04 alters asubset of transcriptional pathways and blocksviability. In mice, JIB-04 reduces tumour burdenand prolongs survival. Importantly, we find thatpatients with breast tumours that overexpressJumonji demethylases have significantly lowersurvival. Thus, JIB-04, a novel inhibitor ofJumonji demethylases in vitro and in vivo,", "metadata": {}}
+{"_id": "13411519", "title": "", "text": "Gq protein alpha subunits Galphaq and Galpha11are localized at postsynaptic extra-junctionalmembrane of cerebellar Purkinje cells andhippocampal pyramidal cells.Following cellsurface receptor activation, the alpha subunit ofthe Gq subclass of GTP-binding proteinsactivates the phosphoinositide signallingpathway. Here we examined the expression andlocalization of Gq protein alpha subunits in theadult mouse brain by in situ hybridization andimmunohistochemistry. Of the four members ofthe Gq protein alpha subunits, Galphaq andGalpha11 were transcribed predominantly in thebrain. The highest transcriptional level ofGalphaq was observed in cerebellar Purkinje cells(PCs) and hippocampal pyramidal cells, whilethat of Galpha11 was noted in hippocampalpyramidal cells. Antibody against the C-terminalpeptide common to Galphaq and Galpha11strongly labelled the cerebellar molecular layerand hippocampal neuropil layers. In theseregions, immunogold preferentially labelled the", "metadata": {}}
+{"_id": "13439128", "title": "", "text": "The Bloom's syndrome gene product ishomologous to RecQ helicasesThe Bloom'ssyndrome (BS) gene, BLM, plays an importantrole in the maintenance of genomic stability insomatic cells. A candidate for BLM was identifiedby direct selection of a cDNA derived from a 250kb segment of the genome to which BLM hadbeen assigned by somatic crossover pointmapping. In this novel mapping method, cellswere used from persons with BS that hadundergone intragenic recombination within BLM.cDNA analysis of the candidate gene identified a4437 bp cDNA that encodes a 1417 amino acidpeptide with homology to the RecQ helicases, asubfamily of DExH box-containing DNA and RNAhelicases. The presence of chain-terminatingmutations in the candidate gene in persons withBS proved that it was BLM.", "metadata": {}}
+{"_id": "13441037", "title": "", "text": "Preventing obesity in children and adolescents.Inthis review, we address the natural history ofobesity in children, the most promising family-and school-based approaches to the preventionof obesity, and the barriers and opportunitiesassociated with secondary prevention. Inchildhood, the most important periods of riskappear to be the periods of adiposity reboundand adolescence. Caution regarding the period ofadiposity rebound is still warranted, because it isnot yet clear that early rebound is attributable tochanges in body fat. Families and schoolsrepresent the most important foci for preventiveefforts in children and adolescents. Oneproductive approach is to proceed from anexamination of factors that affect energy balanceto the identification of more proximal influenceson those factors. This approach may help tonarrow the strategies necessary to prevent ortreat childhood obesity. For example, televisionviewing affects both energy intake and energyexpenditure, and therefore represents a logical", "metadata": {}}
+{"_id": "13441537", "title": "", "text": "Culture of Preimplantation Mouse EmbryosAffects Fetal Development and the Expression ofImprinted Genes1Abstract Culture ofpreimplantation mammalian embryos and cellscan influence their subsequent growth anddifferentiation. Previously, we reported thatculture of mouse embryonic stem cells isassociated with deregulation of genomicimprinting and affects the potential for thesecells to develop into normal fetuses. The purposeof our current study was to determine whetherculture of preimplantation mouse embryos in achemically defined medium (M16) with orwithout fetal calf serum (FCS) can affect theirsubsequent development and imprinted geneexpression. Only one third of the blastocysts thathad been cultured from two-cell embryos in M16medium complemented with FCS developed intoviable Day 14 fetuses after transfer intorecipients. These M16 + FCS fetuses werereduced in weight as compared with controls andM16 fetuses and had decreased expression of the", "metadata": {}}
+{"_id": "13445579", "title": "", "text": "Results of screening for intracranial aneurysms inpatients with coarctation of theaorta.BACKGROUND AND PURPOSE IAs arefound in 2.3% of adults; the mean age atdetection is 52 years. Prevalence is <0.5% inyoung adults. Early studies suggest that10%-50% of patients with aortic coarctationhave IAs. Screening recommendations arevariable. We sought to examine the prevalenceof IAs through screening with MRA. MATERIALSAND METHODS Consecutive patients older than16 years of age with coarctation undergoingbrain MRA between May 1999 and October 2007were included. MRA was performed by using a1.5T scanner with a 3D time-of-flight protocol;simultaneous MR imaging was performed of theheart and aorta. Cerebral MRAs weredouble-reported by a neuroradiologist. Statisticsare described as mean ± SD and median ±range. Continuous variables were compared byusing Student t tests and Mann-Whitney U tests(categoric variables, by using the Fisher exact", "metadata": {}}
+{"_id": "13448422", "title": "", "text": "A new look at the heart in diabetes mellitus:from ailing to failingThis review discusses someof the mechanisms inherent in diabetes thatpredispose patients to increased cardiacmorbidity and mortality. Single photon emissioncomputerized tomography or photon emissiontomography with radioactive labeled analoguesof norepinephrine have shown that cardiacsympathetic dysfunction and incompetence areearly and also late abnormalities in patients withType I (insulin-dependent) and Type II(non-insulin-dependent) diabetes mellitus.Furthermore, myocardial blood flow assessmentwith photon emission tomography has shownthat in patients without myocardial perfusiondeficits, endothelial-dependent vasodilatation isseverely reduced in relation to cardiacsympathetic dysfunction. In addition, signs ofendothelial activation have also been found earlyin patients with Type I and Type II diabetes inwhom vascular disease has not been clinicallydetected. This activation in conjunction with", "metadata": {}}
+{"_id": "13450938", "title": "", "text": "Genetic and epigenetic mutations affect the DNAbinding capability of human ZFP57 in transientneonatal diabetes type 1In the mouse, ZFP57contains three classical Cys2His2 zinc fingerdomains (ZF) and recognizes the methylatedTGC(met)CGC target sequence using the firstand the second ZFs. In this study, wedemonstrate that the human ZFP57 (hZFP57)containing six Cys2His2 ZFs, binds the samemethylated sequence through the third and thefourth ZFs, and identify the aminoacids criticalfor DNA interaction. In addition, we presentevidences indicating that hZFP57 mutations andhypomethylation of the TNDM1 ICR bothassociated with Transient Neonatal DiabetesMellitus type 1 result in loss of hZFP57 binding tothe TNDM1 locus, likely causing PLAGL1activation.", "metadata": {}}
+{"_id": "13458119", "title": "", "text": "Physiological astrocytic calcium levels stimulateglutamate release to modulate adjacentneurons.Astrocytes can release glutamate in acalcium-dependent manner and consequentlysignal to adjacent neurons. Whether thisglutamate release pathway is used duringphysiological signaling or is recruited only underpathophysiological conditions is not well defined.One reason for this lack of understanding is thelimited knowledge about the levels of calciumnecessary to stimulate glutamate release fromastrocytes and about how they compare with therange of physiological calcium levels in thesecells. We used flash photolysis to raise internalcalcium in astrocytes, while monitoring astrocyticcalcium levels and glutamate, which evoked slowinward currents that were recordedelectrophysiologically from single neurons grownon microislands of astrocytes. With thisapproach, we demonstrate that modest changesof astrocytic calcium, from 84 to 140 nM, evokesubstantial glutamatergic currents in neighboring", "metadata": {}}
+{"_id": "13464392", "title": "", "text": "Albumin and furosemide therapy inhypoproteinemic patients with acute lunginjury.OBJECTIVE Hypoproteinemia, fluidretention, and weight gain are associated withdevelopment of acute lung injury and mortalityin critically ill patients, without proof of causeand effect. We designed a clinical trial todetermine whether diuresis and colloidreplacement in hypoproteinemic patients withacute lung injury would improve pulmonaryphysiology. DESIGN Prospective, randomized,double-blind, placebo-controlled trial. SETTINGAll adult intensive care units from two universityhospitals. PATIENTS Thirty-sevenmechanically-ventilated patients with acute lunginjury and serum total protein </=5.0g/dL.   INTERVENTIONS Five-day protocolizedregimen of 25 g of human serum albumin every8 hrs with continuous infusion furosemide, ordual placebo, targeted to diuresis, weight loss,and serum total protein. MEASUREMENTS ANDMAIN RESULTS Measured outcomes included", "metadata": {}}
+{"_id": "13466517", "title": "", "text": "Advances in functional and structural mr imageanalysis and implementation as fslThetechniques available for the interrogation andanalysis of neuroimaging data have a largeinfluence in determining the flexibility,sensitivity, and scope of neuroimagingexperiments. The development of suchmethodologies has allowed investigators toaddress scientific questions that could notpreviously be answered and, as such, hasbecome an important research area in its ownright. In this paper, we present a review of theresearch carried out by the Analysis Group at theOxford Centre for Functional MRI of the Brain(FMRIB). This research has focussed on thedevelopment of new methodologies for theanalysis of both structural and functionalmagnetic resonance imaging data. The majorityof the research laid out in this paper has beenimplemented as freely available software toolswithin FMRIB's Software Library (FSL).", "metadata": {}}
+{"_id": "13466622", "title": "", "text": "Metformin—mode of action and clinicalimplications for diabetes and cancerMetforminhas been the mainstay of therapy for diabetesmellitus for many years; however, themechanistic aspects of metformin actionremained ill-defined. Recent advances revealedthat this drug, in addition to its glucose-loweringaction, might be promising for specificallytargeting metabolic differences between normaland abnormal metabolic signalling. Theknowledge gained from dissecting the principalmechanisms by which metformin works can helpus to develop novel treatments. The centre ofmetformin's mechanism of action is thealteration of the energy metabolism of the cell.Metformin exerts its prevailing, glucose-loweringeffect by inhibiting hepatic gluconeogenesis andopposing the action of glucagon. The inhibition ofmitochondrial complex I results in defectivecAMP and protein kinase A signalling in responseto glucagon. Stimulation of 5′-AMP-activatedprotein kinase, although dispensable for the", "metadata": {}}
+{"_id": "13469921", "title": "", "text": "Characteristics of the Earliest Cross-NeutralizingAntibody Response to HIV-1Recentcross-sectional analyses of HIV-1+ plasmas haveindicated that broadly cross-reactive neutralizingantibody responses are developed by 10%-30%of HIV-1+ subjects. The timing of the initialdevelopment of such anti-viral responses isunknown. It is also unknown whether theemergence of these responses coincides with theappearance of antibody specificities to a single ormultiple regions of the viral envelopeglycoprotein (Env). Here we analyzed thecross-neutralizing antibody responses inlongitudinal plasmas collected soon after and upto seven years after HIV-1 infection. We find thatanti-HIV-1 cross-neutralizing antibody responsesfirst become evident on average at 2.5 yearsand, in rare cases, as early as 1 year followinginfection. If cross-neutralizing antibodyresponses do not develop during the first 2-3years of infection, they most likely will not do sosubsequently. Our results indicate a potential", "metadata": {}}
+{"_id": "13481731", "title": "", "text": "Gender, age, and heart failure with preservedleft ventricular systolic function.OBJECTIVES Thisstudy was designed to determine if women aremore likely than men to have heart failure (HF)with preserved systolic function after adjustmentfor potential confounders, including age.BACKGROUND Although prior evidence suggestsan independent association between femalegender and preserved left ventricular systolicfunction (LVSF) in patients with HF, existingstudies are limited by referral biases, smallsample sizes, or the inability to adjust for a widerange of potential confounding variables.METHODS This is a cross-sectional study usingdata from retrospective medical chart abstractionof a national sample of Medicare beneficiarieshospitalized with the principal dischargediagnosis of HF in acute-care nongovernmentalhospitals in the U.S. between April 1998 andMarch 1999. Patients were eligible for thisanalysis if they were age 65 years or older, haddocumentation of LVSF, and corroboration of the", "metadata": {}}
+{"_id": "13481880", "title": "", "text": "YAP/TAZ-Dependent Reprogramming of ColonicEpithelium Links ECM Remodeling to TissueRegenerationTissue regeneration requiresdynamic cellular adaptation to the woundenvironment. It is currently unclear how this isorchestrated at the cellular level and how cellfate is affected by severe tissue damage. Herewe dissect cell fate transitions during colonicregeneration in a mouse dextran sulfate sodium(DSS) colitis model, and we demonstrate thatthe epithelium is transiently reprogrammed intoa primitive state. This is characterized by denovo expression of fetal markers as well assuppression of markers for adult stem anddifferentiated cells. The fate change isorchestrated by remodeling the extracellularmatrix (ECM), increased FAK/Src signaling, andultimately YAP/TAZ activation. In a defined cellculture system recapitulating the extracellularmatrix remodeling observed in vivo, we showthat a collagen 3D matrix supplemented withWnt ligands is sufficient to sustain endogenous", "metadata": {}}
+{"_id": "13492264", "title": "", "text": "SummaryGlomerular basement membrane(GBM) and podocalyxin are essential forpodocyte morphology. We provide evidence offunctional interconnections between basementmembrane components (collagen IV andlaminin), the expression of podocalyxin and themorphology of human glomerular epithelial cells(podocytes). We demonstrated that GBM andlaminin, but not collagen IV, up-regulated theexpression of podocalyxin. Scanning electronmicroscopy revealed that laminin induced amodified morphology of podocytes with processformation, which was more extensive in thepresence of GBM. Under high magnification,podocytes appeared ruffled. Using transmissionelectron microscopy we observed that raisedareas occurred in the basal cell surface.Furthermore, the presence of anti-podocalyxinantibody increased the extent of adhesion andspreading of podocytes to both collagen IV andlaminin, thus podocalyxin apparently inhibitscell-matrix interactions. We also performed", "metadata": {}}
+{"_id": "13494853", "title": "", "text": "Mfold web server for nucleic acid folding andhybridization predictionThe abbreviated name,'mfold web server', describes a number of closelyrelated software applications available on theWorld Wide Web (WWW) for the prediction of thesecondary structure of single stranded nucleicacids. The objective of this web server is toprovide easy access to RNA and DNA folding andhybridization software to the scientificcommunity at large. By making use ofuniversally available web GUIs (Graphical UserInterfaces), the server circumvents the problemof portability of this software. Detailed output, inthe form of structure plots with or withoutreliability information, single strand frequencyplots and 'energy dot plots', are available for thefolding of single sequences. A variety of 'bulk'servers give less information, but in a shortertime and for up to hundreds of sequences atonce. The portal for the mfold web server ishttp://www.bioinfo.rpi.edu/applications/mfold.This URL will be referred to as 'MFOLDROOT'.", "metadata": {}}
+{"_id": "13496853", "title": "", "text": "Grip strength in healthy caucasian adults:reference values.PURPOSE The aim of this studywas to update reference data of handgripstrength for healthy adults of both gendersspanning a wide age range and to analyzepossible factors of influence. METHODSIntraindividual and interindividual variations ofgrip strength and their relation to severalanthropometric factors were analyzed in astandardized manner for 769 healthy adults(women, n = 403; men, n = 366) aged between20 years and 95 years. Measurements were donein neutral position of arm, forearm, and wrist onsetting II of a Baseline digital hydraulicdynamometer (NexGen Ergonomics Inc. Quebec,Canada). RESULTS Mean strength was about41% less in women (right 29 kg; left 27 kg) thanin men (right 49 kg; left 47 kg) resulting in aratio of left to right hand slightly above .95 inboth genders. During the course of life, handstrength develops comparably in both genderspeaking at 35 years of age and decreasing", "metadata": {}}
+{"_id": "13497630", "title": "", "text": "Association Between Biomarkers of OvarianReserve and Infertility Among Older Women ofReproductive AgeImportance Despite lack ofevidence of their utility, biomarkers of ovarianreserve are being promoted as potential markersof reproductive potential. Objective To determinethe associations between biomarkers of ovarianreserve and reproductive potential amongwomen of late reproductive age. Design, Setting,and Participants Prospective time-to-pregnancycohort study (2008 to date of last follow-up inMarch 2016) of women (N = 981) aged 30 to 44years without a history of infertility who hadbeen trying to conceive for 3 months or less,recruited from the community in theRaleigh-Durham, North Carolina, area.Exposures Early-follicular-phase serum level ofantimüllerian hormone (AMH), follicle-stimulatinghormone (FSH), and inhibin B and urinary levelof FSH. Main Outcomes and Measures Theprimary outcomes were the cumulativeprobability of conception by 6 and 12 cycles of", "metadata": {}}
+{"_id": "13509809", "title": "", "text": "Matrix-embedded osteocytes regulatemobilization of hematopoietic stem/progenitorcells.The bone marrow (BM) niche comprisesmultiple cell types that regulate hematopoieticstem/progenitor cell (HSPC) migration out of theniche and into the circulation. Here, wedemonstrate that osteocytes, the major cellularcomponent of mature bone, are regulators ofHSPC egress. Granulocyte colony-stimulatingfactor (G-CSF), used clinically to mobilize HSPCs,induces changes in the morphology and geneexpression of the osteocytic network thatprecedes changes in osteoblasts. This rapidresponse is likely under control of thesympathetic nervous system, since osteocytesexpress the β2-adrenergic receptor and surgicalsympathectomy prevents it. Mice with targetedablation of osteocytes or a disrupted osteocytenetwork have comparable numbers of HSPCs inthe BM but fail to mobilize HSPCs in response toG-CSF. Taken together, these results indicatethat the BM/bone niche interface is critically", "metadata": {}}
+{"_id": "13513790", "title": "", "text": "Generation of Genetically Modified Mice byOocyte Injection of Androgenetic HaploidEmbryonic Stem CellsHaploid cells are amenablefor genetic analysis. Recent success in thederivation of mouse haploid embryonic stem cells(haESCs) via parthenogenesis has enabledgenetic screening in mammalian cells. However,successful generation of live animals from thesehaESCs, which is needed to extend the geneticanalysis to the organism level, has not beenachieved. Here, we report the derivation ofhaESCs from androgenetic blastocysts. Thesecells, designated as AG-haESCs, partiallymaintain paternal imprints, express classical ESCpluripotency markers, and contribute to varioustissues, including the germline, upon injectioninto diploid blastocysts. Strikingly, live mice canbe obtained upon injection of AG-haESCs intoMII oocytes, and these mice bear haESC-carriedgenetic traits and develop into fertile adults.Furthermore, gene targeting via homologousrecombination is feasible in the AG-haESCs. Our", "metadata": {}}
+{"_id": "13514898", "title": "", "text": "The impact of hydroxyethyl starches in cardiacsurgery: a meta-analysisINTRODUCTION Recentstudies in septic patients showed that adverseeffects of hydroxyethyl starches (HESs) possiblyoutweigh their benefits in severely impairedphysiological haemostasis. It remains unclearwhether this also applies to patient populationsthat are less vulnerable. In this meta-analysis,we evaluated the impact of various HESgenerations on safety and efficacy endpoints inpatients undergoing cardiac surgery. METHODSWe searched the PubMed, Embase and CochraneCentral Register of Controlled Trials databasesfor randomised controlled trials (RCTs) in theEnglish or German language comparing the useof HES to any other colloid or crystalloid duringopen heart surgery. RESULTS Blood loss andtransfusion requirements were higher for olderstarches with mean molecular weights more than200 kDa compared to other volume substitutes.In contrast, this effect was not observed withlatest-generation tetrastarches (130/0.4), which", "metadata": {}}
+{"_id": "13515165", "title": "", "text": "Place of care in advanced cancer: a qualitativesystematic literature review of patientpreferences.BACKGROUND It is commonlywritten that more patients wish to die at homethan currently achieve this. However, theevidence for preferences for place of terminalcare and death has not been systematicallyreviewed. AIM To carry out a systematicliterature review of the preferences for place ofcare and death among advanced cancer patients.METHOD Studies were identified usingsystematic database searches of MEDLINE(1966-1999), PsychLit (1974-1999), and BathInformation Data Service (BIDS) (1981-1999).Studies were assessed and data extracted andsynthesises following the NHS Centre forReviews and Dissemination guidelines, gradingstudies according to design and rigor of methods.Studies of preferences in the general populationand of groups including cancer patients and/ortheir caregivers were included. RESULTSEighteen studies determining preferences in", "metadata": {}}
+{"_id": "13519661", "title": "", "text": "Linkage Disequilibrium Mapping of       CHEK2:Common Variation and Breast CancerRiskBackground Checkpoint kinase 2 (CHEK2)averts cancer development by promoting cellcycle arrest and activating DNA repair ingenetically damaged cells. Previous investigationhas established a role for the CHEK2 gene inbreast cancer aetiology, but studies have largelybeen limited to the rare 1100delC mutation.Whether common polymorphisms in this geneinfluence breast cancer risk remains unknown. Inthis study, we aimed to assess the importance ofcommon CHEK2 variants on population risk forbreast cancer by capturing the majority ofdiversity in the gene using haplotype taggingsingle nucleotide polymorphisms (tagSNPs).Methods and Findings We analyzed 14 commonSNPs spanning 52 kilobases (kb) of the CHEK2gene in 92 Swedish women. Coverage evaluationindicated that these typed SNPs would efficientlyconvey association signal also from untypedSNPs in the same region. Six of the 14 SNPs", "metadata": {}}
+{"_id": "13552682", "title": "", "text": "Decoding Mammalian Ribosome-mRNA States byTranslational GTPase ComplexesIn eukaryotes,accurate protein synthesis relies on a family oftranslational GTPases that pair with specificdecoding factors to decipher the mRNA code onribosomes. We present structures of themammalian ribosome engaged with decodingfactor\u0000GTPase complexes representingintermediates of translation elongation(aminoacyl-tRNA\u0000eEF1A), termination(eRF1\u0000eRF3), and ribosome rescue(Pelota\u0000Hbs1l). Comparative analyses revealthat each decoding factor exploits the plasticityof the ribosomal decoding center to differentiallyremodel ribosomal proteins and rRNA. This leadsto varying degrees of large-scale ribosomemovements and implies distinct mechanisms forcommunicating information from the decodingcenter to each GTPase. Additional structuralsnapshots of the translation termination pathwayreveal the conformational changes thatchoreograph the accommodation of decoding", "metadata": {}}
+{"_id": "13573143", "title": "", "text": "Intestinal Cgi-58 Deficiency ReducesPostprandial Lipid AbsorptionComparative GeneIdentification-58 (CGI-58), a lipid droplet(LD)-associated protein, promotes intracellulartriglyceride (TG) hydrolysis in vitro. Mutations inhuman CGI-58 cause TG accumulation innumerous tissues including intestine.Enterocytes are thought not to store TG-rich LDs,but a fatty meal does induce temporary cytosolicaccumulation of LDs. Accumulated LDs areeventually cleared out, implying existence of TGhydrolytic machinery in enterocytes. However,identities of proteins responsible for LD-TGhydrolysis remain unknown. Here we report thatintestine-specific inactivation of CGI-58 in micesignificantly reduces postprandial plasma TGconcentrations and intestinal TG hydrolaseactivity, which is associated with a 4-foldincrease in intestinal TG content and largecytosolic LD accumulation in absorptiveenterocytes during the fasting state.Intestine-specific CGI-58 knockout mice also", "metadata": {}}
+{"_id": "13578199", "title": "", "text": "Transglutaminase 2 Undergoes a LargeConformational Change upon ActivationHumantransglutaminase 2 (TG2), a member of a largefamily of enzymes that catalyze proteincrosslinking, plays an important role in theextracellular matrix biology of many tissues andis implicated in the gluten-induced pathogenesisof celiac sprue. Although vertebratetransglutaminases have been studiedextensively, thus far all structurally characterizedmembers of this family have been crystallized inconformations with inaccessible active sites. Wehave trapped human TG2 in complex with aninhibitor that mimics inflammatory glutenpeptide substrates and have solved, at 2-Aresolution, its x-ray crystal structure. Theinhibitor stabilizes TG2 in an extendedconformation that is dramatically different fromearlier transglutaminase structures. The activesite is exposed, revealing that catalysis takesplace in a tunnel, bridged by two tryptophanresidues that separate acyl-donor from", "metadata": {}}
+{"_id": "13580614", "title": "", "text": "Lactic acidosis in patients with diabetes treatedwith metformin.To the Editor: From May 1995,when metformin was introduced in the UnitedStates, through June 30, 1996, the Food andDrug Administration (FDA) received reports oflactic acidosis in 66 patients treated withmetformin. In 47 patients, the diagnosis wasconfirmed on the basis of circulating lactatevalues (>5 mmol per liter), in accordance withestablished criteria for the diagnosis of lacticacidosis (Table 1).1,2 Of the 47 patients withconfirmed diagnoses, 43 had one or more riskfactors for lactic acidosis. Thirty (64 percent) hadpreexisting cardiac disease, of whom 18 hadhistories of congestive heart failure. . . .", "metadata": {}}
+{"_id": "13583521", "title": "", "text": "The Apaf-1 apoptosome induces formation ofcaspase-9 homo- and heterodimers with distinctactivitiesAccording to dogma, initiator caspasesare activated through proximity-inducedhomodimerization, but some studies infer thatduring apoptosis caspase-9 may instead form aholoenzyme with the Apaf-1 apoptosome. Usingseveral biochemical approaches, including anovel site-specific crosslinking technique, weprovide the first direct evidence thatprocaspase-9 homodimerizes within theapoptosome, markedly increasing its avidity forthe complex and inducing selectiveintramolecular cleavage at Asp-315. Remarkably,however, procaspase-9 could also bind via itssmall subunit to the NOD domain in Apaf-1,resulting in the formation of a heterodimer thatmore efficiently activated procaspase-3.Following cleavage, the intersubunit linker (andassociated conformational changes) incaspase-9-p35/p12 inhibited its ability to formhomo- and heterodimers, but feedback cleavage", "metadata": {}}
+{"_id": "13583615", "title": "", "text": "Repositioning of aurora B promoted by chiasmataensures sister chromatid mono-orientation inmeiosis I.During meiosis I, kinetochores of sisterchromatids are juxtaposed or fused andmono-orient, while homologous chromosomesthat are paired by chiasmata (bivalents) have tobiorient. In the absence of chiasmata,biorientation of sister chromatids (univalents),which carries a risk of aneuploidy, has beenoccasionally detected in several species,including humans. We show in fission yeast thatbiorientation of fused sister kinetochorespredominates during early prometaphase I.Without chiasmata, this undesirable biorientationof univalents persists and eventually evades thespindle assembly checkpoint, provokingabnormal anaphase. When univalents areconnected by chiasmata or by an artificial tether,this erroneous attachment is converted tomonopolar attachment and stabilized. Thisstabilization is apparently achieved by achromosome configuration that brings", "metadata": {}}
+{"_id": "13592721", "title": "", "text": "Biophysical Constraints Arising fromCompositional Context in Synthetic GeneNetworks.Synthetic gene expression is highlysensitive to intragenic compositional context(promoter structure, spacing regions betweenpromoter and coding sequences, and ribosomebinding sites). However, much less is knownabout the effects of intergenic compositionalcontext (spatial arrangement and orientation ofentire genes on DNA) on expression levels insynthetic gene networks. We compareexpression of induced genes arranged inconvergent, divergent, or tandem orientations.Induction of convergent genes yielded up to400% higher expression, greater ultrasensitivity,and dynamic range than divergent- ortandem-oriented genes. Orientation affects geneexpression whether one or both genes areinduced. We postulate that transcriptionalinterference in divergent and tandem genes,mediated by supercoiling, can explain differencesin expression and validate this hypothesis", "metadata": {}}
+{"_id": "13613916", "title": "", "text": "Glucose repression in SaccharomycescerevisiaeGlucose is the primary source ofenergy for the budding yeast Saccharomycescerevisiae. Although yeast cells can utilize a widerange of carbon sources, presence of glucosesuppresses molecular activities involved in theuse of alternate carbon sources as well as itrepresses respiration and gluconeogenesis. Thisdominant effect of glucose on yeast carbonmetabolism is coordinated by several signalingand metabolic interactions that mainly regulatetranscriptional activity but are also effective atpost-transcriptional and post-translational levels.This review describes effects of glucoserepression on yeast carbon metabolism with afocus on roles of the Snf3/Rgt2 glucose-sensingpathway and Snf1 signal transduction inestablishment and relief of glucose repression.", "metadata": {}}
+{"_id": "13614794", "title": "", "text": "The p21 Cdk-interacting protein Cip1 is a potentinhibitor of G1 cyclin-dependent kinases.Thecyclin-dependent kinase Cdk2 associates withcyclins A, D, and E and has been implicated inthe control of the G1 to S phase transition inmammals. To identify potential Cdk2 regulators,we have employed an improved two-hybridsystem to isolate human genes encodingCdk-interacting proteins (Cips). CIP1 encodes anovel 21 kd protein that is found in cyclin A,cyclin D1, cyclin E, and Cdk2immunoprecipitates. p21CIP1 is a potent,tight-binding inhibitor of Cdks and can inhibit thephosphorylation of Rb by cyclin A-Cdk2, cyclinE-Cdk2, cyclin D1-Cdk4, and cyclin D2-Cdk4complexes. Cotransfection experiments indicatethat CIP1 and SV40 T antigen function in amutually antagonistic manner to control cellcycle progression.", "metadata": {}}
+{"_id": "13618987", "title": "", "text": "Exploring the temporal structure ofheterochronous sequences using TempEst(formerly Path-O-Gen)Gene sequences sampledat different points in time can be used to infermolecular phylogenies on a natural timescale ofmonths or years, provided that the sequences inquestion undergo measurable amounts ofevolutionary change between sampling times.Data sets with this property are termedheterochronous and have become increasinglycommon in several fields of biology, mostnotably the molecular epidemiology of rapidlyevolving viruses. Here we introduce thecross-platform software tool, TempEst (formerlyknown as Path-O-Gen), for the visualization andanalysis of temporally sampled sequence data.Given a molecular phylogeny and the dates ofsampling for each sequence, TempEst uses aninteractive regression approach to explore theassociation between genetic divergence throughtime and sampling dates. TempEst can be usedto (1) assess whether there is sufficient temporal", "metadata": {}}
+{"_id": "13619127", "title": "", "text": "Diabetes treatments and risk of amputation,blindness, severe kidney failure, hyperglycaemia,and hypoglycaemia: open cohort study inprimary careOBJECTIVE To assess the risks ofamputation, blindness, severe kidney failure,hyperglycaemia, and hypoglycaemia in patientswith type 2 diabetes associated with prescribeddiabetes drugs, particularly newer agentsincluding gliptins or glitazones(thiazolidinediones). DESIGN Open cohort studyin primary care. SETTING 1243 practicescontributing data to the QResearch database inEngland. PARTICIPANTS 469,688 patients withtype 2 diabetes aged 25-84 years between 1April 2007 and 31 January 2015. EXPOSURESHypoglycaemic agents (glitazones, gliptins,metformin, sulphonylureas, insulin, and other)alone and in combination. MAIN OUTCOMEMEASURES First recorded diagnoses ofamputation, blindness, severe kidney failure,hyperglycaemia, and hypoglycaemia recorded onpatients' primary care, mortality, or hospital", "metadata": {}}
+{"_id": "13621186", "title": "", "text": "Vertebrate rod photoreceptors express both BKand IK calcium-activated potassium channels,but only BK channels are involved in receptorpotential regulation.In salamander rods,Ca(2+)-activated K(+) current (I(KCa)) providesan effective \"clamp\" of the dark membranepotential to its normal resting level. By acombination of electrophysiological,pharmacological, and immunohistochemicalapproaches, we show that salamander rodsfunctionally express large-conductance Ca(2+)-and voltage-dependent potassium (BK) channeland intermediate-conductanceCa(2+)-dependent potassium (IK) channel, butnot small-conductance Ca(2+)-dependentpotassium channel (SK) subtypes. Application of100 nM iberiotoxin and 100 nM clotrimazolereduced net I(KCa) to 36% and 63%,respectively, whereas the current was unaffectedby application of 1 microM apamin. Consistently,anti- SK1, -SK2, and -SK3 antibodies wereunable to stain rod photoreceptors, whereas both", "metadata": {}}
+{"_id": "13624704", "title": "", "text": "Ondansetron reduces nausea and vomiting afterpaediatric adenotonsillectomy.The efficacy,safety and resource implications of a singleintravenous dose of ondansetron (0.1 mg.kg-1,maximum 4 mg) were assessed in amultinational, multicentre, randomized,double-blind, placebo-controlled trial of 427children aged 1-12 years, undergoingtonsillectomy with/without adenoidectomy.Emesis (retching and/or vomiting) and nauseawere analysed separately. Significantly moreondansetron-treated children had no episodes ofemesis (127/212 (60%) vs 100/215 (47%); P =0.004) and experienced no postoperative nausea(135/211 (64%) vs 108/213 (51%); P = 0.004)in the first 24 h. Ondansetron also reduced thenumber of emetic episodes (P < 0.001), the timeto the first emetic episode (P < 0.001) andoverall nausea severity (P = 0.003). Significantlyfewer ondansetron-treated children were rescuedor withdrawn from the study (5% vs 10%; P =0.042). Fewer ondansetron-treated patients", "metadata": {}}
+{"_id": "13625993", "title": "", "text": "Assessing the cost effectiveness of usingprognostic biomarkers with decision models:case study in prioritising patients waiting forcoronary artery surgeryOBJECTIVE To determinethe effectiveness and cost effectiveness of usinginformation from circulating biomarkers to informthe prioritisation process of patients with stableangina awaiting coronary artery bypass graftsurgery. DESIGN Decision analytical modelcomparing four prioritisation strategies withoutbiomarkers (no formal prioritisation, two urgencyscores, and a risk score) and three strategiesbased on a risk score using biomarkers: aroutinely assessed biomarker (estimatedglomerular filtration rate), a novel biomarker (Creactive protein), or both. The order in which toperform coronary artery bypass grafting in acohort of patients was determined by eachprioritisation strategy, and mean lifetime costsand quality adjusted life years (QALYs) werecompared. DATA SOURCES Swedish CoronaryAngiography and Angioplasty Registry (9935", "metadata": {}}
+{"_id": "13636631", "title": "", "text": "Cytokine control of memory T-cell developmentand survivalEvidence has accumulated thatcytokines have a fundamental role in thedifferentiation of memory T cells. Here, we followthe CD8+ T cell from initial activation tomemory-cell generation, indicating thecheckpoints at which cytokines determine thefate of the T cell. Members of the commoncytokine-receptor γ-chain (γc)-cytokine family —in particular, interleukin-7 (IL-7) and IL-15 — actat each stage of the immune response topromote proliferation and survival. In thismanner, a stable and protective, long-livedmemory CD8+ T-cell pool can be propagated andmaintained.", "metadata": {}}
+{"_id": "13639330", "title": "", "text": "Histone Methylation-Dependent MechanismsImpose Ligand Dependency for Gene Activationby Nuclear ReceptorsNuclear receptors undergoligand-dependent conformational changes thatare required for corepressor-coactivatorexchange, but whether there is an actualrequirement for specific epigenetic landmarks toimpose ligand dependency for gene activationremains unknown. Here we report an unexpectedand general strategy that is based on therequirement for specific cohorts of inhibitoryhistone methyltransferases (HMTs) to imposegene-specific gatekeeper functions that preventunliganded nuclear receptors and other classesof regulated transcription factors from binding totheir target gene promoters and causingconstitutive gene activation in the absence ofstimulating signals. This strategy, based at leastin part on an HMT-dependent inhibitory histonecode, imposes a requirement for specific histonedemethylases, including LSD1, to permit ligand-and signal-dependent activation of regulated", "metadata": {}}
+{"_id": "13651792", "title": "", "text": "Human IRGM Regulates Autophagy and ItsCell-Autonomous Immunity Functions ThroughMitochondriaIRGM, a human immunity-relatedGTPase, confers autophagic defence againstintracellular pathogens by an unknownmechanism. Here, we report an unexpectedmode of IRGM action. IRGM demonstrateddifferential affinity for the mitochondrial lipidcardiolipin, translocated to mitochondria,affected mitochondrial fission and inducedautophagy. Mitochondrial fission was necessaryfor autophagic control of intracellularmycobacteria by IRGM. IRGM influencedmitochondrial membrane polarization and celldeath. Overexpression of IRGMd, but not IRGMbsplice isoforms, caused mitochondrialdepolarization and autophagy-independent, butBax/Bak-dependent, cell death. By acting onmitochondria, IRGM confers autophagicprotection or cell death, explaining IRGM actionboth in defence against tuberculosis and in thedamaging inflammation caused by Crohn's", "metadata": {}}
+{"_id": "13702924", "title": "", "text": "The Developmental Transcriptome of theMosquito Aedes aegypti, an Invasive Species andMajor Arbovirus VectorMosquitoes are vectors ofa number of important human and animaldiseases. The development of novel vectorcontrol strategies requires a thoroughunderstanding of mosquito biology. To facilitatethis, we used RNA-seq to identify novel genesand provide the first high-resolution view of thetranscriptome throughout development and inresponse to blood feeding in a mosquito vector ofhuman disease, Aedes aegypti, the primaryvector for Dengue and yellow fever. Wecharacterized mRNA expression at 34 distincttime points throughout Aedes development,including adult somatic and germline tissues, byusing polyA+ RNA-seq. We identify a total of14,238 novel new transcribed regionscorresponding to 12,597 new loci, as well asmany novel transcript isoforms of previouslyannotated genes. Altogether these resultsincrease the annotated fraction of the", "metadata": {}}
+{"_id": "13714201", "title": "", "text": "Gut microbial diversity is associated with lowerarterial stiffness in womenAims The gutmicrobiome influences metabolic syndrome(MetS) and inflammation and is therapeuticallymodifiable. Arterial stiffness is poorly correlatedwith most traditional risk factors. Our aim was toexamine whether gut microbial composition isassociated with arterial stiffness. Methods andresults We assessed the correlation betweencarotid-femoral pulse wave velocity (PWV), ameasure of arterial stiffness, and gut microbiomecomposition in 617 middle-aged women from theTwinsUK cohort with concurrent serummetabolomics data. Pulse wave velocity wasnegatively correlated with gut microbiome alphadiversity (Shannon index, Beta(SE)=-0.25(0.07), P = 1 × 10-4) after adjustment forcovariates. We identified seven operationaltaxonomic units associated with PWV afteradjusting for covariates and multiple testing-twobelonging to the Ruminococcaceae family.Associations between microbe abundances,", "metadata": {}}
+{"_id": "13717103", "title": "", "text": "ALS-FUS pathology revisited: singleton FUSmutations and an unusual case with both a FUSand TARDBP mutationINTRODUCTION Mutationsin the FUS gene have been shown to be a rarecause of amyotrophic lateral sclerosis (ALS-FUS)and whilst well documented clinically andgenetically there have been relatively fewneuropathological studies. Recent worksuggested a possible correlation betweenpathological features such as frequency ofbasophilic inclusions in neurons and rate ofclinical decline, other studies have revealed adiscrepancy between the upper motor neuronfeatures detected clinically and the associatedpathology. The purpose of this study was todescribe the pathological features associatedwith more recently discovered FUS mutationsand reinvestigate those with well recognisedmutations in an attempt to correlate thepathology with mutation and/or clinicalphenotype. The brains and spinal cords of sevencases of ALS-FUS were examined", "metadata": {}}
+{"_id": "13726379", "title": "", "text": "Coronary heart disease in south Asians overseas:a review.Coronary heart disease rates have beenreported in several parts of the world to beunusually high in people originating from theIndian subcontinent. High coronary disease ratesappear to be common to South Asian groups ofdifferent geographical origin, religion, andlanguage. This presents a challenge to theunderstanding of coronary heart disease: thehigh rates in South Asians are not explained onthe basis of elevated serum cholesterol, smokingor hypertension. Low plasma HDL cholesterol,high plasma triglyceride levels and highprevalence of non-insulin-dependent diabeteshave been consistently found in South Asiansoverseas: this probably reflects an underlyingstate of insulin resistance. Further studies areneeded to determine whether this metabolicdisturbance can account for the high rates ofcoronary heart disease in South Asians, and toidentify possibilities for prevention.", "metadata": {}}
+{"_id": "13732033", "title": "", "text": "A systematic review of parent and clinician viewsand perceptions that influence prescribingdecisions in relation to acute childhood infectionsin primary careOBJECTIVES To investigate theviews of parents, clinicians, and childrenpertaining to prescribing decisions for acutechildhood infection in primary care. METHODS Asystematic review of qualitative studies.Meta-ethnographic methods were used, withdata drawn from the primary studies in aninterpretive analysis. RESULTS A total of 15studies met the inclusion criteria. The literaturewas dominated by concerns about antibioticover-prescription. Children's views were notreported. Clinicians prescribed antibiotics whenthey felt pressured by parents or others (e.g.employers) to do so, when they believed therewas a clear clinical indication, but also when theyfelt uncertain of clinical or social outcomes theyprescribed \"just in case\". Parents wantedantibiotics when they felt they would improve thecurrent illness, and when they felt pressure from", "metadata": {}}
+{"_id": "13734012", "title": "", "text": "Prevalent abnormal prion protein in humanappendixes after bovine spongiformencephalopathy epizootic: large scalesurveyOBJECTIVES To carry out a further surveyof archived appendix samples to understandbetter the differences between existing estimatesof the prevalence of subclinical infection withprions after the bovine spongiformencephalopathy epizootic and to see whether abroader birth cohort was affected, and tounderstand better the implications for themanagement of blood and blood products and forthe handling of surgical instruments. DESIGNIrreversibly unlinked and anonymised large scalesurvey of archived appendix samples. SETTINGArchived appendix samples from the pathologydepartments of 41 UK hospitals participating inthe earlier survey, and additional hospitals inregions with lower levels of participation in thatsurvey. SAMPLE 32,441 archived appendixsamples fixed in formalin and embedded inparaffin and tested for the presence of abnormal", "metadata": {}}
+{"_id": "13757347", "title": "", "text": "Involvement of cortical fast-spikingparvalbumin-positive basket cells inepilepsy.GABAergic interneurons of theparvalbumin-positive fast-spiking basket cellssubtype (PV INs) are important regulators ofcortical network excitability and of gammaoscillations, involved in signal processing andcognition. Impaired development or function ofPV INs has been associated with epilepsy invarious animal models of epilepsy, as well as insome genetic forms of epilepsy in humans. Inthis review, we provide an overview of some ofthe experimental data linking PV INs dysfunctionwith epilepsy, focusing on disorders of thespecification, migration, maturation, synapticfunction, or connectivity of PV INs. Furthermore,we reflect on the potential therapeutic use ofcell-type specific stimulation of PV INs withinactive networks and on the transplantation of PVINs precursors in the treatment of epilepsy andits comorbidities.", "metadata": {}}
+{"_id": "13759726", "title": "", "text": "Dynamic Gene Regulatory Networks of HumanMyeloid Differentiation.The reconstruction ofgene regulatory networks underlying celldifferentiation from high-throughput geneexpression and chromatin data remains achallenge. Here, we derive dynamic generegulatory networks for human myeloiddifferentiation using a 5-day time series ofRNA-seq and ATAC-seq data. We profile HL-60promyelocytes differentiating into macrophages,neutrophils, monocytes, and monocyte-derivedmacrophages. We find a rapid response in theexpression of key transcription factors andlineage markers that only regulate a subset oftheir targets at a given time, which is followed bychromatin accessibility changes that occur lateralong with further gene expression changes. Weobserve differences between promyelocyte- andmonocyte-derived macrophages at both thetranscriptional and chromatin landscape level,despite using the same differentiation stimulus,which suggest that the path taken by cells in the", "metadata": {}}
+{"_id": "13760557", "title": "", "text": "Canonical transient receptor potential 5 channelin conjunction with Orai1 and STIM1 allows Sr2+entry, optimal influx of Ca2+, and degranulationin a rat mast cell line.Degranulation of mast cellsin response to Ag or the calcium mobilizingagent, thapsigargin, is dependent on emptying ofintracellular stores of Ca(2+) and the ensuinginflux of external Ca(2+), also referred to asstore-operated calcium entry. However, it isunlikely that the calcium release-activatedcalcium channel is the sole mechanism for theentry of Ca(2+) because Sr(2+) and otherdivalent cations also permeate and supportdegranulation in stimulated mast cells. In thisstudy we show that influx of Ca(2+) and Sr(2+)as well as degranulation are dependent on thepresence of the canonical transient receptorpotential (TRPC) channel protein TRPC5, inaddition to STIM1 and Orai1, as demonstrated byknock down of each of these proteins byinhibitory RNAs in a rat mast cell (RBL-2H3) line.Overexpression of STIM1 and Orai1, which are", "metadata": {}}
+{"_id": "13763195", "title": "", "text": "LincRNA-p21 suppresses target mRNAtranslation.Mammalian long intergenic noncodingRNAs (lincRNAs) are best known for modulatingtranscription. Here we report aposttranscriptional function for lincRNA-p21 as amodulator of translation. Association of theRNA-binding protein HuR with lincRNA-p21favored the recruitment of let-7/Ago2 tolincRNA-p21, leading to lower lincRNA-p21stability. Under reduced HuR levels, lincRNA-p21accumulated in human cervical carcinoma HeLacells, increasing its association with JUNB andCTNNB1 mRNAs and selectively lowering theirtranslation. With elevated HuR, lincRNA-p21levels declined, which in turn derepressed JunBand β-catenin translation and increased thelevels of these proteins. We propose that HuRcontrols translation of a subset of target mRNAsby influencing lincRNA-p21 levels. Our findingsuncover a role for lincRNA as aposttranscriptional inhibitor of translation.", "metadata": {}}
+{"_id": "13764090", "title": "", "text": "Large intestine-targeted nanoparticle-releasingoral vaccine to control genitorectal viralinfectionBoth rectal and vaginal mucosal surfacesserve as transmission routes for pathogenicmicroorganisms. Vaccination through largeintestinal mucosa, previously proven protectivefor both of these mucosal sites in animal studies,can be achieved successfully by directintracolorectal (i.c.r.) administration, but thisroute is clinically impractical. Oral vaccinedelivery seems preferable but runs the risk of thevaccine's destruction in the uppergastrointestinal tract. Therefore, we designed alarge intestine-targeted oral delivery withpH-dependent microparticles containing vaccinenanoparticles, which induced colorectal immunityin mice comparably to colorectal vaccination andprotected against rectal and vaginal viralchallenge. Conversely, vaccine targeted to thesmall intestine induced only small intestinalimmunity and provided no rectal or vaginalprotection, demonstrating functional", "metadata": {}}
+{"_id": "13765757", "title": "", "text": "Timing of menarche and first full-term birth inrelation to breast cancer risk.Ages at menarcheand first birth are established risk factors forbreast cancer. The interval between these agesmay also affect risk, since the breast is moresusceptible to carcinogenic insults during thisperiod than during the parous period. However,few investigators have studied this relation.Using logistic regression, the authors evaluatedassociations between the timing of reproductiveevents and breast cancer risk among 4,013cases and 4,069 controls enrolled in amulticenter, population-based US case-controlstudy of White and African-American women(1994-1998). For White, parous premenopausaland postmenopausal women, those who had aninterval of > or =16 years between the ages ofmenarche and first birth had 1.5-fold (95%confidence interval (CI): 1.0, 2.2) and 1.4-fold(95% CI: 1.1, 1.8) increased risks of breastcancer, respectively, in comparison with thosewho had < or =5 years between these ages.", "metadata": {}}
+{"_id": "13768432", "title": "", "text": "Prognostic Value of Late GadoliniumEnhancement Cardiovascular MagneticResonance in Cardiac AmyloidosisBACKGROUNDThe prognosis and treatment of the 2 main typesof cardiac amyloidosis, immunoglobulin lightchain (AL) and transthyretin (ATTR) amyloidosis,are substantially influenced by cardiacinvolvement. Cardiovascular magnetic resonancewith late gadolinium enhancement (LGE) is areference standard for the diagnosis of cardiacamyloidosis, but its potential for stratifying risk isunknown. METHODS AND RESULTS Two hundredfifty prospectively recruited subjects, 122patients with ATTR amyloid, 9 asymptomaticmutation carriers, and 119 patients with ALamyloidosis, underwent LGE cardiovascularmagnetic resonance. Subjects were followed upfor a mean of 24±13 months. LGE wasperformed with phase-sensitive inversionrecovery (PSIR) and without (magnitude only).These were compared with extracellular volumemeasured with T1 mapping. PSIR was superior to", "metadata": {}}
+{"_id": "13770184", "title": "", "text": "Global, regional, and national comparative riskassessment of 79 behavioural, environmentaland occupational, and metabolic risks or clustersof risks, 1990–2015: a systematic analysis forthe Global Burden of Disease Study2015BACKGROUND The Global Burden ofDiseases, Injuries, and Risk Factors Study 2015provides an up-to-date synthesis of the evidencefor risk factor exposure and the attributableburden of disease. By providing national andsubnational assessments spanning the past 25years, this study can inform debates on theimportance of addressing risks in context.METHODS We used the comparative riskassessment framework developed for previousiterations of the Global Burden of Disease Studyto estimate attributable deaths,disability-adjusted life-years (DALYs), and trendsin exposure by age group, sex, year, andgeography for 79 behavioural, environmentaland occupational, and metabolic risks or clustersof risks from 1990 to 2015. This study included", "metadata": {}}
+{"_id": "13771184", "title": "", "text": "Human RecQ helicases in DNA repair,recombination, and replication.RecQ helicasesare an important family of genome surveillanceproteins conserved from bacteria to humans.Each of the five human RecQ helicases playscritical roles in genome maintenance andstability, and the RecQ protein family membersare often referred to as guardians of thegenome. The importance of these proteins incellular homeostasis is underscored by the factthat defects in BLM, WRN, and RECQL4 arelinked to distinct heritable human diseasesyndromes. Each human RecQ helicase has aunique set of protein-interacting partners, andthese interactions dictate its specialized functionsin genome maintenance, including DNA repair,recombination, replication, and transcription.Human RecQ helicases also interact with eachother, and these interactions have significantimpact on enzyme function. Future researchgoals in this field include a better understandingof the division of labor among the human RecQ", "metadata": {}}
+{"_id": "13774178", "title": "", "text": "Metabolomics study of the therapeuticmechanism of Schisandra Chinensis lignans indiet-induced hyperlipidemia miceBACKGROUNDSchisandra, a globally distributed plant, has beenwidely applied for the treatment of diseases suchas hyperlipidemia, fatty liver and obesity inChina. In the present work, a rapid resolutionliquid chromatography coupled withquadruple-time-of-flight mass spectrometry(RRLC-Q-TOF-MS)-based metabolomics wasconducted to investigate the intervention effectof Schisandra chinensis lignans (SCL) onhyperlipidemia mice induced by high-fat diet(HFD). METHODS Hyperlipidemia mice wereorally administered with SCL (100 mg/kg) once aday for 4 weeks. Serum biochemistry assay oftriglyceride (TG), total cholesterol (TC),low-density lipoprotein cholesterol (LDL-c) andhigh-density lipoprotein cholesterol (HDL-c) wasconducted to confirm the treatment of SCL onlipid regulation. Metabolomics analysis on serumsamples was carried out, and principal", "metadata": {}}
+{"_id": "13777138", "title": "", "text": "Tet1 and Tet2 regulate 5-hydroxymethylcytosineproduction and cell lineage specification inmouse embryonic stem cells.TET family enzymesconvert 5-methylcytosine (5mC) to5-hydroxymethylcytosine (5hmC) in DNA. Here,we show that Tet1 and Tet2 are Oct4-regulatedenzymes that together sustain 5hmC in mouseembryonic stem cells (ESCs) and are inducedconcomitantly with 5hmC during reprogrammingof fibroblasts to induced pluripotent stem cells.ESCs depleted of Tet1 by RNAi show diminishedexpression of the Nodal antagonist Lefty1 anddisplay hyperactive Nodal signaling and skeweddifferentiation into the endoderm-mesodermlineage in embryoid bodies in vitro. In Fgf4- andheparin-supplemented culture conditions,Tet1-depleted ESCs activate the trophoblaststem cell lineage determinant Elf5 and cancolonize the placenta in midgestation embryochimeras. Consistent with these findings,Tet1-depleted ESCs form aggressivehemorrhagic teratomas with increased", "metadata": {}}
+{"_id": "13777706", "title": "", "text": "Polycomb Associates Genome-wide with aSpecific RNA Polymerase II Variant, andRegulates Metabolic Genes in ESCsPolycombrepressor complexes (PRCs) are importantchromatin modifiers fundamentally implicated inpluripotency and cancer. Polycomb silencing inembryonic stem cells (ESCs) can beaccompanied by active chromatin and primedRNA polymerase II (RNAPII), but the relationshipbetween PRCs and RNAPII remains uncleargenome-wide. We mapped PRC repressionmarkers and four RNAPII states in ESCs usingChIP-seq, and found that PRC targets exhibit arange of RNAPII variants. First, developmentalPRC targets are bound by unproductive RNAPII(S5p(+)S7p(-)S2p(-)) genome-wide. SequentialChIP, Ring1B depletion, and genome-widecorrelations show that PRCs and RNAPII-S5pphysically bind to the same chromatin andfunctionally synergize. Second, we identify acohort of genes marked by PRC and elongatingRNAPII (S5p(+)S7p(+)S2p(+)); they produce", "metadata": {}}
+{"_id": "13778710", "title": "", "text": "Chemokine-like receptor 1 (CMKLR1) andchemokine (C-C motif) receptor-like 2 (CCRL2);two multifunctional receptors with unusualproperties.Chemokine-like receptor 1 (CMKLR1),also known as ChemR23, and chemokine (C-Cmotif) receptor-like 2 (CCRL2) are7-transmembrane receptors that were cloned inthe late 1990s based on their homology toknown G-protein-coupled receptors. They werepreviously orphan receptors without any knownbiological roles; however, recent studiesidentified ligands for these receptors and theirfunctions have begun to be unveiled. The plasmaprotein-derived chemoattractant chemerin is aligand for CMKLR1 and activation of CMKLR1 withchemerin induces the migration of macrophagesand dendritic cells (DCs) in vitro, suggesting aproinflammatory role. However, in vivo studiesusing CMKLR-deficient mice suggest ananti-inflammatory role for this receptor, possiblydue to the recruitment of tolerogenicplasmacytoid DCs. Chemerin/CMKLR1 interaction", "metadata": {}}
+{"_id": "13779605", "title": "", "text": "Identification of vitronectin as an extrinsicinducer of cancer stem cell differentiation andtumor formation.There is mounting evidence thattumors are initiated by a rare subset of cellscalled cancer stem cells (CSCs). CSCs aregenerally quiescent, self-renew, form tumors atlow numbers, and give rise to the heterogeneouscell types found within a tumor. CSCs isolatedfrom multiple tumor types differentiate both invivo and in vitro when cultured in serum, yet thefactors responsible for their differentiation havenot yet been identified. Here we show thatvitronectin is the component of human serumdriving stem cell differentiation through anintegrin alpha V beta 3-dependent mechanism.CSCs cultured on vitronectin result indownregulation of stem cell genes, modulation ofdifferentiation markers, and loss of beta-cateninnuclear localization. Blocking integrin alpha Vbeta 3 inhibits differentiation and subsequentlytumor formation. Thus, CSCs must be engagedby one or more extracellular signals to", "metadata": {}}
+{"_id": "13780287", "title": "", "text": "STIM1 Is a Calcium Sensor Specialized for DigitalSignalingWhen cells are activated bycalcium-mobilizing agonists at low, physiologicalconcentrations, the resulting calcium signalsgenerally take the form of repetitive regenerativedischarges of stored calcium, termed calciumoscillations [1]. These intracellular calciumoscillations have long fascinated biologists as amode of digitized intracellular signaling. Recentwork has highlighted the role of calcium influx asan essential component of calcium oscillations[2]. This influx occurs through a process knownas store-operated calcium entry, which isinitiated by calcium sensor proteins, STIM1 andSTIM2, in the endoplasmic reticulum [3]. STIM2is activated by changes in endoplasmic reticulumcalcium near the resting level, whereas athreshold of calcium depletion is required forSTIM1 activation [4]. Here we show that,surprisingly, it is STIM1 and not STIM2 that isexclusively involved in calcium entry duringcalcium oscillations. The implication is that each", "metadata": {}}
+{"_id": "13782317", "title": "", "text": "Trends in the use of complementary healthapproaches among adults: United States,2002-2012.OBJECTIVE This report presentsnational estimates of the use of complementaryhealth approaches among adults in the UnitedStates across three time points. Trends in theuse of selected complementary healthapproaches are compared for 2002, 2007, and2012, and differences by selected demographiccharacteristics are also examined. METHODSCombined data from 88,962 adults aged 18 andover collected as part of the 2002, 2007, and2012 National Health Interview Survey wereanalyzed for this report. Sample data wereweighted to produce national estimates that arerepresentative of the civilian noninstitutionalizedU.S. adult population. Differences betweenpercentages were evaluated using two-sidedsignificance tests at the 0.05 level. RESULTSAlthough the use of individual approaches variedacross the three time points, nonvitamin,nonmineral dietary supplements remained the", "metadata": {}}
+{"_id": "13790144", "title": "", "text": "Histone structure and nucleosomestability.Histone proteins play essential structuraland functional roles in the transition betweenactive and inactive chromatin states. Althoughhistones have a high degree of conservation dueto constraints to maintain the overall structure ofthe nucleosomal octameric core, variants haveevolved to assume diverse roles in generegulation and epigenetic silencing. Histonevariants, post-translational modifications andinteractions with chromatin remodelingcomplexes influence DNA replication,transcription, repair and recombination. Theauthors review recent findings on the structureof chromatin that confirm previous interparticleinteractions observed in crystal structures.", "metadata": {}}
+{"_id": "13791044", "title": "", "text": "Cerebral palsy among term and posttermbirths.CONTEXT Although preterm delivery is awell-established risk factor for cerebral palsy(CP), preterm deliveries contribute only aminority of affected infants. There is littleinformation on the relation of CP risk togestational age in the term range, where mostCP occurs. OBJECTIVE To determine whethertiming of birth in the term and postterm period isassociated with risk of CP. DESIGN, SETTING,AND PARTICIPANTS Population-based follow-upstudy using the Medical Birth Registry of Norwayto identify 1,682,441 singleton children born inthe years 1967-2001 with a gestational age of 37through 44 weeks and no congenital anomalies.The cohort was followed up through 2005 bylinkage to other national registries. MAINOUTCOME MEASURES Absolute and relative riskof CP for children surviving to at least 4 years ofage. RESULTS Of the cohort of term andpostterm children, 1938 were registered with CPin the National Insurance Scheme. Infants born", "metadata": {}}
+{"_id": "13791206", "title": "", "text": "53BP1 Inhibits Homologous Recombination inBrca1-Deficient Cells by Blocking Resection ofDNA BreaksDefective DNA repair by homologousrecombination (HR) is thought to be a majorcontributor to tumorigenesis in individualscarrying Brca1 mutations. Here, we show thatDNA breaks in Brca1-deficient cells areaberrantly joined into complex chromosomerearrangements by a process dependent on thenonhomologous end-joining (NHEJ) factors53BP1 and DNA ligase 4. Loss of 53BP1alleviates hypersensitivity of Brca1 mutant cellsto PARP inhibition and restores error-free repairby HR. Mechanistically, 53BP1 deletion promotesATM-dependent processing of broken DNA endsto produce recombinogenic single-stranded DNAcompetent for HR. In contrast, Lig4 deficiencydoes not rescue the HR defect in Brca1 mutantcells but prevents the joining of chromatidbreaks into chromosome rearrangements. Ourresults illustrate that HR and NHEJ compete toprocess DNA breaks that arise during DNA", "metadata": {}}
+{"_id": "13791788", "title": "", "text": "The genetics of Mexico recapitulates NativeAmerican substructure and affects biomedicaltraitsMexico harbors great cultural and ethnicdiversity, yet fine-scale patterns of humangenome-wide variation from this region remainlargely uncharacterized. We studied genomicvariation within Mexico from over 1000individuals representing 20 indigenous and 11mestizo populations. We found striking geneticstratification among indigenous populationswithin Mexico at varying degrees of geographicisolation. Some groups were as differentiated asEuropeans are from East Asians. Pre-Columbiangenetic substructure is recapitulated in theindigenous ancestry of admixed mestizoindividuals across the country. Furthermore, twoindependently phenotyped cohorts of Mexicansand Mexican Americans showed a significantassociation between subcontinental ancestry andlung function. Thus, accounting for fine-scaleancestry patterns is critical for medical andpopulation genetic studies within Mexico, in", "metadata": {}}
+{"_id": "13794374", "title": "", "text": "COPI Complex Is a Regulator of LipidHomeostasisLipid droplets are ubiquitoustriglyceride and sterol ester storage organellesrequired for energy storage homeostasis andbiosynthesis. Although little is known about lipiddroplet formation and regulation, it is clear thatmembers of the PAT (perilipin, adipocytedifferentiation related protein, tail interactingprotein of 47 kDa) protein family coat the dropletsurface and mediate interactions with lipasesthat remobilize the stored lipids. We identifiedkey Drosophila candidate genes for lipid dropletregulation by RNA interference (RNAi) screeningwith an image segmentation-based opticalread-out system, and show that these regulatoryfunctions are conserved in the mouse. Thoseinclude the vesicle-mediated Coat ProteinComplex I (COPI) transport complex, which isrequired for limiting lipid storage. We found thatCOPI components regulate the PAT proteincomposition at the lipid droplet surface, andpromote the association of adipocyte triglyceride", "metadata": {}}
+{"_id": "13798951", "title": "", "text": "Differentiation of effector CD4 T cell populations(*).CD4 T cells play critical roles in mediatingadaptive immunity to a variety of pathogens.They are also involved in autoimmunity, asthma,and allergic responses as well as in tumorimmunity. During TCR activation in a particularcytokine milieu, naive CD4 T cells maydifferentiate into one of several lineages of Thelper (Th) cells, including Th1, Th2, Th17, andiTreg, as defined by their pattern of cytokineproduction and function. In this review, wesummarize the discovery, functions, andrelationships among Th cells; the cytokine andsignaling requirements for their development;the networks of transcription factors involved intheir differentiation; the epigenetic regulation oftheir key cytokines and transcription factors; andhuman diseases involving defective CD4 T celldifferentiation.", "metadata": {}}
+{"_id": "13801259", "title": "", "text": "Homocysteine and other thiols in plasma andurine: automated determination and samplestability.We have developed a modified versionof our fully automated column-switching HPLCmethod for determining total plasmahomocysteine based on single-column(reversed-phase) separation. Homocysteine,cysteine, and cysteinylglycine in plasma (totalconcentrations), acid-precipitated plasma(non-protein-bound concentrations), and urinecan be determined. The derivatization andchromatography were performed automaticallyby a sample processor. The successful separationof all thiol species (within 15 min) wasaccomplished by accurate adjustment of the pHof the mobile phase to 3.65 (plasma) or 3.50(acid-precipitated plasma, urine). Maximalfluorescence yield of cysteine, cysteinylglycine,and, to a lesser degree, homocysteine wasdependent on optimal concentrations of EDTAand dithioerythritol during reduction (withNaBH4) and derivatization (with", "metadata": {}}
+{"_id": "13814480", "title": "", "text": "Induced pluripotent stem cells in Alzheimer’sdisease: applications for disease modeling andcell-replacement therapyAlzheimer's disease(AD) is the most common cause of dementia inthose over the age of 65. While a numerous ofdisease-causing genes and risk factors havebeen identified, the exact etiological mechanismsof AD are not yet completely understood, due tothe inability to test theoretical hypotheses onnon-postmortem and patient-specific researchsystems. The use of recently developed andoptimized induced pluripotent stem cells (iPSCs)technology may provide a promising platform tocreate reliable models, not only for betterunderstanding the etiopathological process ofAD, but also for efficient anti-AD drugsscreening. More importantly, human-sourcediPSCs may also provide a beneficial tool forcell-replacement therapy against AD. Althoughconsiderable progress has been achieved, anumber of key challenges still require to beaddressed in iPSCs research, including the", "metadata": {}}
+{"_id": "13823200", "title": "", "text": "Nitrite protects against morbidity and mortalityassociated with TNF- or LPS-induced shock in asoluble guanylate cyclase–dependentmannerNitrite (NO(2)(-)), previously viewed as aphysiologically inert metabolite and biomarker ofthe endogenous vasodilator NO, was recentlyidentified as an important biological NO reservoirin vasculature and tissues, where it contributesto hypoxic signaling, vasodilation, andcytoprotection after ischemia-reperfusion injury.Reduction of nitrite to NO may occurenzymatically at low pH and oxygen tension bydeoxyhemoglobin, deoxymyoglobin, xanthineoxidase, mitochondrial complexes, or NOsynthase (NOS). We show that nitrite treatment,in sharp contrast with the worsening effect ofNOS inhibition, significantly attenuateshypothermia, mitochondrial damage, oxidativestress and dysfunction, tissue infarction, andmortality in a mouse shock model induced by alethal tumor necrosis factor challenge.Mechanistically, nitrite-dependent protection was", "metadata": {}}
+{"_id": "13831558", "title": "", "text": "Mammographic density and the risk anddetection of breast cancer.BACKGROUNDExtensive mammographic density is associatedwith an increased risk of breast cancer andmakes the detection of cancer by mammographydifficult, but the influence of density on riskaccording to method of cancer detection isunknown. METHODS We carried out three nestedcase-control studies in screened populations with1112 matched case-control pairs. We examinedthe association of the measured percentage ofdensity in the baseline mammogram with risk ofbreast cancer, according to method of cancerdetection, time since the initiation of screening,and age. RESULTS As compared with womenwith density in less than 10% of themammogram, women with density in 75% ormore had an increased risk of breast cancer(odds ratio, 4.7; 95% confidence interval [CI],3.0 to 7.4), whether detected by screening (oddsratio, 3.5; 95% CI, 2.0 to 6.2) or less than 12months after a negative screening examination", "metadata": {}}
+{"_id": "13831842", "title": "", "text": "Pooled analysis of prospective cohort studies onheight, weight, and breast cancer risk.Theassociation between anthropometric indices andthe risk of breast cancer was analyzed usingpooled data from seven prospective cohortstudies. Together, these cohorts comprise337,819 women and 4,385 incident invasivebreast cancer cases. In multivariate analysescontrolling for reproductive, dietary, and otherrisk factors, the pooled relative risk (RR) ofbreast cancer per height increment of 5 cm was1.02 (95% confidence interval (CI): 0.96, 1.10)in premenopausal women and 1.07 (95% CI:1.03, 1.12) in postmenopausal women. Bodymass index (BMI) showed significant inverse andpositive associations with breast cancer amongpre- and postmenopausal women, respectively;these associations were nonlinear. Comparedwith premenopausal women with a BMI of lessthan 21 kg/m2, women with a BMI exceeding 31kg/m2 had an RR of 0.54 (95% CI: 0.34, 0.85).In postmenopausal women, the RRs did not", "metadata": {}}
+{"_id": "13843341", "title": "", "text": "Cost effectiveness of ward based non-invasiveventilation for acute exacerbations of chronicobstructive pulmonary disease: economicanalysis of randomised controlledtrial.OBJECTIVE To evaluate the costeffectiveness of standard treatment with andwithout the addition of ward based non-invasiveventilation in patients admitted to hospital withan acute exacerbation of chronic obstructivepulmonary disease. DESIGN Incremental costeffectiveness analysis of a randomised controlledtrial. SETTING Medical wards in 14 hospitals inthe United Kingdom. PARTICIPANTS The trialcomprised 236 patients admitted to hospital withan acute exacerbation of chronic obstructivepulmonary disease and mild to moderate acidosis(pH 7.25-7.35) secondary to respiratory failure.The economic analysis compared the costs oftreatment that these patients received afterrandomisation. MAIN OUTCOME MEASUREIncremental cost per in-hospital death. RESULTS24/118 died in the group receiving standard", "metadata": {}}
+{"_id": "13857083", "title": "", "text": "Persistent human papillomavirus infection andcervical neoplasia: a systematic review andmeta-analysis.Detection of persistent cervicalcarcinogenic human papillomavirus (HPV) DNA isused as a marker for cervical cancer risk inclinical trials. The authors performed asystematic review and meta-analysis of theassociation between persistent HPV DNA andhigh-grade cervical intraepithelial neoplasia(CIN2-3), high-grade squamous intraepitheliallesions (HSIL), and invasive cervical cancer(together designated CIN2-3/HSIL+) to evaluatethe robustness of HPV persistence for clinicaluse. MEDLINE and Current Contents weresearched through January 30, 2006. Relativerisks (RRs) were stratified by HPV comparisongroup. Of 2,035 abstracts, 41 studies wereeligible for inclusion in the meta-analysis. Over22,500 women were included in calculation ofRRs for persistent HPV DNA detection andcervical neoplasia. RRs ranged from 1.3 (95%confidence interval: 1.1, 1.5) to 813.0 (95%", "metadata": {}}
+{"_id": "13867350", "title": "", "text": "Post-transcriptional Wnt Signaling GovernsEpididymal Sperm MaturationThe canonical Wntsignaling pathway is of paramount importance indevelopment and disease. An emergent questionis whether the upstream cascade of the canonicalWnt pathway has physiologically relevant rolesbeyond β-catenin-mediated transcription, whichis difficult to study due to the pervasive role ofthis protein. Here, we show that transcriptionallysilent spermatozoa respond to Wnt signalsreleased from the epididymis and that micemutant for the Wnt regulator Cyclin Y-like 1 aremale sterile due to immotile and malformedspermatozoa. Post-transcriptional Wnt signalingimpacts spermatozoa through GSK3 by (1)reducing global protein poly-ubiquitination tomaintain protein homeostasis; (2) inhibitingseptin 4 phosphorylation to establish amembrane diffusion barrier in the sperm tail;and (3) inhibiting protein phosphatase 1 toinitiate sperm motility. The results indicate thatWnt signaling orchestrates a rich", "metadata": {}}
+{"_id": "13868795", "title": "", "text": "CD28 Costimulation: From Mechanism toTherapy.Ligation of the CD28 receptor on T cellsprovides a critical second signal alongside T cellreceptor (TCR) ligation for naive T cell activation.Here, we discuss the expression, structure, andbiochemistry of CD28 and its ligands. CD28signals play a key role in many T cell processes,including cytoskeletal remodeling, production ofcytokines, survival, and differentiation. CD28ligation leads to unique epigenetic,transcriptional, and post-translational changes inT cells that cannot be recapitulated by TCRligation alone. We discuss the function of CD28and its ligands in both effector and regulatory Tcells. CD28 is critical for regulatory T cell survivaland the maintenance of immune homeostasis.We outline the roles that CD28 and its familymembers play in human disease and we reviewthe clinical efficacy of drugs that block CD28ligands. Despite the centrality of CD28 and itsfamily members and ligands to immune function,many aspects of CD28 biology remain unclear.", "metadata": {}}
+{"_id": "13870943", "title": "", "text": "Recommended diagnostic criteria for multiplesclerosis: guidelines from the International Panelon the diagnosis of multiple sclerosis.TheInternational Panel on MS Diagnosis presentsrevised diagnostic criteria for multiple sclerosis(MS). The focus remains on the objectivedemonstration of dissemination of lesions in bothtime and space. Magnetic resonance imaging isintegrated with dinical and other paraclinicaldiagnostic methods. The revised criteria facilitatethe diagnosis of MS in patients with a variety ofpresentations, including \"monosymptomatic\"disease suggestive of MS, disease with a typicalrelapsing-remitting course, and disease withinsidious progression, without clear attacks andremissions. Previously used terms such as\"clinically definite\" and \"probable MS\" are nolonger recommended. The outcome of adiagnostic evaluation is either MS, \"possible MS\"(for those at risk for MS, but for whom diagnosticevaluation is equivocal), or \"not MS. \"", "metadata": {}}
+{"_id": "13878124", "title": "", "text": "Regulation of radial glial survival by signals fromthe meninges.Radial glial cells (RGCs) in thedeveloping cerebral cortex are progenitors forneurons and glia, and their processes serve asguideposts for migrating neurons. So far, it hasremained unclear whether RGC processes alsocontrol the function of RGCs more directly. Here,we show that RGC numbers and cortical size arereduced in mice lacking beta1 integrins in RGCs.TUNEL stainings and time-lapse video recordingsdemonstrate that beta1-deficient RGCsprocesses detach from the meningeal basementmembrane (BM) followed by apoptotic death ofRGCs. Apoptosis is also induced by surgicalremoval of the meninges. Finally, mice lackingthe BM components laminin alpha2 and alpha4show defects in the attachment of RGC processesat the meninges, a reduction in cortical size, andenhanced apoptosis of RGC cells. Our findingsdemonstrate that attachment of RGC processesat the meninges is important for RGC survivaland the control of cortical size.", "metadata": {}}
+{"_id": "13878643", "title": "", "text": "The sterol regulatory element binding proteinsare essential for the metabolic programming ofeffector T cells and adaptive immunityNewlyactivated CD8(+) T cells reprogram theirmetabolism to meet the extraordinarybiosynthetic demands of clonal expansion;however, the signals that mediate metabolicreprogramming remain poorly defined. Here wedemonstrate an essential role for sterolregulatory element-binding proteins (SREBPs) inthe acquisition of effector-cell metabolism.Without SREBP signaling, CD8(+) T cells wereunable to blast, which resulted in attenuatedclonal expansion during viral infection.Mechanistic studies indicated that SREBPs wereessential for meeting the heightened lipidrequirements of membrane synthesis duringblastogenesis. SREBPs were dispensable forhomeostatic proliferation, which indicated acontext-specific requirement for SREBPs ineffector responses. Our studies provide insightsinto the molecular signals that underlie the", "metadata": {}}
+{"_id": "13882658", "title": "", "text": "Human contribution to the European heatwave of2003The summer of 2003 was probably thehottest in Europe since at latest ad 1500, andunusually large numbers of heat-related deathswere reported in France, Germany and Italy. It isan ill-posed question whether the 2003 heatwavewas caused, in a simple deterministic sense, by amodification of the external influences onclimate—for example, increasing concentrationsof greenhouse gases in theatmosphere—because almost any such weatherevent might have occurred by chance in anunmodified climate. However, it is possible toestimate by how much human activities mayhave increased the risk of the occurrence of sucha heatwave. Here we use this conceptualframework to estimate the contribution ofhuman-induced increases in atmosphericconcentrations of greenhouse gases and otherpollutants to the risk of the occurrence ofunusually high mean summer temperaturesthroughout a large region of continental Europe.", "metadata": {}}
+{"_id": "13883546", "title": "", "text": "Do Antidepressants Cure or Create AbnormalBrain States?The term antidepressant refers to adrug that helps to rectify specific biologicalabnormalities that give rise to the symptoms ofdepression. This exemplifies what we have calledthe “disease-centred” model of psychotropic drugaction [ 1]. Modelled on paradigmatic situationsin general medicine—such as the use of insulin indiabetes, antibiotics in infectious disease,chemotherapy in cancer—the disease-centredmodel suggests that antidepressants help restorenormal functioning by acting on theneuropathology of depression or of depressivesymptoms. In contrast, we propose in this Essaythat an alternative “drug-centred” model canbetter explain observed drug effects inpsychiatric conditions. This drug-centred modelsuggests that instead of relieving a hypotheticalbiochemical abnormality, drugs themselvescause abnormal states, which may coincidentallyrelieve psychiatric symptoms ( Table 1).Alcohol's disinhibiting effects may relieve", "metadata": {}}
+{"_id": "13889430", "title": "", "text": "Cancer exosomes trigger fibroblast tomyofibroblast differentiation.There is a growinginterest in the cell-cell communication roles incancer mediated by secreted vesicles termedexosomes. In this study, we examined whetherexosomes produced by cancer cells couldtransmit information to normal stromalfibroblasts and trigger a cellular response. Wefound that some cancer-derived exosomes couldtrigger elevated α-smooth muscle actinexpression and other changes consistent with theprocess of fibroblast differentiation intomyofibroblasts. We show that TGF-β is expressedat the exosome surface in association with thetransmembrane proteoglycan betaglycan.Although existing in a latent state, this complexwas fully functional in eliciting SMAD-dependentsignaling. Inhibiting either signaling orbetaglycan expression attenuated differentiation.While the kinetics and overall magnitude of theresponse were similar to that achieved withsoluble TGF-β, we identified important qualitative", "metadata": {}}
+{"_id": "13889962", "title": "", "text": "A model of multiple myeloma: culture of 5T33murine myeloma cells and evaluation oftumorigenicity in the C57BL/KaLwRij mouse.The5T33 multiple myeloma is one of a series oftransplantable murine myelomas arisingspontaneously in C57BL/KaLwRij mice. Thisstudy describes the establishment andcharacterisation of the 5T33 murine myeloma invitro as a cultured cell line in terms of itsmorphology, growth rate, expression ofparaprotein (IgG2b) and tumorigenicity insyngeneic animals. The 5T33 cell line has been incontinuous culture for over 10 months and hasachieved more than passage 34. In culture, 5T33myeloma grows as single cells or in smallclusters of loosely adherent cells on an adherentstromal cell layer. Maximum doubling time isapproximately 25 h, and over 90% of the cellsexpress cytoplasmic IgG2b paraprotein. Thecultured 5T33 myeloma cells are highlytumorigenic in C57BL/KaLwRij mice with as fewas 500 cells inducing paralysis and death as early", "metadata": {}}
+{"_id": "13899137", "title": "", "text": "HIV Treatment as Prevention: SystematicComparison of Mathematical Models of thePotential Impact of Antiretroviral Therapy on HIVIncidence in South AfricaBACKGROUND Manymathematical models have investigated theimpact of expanding access to antiretroviraltherapy (ART) on new HIV infections. Comparingresults and conclusions across models ischallenging because models have addressedslightly different questions and have reporteddifferent outcome metrics. This study comparesthe predictions of several mathematical modelssimulating the same ART interventionprogrammes to determine the extent to whichmodels agree about the epidemiological impactof expanded ART. METHODS AND FINDINGSTwelve independent mathematical modelsevaluated a set of standardised ART interventionscenarios in South Africa and reported a commonset of outputs. Intervention scenariossystematically varied the CD4 count threshold fortreatment eligibility, access to treatment, and", "metadata": {}}
+{"_id": "13900610", "title": "", "text": "Self-harm in prisons in England and Wales: anepidemiological study of prevalence, risk factors,clustering, and subsequent suicideBACKGROUNDSelf-harm and suicide are common in prisoners,yet robust information on the full extent andcharacteristics of people at risk of self-harm isscant. Furthermore, understanding howfrequently self-harm is followed by suicide, andin which prisoners this progression is most likelyto happen, is important. We did a case-controlstudy of all prisoners in England and Wales toascertain the prevalence of self-harm in thispopulation, associated risk factors, clusteringeffects, and risk of subsequent suicide afterself-harm. METHODS Records of self-harmincidents in all prisons in England and Waleswere gathered routinely between January, 2004,and December, 2009. We did a case-controlcomparison of prisoners who self-harmed andthose who did not between January, 2006, andDecember, 2009. We also used a Bayesianapproach to look at clustering of people who", "metadata": {}}
+{"_id": "13901073", "title": "", "text": "Elimination of HIV in South Africa throughExpanded Access to Antiretroviral Therapy: AModel Comparison StudyBACKGROUNDExpanded access to antiretroviral therapy (ART)using universal test and treat (UTT) has beensuggested as a strategy to eliminate HIV inSouth Africa within 7 y based on an influentialmathematical modeling study. However, theunderlying deterministic model was criticizedwidely, and other modeling studies did notalways confirm the study's finding. The objectiveof our study is to better understand theimplications of different model structures andassumptions, so as to arrive at the best possiblepredictions of the long-term impact of UTT andthe possibility of elimination of HIV. METHODSAND FINDINGS We developed nine structurallydifferent mathematical models of the SouthAfrican HIV epidemic in a stepwise approach ofincreasing complexity and realism. The simplestmodel resembles the initial deterministic model,while the most comprehensive model is the", "metadata": {}}
+{"_id": "13902570", "title": "", "text": "Bile acid receptor TGR5 agonism induces NOproduction and reduces monocyte adhesion invascular endothelial cells.OBJECTIVE TGR5 is aG-protein-coupled receptor for bile acids. So far,little is known about the function of TGR5 invascular endothelial cells. APPROACH ANDRESULTS In bovine aortic endothelial cells,treatment with a bile acid having a high affinityto TGR5, taurolithocholic acid (TLCA),significantly increased NO production. This effectwas abolished by small interfering RNA-mediateddepletion of TGR5. TLCA-induced NO productionwas also observed in human umbilical veinendothelial cells measured via intracellular cGMPaccumulation. TLCA increased endothelial NOsynthase(ser1177) phosphorylation in humanumbilical vein endothelial cells. This responsewas accompanied by increased Akt(ser473)phosphorylation and intracellular Ca(2+).Inhibition of these signals significantly decreasedTLCA-induced NO production. We next examinedwhether TGR5-mediated NO production affects", "metadata": {}}
+{"_id": "13903052", "title": "", "text": "Structural insights into calicivirus attachmentand uncoating.The Caliciviridae family comprisespositive-sense RNA viruses of medical andveterinary significance. In humans, calicivirusesare a major cause of acute gastroenteritis, whilein animals respiratory illness, conjunctivitis,stomatitis, and hemorrhagic disease aredocumented. Investigation of virus-hostinteractions is limited by a lack of culturesystems for many viruses in this family. Felinecalicivirus (FCV), a member of the Vesivirusgenus, provides a tractable model, since it maybe propagated in cell culture. Feline junctionaladhesion molecule 1 (fJAM-1) was recentlyidentified as a functional receptor for FCV. Wehave analyzed the structure of thisvirus-receptor complex by cryo-electronmicroscopy and three-dimensional imagereconstruction, combined with fitting ofhomology modeled high-resolution coordinates.We show that domain 1 of fJAM-1 binds to theouter face of the P2 domain of the FCV capsid", "metadata": {}}
+{"_id": "13905670", "title": "", "text": "Human SNP Links Differential Outcomes inInflammatory and Infectious Disease to aFOXO3-Regulated PathwayThe clinical courseand eventual outcome, or prognosis, of complexdiseases varies enormously between affectedindividuals. This variability critically determinesthe impact a disease has on a patient's life but isvery poorly understood. Here, we exploit existinggenome-wide association study data to gaininsight into the role of genetics in prognosis. Weidentify a noncoding polymorphism in FOXO3A(rs12212067: T > G) at which the minor (G)allele, despite not being associated with diseasesusceptibility, is associated with a milder courseof Crohn's disease and rheumatoid arthritis andwith increased risk of severe malaria. Minor allelecarriage is shown to limit inflammatoryresponses in monocytes via a FOXO3-drivenpathway, which through TGFβ1 reducesproduction of proinflammatory cytokines,including TNFα, and increases production ofanti-inflammatory cytokines, including IL-10.", "metadata": {}}
+{"_id": "13906581", "title": "", "text": "Patient Outcomes with Teaching VersusNonteaching Healthcare: A SystematicReviewBackground  Extensive debate exists inthe healthcare community over whetheroutcomes of medical care at teaching hospitalsand other healthcare units are better or worsethan those at the respective nonteaching ones.Thus, our goal was to systematically evaluate theevidence pertaining to this question. Methodsand Findings  We reviewed all studies thatcompared teaching versus nonteachinghealthcare structures for mortality or any otherpatient outcome, regardless of health condition.Studies were retrieved from PubMed, contactwith experts, and literature cross-referencing.Data were extracted on setting, patients, datasources, author affiliations, definition ofcompared groups, types of diagnosesconsidered, adjusting covariates, and estimatesof effect for mortality and for each otheroutcome. Overall, 132 eligible studies wereidentified, including 93 on mortality and 61 on", "metadata": {}}
+{"_id": "13906892", "title": "", "text": "DNA damage and Repair Modify DNA methylationand Chromatin Domain of the Targeted Locus:Mechanism of allele methylationpolymorphismWe characterize the changes inchromatin structure, DNA methylation andtranscription during and after homologous DNArepair (HR). We find that HR modifies the DNAmethylation pattern of the repaired segment. HRalso alters local histone H3 methylation as wellchromatin structure by inducing DNA-chromatinloops connecting the 5' and 3' ends of therepaired gene. During a two-week period afterrepair, transcription-associated demethylationpromoted by Base Excision Repair enzymesfurther modifies methylation of the repairedDNA. Subsequently, the repaired genes displaystable but diverse methylation profiles. Theseprofiles govern the levels of expression in eachclone. Our data argue that DNA methylation andchromatin remodelling induced by HR may be asource of permanent variation of geneexpression in somatic cells.", "metadata": {}}
+{"_id": "13907427", "title": "", "text": "DNA repair factor APLF is a histonechaperone.Poly(ADP-ribosyl)ation plays a majorrole in DNA repair, where it regulates chromatinrelaxation as one of the critical events in therepair process. However, the molecularmechanism by which poly(ADP-ribose)modulates chromatin remains poorly understood.Here we identify the poly(ADP-ribose)-regulatedprotein APLF as a DNA-damage-specific histonechaperone. APLF preferentially binds to thehistone H3/H4 tetramer via its C-terminal acidicmotif, which is homologous to the motifconserved in the histone chaperones of theNAP1L family (NAP1L motif). We furtherdemonstrate that APLF exhibits histonechaperone activities in a manner that isdependent on its acidic domain and that theNAP1L motif is critical for the repair capacity ofAPLF in vivo. Finally, we identify structuralanalogs of APLF in lower eukaryotes with theability to bind histones and localize to the sites ofDNA-damage-induced poly(ADP-ribosyl)ation.", "metadata": {}}
+{"_id": "13907928", "title": "", "text": "Regulation of sympathetic nerve activity duringthe cold pressor test in normotensive pregnantand nonpregnant women.Baseline neurovasculartransduction is reduced in normotensivepregnancy; however, little is known aboutchanges to neurovascular transduction duringperiods of heightened sympathetic activation. Wetested the hypothesis that, despite anexacerbated muscle sympathetic nerve activity(microneurography) response to cold pressorstimulation, the blunting of neurovasculartransduction in normotensive pregnant womenwould result in similar changes in vascularresistance and mean arterial pressure(Finometer) relative to nonpregnant controls.Baseline neurovascular transduction was reducedin pregnant women relative to controls whenexpressed as the quotient of both totalresistance and mean arterial pressure andsympathetic burst frequency (0.32±0.07 versus0.58±0.16 mm Hg/L/min/bursts/min, P<0.001and 2.4±0.7 versus 3.6±0.8 mm Hg/bursts/min,", "metadata": {}}
+{"_id": "13910150", "title": "", "text": "The Germ Cell Determinant Blimp1 Is NotRequired for Derivation of Pluripotent StemCellsBlimp1 (Prdm1), the key determinant ofprimordial germ cells (PGCs), plays acombinatorial role with Prdm14 during PGCspecification from postimplantation epiblast cells.They together initiate epigenetic reprogrammingin early germ cells toward an underlyingpluripotent state, which is equivalent toembryonic stem cells (ESCs). Whereas Prdm14alone can promote reprogramming and isimportant for the propagation of the pluripotentstate, it is not known whether Blimp1 is similarlyinvolved. By using a genetic approach, wedemonstrate that Blimp1 is dispensable for thederivation and maintenance of ESCs andpostimplantation epiblast stem cells (epiSCs).Notably, Blimp1 is also dispensable forreprogramming epiSCs to ESCs. Thus, althoughBlimp1 is obligatory for PGC specification, it isnot required for the reversion of epiSCs to ESCsand for their maintenance thereafter. This study", "metadata": {}}
+{"_id": "13912224", "title": "", "text": "A Nexus for Gene Expression—MolecularMechanisms of Spt5 and NusG in the ThreeDomains of LifeEvolutionary related multisubunitRNA polymerases (RNAPs) transcribe thegenomes of all living organisms. Whereas thecore subunits of RNAPs are universally conservedin all three domains of life-indicative of acommon evolutionary descent-this only appliesto one RNAP-associated transcriptionfactor-Spt5, also known as NusG in bacteria. Allother factors that aid RNAP during thetranscription cycle are specific for the individualdomain or only conserved between archaea andeukaryotes. Spt5 and its bacterial homologueNusG regulate gene expression in several waysby (i) modulating transcription processivity andpromoter proximal pausing, (ii) couplingtranscription and RNA processing or translation,and (iii) recruiting termination factors andthereby silencing laterally transferred DNA andprotecting the genome against double-strandedDNA breaks. This review discusses recent", "metadata": {}}
+{"_id": "13914198", "title": "", "text": "Haplotype estimation using sequencingreads.High-throughput sequencing technologiesproduce short sequence reads that can containphase information if they span two or moreheterozygote genotypes. This information is notroutinely used by current methods that inferhaplotypes from genotype data. We haveextended the SHAPEIT2 method to usephase-informative sequencing reads to improvephasing accuracy. Our model incorporates theread information in a probabilistic model throughbase quality scores within each read. Themethod is primarily designed for high-coveragesequence data or data sets that already havegenotypes called. One important application isphasing of single samples sequenced at highcoverage for use in medical sequencing andstudies of rare diseases. Our method can alsouse existing panels of reference haplotypes. Wetested the method by using amother-father-child trio sequenced athigh-coverage by Illumina together with the", "metadata": {}}
+{"_id": "13914633", "title": "", "text": "Time and Money: The True Costs of Health CareUtilization for Patients Receiving \"Free\"HIV/Tuberculosis Care and Treatment in RuralKwaZulu-Natal.BACKGROUND HIV andtuberculosis (TB) services are provided free ofcharge in many sub-Saharan African countries,but patients still incur costs. METHODSPatient-exit interviews were conducted inprimary health care clinics in rural South Africawith representative samples of 200 HIV-infectedpatients enrolled in a pre-antiretroviral treatment(pre-ART) program, 300 patients receivingantiretroviral treatment (ART), and 300 patientsreceiving TB treatment. For each group, wecalculated health expenditures across differentspending categories, time spent traveling to andusing services, and how patients financed theirspending. Associations between patient groupand costs were assessed in multivariateregression models. RESULTS Total monthlyhealth expenditures [1 USD = 7.3 South AfricanRand (ZAR)] were ZAR 171 [95% confidence", "metadata": {}}
+{"_id": "13915464", "title": "", "text": "A new system for naming ribosomal proteins.Asystem for naming ribosomal proteins isdescribed that the authors intend to use in thefuture. They urge others to adopt it. Theobjective is to eliminate the confusion caused bythe assignment of identical names to ribosomalproteins from different species that are unrelatedin structure and function. In the systemproposed here, homologous ribosomal proteinsare assigned the same name, regardless ofspecies. It is designed so that new names aresimilar enough to old names to be easilyrecognized, but are written in a format thatunambiguously identifies them as 'new system'names.", "metadata": {}}
+{"_id": "13916484", "title": "", "text": "COSMIC: mining complete cancer genomes inthe Catalogue of Somatic Mutations inCancerCOSMIC(http://www.sanger.ac.uk/cosmic) curatescomprehensive information on somatic mutationsin human cancer. Release v48 (July 2010)describes over 136,000 coding mutations inalmost 542,000 tumour samples; of the 18,490genes documented, 4803 (26%) have one ormore mutations. Full scientific literaturecurations are available on 83 major cancer genesand 49 fusion gene pairs (19 new cancer genesand 30 new fusion pairs this year) and thisnumber is continually increasing. Key amongstthese is TP53, now available through acollaboration with the IARC p53 database. Inaddition to data from the Cancer Genome Project(CGP) at the Sanger Institute, UK, and TheCancer Genome Atlas project (TCGA), largesystematic screens are also now curated. Majorwebsite upgrades now make these data muchmore mineable, with many new selection filters", "metadata": {}}
+{"_id": "13916951", "title": "", "text": "Quantitative imaging assay for NF-κB nucleartranslocation in primary humanmacrophagesQuantitative measurement ofNF-kappaB nuclear translocation is an importantresearch tool in cellular immunology. Establishedmethodologies have a number of limitations,such as poor sensitivity, high cost or dependenceon cell lines. Novel imaging methods to measurenuclear translocation of transcriptionally activecomponents of NF-kappaB are being used butare also partly limited by the need for specialistimaging equipment or image analysis software.Herein we present a method for quantitativedetection of NF-kappaB rel A nucleartranslocation, using immunofluorescencemicroscopy and the public domain imageanalysis software ImageJ that can be easilyadopted for cellular immunology researchwithout the need for specialist image analysisexpertise and at low cost. The method presentedhere is validated by demonstrating the timecourse and dose response of NF-kappaB nuclear", "metadata": {}}
+{"_id": "13921526", "title": "", "text": "An RNA-sequencing transcriptome and splicingdatabase of glia, neurons, and vascular cells ofthe cerebral cortex.The major cell classes of thebrain differ in their developmental processes,metabolism, signaling, and function. To betterunderstand the functions and interactions of thecell types that comprise these classes, weacutely purified representative populations ofneurons, astrocytes, oligodendrocyte precursorcells, newly formed oligodendrocytes,myelinating oligodendrocytes, microglia,endothelial cells, and pericytes from mousecerebral cortex. We generated a transcriptomedatabase for these eight cell types by RNAsequencing and used a sensitive algorithm todetect alternative splicing events in each celltype. Bioinformatic analyses identified thousandsof new cell type-enriched genes and splicingisoforms that will provide novel markers for cellidentification, tools for genetic manipulation, andinsights into the biology of the brain. Forexample, our data provide clues as to how", "metadata": {}}
+{"_id": "13921783", "title": "", "text": "C9orf72 repeat expansions causeneurodegeneration in Drosophila througharginine-rich proteinsAn expanded GGGGCCrepeat in C9orf72 is the most common geneticcause of frontotemporal dementia andamyotrophic lateral sclerosis. A fundamentalquestion is whether toxicity is driven by therepeat RNA itself and/or by dipeptide repeatproteins generated by repeat-associated,non-ATG translation. To address this question,we developed in vitro and in vivo models todissect repeat RNA and dipeptide repeat proteintoxicity. Expression of pure repeats, but not stopcodon–interrupted “RNA-only” repeats inDrosophila caused adult-onsetneurodegeneration. Thus, expanded repeatspromoted neurodegeneration through dipeptiderepeat proteins. Expression of individualdipeptide repeat proteins with a non-GGGGCCRNA sequence revealed that bothpoly-(glycine-arginine) andpoly-(proline-arginine) proteins caused", "metadata": {}}
+{"_id": "13923069", "title": "", "text": "Targeted nanoparticles containing theproresolving peptide Ac2-26 protect againstadvanced atherosclerosis inhypercholesterolemic miceChronic, nonresolvinginflammation is a critical factor in the clinicalprogression of advanced atherosclerotic lesions.In the normal inflammatory response, resolutionis mediated by several agonists, among which isthe glucocorticoid-regulated protein calledannexin A1. The proresolving actions of annexinA1, which are mediated through its receptorN-formyl peptide receptor 2 (FPR2/ALX), can bemimicked by an amino-terminal peptideencompassing amino acids 2–26 (Ac2-26).Collagen IV (Col IV)–targeted nanoparticles(NPs) containing Ac2-26 were evaluated for theirtherapeutic effect on chronic, advancedatherosclerosis in fat-fed Ldlr−/− mice. Whenadministered to mice with preexisting lesions,Col IV–Ac2-26 NPs were targeted to lesions andled to a marked improvement in key advancedplaque properties, including an increase in the", "metadata": {}}
+{"_id": "13923140", "title": "", "text": "Interleukin-2 gene variation impairs regulatory Tcell function and causesautoimmunityAutoimmune diseases are thoughtto result from imbalances in normal immunephysiology and regulation. Here, we show thatautoimmune disease susceptibility and resistancealleles on mouse chromosome 3 (Idd3) correlatewith differential expression of the keyimmunoregulatory cytokine interleukin-2 (IL-2).In order to test directly that an approximatelytwofold reduction in IL-2 underpins theIdd3-linked destabilization of immunehomeostasis, we show that engineeredhaplodeficiency of Il2 gene expression not onlyreduces T cell IL-2 production by twofold but alsomimics the autoimmune dysregulatory effects ofthe naturally occurring susceptibility alleles ofIl2. Reduced IL-2 production achieved by eithergenetic mechanism correlates with reducedfunction of CD4+ CD25+ regulatory T cells,which are critical for maintaining immunehomeostasis.", "metadata": {}}
+{"_id": "13931771", "title": "", "text": "GRSF1 Regulates RNA Processing inMitochondrial RNA GranulesVarious specializeddomains have been described in the cytosol andthe nucleus; however, little is known aboutcompartmentalization within the mitochondrialmatrix. GRSF1 (G-rich sequence factor 1) is anRNA binding protein that was previously reportedto localize in the cytosol. We found that anisoform of GRSF1 accumulates in discrete foci inthe mitochondrial matrix. These foci arecomposed of nascent mitochondrial RNA and alsocontain RNase P, an enzyme that participates inmitochondrial RNA processing. GRSF1 was foundto interact with RNase P and to be required forprocessing of both classical and tRNA-less RNAprecursors. In its absence, cleavage of primaryRNA transcripts is abnormal, leading todecreased expression of mitochondrially encodedproteins and mitochondrial dysfunction. Ourfindings suggest that the foci containing GRSF1and RNase P correspond to sites where primaryRNA transcripts converge to be processed. We", "metadata": {}}
+{"_id": "13933299", "title": "", "text": "Midlife Serum Cholesterol and Increased Risk ofAlzheimer’s and Vascular Dementia ThreeDecades LaterAims: To investigate midlifecholesterol in relation to Alzheimer’s disease(AD) and vascular dementia (VaD) in a largemultiethnic cohort of women and men. Methods:The Kaiser Permanente Northern CaliforniaMedical Group (healthcare delivery organization)formed the database for this study. The 9,844participants underwent detailed healthevaluations during 1964–1973 at ages 40–45years; they were still members of the health planin 1994. AD and VaD were ascertained bymedical records between 1 January 1994 and 1June 2007. Cox proportional hazards models –adjusted for age, education, race/ethnic group,sex, midlife diabetes, hypertension, BMI andlate-life stroke – were conducted. Results: Intotal, 469 participants had AD and 127 had VaD.With desirable cholesterol levels (<200 mg/dl) asa reference, hazard ratios (HR) and 95% CI forAD were 1.23 (0.97–1.55) and 1.57 (1.23–2.01)", "metadata": {}}
+{"_id": "13934676", "title": "", "text": "\"The contribution of chronic diseases to theprevalence of dependence among older people inLatin America, China and India: a 10/66Dementia Research Group population-basedsurvey\"BACKGROUND The number of olderpeople is set to increase dramatically worldwide.Demographic changes are likely to result in therise of age-related chronic diseases which largelycontribute to years lived with a disability andfuture dependence. However dependence ismuch less studied although intrinsically linked todisability. We investigated the prevalence andcorrelates of dependence among older peoplefrom middle income countries. METHODS Aone-phase cross-sectional survey was carried outat 11 sites in seven countries (urban sites inCuba, Venezuela, and Dominican Republic, urbanand rural sites in Peru, Mexico, China and India).All those aged 65 years and over living ingeographically defined catchment areas wereeligible. In all, 15,022 interviews were completedwith an informant interview for each participant.", "metadata": {}}
+{"_id": "13936152", "title": "", "text": "An actomyosin-based barrier inhibits cell mixingat compartmental boundaries in DrosophilaembryosPartitioning tissues into compartmentsthat do not intermix is essential for the correctmorphogenesis of animal embryos and organs.Several hypotheses have been proposed toexplain compartmental cell sorting, mainlydifferential adhesion, but also regulation of thecytoskeleton or of cell proliferation.Nevertheless, the molecular and cellularmechanisms that keep cells apart at boundariesremain unclear. Here we demonstrate, in earlyDrosophila melanogaster embryos, thatactomyosin-based barriers stop cells frominvading neighbouring compartments. Ouranalysis shows that cells can transiently invadeneighbouring compartments, especially whenthey divide, but are then pushed back into theircompartment of origin. Actomyosin cytoskeletalcomponents are enriched at compartmentalboundaries, forming cable-like structures whenthe epidermis is mitotically active. When MyoII", "metadata": {}}
+{"_id": "13938878", "title": "", "text": "Clinical algorithms for malaria diagnosis lackutility among people of different age groups.Weconducted a study to determine whether clinicalalgorithms would be useful in malaria diagnosisamong people living in an area of moderatemalaria transmission within Kilifi District inKenya. A total of 1602 people of all age groupsparticipated. We took smears and recordedclinical signs and symptoms (prompted orspontaneous) of all those presenting to the studyclinic with a history of fever. A malaria case wasdefined as a person presenting to the clinic witha history of fever and concurrent parasitaemia. Aset of clinical signs and symptoms (algorithms)with the highest sensitivity and specificity fordiagnosing a malaria case was selected for theage groups </=5 years, 6-14 years and >/=15years. These age-optimized derived algorithmswere able to identify about 66% of the casesamong those <15 years of age but only 23% ofcases among adults. Were these algorithms to beused as a basis for a decision on treatment", "metadata": {}}
+{"_id": "13940200", "title": "", "text": "Large-scale genetic fine mapping andgenotype-phenotype associations implicatepolymorphism in the IL2RA region in type 1diabetesGenome-wide association studies arenow identifying disease-associated chromosomeregions. However, even after convincingreplication, the localization of the causalvariant(s) requires comprehensive resequencing,extensive genotyping and statistical analyses inlarge sample sets leading to targeted functionalstudies. Here, we have localized the type 1diabetes (T1D) association in the interleukin 2receptor alpha (IL2RA) gene region to twoindependent groups of SNPs, spanningoverlapping regions of 14 and 40 kb,encompassing IL2RA intron 1 and the 5′ regionsof IL2RA and RBM17 (odds ratio = 2.04, 95%confidence interval = 1.70–2.45; P = 1.92 ×10−28; control frequency = 0.635).Furthermore, we have associated IL2RA T1Dsusceptibility genotypes with lower circulatinglevels of the biomarker, soluble IL-2RA (P = 6.28", "metadata": {}}
+{"_id": "13944805", "title": "", "text": "Maternal obesity epigenetically alters visceral fatprogenitor cell properties in male offspringmice.KEY POINTS Maternal obesity reducesadipogenic progenitor density in offspringadipose tissue. The ability of adipose tissueexpansion in the offspring of obese mothers islimited and is associated with metabolicdysfunction of adipose tissue when challengedwith a high-fat diet. Maternal obesity inducesDNA demethylation in the promoter of zinc fingerprotein 423, which renders progenitor cells witha high adipogenic capacity. Maternal obesitydemonstrates long-term effects on theadipogenic capacity of progenitor cells inoffspring adipose tissue, demonstrating adevelopmental programming effect. ABSTRACTMaternal obesity (MO) programs offspringobesity and metabolic disorders, although theunderlying mechanisms remain poorly defined.Progenitor cells are the source of newadipocytes. The present study aimed to testwhether MO epigenetically predisposes adipocyte", "metadata": {}}
+{"_id": "13948920", "title": "", "text": "Quality Testing of Artemisinin-Based AntimalarialDrugs in Myanmar.Artemisinin-basedcombination therapies are the frontlinetreatment of Plasmodium falciparum malaria.The circulation of falsified and substandardartemisinin-based antimalarials in Southeast Asiahas been a major predicament for the malariaelimination campaign. To provide an update ofthis situation, we purchased 153artemisinin-containing antimalarials, asconvenience samples, in private drug stores fromdifferent regions of Myanmar. The quality ofthese drugs in terms of their artemisininderivative content was tested using specificdipsticks for these artemisinin derivatives, aspoint-of-care devices. A subset of these sampleswas further tested by high-performance liquidchromatography (HPLC). This survey identifiedthat > 35% of the collected drugs were oralartesunate and artemether monotherapies.When tested with the dipsticks, all but onesample passed the assays, indicating that the", "metadata": {}}
+{"_id": "13949015", "title": "", "text": "LINE-1 Retrotransposition Activity in HumanGenomesHighly active (i.e., \"hot\") longinterspersed element-1 (LINE-1 or L1) sequencescomprise the bulk of retrotransposition activity inthe human genome; however, the abundance ofhot L1s in the human population remains largelyunexplored. Here, we used a fosmid-based,paired-end DNA sequencing strategy to identify68 full-length L1s that are differentially presentamong individuals but are absent from thehuman genome reference sequence. Themajority of these L1s were highly active in acultured cell retrotransposition assay.Genotyping 26 elements revealed that two L1sare only found in Africa and that two more areabsent from the H952 subset of the HumanGenome Diversity Panel. Therefore, these resultssuggest that hot L1s are more abundant in thehuman population than previously appreciated,and that ongoing L1 retrotransposition continuesto be a major source of interindividual geneticvariation.", "metadata": {}}
+{"_id": "13952658", "title": "", "text": "Immune cell promotion of metastasisMetastaticdisease is the major cause of death from cancer,and immunotherapy and chemotherapy have hadlimited success in reversing its progression. Datafrom mouse models suggest that the recruitmentof immunosuppressive cells to tumours protectsmetastatic cancer cells from surveillance by killercells, which nullifies the effects ofimmunotherapy and thus establishes metastasis.Furthermore, in most cases, tumour-infiltratingimmune cells differentiate into cells that promoteeach step of the metastatic cascade and thus arenovel targets for therapy. In this Review, wedescribe how tumour-infiltrating immune cellscontribute to the metastatic cascade and wediscuss potential therapeutic strategies to targetthese cells.", "metadata": {}}
+{"_id": "13953762", "title": "", "text": "PICH: a DNA translocase specially adapted forprocessing anaphase bridge DNA.ThePlk1-interacting checkpoint helicase (PICH)protein localizes to ultrafine anaphase bridges(UFBs) in mitosis alongside a complex of DNArepair proteins, including the Bloom's syndromeprotein (BLM). However, very little is knownabout the function of PICH or how it is recruitedto UFBs. Using a combination of microfluidics,fluorescence microscopy, and optical tweezers,we have defined the properties of PICH in an invitro model of an anaphase bridge. We show thatPICH binds with a remarkably high affinity toduplex DNA, resulting in ATP-dependent proteintranslocation and extension of the DNA. Moststrikingly, the affinity of PICH for binding DNAincreases with tension-induced DNA stretching,which mimics the effect of the mitotic spindle ona UFB. PICH binding also appears to diminishforce-induced DNA melting. We propose a modelin which PICH recognizes and stabilizes DNAunder tension during anaphase, thereby", "metadata": {}}
+{"_id": "13955536", "title": "", "text": "The Dynamics of Genome-wide DNA MethylationReprogramming in Mouse Primordial GermCellsGenome-wide DNA methylationreprogramming occurs in mouse primordial germcells (PGCs) and preimplantation embryos, butthe precise dynamics and biological outcomesare largely unknown. We have carried outwhole-genome bisulfite sequencing (BS-Seq) andRNA-Seq across key stages from E6.5 epiblast toE16.5 PGCs. Global loss of methylation takesplace during PGC expansion and migration withevidence for passive demethylation, butsequences that carry long-term epigeneticmemory (imprints, CpG islands on the Xchromosome, germline-specific genes) onlybecome demethylated upon entry of PGCs intothe gonads. The transcriptional profile of PGCs istightly controlled despite globalhypomethylation, with transient expression ofthe pluripotency network, suggesting thatreprogramming and pluripotency are inextricablylinked. Our results provide a framework for the", "metadata": {}}
+{"_id": "13956305", "title": "", "text": "Major histocompatibility complex associations ofankylosing spondylitis are complex and involvefurther epistasis with ERAP1Ankylosingspondylitis (AS) is a common, highly heritable,inflammatory arthritis for which HLA-B*27 is themajor genetic risk factor, although its role in theaetiology of AS remains elusive. To betterunderstand the genetic basis of the MHCsusceptibility loci, we genotyped 7,264 MHCSNPs in 22,647 AS cases and controls ofEuropean descent. We impute SNPs, classicalHLA alleles and amino-acid residues within HLAproteins, and tested these for association to ASstatus. Here we show that in addition to effectsdue to HLA-B*27 alleles, several other HLA-Balleles also affect susceptibility. After controllingfor the associated haplotypes in HLA-B, weobserve independent associations with variantsin the HLA-A, HLA-DPB1 and HLA-DRB1 loci. Wealso demonstrate that the ERAP1 SNP rs30187association is not restricted only to carriers ofHLA-B*27 but also found in HLA-B*40:01", "metadata": {}}
+{"_id": "13958154", "title": "", "text": "RNA sequencing identifies dysregulation of thehuman pancreatic islet transcriptome by thesaturated fatty acid palmitate.Pancreatic β-celldysfunction and death are central in thepathogenesis of type 2 diabetes (T2D).Saturated fatty acids cause β-cell failure andcontribute to diabetes development in geneticallypredisposed individuals. Here we used RNAsequencing to map transcripts expressed in fivepalmitate-treated human islet preparations,observing 1,325 modified genes. Palmitateinduced fatty acid metabolism and endoplasmicreticulum (ER) stress. Functional studiesidentified novel mediators of adaptive ER stresssignaling. Palmitate modified genes regulatingubiquitin and proteasome function, autophagy,and apoptosis. Inhibition of autophagic flux andlysosome function contributed to lipotoxicity.Palmitate inhibited transcription factorscontrolling β-cell phenotype, including PAX4 andGATA6. Fifty-nine T2D candidate genes wereexpressed in human islets, and 11 were modified", "metadata": {}}
+{"_id": "13959707", "title": "", "text": "The Ratio of Monocytes to Lymphocytes inPeripheral Blood Correlates with IncreasedSusceptibility to Clinical Malaria in KenyanChildrenBACKGROUND Plasmodium falciparummalaria remains a major cause of illness anddeath in sub-Saharan Africa. Young children bearthe brunt of the disease and though olderchildren and adults suffer relatively fewer clinicalattacks, they remain susceptible toasymptomatic P. falciparum infection. A betterunderstanding of the host factors associated withimmunity to clinical malaria and the ability tosustain asymptomatic P. falciparum infection willaid the development of improved strategies fordisease prevention. METHODS AND FINDINGSHere we investigate whether full differentialblood counts can predict susceptibility to clinicalmalaria among Kenyan children sampled at fiveannual cross-sectional surveys. We find that theratio of monocytes to lymphocytes, measured inperipheral blood at the time of survey, directlycorrelates with risk of clinical malaria during", "metadata": {}}
+{"_id": "13963620", "title": "", "text": "Dynamic analysis of filopodial interactions duringthe zippering phase of Drosophila dorsalclosure.Dorsal closure is a paradigm epithelialfusion episode that occurs late in Drosophilaembryogenesis and leads to sealing of a midlinehole by bonding of two opposing epithelialsheets. The leading edge epithelial cells expressfilopodia and fusion is dependent oninterdigitation of these filopodia to primeformation of adhesions. Since the opposingepithelia are molecularly patterned there mustexist some mechanism for accurately aligningthe two sheets across this fusion seam. Toaddress this, we generated a fly in whichRFP-Moesin and GFP-Moesin are expressed inmutually exclusive stripes within each segmentusing the engrailed and patched promoters. Weobserve mutually exclusive interactions betweenthe filopodia of engrailed and patched cells.Interactions between filopodia from matchingcells leads to formation of tethers between them,and these tethers can pull misaligned epithelial", "metadata": {}}
+{"_id": "13964633", "title": "", "text": "Expression of Versican 3′-Untranslated RegionModulates Endogenous MicroRNAFunctionsBACKGROUND Mature microRNAs(miRNAs) are single-stranded RNAs that regulatepost-transcriptional gene expression. In ourprevious study, we have shown that versican3'UTR, a fragment of non-coding transcript, hasthe ability to antagonize miR-199a-3p functionthereby regulating expression of the matrixproteins versican and fibronectin, and thusresulting in enhanced cell-cell adhesion andorgan adhesion. However, the impact of thisnon-coding fragment on tumorigenesis is yet tobe determined. METHODS AND FINDINGS Usingcomputational prediction confirmed with in vitroand in vivo experiments, we report that theexpression of versican 3'UTR not onlyantagonizes miR-199a-3p but can also lower itssteady state expression. We found thatexpression of versican 3'UTR in a mouse breastcarcinoma cell line, 4T1, decreased miR-199a-3plevels. The decrease in miRNA activity", "metadata": {}}
+{"_id": "13965483", "title": "", "text": "Prophylactic and therapeutic efficacy of theepitope vaccine CTB-UA against Helicobacterpylori infection in a BALB/c mice modelEpitopevaccine based on the enzyme urease ofHelicobacter pylori is a promising option forprophylactic and therapeutic vaccination againstH. pylori infection. In our previous study, theepitope vaccine CTB-UA, which was composed ofthe mucosal adjuvant cholera toxin B subunit(CTB) and an epitope (UreA183–203) from theH. pylori urease A subunit (UreA) wasconstructed. This particular vaccine was shownto have good immunogenicity andimmunoreactivity and could induce specificneutralizing antibodies, which exhibitedeffectively inhibitory effects on the enzymaticactivity of H. pylori urease. In this study, theprophylactic and therapeutic efficacy of theepitope vaccine CTB-UA was evaluated in aBALB/c mice model. The experimental resultsindicated that oral prophylactic or therapeuticimmunization with CTB-UA significantly", "metadata": {}}
+{"_id": "13966946", "title": "", "text": "Spatial co-distribution of neglected tropicaldiseases in the east African great lakes region:revisiting the justification for integratedcontrol.OBJECTIVE To determine spatial patternsof co-endemicity of schistosomiasis mansoni andthe soil-transmitted helminths (STHs) Ascarislumbricoides, Trichuris trichiura and hookwormin the Great Lakes region of East Africa, to helpplan integrated neglected tropical diseaseprogrammes in this region. METHODParasitological surveys were conducted inUganda, Tanzania, Kenya and Burundi in 28 213children in 404 schools. Bayesian geostatisticalmodels were used to interpolate prevalence ofthese infections across the study area.Interpolated prevalence maps were overlaid todetermine areas of co-endemicity. RESULTS Inthe Great Lakes region, prevalence was 18.1%for Schistosoma mansoni, 50.0% for hookworm,6.8% for A. lumbricoides and 6.8% for T.trichiura. Hookworm infection was ubiquitous,whereas S. mansoni, A. lumbricoides and T.", "metadata": {}}
+{"_id": "13969173", "title": "", "text": "Direct conversion of patient fibroblastsdemonstrates non-cell autonomous toxicity ofastrocytes to motor neurons in familial andsporadic ALS.Amyotrophic lateral sclerosis (ALS)causes motor neuron degeneration, paralysis,and death. Accurate disease modeling,identifying disease mechanisms, and developingtherapeutics is urgently needed. We previouslyreported motor neuron toxicity throughpostmortem ALS spinal cord-derived astrocytes.However, these cells can only be harvested afterdeath, and their expansion is limited. We nowreport a rapid, highly reproducible method toconvert adult human fibroblasts from living ALSpatients to induced neuronal progenitor cells andsubsequent differentiation into astrocytes(i-astrocytes). Non-cell autonomous toxicity tomotor neurons is found following coculture ofi-astrocytes from familial ALS patients withmutation in superoxide dismutase orhexanucleotide expansion in C9orf72 (ORF 72 onchromosome 9) the two most frequent causes of", "metadata": {}}
+{"_id": "13980338", "title": "", "text": "Combined Single-Cell Functional and GeneExpression Analysis Resolves Heterogeneitywithin Stem Cell PopulationsHeterogeneity withinthe self-renewal durability of adult hematopoieticstem cells (HSCs) challenges our understandingof the molecular framework underlying HSCfunction. Gene expression studies have beenhampered by the presence of multiple HSCsubtypes and contaminating non-HSCs in bulkHSC populations. To gain deeper insight into thegene expression program of murine HSCs, wecombined single-cell functional assays with flowcytometric index sorting and single-cell geneexpression assays. Through bioinformaticintegration of these datasets, we designed anunbiased sorting strategy that separatesnon-HSCs away from HSCs, and single-celltransplantation experiments using the enrichedpopulation were combined with RNA-seq data toidentify key molecules that associate withlong-term durable self-renewal, producing asingle-cell molecular dataset that is linked to", "metadata": {}}
+{"_id": "13989491", "title": "", "text": "Acids: Structures, Properties, and Functions(University Science Books, Sausalito, CA,2000).Humans expressing a defective form ofthe transcription factor AIRE (autoimmuneregulator) develop multiorgan autoimmunedisease. We used aire- deficient mice to test thehypothesis that this transcription factor regulatesautoimmunity by promoting the ectopicexpression of peripheral tissue- restrictedantigens in medullary epithelial cells of thethymus. This hypothesis proved correct. Themutant animals exhibited a defined profile ofautoimmune diseases that depended on theabsence of aire in stromal cells of the thymus.Aire-deficient thymic medullary epithelial cellsshowed a specific reduction in ectopictranscription of genes encoding peripheralantigens. These findings highlight the importanceof thymically imposed \"central\" tolerance incontrolling autoimmunity.", "metadata": {}}
+{"_id": "13992047", "title": "", "text": "Directed Actin Polymerization Is the DrivingForce for Epithelial Cell–Cell AdhesionWe havefound that epithelial cells engage in a process ofcadherin-mediated intercellular adhesion thatutilizes calcium and actin polymerization inunexpected ways. Calcium stimulates filopodia,which penetrate and embed into neighboringcells. E-cadherin complexes cluster at filopodiatips, generating a two-rowed zipper of embeddedpuncta. Opposing cell surfaces are clamped bydesmosomes, while vinculin, zyxin, VASP, andMena are recruited to adhesion zippers by amechanism that requires alpha-catenin. Actinreorganizes and polymerizes to merge punctainto a single row and seal cell borders. Inkeratinocytes either null for alpha-catenin orblocked in VASP/Mena function, filopodia embed,but actin reorganization/polymerization isprevented, and membranes cannot seal. Takentogether, a dynamic mechanism for intercellularadhesion is unveiled involving calcium-activatedfilopodia penetration and VASP/Mena-dependent", "metadata": {}}
+{"_id": "14019636", "title": "", "text": "Ribosomal DNA copy number loss and sequencevariation in cancerRibosomal DNA is one of themost variable regions in the human genome withrespect to copy number. Despite the importanceof rDNA for cellular function, we know virtuallynothing about what governs its copy number,stability, and sequence in the mammaliangenome due to challenges associated withmapping and analysis. We applied computationaland droplet digital PCR approaches to measurerDNA copy number in normal and cancer statesin human and mouse genomes. We find thatcopy number and sequence can change in cancergenomes. Counterintuitively, human cancergenomes show a loss of copies, accompanied byglobal copy number co-variation. The sequencecan also be more variable in the cancer genome.Cancer genomes with lower copies havemutational evidence of mTOR hyperactivity. ThePTEN phosphatase is a tumor suppressor that iscritical for genome stability and a negativeregulator of the mTOR kinase pathway.", "metadata": {}}
+{"_id": "14021596", "title": "", "text": "The association of Red cell distribution width andin-hospital mortality in older adults admitted tothe emergency departmentBACKGROUND Theobjective of the study was to test the hypothesisthat elevated red cell distribution width (RDW) atadmission increases the risk of mortality in olderpatients admitted to the emergency department(ED). METHODS We performed a retrospectiveanalysis of patients admitted to the ED betweenMay 2013 and October 2013. We includedpatients who were older than 65 years whovisited the ED with any medical problems.Baseline RDW values were measured at the timeof admission to the ED. The primary outcomewas all-cause in-hospital mortality. Multivariatelogistic analysis was performed. RESULTS A totalof 1,990 patients were finally included in thisstudy. The mean age was 75 years (SD 7), and936 (47 %) subjects were male. The in-hospitalmortality rate was 3.76 % (74 patients). RDWvalues higher in non-survivors than in survivors(15.9 ± 2.5 vs. 13.8 ± 1.7, p < 0.001).", "metadata": {}}
+{"_id": "14050257", "title": "", "text": "Gene regulation by the act of long non-codingRNA transcriptionLong non-protein-coding RNAs(lncRNAs) are proposed to be the largesttranscript class in the mouse and humantranscriptomes. Two important questions arewhether all lncRNAs are functional and how theycould exert a function. Several lncRNAs havebeen shown to function through their product,but this is not the only possible mode of action.In this review we focus on a role for the processof lncRNA transcription, independent of thelncRNA product, in regulatingprotein-coding-gene activity in cis. We discussexamples where lncRNA transcription leads togene silencing or activation, and describestrategies to determine if the lncRNA product orits transcription causes the regulatory effect.", "metadata": {}}
+{"_id": "14060030", "title": "", "text": "Life and death of cardiac stem cells: a paradigmshift in cardiac biology.The recognition thatmyocyte mitosis occurs in the fetal, neonatal,adult, and hypertrophied heart and that a pool ofprimitive, undifferentiated cells is present in themyocardium has put forward a different view ofthe biology of the heart. The new paradigmsuggests that myocyte formation is preservedduring postnatal life, in adulthood or senescence,pointing to a remarkable growth reserve of theheart throughout the course of life of theorganism. This article reviews a large body ofnovel information, which has been obtained inthe last 2 decades, in favor of the notion that themammalian heart has the inherent ability tocontinuously replace its parenchymal cells andthat this unexpected characteristic has importantimplications in understanding myocardialhomeostasis, cardiac aging, and tissue repair.The paradigm that the heart is a postmitoticorgan incapable of regenerating parenchymalcells was established in the 1970s, and this", "metadata": {}}
+{"_id": "14075252", "title": "", "text": "Paraneoplastic thrombocytosis: the secrets oftumor self-promotion.Paraneoplasticthrombocytosis is associated with many solidtumors and often correlates with reducedsurvival. Recent studies suggest that apathogenic feed back loop may be operativebetween platelets and tumor cells, withreciprocal interactions between tumorgrowth/metastasis and thrombocytosis/plateletactivation. Specific molecular pathways havebeen identified in which tumors can stimulateplatelet production and activation; activatedplatelets can, in turn, promote tumor growth andmetastasis. Taken together, these findingsprovide exciting new potential targets fortherapeutic intervention.", "metadata": {}}
+{"_id": "14079881", "title": "", "text": "Perceived age as clinically useful biomarker ofageing: cohort study.OBJECTIVE To determinewhether perceived age correlates with survivaland important age related phenotypes. DESIGNFollow-up study, with survival of twinsdetermined up to January 2008, by which time675 (37%) had died. SETTING Population basedtwin cohort in Denmark. PARTICIPANTS 20nurses, 10 young men, and 11 older women(assessors); 1826 twins aged >or=70. MAINOUTCOME MEASURES Assessors: perceived ageof twins from photographs. Twins: physical andcognitive tests and molecular biomarker ofageing (leucocyte telomere length). RESULTS Forall three groups of assessors, perceived age wassignificantly associated with survival, even afteradjustment for chronological age, sex, andrearing environment. Perceived age was stillsignificantly associated with survival after furtheradjustment for physical and cognitivefunctioning. The likelihood that the older lookingtwin of the pair died first increased with", "metadata": {}}
+{"_id": "14082855", "title": "", "text": "Inflammatory Reaction as Determinant ofForeign Body Reaction Is an Early andSusceptible Event after MeshImplantationPURPOSE To investigate and relatethe ultrashort-term and long-term courses ofdeterminants for foreign body reaction asbiocompatibility predictors for meshes in ananimal model. MATERIALS AND METHODS Threedifferent meshes (TVT, UltraPro, and PVDF) wereimplanted in sheep. Native and plasma coatedmeshes were placed bilaterally: (a)interaperitoneally, (b) as fascia onlay, and (c) asmuscle onlay (fascia sublay). At 5 min, 20 min,60 min, and 120 min meshes were explantedand histochemically investigated forinflammatory infiltrate, macrophage infiltration,vessel formation, myofibroblast invasion, andconnective tissue accumulation. The results wererelated to long-term values over 24 months.RESULTS Macrophage invasion reached highestextents with up to 60% in short-term anddecreased within 24 months to about 30%.", "metadata": {}}
+{"_id": "14083283", "title": "", "text": "Riesz pyramids for fast phase-based videomagnificationWe present a new compact imagepyramid representation, the Riesz pyramid, thatcan be used for real-time phase-based motionmagnification. Our new representation is lessovercomplete than even the smallest twoorientation, octave-bandwidth complex steerablepyramid, and can be implemented usingcompact, efficient linear filters in the spatialdomain. Motion-magnified videos produced withthis new representation are of comparablequality to those produced with the complexsteerable pyramid. When used with phase-basedvideo magnification, the Riesz pyramidphase-shifts image features along only theirdominant orientation rather than everyorientation like the complex steerable pyramid.", "metadata": {}}
+{"_id": "14092737", "title": "", "text": "Alpha-Synuclein Induces Lysosomal Rupture andCathepsin Dependent Reactive Oxygen SpeciesFollowing Endocytosisα-synuclein dysregulationis a critical aspect of Parkinson's diseasepathology. Recent studies have observed thatα-synuclein aggregates are cytotoxic to cells inculture and that this toxicity can be spreadbetween cells. However, the molecularmechanisms governing this cytotoxicity andspread are poorly characterized. Recent studiesof viruses and bacteria, which achieve theircytoplasmic entry by rupturing intracellularvesicles, have utilized the redistribution ofgalectin proteins as a tool to measure vesiclerupture by these organisms. Using this approach,we demonstrate that α-synuclein aggregates caninduce the rupture of lysosomes following theirendocytosis in neuronal cell lines. This rupturecan be induced by the addition of α-synucleinaggregates directly into cells as well as bycell-to-cell transfer of α-synuclein. We alsoobserve that lysosomal rupture by α-synuclein", "metadata": {}}
+{"_id": "14103509", "title": "", "text": "Mechanistic Fracture Criteria For The Failure OfHuman Cortical BoneA mechanisticunderstanding of fracture in human bone iscritical to predicting fracture risk associated withage and disease. Despite extensive work, amechanistic framework for describing how themicrostructure affects the failure of bone islacking. Although micromechanical modelsincorporating local failure criteria have beendeveloped for metallic and ceramic materials,few such models exist for biological materials. Infact, there is no proof to support the widely heldbelief that fracture in bone is locallystrain-controlled, as for example has been shownfor ductile fracture in metallic materials. In thepresent study, we provide such evidence througha novel series of experiments involving adouble-notch-bend geometry, designed to shedlight on the nature of the critical failure events inbone. We examine how the propagating crackinteracts with the bone microstructure to providesome mechanistic understanding of fracture and", "metadata": {}}
+{"_id": "14105446", "title": "", "text": "Inhibition of limb regeneration in the axolotl aftertreatment of the skin with actinomycin D.In thisexperiment actinomycin D was used to explorethe action of the wound epidermis on underlyingtissues during limb regeneration. In axolotlforelimbs the skin was removed from the elbowto the shoulder. Skin from the right limbs wassoaked for three hours in actinomycin D (5.0 or10.0 μg/ml 0.6% NaCl). For controls, skin fromleft limbs was soaked in 0.6% NaCl for the sameperiod of time. Each piece of skin wasorthotopically replanted, and both limbs wereamputated through the treated skin, proximal tothe elbow. After an initial healing period, thecontrol limbs regenerated normally. Except for aslightly paler color, limbs bearingactinomycin-treated skin were indistinguishablefrom the controls, both grossly and histologically,during the first week following amputation. Whilethe control limbs formed early blastemas, nogrossly visible evidence of regeneration wasapparent in the experimental limbs, but", "metadata": {}}
+{"_id": "14116046", "title": "", "text": "Retinoic acid-related orphan receptors α and γ:key regulators of lipid/glucose metabolism,inflammation, and insulin sensitivityRetinoicacid-related orphan receptors RORα and RORγplay a regulatory role in lipid/glucosehomeostasis and various immune functions, andhave been implicated in metabolic syndrome andseveral inflammatory diseases. RORα-deficientmice are protected against age- and diet-inducedobesity, hepatosteatosis, and insulin resistance.The resistance to hepatosteatosis inRORα-deficient mice is related to the reducedexpression of several genes regulating lipidsynthesis, transport, and storage. Adiposetissue-associated inflammation, which plays acritical role in the development of insulinresistance, is considerably diminished inRORα-deficient mice as indicated by the reducedinfiltration of M1 macrophages and decreasedexpression of many proinflammatory genes.Deficiency in RORγ also protects againstdiet-induced insulin resistance by a mechanism", "metadata": {}}
+{"_id": "14118484", "title": "", "text": "ERS/ESTS clinical guidelines on fitness for radicaltherapy in lung cancer patients (surgery andchemo-radiotherapy).A collaboration ofmultidisciplinary experts on the functionalevaluation of lung cancer patients has beenfacilitated by the European Respiratory Society(ERS) and the European Society of ThoracicSurgery (ESTS), in order to draw uprecommendations and provide clinicians withclear, up-to-date guidelines on fitness forsurgery and chemo-radiotherapy. The subjectwas divided into different topics, which werethen assigned to at least two experts. Theauthors searched the literature according to theirown strategies, with no central literature reviewbeing performed. The draft reports written by theexperts on each topic were reviewed, discussedand voted on by the entire expert panel. Theevidence supporting each recommendation wassummarised, and graded as described by theScottish Intercollegiate Guidelines NetworkGrading Review Group. Clinical practice", "metadata": {}}
+{"_id": "14119470", "title": "", "text": "The Ran GTPase regulates mitotic spindleassemblyRan is an abundant nuclear GTPasewith a clear role in nuclear transport duringinterphase but with roles in mitotic regulationthat are less well understood. Thenucleotide-binding state of Ran is regulated by aGTPase activating protein, RanGAP1, and by aguanine nucleotide exchange factor, RCC1. Ranalso interacts with a guanine nucleotidedissociation inhibitor, RanBP1. RanBP1 has ahigh affinity for GTP-bound Ran, and it acts as acofactor for RanGAP1, increasing the rate ofGAP-mediated GTP hydrolysis on Ranapproximately tenfold. RanBP1 levels oscillateduring the cell cycle [4], and increasedconcentrations of RanBP1 prolong mitosis inmammalian cells and in Xenopus egg extracts(our unpublished observations). We investigatedhow increased concentrations of RanBP1 disturbmitosis. We found that spindle assembly isdramatically disrupted when exogenous RanBP1is added to M phase Xenopus egg extracts. We", "metadata": {}}
+{"_id": "14121786", "title": "", "text": "A summary of the effects of antihypertensivemedications on measured bloodpressure.BACKGROUND Epidemiologic analysis offamily data on blood pressure (BP) is oftencompromised by the effects of antihypertensivemedications. A review of numerous clinical trialsthat investigated the effects of BP-loweringmedications is summarized here. METHODSPublished clinical trials, including 137 clinicaltrials with monodrug therapies and 28 clinicaltrials of combination drug therapies with a totalof 11,739 participants, were reviewed fromPubMed. Six major classes/groups ofantihypertensive medications were categorizedby ethnicity, including angiotensin-convertingenzyme (ACE) inhibitors, alpha1-blockers,cardioselective beta-blockers (beta1-blockers),calcium channel blockers, thiazide andthiazide-like diuretics, and loop diuretics.RESULTS Using sitting or supine BP, for ethnicgroups combined, monodrug therapy with ACEinhibitors showed a weighted average effect of", "metadata": {}}
+{"_id": "14128314", "title": "", "text": "Stem Cells and Early Lineage DevelopmentTherecent derivation of pluripotent stem cell linesfrom a number of different sources, includingreprogrammed adult somatic cells, raises theissue of the developmental equivalence of thesedifferent pluripotent states. At least two differentstates representing the epiblast progenitors inthe blastocyst and the pluripotent progenitors ofthe later gastrulating embryo have beenrecognized. Understanding the initialdevelopmental status of the different pluripotentlines is critical for defining starting conditions fordifferentiation toward therapeutically relevantcell types.", "metadata": {}}
+{"_id": "14131683", "title": "", "text": "Divergent clonal evolution of castration resistantneuroendocrine prostate cancerAn increasinglyrecognized resistance mechanism to androgenreceptor (AR)-directed therapy in prostate cancerinvolves epithelial plasticity, in which tumor cellsdemonstrate low to absent AR expression andoften have neuroendocrine features. The etiologyand molecular basis for this 'alternative'treatment-resistant cell state remainincompletely understood. Here, by analyzingwhole-exome sequencing data of metastaticbiopsies from patients, we observed substantialgenomic overlap between castration-resistanttumors that were histologically characterized asprostate adenocarcinomas (CRPC-Adeno) andneuroendocrine prostate cancer (CRPC-NE);analysis of biopsy samples from the sameindividuals over time points to a model mostconsistent with divergent clonal evolution.Genome-wide DNA methylation analysis revealedmarked epigenetic differences between CRPC-NEtumors and CRPC-Adeno, and also designated", "metadata": {}}
+{"_id": "14145440", "title": "", "text": "S-phase-promoting cyclin-dependent kinasesprevent re-replication by inhibiting the transitionof replication origins to a pre-replicativestateBACKGROUND DNA replication and mitosisare triggered by activation of kinase complexes,each made up of a cyclin and a cyclin-dependentkinase (Cdk). It had seemed possible that theassociation of Cdks with different classes ofcyclins specifies whether S phase (replication) orM phase (mitosis) will occur. The recent findingthat individual B-type cyclins (encoded by thegenes CLB1-CLB6) can have functions in bothprocesses in the budding yeast Saccharomycescerevisiae casts doubt on this notion. RESULTSS. cerevisiae strains lacking C1b1-C1b4 undergoDNA replication once but fail to enter mitosis. Wehave isolated mutations in two genes, SIM1 andSIM2 (SIM2 is identical to SEC72), which allowsuch cells to undergo an extra round of DNAreplication without mitosis. The Clb5 kinase,which promotes S phase, remains active duringthe G2-phase arrest of cells of the parental", "metadata": {}}
+{"_id": "14149065", "title": "", "text": "E-cadherin engagement stimulates proliferationvia Rac1E-cadherin has been linked to thesuppression of tumor growth and the inhibition ofcell proliferation in culture. We observed thatprogressively decreasing the seeding density ofnormal rat kidney-52E (NRK-52E) or MCF-10Aepithelial cells from confluence, indeed, releasedcells from growth arrest. Unexpectedly, a furtherdecrease in seeding density so that cells wereisolated from neighboring cells decreasedproliferation. Experiments using microengineeredsubstrates showed that E-cadherin engagementstimulated the peak in proliferation atintermediate seeding densities, and that theproliferation arrest at high densities did notinvolve E-cadherin, but rather resulted from acrowding-dependent decrease in cell spreadingagainst the underlying substrate. Rac1 activity,which was induced by E-cadherin engagementspecifically at intermediate seeding densities,was required for the cadherin-stimulatedproliferation, and the control of Rac1 activation", "metadata": {}}
+{"_id": "14155726", "title": "", "text": "Structure of Actin-related protein 8 and itscontribution to nucleosome bindingNuclearactin-related proteins (Arps) are subunits ofseveral chromatin remodelers, but theirmolecular functions within these complexes areunclear. We report the crystal structure of theINO80 complex subunit Arp8 in its ATP-boundform. Human Arp8 has several insertions in theconserved actin fold that explain its inability topolymerize. Most remarkably, one insertionwraps over the active site cleft and appears torigidify the domain architecture, while active sitefeatures shared with actin suggest anallosterically controlled ATPase activity.Quantitative binding studies with nucleosomesand histone complexes reveal that Arp8 and theArp8-Arp4-actin-HSA sub-complex of INO80strongly prefer nucleosomes and H3-H4tetramers over H2A-H2B dimers, suggesting thatArp8 functions as a nucleosome recognitionmodule. In contrast, Arp4 prefers free(H3-H4)(2) over nucleosomes and may serve", "metadata": {}}
+{"_id": "14171859", "title": "", "text": "Regulation of β-Adrenergic Receptor Signaling byS-Nitrosylation of G-Protein-Coupled ReceptorKinase 2beta-adrenergic receptors (beta-ARs),prototypic G-protein-coupled receptors (GPCRs),play a critical role in regulating numerousphysiological processes. The GPCR kinases(GRKs) curtail G-protein signaling and targetreceptors for internalization. Nitric oxide (NO)and/or S-nitrosothiols (SNOs) can prevent theloss of beta-AR signaling in vivo, but themolecular details are unknown. Here we show inmice that SNOs increase beta-AR expression andprevent agonist-stimulated receptordownregulation; and in cells, SNOs decreaseGRK2-mediated beta-AR phosphorylation andsubsequent recruitment of beta-arrestin to thereceptor, resulting in the attenuation of receptordesensitization and internalization. In both cellsand tissues, GRK2 is S-nitrosylated by SNOs aswell as by NO synthases, and GRK2S-nitrosylation increases following stimulation ofmultiple GPCRs with agonists. Cys340 of GRK2 is", "metadata": {}}
+{"_id": "14174055", "title": "", "text": "Electroporation enables the efficient mRNAdelivery into the mouse zygotes and facilitatesCRISPR/Cas9-based genome editingRecent useof the CRISPR/Cas9 system has dramaticallyreduced the time required to produce mutantmice, but the involvement of a time-consumingmicroinjection step still hampers its applicationfor high-throughput genetic analysis. Here wedeveloped a simple, highly efficient, andlarge-scale genome editing method, in which theRNAs for the CRISPR/Cas9 system areelectroporated into zygotes rather thanmicroinjected. We used this method to performsingle-stranded oligodeoxynucleotide(ssODN)-mediated knock-in in mouse embryos.This method facilitates large-scale geneticanalysis in the mouse.", "metadata": {}}
+{"_id": "14178995", "title": "", "text": "SummaryThe genetic diseasesHutchinson-Gilford progeria syndrome (HGPS)and restrictive dermopathy (RD) arise fromaccumulation of farnesylated prelamin A becauseof defects in the lamin A maturation pathway.Both of these diseases exhibit symptoms thatcan be viewed as accelerated aging. Themechanism by which accumulation offarnesylated prelamin A leads to theseaccelerated aging phenotypes is not understood.Here we present evidence that in HGPS and RDfibroblasts, DNA damage checkpoints arepersistently activated because of thecompromise in genomic integrity. Inactivation ofcheckpoint kinasesAtaxia-telangiectasia-mutated (ATM) and ATR(ATM- and Rad3-related) in these patient cellscan partially overcome their early replicationarrest. Treatment of patient cells with a proteinfarnesyltransferase inhibitor (FTI) did not resultin reduction of DNA double-strand breaks anddamage checkpoint signaling, although the", "metadata": {}}
+{"_id": "14180217", "title": "", "text": "The Buccaneer software for automated modelbuilding. 1. Tracing protein chains.A newtechnique for the automated tracing of proteinchains in experimental electron-density maps isdescribed. The technique relies on the repeatedapplication of an oriented electron-densitylikelihood target function to identify likelyC(alpha) positions. This function is applied bothin the location of a few promising ;seed'positions in the map and to grow those initialC(alpha) positions into extended chainfragments. Techniques for assembling the chainfragments into an initial chain trace arediscussed.", "metadata": {}}
+{"_id": "14180565", "title": "", "text": "Expression profile of genes modulated by Aloeemodin in human U87 glioblastomacells.Glioblastoma, the most aggressive andmalignant form of glioma, appears to beresistant to various chemotherapeutic agents.Hence, approaches have been intensivelyinvestigated to targeti specific molecularpathways involved in glioblastoma developmentand progression. Aloe emodin is believed tomodulate the expression of several genes incancer cells. We aimed to understand themolecular mechanisms underlying thetherapeutic effect of Aloe emodin on geneexpression profiles in the human U87glioblastoma cell line utilizing microarraytechnology. The gene expression analysisrevealed that a total of 8,226 gene alterationsout of 28,869 genes were detected aftertreatment with 58.6 μg/ml for 24 hours. Out ofthis total, 34 genes demonstrated statisticallysignificant change (p<0.05) ranging from 1.07 to1.87 fold. The results revealed that 22 genes", "metadata": {}}
+{"_id": "14185503", "title": "", "text": "The miniature genome of a carnivorous plantGenlisea aurea contains a low number of genesand short non-coding sequencesBACKGROUNDGenlisea aurea (Lentibulariaceae) is acarnivorous plant with unusually small genomesize - 63.6 Mb - one of the smallest knownamong higher plants. Data on the genome sizesand the phylogeny of Genlisea suggest that thisis a derived state within the genus. Thus, G.aurea is an excellent model organism forstudying evolutionary mechanisms of genomecontraction. RESULTS Here we report sequencingand de novo draft assembly of G. aurea genome.The assembly consists of 10,687 contigs of thetotal length of 43.4 Mb and includes 17,755complete and partial protein-coding genes. Itscomparison with the genome of Mimulusguttatus, another representative of higher coreLamiales clade, reveals striking differences ingene content and length of non-coding regions.CONCLUSIONS Genome contraction was acomplex process, which involved gene loss and", "metadata": {}}
+{"_id": "14188138", "title": "", "text": "Abnormal Spine Morphology and Enhanced LTP inLIMK-1 Knockout MiceIn vitro studies indicate arole for the LIM kinase family in the regulation ofcofilin phosphorylation and actin dynamics. Inaddition, abnormal expression of LIMK-1 isassociated with Williams syndrome, a mentaldisorder with profound deficits in visuospatialcognition. However, the in vivo function of thisfamily of kinases remains elusive. Using LIMK-1knockout mice, we demonstrate a significant rolefor LIMK-1 in vivo in regulating cofilin and theactin cytoskeleton. Furthermore, we show thatthe knockout mice exhibited significantabnormalities in spine morphology and insynaptic function, including enhancedhippocampal long-term potentiation. Theknockout mice also showed altered fearresponses and spatial learning. These resultsindicate that LIMK-1 plays a critical role indendritic spine morphogenesis and brainfunction.", "metadata": {}}
+{"_id": "14191255", "title": "", "text": "Wdr5 Mediates Self-Renewal andReprogramming via the Embryonic Stem CellCore Transcriptional NetworkThe embryonic stem(ES) cell transcriptional and chromatin-modifyingnetworks are critical for self-renewalmaintenance. However, it remains unclearwhether these networks functionally interactand, if so, what factors mediate suchinteractions. Here, we show that WD repeatdomain 5 (Wdr5), a core member of themammalian Trithorax (trxG) complex, positivelycorrelates with the undifferentiated state and is aregulator of ES cell self-renewal. Wedemonstrate that Wdr5, an \"effector\" of H3K4methylation, interacts with the pluripotencytranscription factor Oct4. Genome-wide proteinlocalization and transcriptome analysesdemonstrate overlapping gene regulatoryfunctions between Oct4 and Wdr5. TheOct4-Sox2-Nanog circuitry and trxG cooperate inactivating transcription of key self-renewalregulators, and furthermore, Wdr5 expression is", "metadata": {}}
+{"_id": "14192687", "title": "", "text": "Neurons derived from reprogrammed fibroblastsfunctionally integrate into the fetal brain andimprove symptoms of rats with Parkinson'sdisease.The long-term goal of nuclear transfer oralternative reprogramming approaches is tocreate patient-specific donor cells fortransplantation therapy, avoidingimmunorejection, a major complication incurrent transplantation medicine. It was recentlyshown that the four transcription factors Oct4,Sox2, Klf4, and c-Myc induce pluripotency inmouse fibroblasts. However, the therapeuticpotential of induced pluripotent stem (iPS) cellsfor neural cell replacement strategies remainedunexplored. Here, we show that iPS cells can beefficiently differentiated into neural precursorcells, giving rise to neuronal and glial cell typesin culture. Upon transplantation into the fetalmouse brain, the cells migrate into various brainregions and differentiate into glia and neurons,including glutamatergic, GABAergic, andcatecholaminergic subtypes. Electrophysiological", "metadata": {}}
+{"_id": "14195528", "title": "", "text": "Responses of primate frontal cortex neuronsduring natural vocal communication.The role ofprimate frontal cortex in vocal communicationand its significance in language evolution have acontroversial history. While evidence indicatesthat vocalization processing occurs inventrolateral prefrontal cortex neurons,vocal-motor activity has been conjectured to beprimarily subcortical and suggestive of adistinctly different neural architecture fromhumans. Direct evidence of neural activity duringnatural vocal communication is limited, asprevious studies were performed inchair-restrained animals. Here we recorded theactivity of single neurons across multiple regionsof prefrontal and premotor cortex while freelymoving marmosets engaged in a natural vocalbehavior known as antiphonal calling. Our aimwas to test whether neurons in marmoset frontalcortex exhibited responses during vocal-signalprocessing and/or vocal-motor production in thecontext of active, natural communication. We", "metadata": {}}
+{"_id": "14198646", "title": "", "text": "Salt-inducible kinase 2 links transcriptionalcoactivator p300 phosphorylation to theprevention of ChREBP-dependent hepaticsteatosis in mice.Obesity and type 2 diabetes areassociated with increased lipogenesis in the liver.This results in fat accumulation in hepatocytes, acondition known as hepatic steatosis, which is aform of nonalcoholic fatty liver disease (NAFLD),the most common cause of liver dysfunction inthe United States. Carbohydrate-responsiveelement-binding protein (ChREBP), atranscriptional activator of glycolytic andlipogenic genes, has emerged as a major playerin the development of hepatic steatosis in mice.However, the molecular mechanisms enhancingits transcriptional activity remain largelyunknown. In this study, we have identified thehistone acetyltransferase (HAT) coactivator p300and serine/threonine kinase salt-inducible kinase2 (SIK2) as key upstream regulators of ChREBPactivity. In cultured mouse hepatocytes, weshowed that glucose-activated p300 acetylated", "metadata": {}}
+{"_id": "14205246", "title": "", "text": "A Role for NuSAP in Linking Microtubules toMitotic ChromosomesThe spindle apparatus is amicrotubule (MT)-based machinery that attachesto and segregates the chromosomes duringmitosis and meiosis. Self-organization of thespindle around chromatin involves the assemblyof MTs, their attachment to the chromosomes,and their organization into a bipolar array. Oneregulator of spindle self-organization is RanGTP.RanGTP is generated at chromatin and activatesa set of soluble, Ran-regulated spindle factorssuch as TPX2, NuMA, and NuSAP . How thespindle factors direct and attach MTs to thechromosomes are key open questions. Nucleolarand Spindle-Associated Protein (NuSAP) wasrecently identified as an essential MT-stabilizingand bundling protein that is enriched at thecentral part of the spindle . Here, we show bybiochemical reconstitution that NuSAP efficientlyadsorbs to isolated chromatin and DNA and thatit can directly produce and retain highconcentrations of MTs in the immediate vicinity", "metadata": {}}
+{"_id": "14225271", "title": "", "text": "Molecular features of cellular reprogramming anddevelopmentDifferentiating somatic cells areprogressively restricted to specialized functionsduring ontogeny, but they can be experimentallydirected to form other cell types, including thosewith complete embryonic potential. Early nuclearreprogramming methods, such as somatic cellnuclear transfer (SCNT) and cell fusion, posedsignificant technical hurdles to precise dissectionof the regulatory programmes governing cellidentity. However, the discovery ofreprogramming by ectopic expression of adefined set of transcription factors, known asdirect reprogramming, provided a tractableplatform to uncover molecular characteristics ofcellular specification and differentiation, cell typestability and pluripotency. We discuss the controland maintenance of cellular identity duringdevelopmental transitions as they have beenstudied using direct reprogramming, with anemphasis on transcriptional and epigeneticregulation.", "metadata": {}}
+{"_id": "14240343", "title": "", "text": "Small molecule modifiers of circadianclocksCircadian clocks orchestrate 24-hoscillations of essential physiological andbehavioral processes in response to dailyenvironmental changes. These clocks areremarkably precise under constant conditions yethighly responsive to resetting signals. With themolecular composition of the core oscillatorlargely established, recent research hasincreasingly focused on clock-modifyingmechanisms/molecules. In particular, smallmolecule modifiers, intrinsic or extrinsic, areemerging as powerful tools for understandingbasic clock biology as well as developing putativetherapeutic agents for clock-associated diseases.In this review, we will focus on syntheticcompounds capable of modifying the period,phase, or amplitude of circadian clocks, withparticular emphasis on the mammalian clock. Wewill discuss the potential of exploiting these smallmolecule modifiers in both basic andtranslational research.", "metadata": {}}
+{"_id": "14241418", "title": "", "text": "NVP-BEZ235, a dual PI3K/mTOR inhibitor,prevents PI3K signaling and inhibits the growthof cancer cells with activating PI3Kmutations.Phosphatidylinositol-3-kinase (PI3K)pathway deregulation is a common event inhuman cancer, either through inactivation of thetumor suppressor phosphatase and tensinhomologue deleted from chromosome 10 oractivating mutations of p110-alpha. Thesehotspot mutations result in oncogenic activity ofthe enzyme and contribute to therapeuticresistance to the anti-HER2 antibodytrastuzumab. The PI3K pathway is, therefore, anattractive target for cancer therapy. We havestudied NVP-BEZ235, a dual inhibitor of the PI3Kand the downstream mammalian target ofrapamycin (mTOR). NVP-BEZ235 inhibited theactivation of the downstream effectors Akt, S6ribosomal protein, and 4EBP1 in breast cancercells. The antiproliferative activity ofNVP-BEZ235 was superior to the allostericselective mTOR complex inhibitor everolimus in a", "metadata": {}}
+{"_id": "14252892", "title": "", "text": "Pharmacokinetic, pharmacodynamic, andpharmacogenetic determinants of osteonecrosisin children with acute lymphoblasticleukemia.Osteonecrosis is a severeglucocorticoid-induced complication of acutelymphoblastic leukemia treatment. Weprospectively screened children (n = 364) withmagnetic resonance imaging of hips and knees,regardless of symptoms; the cumulativeincidence of any (grade 1-4) versus symptomatic(grade 2-4) osteonecrosis was 71.8% versus17.6%, respectively. We investigated whetherage, race, sex, acute lymphoblastic leukemiatreatment arm, body mass, serum lipids,albumin and cortisol levels, dexamethasonepharmacokinetics, and genome-wide germlinegenetic polymorphisms were associated withsymptomatic osteonecrosis. Age more than 10years (odds ratio, = 4.85; 95% confidenceinterval, 2.5-9.2; P = .00001) and moreintensive treatment (odds ratio = 2.5; 95%confidence interval, 1.2-4.9; P = .011) were risk", "metadata": {}}
+{"_id": "14260013", "title": "", "text": "Prevention of Rectal SHIV Transmission inMacaques by Daily or Intermittent Prophylaxiswith Emtricitabine and TenofovirBACKGROUNDIn the absence of an effective vaccine, HIVcontinues to spread globally, emphasizing theneed for novel strategies to limit itstransmission. Pre-exposure prophylaxis (PrEP)with antiretroviral drugs could prove to be aneffective intervention strategy if highlyefficacious and cost-effective PrEP modalities areidentified. We evaluated daily and intermittentPrEP regimens of increasing antiviral activity in amacaque model that closely resembles humantransmission. METHODS AND FINDINGS We useda repeat-exposure macaque model with 14weekly rectal virus challenges. Three drugtreatments were given once daily, each to adifferent group of six rhesus macaques. Group 1was treated subcutaneously with ahuman-equivalent dose of emtricitabine (FTC),group 2 received orally the human-equivalentdosing of both FTC and tenofovir-disoproxil", "metadata": {}}
+{"_id": "14275671", "title": "", "text": "Direct-coupling analysis of residue co-evolutioncaptures native contacts across many proteinfamiliesThe similarity in the three-dimensionalstructures of homologous proteins imposesstrong constraints on their sequence variability.It has long been suggested that the resultingcorrelations among amino acid compositions atdifferent sequence positions can be exploited toinfer spatial contacts within the tertiary proteinstructure. Crucial to this inference is the abilityto disentangle direct and indirect correlations, asaccomplished by the recently introduced DirectCoupling Analysis (DCA) (Weigt et al. (2009)Proc Natl Acad Sci 106:67). Here we develop acomputationally efficient implementation of DCA,which allows us to evaluate the accuracy ofcontact prediction by DCA for a large number ofprotein domains, based purely on sequenceinformation. DCA is shown to yield a largenumber of correctly predicted contacts,recapitulating the global structure of the contactmap for the majority of the protein domains", "metadata": {}}
+{"_id": "14290854", "title": "", "text": "Variation in antibiotic prescribing and its impacton recovery in patients with acute cough inprimary care: prospective study in 13countries.OBJECTIVE To describe variation inantibiotic prescribing for acute cough incontrasting European settings and the impact onrecovery. DESIGN Cross sectional observationalstudy with clinicians from 14 primary careresearch networks in 13 European countries whorecorded symptoms on presentation andmanagement. Patients followed up for 28 dayswith patient diaries. SETTING Primary care.PARTICIPANTS Adults with a new or worseningcough or clinical presentation suggestive of lowerrespiratory tract infection. MAIN OUTCOMEMEASURES Prescribing of antibiotics by cliniciansand total symptom severity scores over time.RESULTS 3402 patients were recruited (clinicianscompleted a case report form for 99% (3368) ofparticipants and 80% (2714) returned asymptom diary). Mean symptom severity scoresat presentation ranged from 19 (scale range 0 to", "metadata": {}}
+{"_id": "14296612", "title": "", "text": "Dorsomorphin, a Selective Small MoleculeInhibitor of BMP Signaling, PromotesCardiomyogenesis in Embryonic StemCellsBACKGROUND Pluripotent embryonic stem(ES) cells, which have the capacity to give rise toall tissue types in the body, show great promiseas a versatile source of cells for regenerativetherapy. However, the basic mechanisms oflineage specification of pluripotent stem cells arelargely unknown, and generating sufficientquantities of desired cell types remains aformidable challenge. Small molecules,particularly those that modulate keydevelopmental pathways like the bonemorphogenetic protein (BMP) signaling cascade,hold promise as tools to study in vitro lineagespecification and to direct differentiation of stemcells toward particular cell types.METHODOLOGY/ PRINCIPAL FINDINGS Wedescribe the use of dorsomorphin, a selectivesmall molecule inhibitor of BMP signaling, toinduce myocardial differentiation in mouse ES", "metadata": {}}
+{"_id": "14300799", "title": "", "text": "Cineradiography of Monkey Lip-SmackingReveals Putative Precursors of SpeechDynamicsA key feature of speech is itsstereotypical 5 Hz rhythm. One theory positsthat this rhythm evolved through themodification of rhythmic facial movements inancestral primates. If the hypothesis has anyvalidity, then a comparative approach may shedsome light. We tested this idea by usingcineradiography (X-ray movies) to characterizeand quantify the internal dynamics of themacaque monkey vocal tract during lip-smacking(a rhythmic facial expression) versus chewing.Previous human studies showed that speechmovements are faster than chewing movements,and the functional coordination between vocaltract structures is different between the twobehaviors. If rhythmic speech evolved through arhythmic ancestral facial movement, then onehypothesis is that monkey lip-smacking versuschewing should also exhibit these differences.We found that the lips, tongue, and hyoid move", "metadata": {}}
+{"_id": "14308244", "title": "", "text": "Interneuronal DISC1 regulates NRG1-ErbB4signalling and excitatory-inhibitory synapseformation in the mature cortex.Neuregulin-1(NRG1) and its receptor ErbB4 influence severalprocesses of neurodevelopment, but themechanisms regulating this signalling in themature brain are not well known. DISC1 is amultifunctional scaffold protein that mediatesmany cellular processes. Here we present afunctional relationship between DISC1 andNRG1-ErbB4 signalling in mature corticalinterneurons. By cell type-specific genemodulation in vitro and in vivo including in amutant DISC1 mouse model, we demonstratethat DISC1 inhibits NRG1-induced ErbB4activation and signalling. This effect is likelymediated by competitive inhibition of binding ofErbB4 to PSD95. Finally, we show thatinterneuronal DISC1 affectsNRG1-ErbB4-mediated phenotypes in the fastspiking interneuron-pyramidal neuron circuit.Post-mortem brain analyses and some genetic", "metadata": {}}
+{"_id": "14311986", "title": "", "text": "The Proto-Oncogene c-maf Is Responsible forTissue-Specific Expression of Interleukin-4Themolecular basis for the distinctive cytokineexpression of CD4+ T helper 1 (Th1) and Thelper 2 (Th2) subsets remains elusive. Here, wereport that the proto-oncogene c-maf, a basicregion/leucine zipper transcription factor,controls tissue-specific expression of IL-4. c-Mafis expressed in Th2 but not Th1 clones and isinduced during normal precursor celldifferentiation along a Th2 but not Th1 lineage.c-Maf binds to a c-Maf response element (MARE)in the proximal IL-4 promoter adjacent to a sitefootprinted by extracts from Th2 but not Th1clones. Ectopic expression of c-Maftransactivates the IL-4 promoter in Th1 cells, Bcells, and nonlymphoid cells, a function thatmaps to the MARE and Th2-specific footprint.Furthermore, c-Maf acts in synergy with thenuclear factor of activated T cells (NF-ATp) toinitiate endogeneous IL-4 production by B cells.Manipulation of c-Maf may alter Th subset ratios", "metadata": {}}
+{"_id": "14315749", "title": "", "text": "hClock gene expression in human colorectalcarcinoma.In this study, we aimed to investigatechanges in the expression of human Clock(hClock), a gene at the core of the circadiangene family, in colorectal carcinomas (CRCs) andto discuss the possible effects. Previous studieshave revealed that the disruption of circadianrhythms is one of the endogenous factors thatcontribute to the initiation and development ofCRCs. However, the underlying molecularchanges to the circadian genes associated withCRCs have not been explored.Immunofluorescence and quantitativepolymerase chain reaction (qPCR) analysis of thehCLOCK protein and gene expression wereperformed in 30 cases of CRC. The hCLOCKprotein was expressed in all specimens obtainedfrom 30 CRC patients. Higher levels of hCLOCKexpression were observed in human CRC tissuescompared with the paired non-cancerous tissues.hCLOCK expression was significantly higher inpoorly differentiated, or late-stage, Dukes' grade", "metadata": {}}
+{"_id": "14319754", "title": "", "text": "The Antiretroviral Therapy in Lower IncomeCountries (ART-LINC) Collaboration and ARTCohort Collaboration (ART-CC) groupsSummaryBACKGROUND Highly activeantiretroviral therapy (HAART) is being scaled upin developing countries. We compared baselinecharacteristics and outcomes during the firstyear of HAART between HIV-1-infected patientsin low-income and high-income settings.METHODS 18 HAART programmes in Africa, Asia,and South America (low-income settings) and 12HIV cohort studies from Europe and NorthAmerica (high-income settings) provided data for4810 and 22,217, respectively, treatment-naïveadult patients starting HAART. All patients fromhigh-income settings and 2725 (57%) patientsfrom low-income settings were activelyfollowed-up and included in survival analyses.FINDINGS Compared with high-incomecountries, patients starting HAART in low-incomesettings had lower CD4 cell counts (median 108cells per muL vs 234 cells per muL), were more", "metadata": {}}
+{"_id": "14328288", "title": "", "text": "A family of phosphoinositide 3-kinases inDrosophila identifies a new mediator of signaltransductionBACKGROUND Mammalianphosphoinositide 3-kinases (PI 3-kinases) areinvolved in receptor-mediated signaltransduction and have been implicated inprocesses such as transformation andmitogenesis through their role in elevatingcellular phosphatidylinositol(3,4,5)-trisphosphate. Additionally, a PI 3-kinaseactivity which generates phosphatidylinositol3-phosphate has been shown to be required forprotein trafficking in yeast. RESULTS We haveidentified a family of three distinct PI 3-kinasesin Drosophila, using an approach based on thepolymerase chain reaction to amplify a regioncorresponding to the conserved catalytic domainof PI 3-kinases. One of these family members,PI3K_92D, is closely related to the prototypicalPI 3-kinase, p110 alpha; PI3K_59F ishomologous to Vps34p, whereas the third,PI3K_68D, is a novel PI 3-kinase which is widely", "metadata": {}}
+{"_id": "14332945", "title": "", "text": "Mammalian RAD52 Functions in Break-InducedReplication Repair of Collapsed DNA ReplicationForksHuman cancers are characterized by thepresence of oncogene-induced DNA replicationstress (DRS), making them dependent on repairpathways such as break-induced replication(BIR) for damaged DNA replication forks. Tobetter understand BIR, we performed a targetedsiRNA screen for genes whose depletion inhibitedG1 to S phase progression when oncogenic cyclinE was overexpressed. RAD52, a genedispensable for normal development in mice, wasamong the top hits. In cells in which forkcollapse was induced by oncogenes or chemicals,the Rad52 protein localized to DRS foci.Depletion of Rad52 by siRNA or knockout of thegene by CRISPR/Cas9 compromised restart ofcollapsed forks and led to DNA damage in cellsexperiencing DRS. Furthermore, in cancer-prone,heterozygous APC mutant mice, homozygousdeletion of the Rad52 gene suppressed tumorgrowth and prolonged lifespan. We therefore", "metadata": {}}
+{"_id": "14333540", "title": "", "text": "Neural crest cell lineage segregation in themouse neural tube.Neural crest (NC) cells arisein the dorsal neural tube (NT) and migrate intothe embryo to develop into many different celltypes. A major unresolved question is when andhow the fate of NC cells is decided. There iswidespread evidence for multipotential NC cells,whose fates are decided during or aftermigration. There is also some evidence that theNC is already divided into subpopulations ofdiscrete precursors within the NT. We haveinvestigated this question in the mouse embryo.We find that a subpopulation of cells on the mostdorsomedial aspect of the NT express thereceptor tyrosine kinase Kit (previously known asc-kit), emigrate exclusively into the developingdermis, and then express definitive markers ofthe melanocyte lineage. These are thusmelanocyte progenitor cells. They are generatedpredominantly at the midbrain-hindbrain junctionand cervical trunk, with significant numbers alsoin lower trunk. Other cells within the dorsal NT", "metadata": {}}
+{"_id": "14337960", "title": "", "text": "How absolute is zero? An evaluation of historicaland current definitions of malariaeliminationDecisions to eliminate malaria from allor part of a country involve a complex set offactors, and this complexity is compounded byambiguity surrounding some of the keyterminology, most notably \"control\" and\"elimination. \" It is impossible to forecastresource and operational requirementsaccurately if endpoints have not been definedclearly, yet even during the Global MalariaEradication Program, debate raged over theprecise definition of \"eradication. \" Analogousdeliberations regarding the meaning of\"elimination\" and \"control\" are basicallynonexistent today despite these terms' coreimportance to programme planning. To advancethe contemporary debate about these issues,this paper presents a historical review ofcommonly used terms, including control,elimination, and eradication, to helpcontextualize current understanding of these", "metadata": {}}
+{"_id": "14338915", "title": "", "text": "Fission Yeast Scm3: A CENP-A Receptor Requiredfor Integrity of Subkinetochore ChromatinThemechanisms ensuring specific incorporation ofCENP-A at centromeres are poorly understood.Mis16 and Mis18 are required for CENP-Alocalization at centromeres and form a complexthat is conserved from fission yeast to human.Fission yeast sim1 mutants that alleviatekinetochore domain silencing are defective inScm3(Sp), the ortholog of budding yeastScm3(Sc). Scm3(Sp) depends on Mis16/18 forits centromere localization and like them isrecruited to centromeres in late anaphase.Importantly, Scm3(Sp) coaffinity purifies withCENP-A(Cnp1) and associates withCENP-A(Cnp1) in vitro, yet localizesindependently of intact CENP-A(Cnp1) chromatinand is differentially released from chromatin.While Scm3(Sc) has been proposed to form aunique hexameric nucleosome withCENP-A(Cse4) and histone H4 at budding yeastpoint centromeres, we favor a model in which", "metadata": {}}
+{"_id": "14340571", "title": "", "text": "The Molecular Basis for Oat Intolerance inPatients with Celiac DiseaseBackground  Celiacdisease is a small intestinal inflammatorydisorder characterized by malabsorption,nutrient deficiency, and a range of clinicalmanifestations. It is caused by an inappropriateimmune response to dietary gluten and is treatedwith a gluten-free diet. Recent feeding studieshave indicated oats to be safe for celiac diseasepatients, and oats are now often included in theceliac disease diet. This study aimed toinvestigate whether oat intolerance exists inceliac disease and to characterize the cells andprocesses underlying this intolerance. Methodsand Findings  We selected for study nine adultswith celiac disease who had a history of oatsexposure. Four of the patients had clinicalsymptoms on an oats-containing diet, and threeof these four patients had intestinal inflammationtypical of celiac disease at the time of oatsexposure. We established oats-avenin-specificand -reactive intestinal T-cell lines from these", "metadata": {}}
+{"_id": "14361849", "title": "", "text": "A comparison of continuous and bi-level positiveairway pressure non-invasive ventilation inpatients with acute cardiogenic pulmonaryoedema: a meta-analysisIntroductionWeconducted the present study to investigate thepotential beneficial and adverse effects ofcontinuous positive airway pressure (CPAP)compared with bi-level positive airway pressure(BiPAP) noninvasive ventilation in patients withcardiogenic pulmonary oedema. MethodWeincluded randomized controlled studiescomparing CPAP and BiPAP treatment in patientswith cardiogenic pulmonary oedema from theCochrane Controlled Trials Register (2005 issue3), and EMBASE and MEDLINE databases (1966to 1 December 2005), without languagerestriction. Two reviewers reviewed the quality ofthe studies and independently performed dataextraction. ResultsSeven randomized controlledstudies, including a total of 290 patients withcardiogenic pulmonary oedema, wereconsidered. The hospital mortality (relative risk", "metadata": {}}
+{"_id": "14362678", "title": "", "text": "CaMKII induces permeability transition throughDrp1 phosphorylation during chronic β-ARstimulationMitochondrial permeability transitionpore (mPTP) is involved in cardiac dysfunctionduring chronic β-adrenergic receptor (β-AR)stimulation. The mechanism by which chronicβ-AR stimulation leads to mPTP openings iselusive. Here, we show that chronicadministration of isoproterenol (ISO) persistentlyincreases the frequency of mPTP openingsfollowed by mitochondrial damage and cardiacdysfunction. Mechanistically, this effect ismediated by phosphorylation of mitochondrialfission protein, dynamin-related protein 1(Drp1), by Ca2+/calmodulin-dependent kinase II(CaMKII) at a serine 616 (S616) site. Mutatingthis phosphorylation site or inhibiting Drp1activity blocks CaMKII- or ISO-induced mPTPopening and myocyte death in vitro and rescuesheart hypertrophy in vivo. In human failinghearts, Drp1 phosphorylation at S616 isincreased. These results uncover a pathway", "metadata": {}}
+{"_id": "14362780", "title": "", "text": "MicroRNA Response of Primary HumanMacrophages to Arcobacter Butzleri InfectionTherole of microRNAs (miRNAs) in infectiousdiseases is becoming more and more apparent,and the use of miRNAs as a diagnostic tool andtheir therapeutic application has become themajor focus of investigation. The aim of thisstudy was to identify miRNAs involved in theimmune signaling of macrophages in response toArcobacter (A.) butzleri infection, an emergingfoodborne pathogen causing gastroenteritis.Therefore, primary human macrophages wereisolated and infected, and miRNA expression wasstudied by means of RNAseq. Analysis of thedata revealed the expression of several miRNAs,which were previously associated with bacterialinfections such as miR-155, miR-125, andmiR-212. They were shown to play a key role inToll-like receptor signaling where they act asfine-tuners to establish a balanced immuneresponse. In addition, miRNAs which have yetnot been identified during bacterial infections", "metadata": {}}
+{"_id": "14367469", "title": "", "text": "The circadian factor Period 2 modulates p53stability and transcriptional activity in unstressedcellsHuman Period 2 (hPer2) is a transcriptionalregulator at the core of the circadian clockmechanism that is responsible for generating thenegative feedback loop that sustains the clock.Its relevance to human disease is underlined byalterations in its function that affect numerousbiochemical and physiological processes. Whenabsent, it results in the development of variouscancers and an increase in the cell'ssusceptibility to genotoxic stress. Thus wesought to define a yet-uncharacterizedcheckpoint node in which circadian componentsintegrate environmental stress signals to theDNA-damage response. We found that hPer2binds the C-terminal half of human p53 (hp53)and forms a stable trimeric complex with hp53'snegative regulator, Mdm2. We determined thathPer2 binding to hp53 prevents Mdm2 frombeing ubiquitinated and targeting hp53 by theproteasome. Down-regulation of hPer2", "metadata": {}}
+{"_id": "14376683", "title": "", "text": "Properties of Commelina yellow mottle virus'scomplete DNA sequence, genomic discontinuitiesand transcript suggest that it is apararetrovirus.The non-enveloped bacilliformviruses are the second group of plant virusesknown to possess a genome consisting of circulardouble-stranded DNA. We have characterized theviral transcript and determined the completesequence of the genome of Commelina mellowmottle virus (CoYMV), a member of this group.Analysis of the viral transcript indicates that thevirus encodes a single terminally-redundantgenome-length plus 120 nucleotide transcript. Afraction of the transcripts is polyadenylated,although the majority of the transcript is notpolyadenylated. Analysis of the genomesequence indicates that the genome is 7489 bpin size and that the transcribed strand containsthree open reading frames capable of encodingproteins of 23, 15 and 216 kd. The function ofthe 25 and 15 kd proteins is unknown.Similarities between the 216 kd polypeptide and", "metadata": {}}
+{"_id": "14380875", "title": "", "text": "The Glucocorticoid ReceptorInhibitsGlucocorticoids repressNFkappaB-mediated activation ofproinflammatory genes such as interleukin-8(IL-8) and ICAM-1. Our experiments suggestthat the glucocorticoid receptor (GR) confers thiseffect by associating through protein-proteininteractions with NFkappaB bound at each ofthese genes. That is, we show that the GR zincbinding region (ZBR), which includes the DNAbinding and dimerization functions of thereceptor, binds directly to the dimerizationdomain of the RelA subunit of NFkappaB in vitroand that the ZBR is sufficient to associate withRelA bound at NFkappaB response elements invivo. Moreover, we demonstrate in vivo and invitro that GR does not disrupt DNA binding byNFkappaB. In transient transfections, we foundthat the GR ligand binding domain is essential forrepression of NFkappaB but not for associationwith it and that GR can repress an NFkappaBderivative bearing a heterologous activation", "metadata": {}}
+{"_id": "14386505", "title": "", "text": "Regulation of myeloid cell function through theCD200 receptor.Myeloid cells play pivotal roles inchronic inflammatory diseases through theirbroad proinflammatory, destructive, andremodeling capacities. CD200 is widelyexpressed on a variety of cell types, while therecently identified CD200R is expressed onmyeloid cells and T cells. CD200 deletion in vivoresults in myeloid cell dysregulation andenhanced susceptibility to autoimmuneinflammation, suggesting that theCD200-CD200R interaction is involved inimmune suppression. We demonstrate in thisstudy that CD200R agonists suppress mouse andhuman myeloid cell function in vitro, and alsodefine a dose relationship between receptorexpression and cellular inhibition. IFN-gamma-and IL-17-stimulated cytokine secretion frommouse peritoneal macrophages was inhibited byCD200R engagement. Inhibitory effects were notuniversal, as LPS-stimulated responses wereunaffected. Inhibition of U937 cell cytokine", "metadata": {}}
+{"_id": "14390137", "title": "", "text": "Management of hepatitis C disease among VApatients with schizophrenia and substance usedisorders.OBJECTIVE Rates of hepatitis C (HCV)infection, testing, and treatment were comparedamong patients with schizophrenia, a substanceuse disorder, or co-occurring schizophrenia orschizoaffective disorder and a substance usedisorder and a control group. METHODSInformation about 293,445 patients of theNorthwest Veterans Healthcare Administrationwas obtained. RESULTS The substance usedisorder group constituted 13.6 percent of thesample; the schizophrenia group, 1.6 percent;and the co-occurring-disorders group, 1.4percent. Respectively, these groups wereapproximately four, two, and six times as likelyas the control group to receive HCV testing andabout seven, two, and eight times as likely to beinfected. The rate of interferon (IFN) therapywas significantly lower for the substance usegroup and the group with co-occurring disorders.However, the magnitude of the differences was", "metadata": {}}
+{"_id": "14395738", "title": "", "text": "Equity in adherence to antiretroviral therapyamong economically vulnerable adolescentsliving with HIV in UgandaStudies fromsub-Saharan Africa indicate that children madevulnerable by poverty have beendisproportionately affected by HIV with manyexposed via mother-to-child transmission. Foryouth living with HIV, adherence to life-savingtreatment regimens are likely to be affected bythe complex set of economic and socialcircumstances that challenge their families andalso exacerbate health problems. Using baselinedata from the National Institute of Child andHuman Development (NICHD) fundedSuubi+Adherence study, we examined theextent to which individual and compositemeasures of equity predict self-reportedadherence among Ugandan adolescents aged10-16 (n = 702) living with HIV. Results showedthat greater asset ownership, specifically familialpossession of seven or more tangible assets, wasassociated with greater odds of self-reported", "metadata": {}}
+{"_id": "14402338", "title": "", "text": "High-Resolution Phenotypic Profiling DefinesGenes Essential for Mycobacterial Growth andCholesterol CatabolismThe pathways thatcomprise cellular metabolism are highlyinterconnected, and alterations in individualenzymes can have far-reaching effects. As aresult, global profiling methods that measuregene expression are of limited value in predictinghow the loss of an individual function will affectthe cell. In this work, we employed a newmethod of global phenotypic profiling to directlydefine the genes required for the growth ofMycobacterium tuberculosis. A combination ofhigh-density mutagenesis and deep-sequencingwas used to characterize the composition ofcomplex mutant libraries exposed to differentconditions. This allowed the unambiguousidentification of the genes that are essential forMtb to grow in vitro, and proved to be asignificant improvement over previousapproaches. To further explore functions that arerequired for persistence in the host, we defined", "metadata": {}}
+{"_id": "14405193", "title": "", "text": "Tyrosine phosphorylation regulates theendocytosis and surface expression ofGluN3A-containing NMDA receptors.Selectivecontrol of receptor trafficking provides amechanism for remodeling the receptorcomposition of excitatory synapses, and thussupports synaptic transmission, plasticity, anddevelopment. GluN3A (formerly NR3A) is anonconventional member of the NMDA receptor(NMDAR) subunit family, which endows NMDARchannels with low calcium permeability andreduced magnesium sensitivity compared withNMDARs comprising only GluN1 and GluN2subunits. Because of these special properties,GluN3A subunits act as a molecular brake to limitthe plasticity and maturation of excitatorysynapses, pointing toward GluN3A removal as acritical step in the development of neuronalcircuitry. However, the molecular signalsmediating GluN3A endocytic removal remainunclear. Here we define a novel endocytic motif(YWL), which is located within the cytoplasmic", "metadata": {}}
+{"_id": "14407673", "title": "", "text": "Myeloid-specific Krüppel-like factor 2 inactivationincreases macrophage and neutrophil adhesionand promotes atherosclerosis.RATIONALEHemizygous deficiency of the transcription factorKrüppel-like factor 2 (KLF2) has been shownpreviously to augment atherosclerosis inhypercholesterolemic mice. However, the celltype responsible for the increased atherosclerosisdue to KLF2 deficiency has not been identified.This study examined the consequence of myeloidcell-specific KLF2 inactivation in atherosclerosis.METHODS AND RESULTS Cell-specific knockoutmice were generated by Cre/loxP recombination.Macrophages isolated from myeloid-specific Klf2knockout (myeKlf2(-/-)) mice were similar tomyeKlf2(+/+) macrophages in response toactivation, polarization, and lipid accumulation.However, in comparison to myeKlf2(+/+)macrophages, myeKlf2(-/-) macrophagesadhered more robustly to endothelial cells.Neutrophils from myeKlf2(-/-) mice also adheredmore robustly to endothelial cells, and fewer", "metadata": {}}
+{"_id": "14408200", "title": "", "text": "Epidemiology of Staphylococcus aureus bloodand skin and soft tissue infections in the USmilitary health system, 2005-2010.CONTEXTRates of hospital-onset methicillin-resistantStaphylococcus aureus (MRSA) infections arereported as decreasing, but recent rates ofcommunity-onset S. aureus infections are lessknown. OBJECTIVES To characterize the overalland annual incidence rates of community-onsetand hospital-onset S. aureus bacteremia andskin and soft tissue infections (SSTIs) in anational health care system and to evaluatetrends in the incidence rates of S. aureusbacteremia and SSTIs and the proportion due toMRSA. DESIGN, SETTING, AND PARTICIPANTSObservational study of all Department of DefenseTRICARE beneficiaries from January 2005through December 2010. Medical recorddatabases were used to identify and classify allannual first-positive S. aureus blood and woundor abscess cultures as methicillin-susceptible S.aureus or MRSA, and as community-onset or", "metadata": {}}
+{"_id": "14419116", "title": "", "text": "Potentiation of NMDA currents by pituitaryadenylate cyclase activating polypeptide inneonatal rat sympathetic preganglionicneurons.Whole cell patch-clamp recordings weremade from sympathetic preganglionic neurons(SPNs) in the intermediolateral cell column ofthoracolumbar spinal cord slices of 12- to16-day-old rats, and the effects of pituitaryadenylate cyclase activating polypeptide(PACAP)-38 on N-methyl-D-aspartate (NMDA)-and kainate (KA)-induced inward currents wereexamined. PACAP, in concentrations (10-30 nM)that caused no significant change of holdingcurrents, reversibly increased NMDA-inducedcurrents but not KA-induced currents. At higherconcentrations (>30 nM), the peptide produced asustained inward current. The potentiating effectof PACAP was nullified by prior incubation of theslices with the adenylate cyclase inhibitorMDL-12,330A (25 microM). Further, superfusingthe slices with the membrane-permeable cyclicAMP analogue N6,2'-O-dibutyryladenosine", "metadata": {}}
+{"_id": "14434123", "title": "", "text": "Aberrant Expression of RCAN1 in Alzheimer’sPathogenesis: A New Molecular Mechanism and aNovel Drug TargetAD, a devastatingneurodegenerative disorder, is the most commoncause of dementia in the elderly. Patients withAD are characterized by three hallmarks ofneuropathology including neuritic plaquedeposition, neurofibrillary tangle formation, andneuronal loss. Growing evidences indicate thatdysregulation of regulator of calcineurin 1(RCAN1) plays an important role in thepathogenesis of AD. Aberrant RCAN1 expressionfacilitates neuronal apoptosis and Tauhyperphosphorylation, leading to neuronal lossand neurofibrillary tangle formation. This reviewaims to describe the recent advances of theregulation of RCAN1 expression and itsphysiological functions. Moreover, the AD riskfactors-induced RCAN1 dysregulation and its rolein promoting neuronal loss, synaptic impairmentsand neurofibrillary tangle formation aresummarized. Furthermore, we provide an", "metadata": {}}
+{"_id": "14437255", "title": "", "text": "Congruent Visual Speech Enhances CorticalEntrainment to Continuous Auditory Speech inNoise-Free Conditions.UNLABELLED Congruentaudiovisual speech enhances our ability tocomprehend a speaker, even in noise-freeconditions. When incongruent auditory and visualinformation is presented concurrently, it canhinder a listener's perception and even causehim or her to perceive information that was notpresented in either modality. Efforts toinvestigate the neural basis of these effects haveoften focused on the special case of discreteaudiovisual syllables that are spatially andtemporally congruent, with less work done onthe case of natural, continuous speech. Recentelectrophysiological studies have demonstratedthat cortical response measures to continuousauditory speech can be easily obtained usingmultivariate analysis methods. Here, we applysuch methods to the case of audiovisual speechand, importantly, present a novel framework forindexing multisensory integration in the context", "metadata": {}}
+{"_id": "14446279", "title": "", "text": "Telomere tethering at the nuclear periphery isessential for efficient DNA double strand breakrepair in subtelomeric regionIn the yeastSaccharomyces cerevisiae that lacks lamins, thenuclear pore complex (NPC) has been proposedto serve a role in chromatin organization. Here,using fluorescence microscopy in living cells, weshow that nuclear pore proteins of the Nup84core complex, Nup84p, Nup145Cp, Nup120p,and Nup133p, serve to anchor telomere XI-L atthe nuclear periphery. The integrity of thiscomplex is shown to be required for repression ofa URA3 gene inserted in the subtelomeric regionof this chromosome end. Furthermore, alteringthe integrity of this complex decreases theefficiency of repair of a DNA double-strand break(DSB) only when it is generated in thesubtelomeric region, even though the repairmachinery is functional. These effects arespecific to the Nup84 complex. Our observationsthus confirm and extend the role played by theNPC, through the Nup84 complex, in the", "metadata": {}}
+{"_id": "14460402", "title": "", "text": "p63 Regulates adult neural precursor and newlyborn neuron survival to controlhippocampal-dependent Behavior.The molecularmechanisms that regulate adult neural precursorcell (NPC) survival, and thus maintain adultneurogenesis, are not well defined. Here, weinvestigate the role of p63, a p53 familymember, in adult NPC function in mice.Conditional ablation of p63 in adult NPCs or p63haploinsufficiency led to reduced numbers ofNPCs and newborn neurons in the neurogeniczones of the hippocampus and lateral ventriclesand in the olfactory bulb. These reductions wereattributable to enhanced apoptosis of NPCs andnewborn neurons and were rescued by inhibitionof caspase activity, p53, or the p53 apoptoticeffector PUMA (p53-upregulated modulator ofapoptosis). Moreover, these cellular deficits werefunctionally important because they led toperturbations in hippocampus-dependentmemory formation. These results indicate thatp63 regulates the numbers of adult NPCs and", "metadata": {}}
+{"_id": "14461101", "title": "", "text": "Tyrosine-Phosphorylated Caveolin-1 BlocksBacterial Uptake by InducingVav2-RhoA-Mediated CytoskeletalRearrangementsCertain bacterial adhesinsappear to promote a pathogen's extracellularlifestyle rather than its entry into host cells.However, little is known about the stimuli elicitedupon such pathogen host-cell interactions. Here,we report that type IV pili (Tfp)-producingNeisseria gonorrhoeae (P(+)GC) induces animmediate recruitment of caveolin-1 (Cav1) inthe host cell, which subsequently preventsbacterial internalization by triggering cytoskeletalrearrangements via downstreamphosphotyrosine signaling. A broad and unbiasedanalysis of potential interaction partners fortyrosine-phosphorylated Cav1 revealed a directinteraction with the Rho-family guaninenucleotide exchange factor Vav2. Both Vav2 andits substrate, the small GTPase RhoA, were foundto play a direct role in the Cav1-mediatedprevention of bacterial uptake. Our findings,", "metadata": {}}
+{"_id": "14464451", "title": "", "text": "Effects of GC Bias inNext-Generation-Sequencing Data on De NovoGenome AssemblyNext-generation-sequencing(NGS) has revolutionized the field of genomeassembly because of its much higher datathroughput and much lower cost compared withtraditional Sanger sequencing. However, NGSposes new computational challenges to de novogenome assembly. Among the challenges, GCbias in NGS data is known to aggravate genomeassembly. However, it is not clear to what extentGC bias affects genome assembly in general. Inthis work, we conduct a systematic analysis onthe effects of GC bias on genome assembly. Ouranalyses reveal that GC bias only lowersassembly completeness when the degree of GCbias is above a threshold. At a strong GC bias,the assembly fragmentation due to GC bias canbe explained by the low coverage of reads in theGC-poor or GC-rich regions of a genome. Thiseffect is observed for all the assemblers understudy. Increasing the total amount of NGS data", "metadata": {}}
+{"_id": "14471161", "title": "", "text": "Cancer inhibition through circadianreprogramming of tumor transcriptome withmeal timing.Circadian disruption acceleratescancer progression, whereas circadianreinforcement could halt it. Mice with P03pancreatic adenocarcinoma (n = 77) weresynchronized and fed ad libitum (AL) or withmeal timing (MT) from Zeitgeber time (ZT) 2 toZT6 with normal or fat diet. Tumor geneexpression profiling was determined with DNAmicroarrays at endogenous circadian time (CT) 4and CT16. Circadian mRNA expression patternswere determined for clock genes Rev-erbalpha,Per2, and Bmal1, cellular stress genes Hspa8 andCirbp, and cyclin A2 gene Ccna2 in liver andtumor. The 24-hour patterns in telemeteredrest-activity and body temperature and plasmacorticosterone and insulin-like growth factor-I(IGF-I) were assessed. We showed that MTinhibited cancer growth by approximately 40%as compared with AL (P = 0.011) irrespective ofcalorie intake. Clock gene transcription remained", "metadata": {}}
+{"_id": "14474178", "title": "", "text": "Role of chicken melanomadifferentiation-associated gene 5 in induction andactivation of innate and adaptive immuneresponses to infectious bursal disease virus incultured macrophagesThe objective of thepresent study was to determine if chickenmelanoma-differentiation-associated gene 5(MDA5) senses infectious bursal disease virusinfection to induce innate immunity that bridgesto adaptive immunity. During IBDV infection inHD11 cells, IBDV titers and RNA loads increasedup to 3.4 × 107 plaque-forming units (PFU)/mLand 1114 ng/µL, respectively, at 24 hourspostinfection (hpi). IBDV infection in HD11 cellsinduced significantly upregulated (p < 0.05)expression levels of chicken MDA5 (59-fold),interferon-β (IFN-β) (693-fold),dsRNA-dependent protein kinase (PKR) (4-fold),2’, 5’-oligoadenylate synthetase (OAS)(286-fold), myxovirus resistance gene (Mx)(22-fold), interleukin-1β (IL-1β) (5-fold), IL-6(146-fold), IL-8 (4-fold), IL-10 (4-fold), inducible", "metadata": {}}
+{"_id": "14475235", "title": "", "text": "Age-Associated Sperm DNA MethylationAlterations: Possible Implications in OffspringDisease SusceptibilityRecent evidencedemonstrates a role for paternal aging onoffspring disease susceptibility. It is wellestablished that various neuropsychiatricdisorders (schizophrenia, autism, etc.),trinucleotide expansion associated diseases(myotonic dystrophy, Huntington's, etc.) andeven some forms of cancer have increasedincidence in the offspring of older fathers.Despite strong epidemiological evidence thatthese alterations are more common in offspringsired by older fathers, in most cases themechanisms that drive these processes areunclear. However, it is commonly believed thatepigenetics, and specifically DNA methylationalterations, likely play a role. In this study wehave investigated the impact of aging on DNAmethylation in mature human sperm. Using amethylation array approach we evaluatedchanges to sperm DNA methylation patterns in", "metadata": {}}
+{"_id": "14479433", "title": "", "text": "Mutations in the nuclear bile acid receptor FXRcause progressive familial intrahepaticcholestasisNeonatal cholestasis is a potentiallylife-threatening condition requiring promptdiagnosis. Mutations in several different genescan cause progressive familial intrahepaticcholestasis, but known genes cannot account forall familial cases. Here we report four individualsfrom two unrelated families with neonatalcholestasis and mutations in NR1H4, whichencodes the farnesoid X receptor (FXR), a bileacid-activated nuclear hormone receptor thatregulates bile acid metabolism. Clinical featuresof severe, persistent NR1H4-related cholestasisinclude neonatal onset with rapid progression toend-stage liver disease, vitamin K-independentcoagulopathy, low-to-normal serumgamma-glutamyl transferase activity, elevatedserum alpha-fetoprotein and undetectable liverbile salt export pump (ABCB11) expression. Ourfindings demonstrate a pivotal function for FXRin bile acid homeostasis and liver protection.", "metadata": {}}
+{"_id": "14482051", "title": "", "text": "Phase II study of panobinostat in combinationwith bevacizumab for recurrent glioblastoma andanaplastic glioma.BACKGROUND Panobinostat isa histone deacetylase inhibitor withantineoplastic and antiangiogenic effects inglioma that may work synergistically withbevacizumab. We conducted a multicenter phaseII trial of panobinostat combined withbevacizumab in patients with recurrenthigh-grade glioma (HGG). METHODS Patientswith recurrent HGG were treated with oralpanobinostat 30 mg 3 times per week, everyother week, in combination with bevacizumab 10mg/kg every other week. The primary endpointwas a 6-month progression-fee survival (PFS6)rate for participants with recurrent glioblastoma(GBM). Patients with recurrent anaplastic glioma(AG) were evaluated as an exploratory arm ofthe study. RESULTS At interim analysis, the GBMarm did not meet criteria for continued accrual,and the GBM arm was closed. A total of 24patients with GBM were accrued prior to closure.", "metadata": {}}
+{"_id": "14492339", "title": "", "text": "Blood monocytes consist of two principal subsetswith distinct migratory propertiesPeripheral bloodmonocytes are a heterogeneous population ofcirculating leukocytes. Using a murine adoptivetransfer system to probe monocyte homing anddifferentiation in vivo, we identified twofunctional subsets among murine bloodmonocytes: a short-livedCX(3)CR1(lo)CCR2(+)Gr1(+) subset that isactively recruited to inflamed tissues and aCX(3)CR1(hi)CCR2(-)Gr1(-) subset characterizedby CX(3)CR1-dependent recruitment tononinflamed tissues. Both subsets have thepotential to differentiate into dendritic cells invivo. The level of CX(3)CR1 expression alsodefines the two major human monocyte subsets,the CD14(+)CD16(-) and CD14(lo)CD16(+)monocytes, which share phenotype and homingpotential with the mouse subsets. These findingsraise the potential for novel therapeuticstrategies in inflammatory diseases.", "metadata": {}}
+{"_id": "14492964", "title": "", "text": "The Spemann Organizer Signal noggin Binds andInactivates Bone Morphogenetic Protein 4Signalsreleased by the Spemann organizer of theamphibian gastrula can directly induce neuraltissue from ectoderm and can dorsalize ventralmesoderm to form muscle. The secretedpolypeptide noggin mimics these activities and isexpressed at the appropriate time and place toparticipate in the organizer signal. Neuralinduction and mesoderm dorsalization areantagonized by bone morphogenetic proteins(BMPs), which induce epidermis and ventralmesoderm instead. Here we report that nogginprotein binds BMP4 with high affinity and canabolish BMP4 activity by blocking binding tocognate cell-surface receptors. These datasuggest that noggin secreted by the organizerpatterns the embryo by interrupting BMPsignaling.", "metadata": {}}
+{"_id": "14496749", "title": "", "text": "A Conserved MST-FOXO Signaling PathwayMediates Oxidative-Stress Responses andExtends Life SpanOxidative stress influences cellsurvival and homeostasis, but the mechanismsunderlying the biological effects of oxidativestress remain to be elucidated. Here, wedemonstrate that the protein kinase MST1mediates oxidative-stress-induced cell death inprimary mammalian neurons by directlyactivating the FOXO transcription factors. MST1phosphorylates FOXO proteins at a conservedsite within the forkhead domain that disruptstheir interaction with 14-3-3 proteins, promotesFOXO nuclear translocation, and thereby inducescell death in neurons. We also extend theMST-FOXO signaling link to nematodes.Knockdown of the C. elegans MST1 orthologCST-1 shortens life span and accelerates tissueaging, while overexpression of cst-1 promoteslife span and delays aging. The cst-1-inducedlife-span extension occurs in a daf-16-dependentmanner. The identification of the FOXO", "metadata": {}}
+{"_id": "14500725", "title": "", "text": "Physician Emigration from Sub-Saharan Africa tothe United States: Analysis of the 2011 AMAPhysician MasterfileBACKGROUND Thelarge-scale emigration of physicians fromsub-Saharan Africa (SSA) to high-income nationsis a serious development concern. Our objectivewas to determine current emigration trends ofSSA physicians found in the physician workforceof the United States. METHODS AND FINDINGSWe analyzed physician data from the WorldHealth Organization (WHO) Global HealthWorkforce Statistics along with graduation andresidency data from the 2011 American MedicalAssociation Physician Masterfile (AMA-PM) onphysicians trained or born in SSA countries whocurrently practice in the US. We estimatedemigration proportions, year of US entry, yearsof practice before emigration, and length of timein the US. According to the 2011 AMA-PM,10,819 physicians were born or trained in 28SSA countries. Sixty-eight percent (n = 7,370)were SSA-trained, 20% (n = 2,126) were", "metadata": {}}
+{"_id": "14501880", "title": "", "text": "Kynurenic Acid Is a Nutritional Cue that EnablesBehavioral PlasticityThe kynurenine pathway oftryptophan metabolism is involved in thepathogenesis of several brain diseases, but itsphysiological functions remain unclear. We reportthat kynurenic acid, a metabolite in thispathway, functions as a regulator offood-dependent behavioral plasticity in C.elegans. The experience of fasting in C. elegansalters a variety of behaviors, including feedingrate, when food is encountered post-fast. Levelsof neurally produced kynurenic acid are depletedby fasting, leading to activation ofNMDA-receptor-expressing interneurons andinitiation of a neuropeptide-y-like signaling axisthat promotes elevated feeding throughenhanced serotonin release when animalsre-encounter food. Upon refeeding, kynurenicacid levels are eventually replenished, ending theelevated feeding period. Because tryptophan isan essential amino acid, these findings suggestthat a physiological role of kynurenic acid is in", "metadata": {}}
+{"_id": "14530534", "title": "", "text": "Comprehensive Identification and Annotation ofCell Type-Specific and Ubiquitous CTCF-BindingSites in the Human GenomeChromatin insulatorsare DNA elements that regulate the level of geneexpression either by preventing gene silencingthrough the maintenance of heterochromatinboundaries or by preventing gene activation byblocking interactions between enhancers andpromoters. CCCTC-binding factor (CTCF), aubiquitously expressed 11-zinc-fingerDNA-binding protein, is the only proteinimplicated in the establishment of insulators invertebrates. While CTCF has been implicated indiverse regulatory functions, CTCF has only beenstudied in a limited number of cell types acrosshuman genome. Thus, it is not clear whether theidentified cell type-specific differences inCTCF-binding sites are functionally significant.Here, we identify and characterize celltype-specific and ubiquitous CTCF-binding sitesin the human genome across 38 cell typesdesignated by the Encyclopedia of DNA Elements", "metadata": {}}
+{"_id": "14535322", "title": "", "text": "Experimental and Theoretical Approaches toConscious ProcessingRecent experimentalstudies and theoretical models have begun toaddress the challenge of establishing a causallink between subjective conscious experienceand measurable neuronal activity. The presentreview focuses on the well-delimited issue of howan external or internal piece of information goesbeyond nonconscious processing and gainsaccess to conscious processing, a transitioncharacterized by the existence of a reportablesubjective experience. Converging neuroimagingand neurophysiological data, acquired duringminimal experimental contrasts betweenconscious and nonconscious processing, point toobjective neural measures of conscious access:late amplification of relevant sensory activity,long-distance cortico-cortical synchronization atbeta and gamma frequencies, and \"ignition\" of alarge-scale prefronto-parietal network. Wecompare these findings to current theoreticalmodels of conscious processing, including the", "metadata": {}}
+{"_id": "14541844", "title": "", "text": "Reconstruction of the yeast Snf1 kinaseregulatory network reveals its role as a globalenergy regulatorHighly conserved amongeukaryotic cells, the AMP-activated kinase(AMPK) is a central regulator of carbonmetabolism. To map the complete network ofinteractions around AMPK in yeast (Snf1) and toevaluate the role of its regulatory subunit Snf4,we measured global mRNA, protein andmetabolite levels in wild type, Deltasnf1,Deltasnf4, and Deltasnf1Deltasnf4 knockoutstrains. Using four newly developedcomputational tools, including novel DOGMAsub-network analysis, we showed the benefits ofthree-level ome-data integration to uncover theglobal Snf1 kinase role in yeast. We for the firsttime identified Snf1's global regulation on geneand protein expression levels, and showed thatyeast Snf1 has a far more extensive function incontrolling energy metabolism than reportedearlier. Additionally, we identifiedcomplementary roles of Snf1 and Snf4. Similar to", "metadata": {}}
+{"_id": "14544564", "title": "", "text": "Influence of Steroid Hormone Signaling on LifeSpan Control by Caenorhabditis elegansInsulin-Like SignalingSterol-sensing nuclearreceptors and insulin-like growth factor signalingplay evolutionarily conserved roles in the controlof aging. In the nematode Caenorhabditiselegans, bile acid-like steroid hormones knownas dafachronic acids (DAs) influence longevity bybinding to and regulating the activity of theconserved nuclear receptor DAF-12, and theinsulin receptor (InsR) ortholog DAF-2 controlslife span by inhibiting the FoxO transcriptionfactor DAF-16. How the DA/DAF-12 pathwayinteracts with DAF-2/InsR signaling to control lifespan is poorly understood. Here we specificallyinvestigated the roles of liganded and unligandedDAF-12 in life span control in the context ofreduced DAF-2/InsR signaling. In animals withreduced daf-2/InsR activity, mutations thateither reduce DA biosynthesis or fully abrogateDAF-12 activity shorten life span, suggestingthat liganded DAF-12 promotes longevity. In", "metadata": {}}
+{"_id": "14550841", "title": "", "text": "Asymmetric Cell Divisions SustainLong-Term  Hematopoiesis from Single-sortedHuman Fetal Liver CellsHematopoietic stem cells(HSCs) in adult marrow are believed to bederived from fetal liver precursors. To study cellkinetics involved in long-term hematopoiesis, westudied single-sorted candidate HSCs from fetalliver that were cultured in the presence of amixture of stimulatory cytokines. After 8–10 d,the number of cells in primary cultures variedfrom 10,000 cells. Single cells in slow growingcolonies were recloned upon reaching a 100–200cell stage. Strikingly, the number of cells insubclones varied widely again. These results areindicative of asymmetric divisions in primitivehematopoietic cells in which proliferativepotential and cell cycle properties are unevenlydistributed among daughter cells. The continuousgeneration of functional heterogeneity amongthe clonal progeny of HSCs is in support ofintrinsic control of stem cell fate and provides amodel for the long-term maintenance of", "metadata": {}}
+{"_id": "14555750", "title": "", "text": "Reprogramming factor expression initiateswidespread targeted chromatinremodeling.Despite rapid progress incharacterizing transcription factor-drivenreprogramming of somatic cells to an inducedpluripotent stem cell (iPSC) state, manymechanistic questions still remain. To gaininsight into the earliest events in thereprogramming process, we systematicallyanalyzed the transcriptional and epigeneticchanges that occur during early factor inductionafter discrete numbers of divisions. We observedrapid, genome-wide changes in the euchromatichistone modification, H3K4me2, at more than athousand loci including large subsets ofpluripotency-related or developmentallyregulated gene promoters and enhancers. Incontrast, patterns of the repressive H3K27me3modification remained largely unchanged exceptfor focused depletion specifically at positionswhere H3K4 methylation is gained. Thesechromatin regulatory events precede", "metadata": {}}
+{"_id": "14566771", "title": "", "text": "Stroke and migraine--the spectrum of cause andeffect.The relationship of migraine and stroke iscomplex. Stroke may be coincidental withmigraine but migraine may confer an increasedrisk of stroke in women under 45 years of ageand possibly in men who have migraine withaura. Stroke may mimic migraine but migrainesyndromes may be symptomatic of underlyingcerebrovascular disorders. Truemigraine-induced stroke is rare. The mechanismsof stroke induced during a migraine attackremain to be determined but probably involve aninteraction between the dynamic shifts incerebral blood flow and stroke risk factors.", "metadata": {}}
+{"_id": "14581009", "title": "", "text": "MicroRNA Regulation of Cbx7 Mediates a Switchof Polycomb Orthologs during ESCDifferentiationThe Polycomb Group (PcG) ofchromatin modifiers regulates pluripotency anddifferentiation. Mammalian genomes encodemultiple homologs of the Polycomb repressivecomplex 1 (PRC1) components, including fiveorthologs of the Drosophila Polycomb protein(Cbx2, Cbx4, Cbx6, Cbx7, and Cbx8). We haveidentified Cbx7 as the primary Polycomb orthologof PRC1 complexes in embryonic stem cells(ESCs). The expression of Cbx7 is downregulatedduring ESC differentiation, preceding theupregulation of Cbx2, Cbx4, and Cbx8, which aredirectly repressed by Cbx7. Ectopic expression ofCbx7 inhibits differentiation and X chromosomeinactivation and enhances ESC self-renewal.Conversely, Cbx7 knockdown inducesdifferentiation and derepresses lineage-specificmarkers. In a functional screen, we identified themiR-125 and miR-181 families as regulators ofCbx7 that are induced during ESC differentiation.", "metadata": {}}
+{"_id": "14584755", "title": "", "text": "Differences in the Clinical Effects ofAngiotensin-Converting Enzyme Inhibitors andAngiotensin Receptor Blockers: A Critical Reviewof the EvidenceTherenin-angiotensin-aldosterone system plays amajor role in the pathophysiology ofhypertension and closely related cardio- andcerebrovascular events. Although bothangiotensin-converting enzyme (ACE) inhibitorsand angiotensin receptor antagonists(angiotensin receptor blockers; ARBs) areequally important in the treatment ofhypertension, according to the results of recentyears, there might be substantial differences intheir cardiovascular protective effects, and thesedifferences might be explained by our increasingknowledge of their non-overlapping mechanismsof action. The number of studies investigatinghow ACE inhibitors and ARB agents differ willcertainly be increasing in the future. ACEinhibitors are the safe therapeutic opportunity forhypertensive patients at high risk, with a", "metadata": {}}
+{"_id": "14591894", "title": "", "text": "A talin-dependent LFA-1 focal zone is formed byrapidly migrating T lymphocytesCells such asfibroblasts and endothelial cells migrate throughthe coordinated responses of discreteintegrin-containing focal adhesions andcomplexes. In contrast, little is known about theorganization of integrins on the highly motile Tlymphocyte. We have investigated thedistribution, activity, and cytoskeletal linkage ofthe integrin lymphocyte function associatedantigen-1 (LFA-1) on human T lymphocytesmigrating on endothelial cells and on ligandintercellular adhesion molecule-1 (ICAM-1). Thepattern of total LFA-1 varies from low expressionin the lamellipodia to high expression in theuropod. However, high affinity, clustered LFA-1is restricted to a mid-cell zone that remainsstable over time and over a range of ICAM-1densities. Talin is essential for the stability andformation of the LFA-1 zone. Disruption of thetalin–integrin link leads to loss of zone integrityand a substantial decrease in speed of migration", "metadata": {}}
+{"_id": "14606752", "title": "", "text": "Tricyclic antidepressants and headaches:systematic review and meta-analysisOBJECTIVETo evaluate the efficacy and relative adverseeffects of tricyclic antidepressants in thetreatment of migraine, tension-type, and mixedheadaches. DESIGN Meta-analysis. DATASOURCES Medline, Embase, the Cochrane TrialsRegistry, and PsycLIT. Studies reviewedRandomised trials of adults receiving tricyclics asonly treatment for a minimum of four weeks.DATA EXTRACTION Frequency of headaches(number of headache attacks for migraine andnumber of days with headache for tension-typeheadaches), intensity of headache, andheadache index. RESULTS 37 studies met theinclusion criteria. Tricyclics significantly reducedthe number of days with tension-type headacheand number of headache attacks from migrainethan placebo (average standardised meandifference -1.29, 95% confidence interval -2.18to -0.39 and -0.70, -0.93 to -0.48) but notcompared with selective serotonin reuptake", "metadata": {}}
+{"_id": "14610165", "title": "", "text": "Functional Consequences of Splicing of theAntisense Transcript COOLAIR on FLCTranscriptionAntisense transcription iswidespread in many genomes; however, howmuch is functional is hotly debated. We areinvestigating functionality of a set of longnoncoding antisense transcripts, collectivelycalled COOLAIR, produced at ArabidopsisFLOWERING LOCUS C (FLC). COOLAIR initiatesjust downstream of the major sense transcriptpoly(A) site and terminates either early orextends into the FLC promoter region. We nowshow that splicing of COOLAIR is functionallyimportant. This was revealed through analysis ofa hypomorphic mutation in the core spliceosomecomponent PRP8. The prp8 mutation perturbs acotranscriptional feedback mechanism linkingCOOLAIR processing to FLC gene body histonedemethylation and reduced FLC transcription.The importance of COOLAIR splicing in thisrepression mechanism was confirmed bydisrupting COOLAIR production and mutating the", "metadata": {}}
+{"_id": "14615911", "title": "", "text": "Nuclear Factor-\u0000B Affects Tumor Progression ina Mouse Model of Malignant Pleural EffusionWedeveloped a novel mouse model of malignantpleural effusion (MPE) by injecting Lewis lungcancer (LLC) cells directly into the pleural spaceof syngeneic C57B/6 mice. The pleural effusionsin this model share common cellular andbiochemical features with human MPEs.Implantation and growth of pleural tumorstriggers a host inflammatory responsecharacterized by a mixed inflammatory cell influxinto the pleural fluid. LLC cells exhibited highbasal nuclear factor (NF)-κB activity in vitro andin vivo, which we used to drive expression of aNF-κB–dependent green fluorescentprotein-firefly luciferase fusion reporterconstruct. NF-κB–dependent reporter expressionallowed intravital tracing of pleural tumors.Inhibition of NF-κB in LLC cells did not affect cellviability in culture; however, injection of LLCcells expressing a dominant NF-κB inhibitorresulted in decreased tumor burden, decreased", "metadata": {}}
+{"_id": "14626540", "title": "", "text": "A phase I study of PF-04449913, an oralhedgehog inhibitor, in patients with advancedsolid tumors.PURPOSE To estimate the maximumtolerated dose (MTD) of single-agentPF-04449913, and to evaluate safety,tolerability, pharmacokinetics,pharmacodynamics, and preliminary antitumoractivity in patients with advanced tumors.EXPERIMENTAL DESIGN A 3+3 design was usedin this open-label, multicenter, phase I study anddose escalation/de-escalation applied untilidentification of the MTD. PF-04449913 wasorally administered once daily in continuous28-day treatment cycles. The starting dose was80 mg. RESULTS A total of 23 patients wereenrolled; 19 were evaluable for first-cycledose-limiting toxicity (DLT). The first-cycle DLTrate at the 640 mg dose level was 33.3%, andthe MTD was estimated to be 320 mg once daily.The recommended phase II dose was notdetermined. PF-04449913 was generally welltolerated at doses of 80 to 320 mg once daily.", "metadata": {}}
+{"_id": "14637235", "title": "", "text": "Histone levels are regulated by phosphorylationand ubiquitylation dependent proteolysisHistonelevels are tightly regulated to prevent harmfuleffects such as genomic instability andhypersensitivity to DNA-damaging agents due tothe accumulation of these highly basic proteinswhen DNA replication slows down or stops.Although chromosomal histones are stable,excess (non-chromatin bound) histones arerapidly degraded in a Rad53 (radiation sensitive53) kinase-dependent manner in Saccharomycescerevisiae. Here we demonstrate that excesshistones associate with Rad53 in vivo and seemto undergo modifications such as tyrosinephosphorylation and polyubiquitylation, beforetheir proteolysis by the proteasome. We haveidentified the Tyr 99 residue of histone H3 asbeing critical for the efficient ubiquitylation anddegradation of this histone. We have alsoidentified the ubiquitin conjugating enzymes (E2)Ubc4 and Ubc5, as well as the ubiquitin ligase(E3) Tom1 (temperature dependent organization", "metadata": {}}
+{"_id": "14644164", "title": "", "text": "TLR-activated B cells suppress T cell-mediatedautoimmunity.TLR sense microbial infections,and control activation of immune responses.Dendritic cells, macrophages, and B lymphocytesexpress TLR and the TLR-signaling adaptorprotein MyD88. The impact of TLR-activated Bcells on T cell-mediated inflammation isunknown. In this study, we have used micecarrying B cell-restricted deficiencies in MyD88 orin distinct TLR to examine the impact ofTLR-activated B cells on a T cell-mediatedautoimmune disease, experimental autoimmuneencephalomyelitis (EAE). We demonstrate thatTLR-signaling in B cells suppresses inflammatoryT cell responses (both Th1 and Th17), andstimulates recovery from EAE. Only certain TLRare required on B cells for resolution of EAE, andthese are dispensable for disease initiation,indicating that a category of TLR agonistspreferentially triggers a suppressive function in Bcells and thereby limits autoimmune disease. TheTLR agonists controlling the regulatory function", "metadata": {}}
+{"_id": "14647747", "title": "", "text": "Successful expansion of functional and stableregulatory T cells for immunotherapy in livertransplantationStrategies to prevent organtransplant rejection whilst minimizing long-termimmunosuppression are currently under intenseinvestigation with regulatory T cells (Tregs)nearing clinical application. The clinical trial,ThRIL, recently commenced at King's CollegeLondon, proposes to use Treg cell therapy toinduce tolerance in liver transplant recipients,the success of which has the potential torevolutionize the management of these patientsand enable a future of drug-free transplants. Thisis the first report of the manufacture of clinicalgrade Tregs from prospective liver transplantrecipients via a CliniMACS-based GMP isolationtechnique and expanded using anti-CD3/CD28beads, IL-2 and rapamycin. We report theenrichment of a pure, stable population of Tregs(>95% CD4(+)CD25(+)FOXP3(+)), reachingadequate numbers for their clinical application.Our protocol proved successful in, influencing the", "metadata": {}}
+{"_id": "14652521", "title": "", "text": "A framework for improving microRNA predictionin non-human genomesThe prediction of novelpre-microRNA (miRNA) from genomic sequencehas received considerable attention recently.However, the majority of studies have focusedon the human genome. Previous studies havedemonstrated that sensitivity (correctly detectingtrue miRNA) is sustained when human-trainedmethods are applied to other species, howeverthey have failed to report the dramatic drop inspecificity (the ability to correctly rejectnon-miRNA sequences) in non-human genomes.Considering the ratio of true miRNA sequences topseudo-miRNA sequences is on the order of1:1000, such low specificity prevents theapplication of most existing tools to non-humangenomes, as the number of false positivesoverwhelms the true predictions. We hereintroduce a framework (SMIRP) for creatingspecies-specific miRNA prediction systems,leveraging sequence conservation andphylogenetic distance information. Substantial", "metadata": {}}
+{"_id": "14657344", "title": "", "text": "CD8 Cells of Patients with Diffuse CutaneousLeishmaniasis Display Functional Exhaustion:The Latter Is Reversed, In Vitro, by TLR2AgonistsLeishmania mexicana (Lm) causeslocalized (LCL) and diffuse (DCL) cutaneousleishmaniasis. DCL patients have a poor cellularimmune response leading to chronicity. It hasbeen proposed that CD8 T lymphocytes (CD8)play a crucial role in infection clearance,although the role of CD8 cytotoxicity in diseasecontrol has not been elucidated. Lesions of DCLpatients have been shown to harbor low numbersof CD8, as compared to patients with LCL, andleishmanicidal treatment restores CD8 numbers.The marked response of CD8 towardsLeishmania parasites led us to analyze possiblefunctional differences between CD8 from patientswith LCL and DCL. We compared IFNγproduction, antigen-specific proliferation, andcytotoxicity of CD8 purified from PBMC againstautologous macrophages (MO) infected withLeishmania mexicana (MOi). Additionally, we", "metadata": {}}
+{"_id": "14658685", "title": "", "text": "Enhancer Evolution across 20 MammalianSpeciesThe mammalian radiation hascorresponded with rapid changes in noncodingregions of the genome, but we lack acomprehensive understanding of regulatoryevolution in mammals. Here, we track theevolution of promoters and enhancers active inliver across 20 mammalian species from sixdiverse orders by profiling genomic enrichmentof H3K27 acetylation and H3K4 trimethylation.We report that rapid evolution of enhancers is auniversal feature of mammalian genomes. Mostof the recently evolved enhancers arise fromancestral DNA exaptation, rather thanlineage-specific expansions of repeat elements.In contrast, almost all liver promoters arepartially or fully conserved across these species.Our data further reveal that recently evolvedenhancers can be associated with genes underpositive selection, demonstrating the power ofthis approach for annotating regulatoryadaptations in genomic sequences. These results", "metadata": {}}
+{"_id": "14663842", "title": "", "text": "IDH1 mutations alter citric acid cycle metabolismand increase dependence on oxidativemitochondrial metabolism.Oncogenic mutationsin isocitrate dehydrogenase 1 and 2 (IDH1/2)occur in several types of cancer, but themetabolic consequences of these geneticchanges are not fully understood. In this study,we performed (13)C metabolic flux analysis on apanel of isogenic cell lines containingheterozygous IDH1/2 mutations. We observedthat under hypoxic conditions, IDH1-mutant cellsexhibited increased oxidative tricarboxylic acidmetabolism along with decreased reductiveglutamine metabolism, but not IDH2-mutantcells. However, selective inhibition of mutantIDH1 enzyme function could not reverse thedefect in reductive carboxylation activity.Furthermore, this metabolic reprogrammingincreased the sensitivity of IDH1-mutant cells tohypoxia or electron transport chain inhibition invitro. Lastly, IDH1-mutant cells also grew poorlyas subcutaneous xenografts within a hypoxic in", "metadata": {}}
+{"_id": "14664424", "title": "", "text": "The assessment of the prognostic value of tumormarkers and cytokines as SCCAg, CYFRA 21.1,IL-6, VEGF and sTNF receptors in patients withsquamous cell cervical cancer, particularly withearly stage of the diseaseThe aim of this study isto determine the prognostic value of tumormarkers, as squamous cell carcinoma antigen(SCCAg) and cytokeratin-19 fragment (CYFRA21.1) and interleukin 6 (IL-6), vascularendothelial growth factor (VEGF), soluble tumornecrosis factor receptor I (sTNF RI), and sTNFRII in patients with squamous cell carcinoma ofthe cervix. The subjects of analysis were 138patients with stage I-IVA according to theInternational Federation of Gynecology andObstetrics (FIGO) classification. The collectedresearch material comes from one oncologycenter. During the 10 years of follow-up, 56relapses and 53 deaths were observed, andrecurrent disease in early stage was confirmed in45 % of patients. The pretreatment serum levelsof SCCAg and CYFRA 21.1, and cytokines IL-6,", "metadata": {}}
+{"_id": "14672919", "title": "", "text": "Combination of platelet count and mean plateletvolume (COP-MPV) predicts postoperativeprognosis in both resectable early and advancedstage esophageal squamous cell cancerpatientsThe aim of this study is to search themost powerful prognostic factor from routineblood test for esophageal squamous cell cancer(ESCC) patients. Multiple laboratory tests wereevaluated including those reflecting red blood cellparameters (hemoglobin (Hb), mean corpuscularvolume (MCV), mean corpuscular hemoglobinconcentration (MCHC), and red blood celldistribution width (RDW)), platelet morphologicalparameters (mean platelet volume (MPV) andplatelet count (PLT)), blood coagulation status(D-dimer), and tumor biomarker (CA19-9).Known inflammatory indices (NLR and PLR) werealso calculated. A total of 468 patients who werediagnosed with ESCC between December 2005and December 2008 were retrospectivelyanalyzed in this study. By utilizing univariate andmultivariate Cox proportional hazard analyses,", "metadata": {}}
+{"_id": "14682243", "title": "", "text": "Dementia incidence and mortality inmiddle-income countries, and associations withindicators of cognitive reserve: a 10/66Dementia Research Group population-basedcohort studyBACKGROUND Results of the fewcohort studies from countries with low incomesor middle incomes suggest a lower incidence ofdementia than in high-income countries. Weassessed incidence of dementia according tocriteria from the 10/66 Dementia ResearchGroup and Diagnostic and Statistical Manual ofMental Disorders (DSM) IV, the effect ofdementia at baseline on mortality, and theindependent effects of age, sex, socioeconomicposition, and indicators of cognitive reserve.METHODS We did a population-based cohortstudy of all people aged 65 years and older livingin urban sites in Cuba, the Dominican Republic,and Venezuela, and rural and urban sites in Peru,Mexico, and China, with ascertainment ofincident 10/66 and DSM-IV dementia 3-5 yearsafter cohort inception. We used questionnaires to", "metadata": {}}
+{"_id": "14692646", "title": "", "text": "Regulation of immune responses by extracellularvesiclesExtracellular vesicles, includingexosomes, are small membrane vesicles derivedfrom multivesicular bodies or from the plasmamembrane. Most, if not all, cell types releaseextracellular vesicles, which then enter the bodilyfluids. These vesicles contain a subset ofproteins, lipids and nucleic acids that are derivedfrom the parent cell. It is thought thatextracellular vesicles have important roles inintercellular communication, both locally andsystemically, as they transfer their contents,including proteins, lipids and RNAs, betweencells. Extracellular vesicles are involved innumerous physiological processes, and vesiclesfrom both non-immune and immune cells haveimportant roles in immune regulation. Moreover,extracellular vesicle-based therapeutics arebeing developed and clinically tested for thetreatment of inflammatory diseases,autoimmune disorders and cancer. Given thetremendous therapeutic potential of extracellular", "metadata": {}}
+{"_id": "14700857", "title": "", "text": "Risk of cancer after low doses of ionisingradiation: retrospective cohort study in 15countries.OBJECTIVES To provide directestimates of risk of cancer after protracted lowdoses of ionising radiation and to strengthen thescientific basis of radiation protection standardsfor environmental, occupational, and medicaldiagnostic exposures. DESIGN Multinationalretrospective cohort study of cancer mortality.SETTING Cohorts of workers in the nuclearindustry in 15 countries. PARTICIPANTS 407 391workers individually monitored for externalradiation with a total follow-up of 5.2 millionperson years. MAIN OUTCOME MEASUREMENTSEstimates of excess relative risks per sievert (Sv)of radiation dose for mortality from cancers otherthan leukaemia and from leukaemia excludingchronic lymphocytic leukaemia, the main causesof death considered by radiation protectionauthorities. RESULTS The excess relative risk forcancers other than leukaemia was 0.97 per Sv,95% confidence interval 0.14 to 1.97. Analyses", "metadata": {}}
+{"_id": "14706752", "title": "", "text": "Gamma-Secretase Represents a TherapeuticTarget for the Treatment of Invasive GliomaMediated by the p75 Neurotrophin ReceptorThemultifunctional signaling protein p75neurotrophin receptor (p75(NTR)) is a centralregulator and major contributor to the highlyinvasive nature of malignant gliomas. Here, weshow that neurotrophin-dependent regulatedintramembrane proteolysis (RIP) of p75(NTR) isrequired for p75(NTR)-mediated glioma invasion,and identify a previously unnamed process fortargeted glioma therapy. Expression ofcleavage-resistant chimeras of p75(NTR) ortreatment of animals bearing p75(NTR)-positiveintracranial tumors with clinically applicablegamma-secretase inhibitors resulted indramatically decreased glioma invasion andprolonged survival. Importantly, proteolyticprocessing of p75(NTR) was observed inp75(NTR)-positive patient tumor specimens andbrain tumor initiating cells. This work highlightsthe importance of p75(NTR) as a therapeutic", "metadata": {}}
+{"_id": "14711483", "title": "", "text": "Preliminary assessment of inhaled nitric oxide foracute vaso-occlusive crisis in pediatric patientswith sickle cell disease.CONTEXT Vaso-occlusionis central to the painful crises and acute andchronic organ damage in sickle cell disease.Abnormal nitric oxide-dependent regulation ofvascular tone, adhesion, platelet activation, andinflammation contributes to the pathophysiologyof vaso-occlusion. Nitric oxide may have promiseas a mechanism-of-disease-based therapy fortreatment of vaso-occlusion. OBJECTIVE Toexplore the efficacy and safety of inhaled nitricoxide (INO) for treatment of vaso-occlusive crisisin pediatric patients. DESIGN Prospective,double-blind, placebo-controlled, randomizedclinical trial with enrollment between September1999 and October 2001. SETTING Urban, tertiarycare children's hospital in the United States.PARTICIPANTS Twenty patients aged 10 to 21years with sickle cell disease and severe acutevaso-occlusive crisis. INTERVENTION Patientswere randomly assigned to receive INO (80 ppm", "metadata": {}}
+{"_id": "14717213", "title": "", "text": "Corresponding author:Over the years, methodsof cytogenetic analysis evolved and became partof routine laboratory testing, providing valuablediagnostic and prognostic information inhematologic disorders. Karyotypic aberrationscontribute to the understanding of the molecularpathogenesis of disease and thereby to rationalapplication of therapeutic modalities. Most of theprogress in this field stems from the applicationof metaphase cytogenetics (MC), but recently,novel molecular technologies have beenintroduced that complement MC and overcomemany of the limitations of traditionalcytogenetics, including a need for cell culture.Whole genome scanning using comparativegenomic hybridization and single nucleotidepolymorphism arrays (CGH-A; SNP-A) can beused for analysis of somatic or clonal unbalancedchromosomal defects. In SNP-A, the combinationof copy number detection and genotypingenables diagnosis of copy-neutral loss ofheterozygosity, a lesion that cannot be detected", "metadata": {}}
+{"_id": "14717500", "title": "", "text": "Rare Variants Create Synthetic Genome-WideAssociationsGenome-wide association studies(GWAS) have now identified at least 2,000common variants that appear associated withcommon diseases or related traits(http://www.genome.gov/gwastudies), hundredsof which have been convincingly replicated. It isgenerally thought that the associated markersreflect the effect of a nearby common (minorallele frequency >0.05) causal site, which isassociated with the marker, leading to extensiveresequencing efforts to find causal sites. Wepropose as an alternative explanation thatvariants much less common than the associatedone may create \"synthetic associations\" byoccurring, stochastically, more often inassociation with one of the alleles at the commonsite versus the other allele. Although syntheticassociations are an obvious theoreticalpossibility, they have never been systematicallyexplored as a possible explanation for GWASfindings. Here, we use simple computer", "metadata": {}}
+{"_id": "14719322", "title": "", "text": "Decoding of Cytoplasmic Ca2+ Oscillationsthrough the Spatial Signature Drives GeneExpressionCytoplasmic Ca(2+) oscillations are auniversal signaling mode that activatesnumerous cellular responses [1, 2]. Oscillationsare considered the physiological mechanism ofCa(2+) signaling because they occur at lowlevels of stimulus intensity [3]. Ca(2+)oscillations are proposed to convey informationin their amplitude and frequency, leading toactivation of specific downstream targets [4-6].Here, we report that the spatial Ca(2+) gradientwithin the oscillation is key. Ca(2+) oscillationsin mast cells evoked over a range of agonistconcentrations in the presence of externalCa(2+) were indistinguishable from those in theabsence of Ca(2+) when plasmalemmal Ca(2+)extrusion was suppressed. Nevertheless, onlyoscillations with accompanying Ca(2+) entrythrough store-operated CRAC channels triggeredgene expression. Increased cytoplasmic Ca(2+)buffering prevented oscillations but not gene", "metadata": {}}
+{"_id": "14724693", "title": "", "text": "Effect of glucosamine on pain-related disability inpatients with chronic low back pain anddegenerative lumbar osteoarthritis: arandomized controlled trial.CONTEXT Chronic lowback pain (LBP) with degenerative lumbarosteoarthritis (OA) is widespread in the adultpopulation. Although glucosamine is increasinglyused by patients with chronic LBP, little is knownabout its effect in this setting. OBJECTIVE Toinvestigate the effect of glucosamine in patientswith chronic LBP and degenerative lumbar OA.DESIGN, SETTING, AND PARTICIPANTS Adouble-blind, randomized, placebo-controlledtrial conducted at Oslo University HospitalOutpatient Clinic, Oslo, Norway, with 250patients older than 25 years of age with chronicLBP (>6 months) and degenerative lumbar OA.INTERVENTIONS Daily intake of 1500 mg of oralglucosamine (n = 125) or placebo (n = 125) for6 months, with assessment of effect after the6-month intervention period and at 1 year (6months postintervention). MAIN OUTCOME", "metadata": {}}
+{"_id": "14726759", "title": "", "text": "Adult cervicocerebral artery dissection: asingle-center study of 301 Finnishpatients.BACKGROUND AND PURPOSE There areonly few small studies assessing potential riskfactors, comorbidity, and prognostic factors inadult spontaneous cervicocerebral arterydissection (CAD). METHODS We conducted aretrospective, hospital-based analysis on theprognostic factors and association of CAD withvascular risk factors in 301 consecutive Finnishpatients, diagnosed from 1994 to 2007.RESULTS Two thirds of the patients were men(68%). Women were younger than men.Migraine (36% of all patients), especially withvisual aura (63% of all migraineurs), andsmoking were more common in patients withCAD compared with the general Finnishpopulation. At 3 months, 247 (83%) patientsreached a favorable outcome. Occlusion of thedissected artery, internal carotid arterydissection (ICAD), and recent infection ininfarction patients were associated with a poorer", "metadata": {}}
+{"_id": "14729253", "title": "", "text": "Genetic variation and gastric cancer risk: a fieldsynopsis and meta-analysis.BACKGROUND Dataon genetic susceptibility to sporadic gastriccarcinoma have been published at a growingpace, but to date no comprehensive overviewand quantitative summary has been available.METHODS We conducted a systematic reviewand meta-analysis of the evidence on theassociation between DNA variation and risk ofdeveloping stomach cancer. To assess resultcredibility, summary evidence was gradedaccording to the Venice criteria and false positivereport probability (FPRP) was calculated tofurther validate result noteworthiness.Meta-analysis was also conducted for subgroups,which were defined by ethnicity (Asian vsCaucasian), tumour histology (intestinal vsdiffuse), tumour site (cardia vs non-cardia) andHelicobacter pylori infection status (positive vsnegative). RESULTS Literature search identified824 eligible studies comprising 2 530 706subjects (cases: 261 386 (10.3%)) and", "metadata": {}}
+{"_id": "14753395", "title": "", "text": "Structure and function of the blood–brainbarrierNeural signalling within the centralnervous system (CNS) requires a highlycontrolled microenvironment. Cells at three keyinterfaces form barriers between the blood andthe CNS: the blood-brain barrier (BBB),blood-CSF barrier and the arachnoid barrier. TheBBB at the level of brain microvesselendothelium is the major site of blood-CNSexchange. The structure and function of the BBBis summarised, the physical barrier formed bythe endothelial tight junctions, and the transportbarrier resulting from membrane transportersand vesicular mechanisms. The roles ofassociated cells are outlined, especially theendfeet of astrocytic glial cells, and pericytes andmicroglia. The embryonic development of theBBB, and changes in pathology are described.The BBB is subject to short and long-termregulation, which may be disturbed in pathology.Any programme for drug discovery or delivery,to target or avoid the CNS, needs to consider the", "metadata": {}}
+{"_id": "14767844", "title": "", "text": "Golli protein negatively regulates storedepletion-induced calcium influx in Tcells.Calcium influx is crucial for T cell activationand differentiation. The detailed regulation ofthis process remains unclear. We report herethat golli protein, an alternatively spliced productof the myelin basic protein gene, plays a criticalrole in regulating calcium influx in T cells.Golli-deficient T cells were hyperproliferative andshowed enhanced calcium entry upon T cellreceptor stimulation. We further found that golliregulates calcium influx in T cells through theinhibition of the store depletion-induced calciuminflux. Mutation of the myristoylation site on gollidisrupted its association with the plasmamembrane and reversed its inhibitory action onCa2+ influx, indicating that membraneassociation of golli was essential for its inhibitoryaction. These results indicate that golli functionsin a unique way to regulate T cell activationthrough a mechanism involving the modulationof the calcium homeostasis.", "metadata": {}}
+{"_id": "14768471", "title": "", "text": "Extracellular vesicles derived from renal cancerstem cells induce a pro-tumorigenic phenotype inmesenchymal stromal cellsRenal carcinomashave been shown to contain a population ofcancer stem cells (CSCs) that presentself-renewing capacity and support tumor growthand metastasis. CSCs were shown to secretelarge amount of extracellular vesicles (EVs) thatcan transfer several molecules (proteins, lipidsand nucleic acids) and induce epigenetic changesin target cells. Mesenchymal Stromal Cells(MSCs) are susceptible to tumor signalling andcan be recruited to tumor regions. The preciserole of MSCs in tumor development is still underdebate since both pro- and anti-tumorigeniceffects have been reported. In this study weanalysed the participation of renal CSC-derivedEVs in the interaction between tumor and MSCs.We found that CSC-derived EVs promotedpersistent phenotypical changes in MSCscharacterized by an increased expression ofgenes associated with cell migration (CXCR4,", "metadata": {}}
+{"_id": "14782049", "title": "", "text": "In vivo effect of chronic hypoxia on theneurochemical profile of the developing rathippocampus.The cognitive deficits observed inchildren with cyanotic congenital heart diseasesuggest involvement of the developinghippocampus. Chronic postnatal hypoxia presentduring infancy in these children may play a rolein these impairments. To understand thebiochemical mechanisms of hippocampal injuryin chronic hypoxia, a neurochemical profileconsisting of 15 metabolite concentrations and 2metabolite ratios in the hippocampus wasevaluated in a rat model of chronic postnatalhypoxia using in vivo 1H NMR spectroscopy at9.4 T. Chronic hypoxia was induced bycontinuously exposing rats (n = 23) to 10% O2from postnatal day (P) 3 to P28. Fifteenmetabolites were quantified from a volume of9-11 microl centered on the left hippocampus onP14, P21, and P28 and were compared withnormoxic controls (n = 14). The developmentaltrajectory of neurochemicals in chronic hypoxia", "metadata": {}}
+{"_id": "14797520", "title": "", "text": "Noncoding Transcription by RNA Polymerase PolIVb/Pol V Mediates Transcriptional Silencing ofOverlapping and Adjacent GenesNucleartranscription is not restricted to genes but occursthroughout the intergenic and noncoding spaceof eukaryotic genomes. The functionalsignificance of this widespread noncodingtranscription is mostly unknown. We show thatArabidopsis RNA polymerase IVb/Pol V, amultisubunit nuclear enzyme required forsiRNA-mediated gene silencing of transposonsand other repeats, transcribes intergenic andnoncoding sequences, thereby facilitatingheterochromatin formation and silencing ofoverlapping and adjacent genes. Pol IVb/Pol Vtranscription requires the chromatin-remodelingprotein DRD1 but is independent of siRNAbiogenesis. However, Pol IVb/Pol V transcriptionand siRNA production are both required tosilence transposons, suggesting that Pol IVb/PolV generates RNAs or chromatin structures thatserve as scaffolds for siRNA-mediated", "metadata": {}}
+{"_id": "14803797", "title": "", "text": "Intestinal microbiota metabolism of L-carnitine, anutrient in red meat, promotesatherosclerosisIntestinal microbiota metabolismof choline and phosphatidylcholine producestrimethylamine (TMA), which is furthermetabolized to a proatherogenic species,trimethylamine-N-oxide (TMAO). Wedemonstrate here that metabolism by intestinalmicrobiota of dietary L-carnitine, atrimethylamine abundant in red meat, alsoproduces TMAO and accelerates atherosclerosisin mice. Omnivorous human subjects producedmore TMAO than did vegans or vegetariansfollowing ingestion of L-carnitine through amicrobiota-dependent mechanism. The presenceof specific bacterial taxa in human feces wasassociated with both plasma TMAO concentrationand dietary status. Plasma L-carnitine levels insubjects undergoing cardiac evaluation (n =2,595) predicted increased risks for bothprevalent cardiovascular disease (CVD) andincident major adverse cardiac events", "metadata": {}}
+{"_id": "14806256", "title": "", "text": "Hepatotoxicity associated with antiretroviraltherapy in adults infected with humanimmunodeficiency virus and the role of hepatitisC or B virus infection.CONTEXT Use ofantiretroviral drugs, including proteaseinhibitors, for treatment of humanimmunodeficiency virus (HIV) infection has beenanecdotally associated with hepatotoxicity,particularly in persons coinfected with hepatitis Cor B virus. OBJECTIVES To ascertain if incidenceof severe hepatotoxicity during antiretroviraltherapy is similar for all antiretroviral drugcombinations, and to define the role of chronicviral hepatitis in its development. DESIGNProspective cohort study. SETTINGUniversity-based urban HIV clinic. PATIENTS Atotal of 298 patients who were prescribed newantiretroviral therapies between January 1996and January 1998, 211 (71%) of whom receivedprotease inhibitors as part of combinationtherapy (median follow-up, 182 days) and 87(29%) of whom received dual nucleoside analog", "metadata": {}}
+{"_id": "14819804", "title": "", "text": "Mutations in the phosphatidylinositol-3-kinasepathway predict for antitumor activity of theinhibitor PX-866 whereas oncogenic Ras is adominant predictor for resistance.The novelphosphatidylinositol-3-kinase (PI3K) inhibitorPX-866 was tested against 13 experimentalhuman tumor xenografts derived from cell linesof various tissue origins. Mutant PI3K (PIK3CA)and loss of PTEN activity were sufficient, but notnecessary, as predictors of sensitivity to theantitumor activity of the PI3K inhibitor PX-866 inthe presence of wild-type Ras, whereas mutantoncogenic Ras was a dominant determinant ofresistance, even in tumors with coexistingmutations in PIK3CA. The level of activation ofPI3K signaling measured by tumorphosphorylated Ser(473)-Akt was insufficient topredict in vivo antitumor response to PX-866.Reverse-phase protein array revealed that theRas-dependent downstream targets c-Myc andcyclin B were elevated in cell lines resistant toPX-866 in vivo. Studies using an H-Ras construct", "metadata": {}}
+{"_id": "14823313", "title": "", "text": "Changing mortality patterns in East and WestGermany and Poland. II: short-term trendsduring transition and in the 1990s.OBJECTIVESTo examine trends in life expectancy at birth andage and cause specific patterns of mortality inthe former German Democratic Republic (GDR)and Poland during political transition andthroughout the 1990s in both parts of Germanyand in Poland. METHODS Decomposition of lifeexpectancy by age and cause of death. Changesin life expectancy during transition by cause ofdeath were examined using data for 1988/89and 1990/91 for the former GDR and Poland;examination of life expectancy changes aftertransition were based on 1992-97 data forGermany and 1991-96 data for Poland. RESULTSIn both the former GDR and Poland male lifeexpectancy at birth declined by almost one yearduring transition, mainly attributable to risingdeath rates from external causes and circulatorydiseases. Female life expectancy in Polanddeteriorated by 0.3 years, largely attributable to", "metadata": {}}
+{"_id": "14827874", "title": "", "text": "0021-972X/06/$15.00/0 The Journal of ClinicalEndocrinology & Metabolism 91(3):760–771Printed in U.S.A. Copyright © 2006 by TheEndocrine Society doi: 10.1210/jc.2005-1923REVIEW: Aromatase Inhibitors for OvulationInductionCONTEXT For the last 40 yr, the firstline of treatment for anovulation in infertilewomen has been clomiphene citrate (CC). CC isa safe, effective oral agent but is known to haverelatively common antiestrogenic endometrialand cervical mucous side effects that couldprevent pregnancy in the face of successfulovulation. In addition, there is a significant riskof multiple pregnancy with CC, compared withnatural cycles. Because of these problems, weproposed the concept of aromatase inhibition asa new method of ovulation induction that couldavoid many of the adverse effects of CC. Theobjective of this review was to describe thedifferent physiological mechanisms of action forCC and aromatase inhibitors (AIs) and comparestudies of efficacy for both agents for ovulation", "metadata": {}}
+{"_id": "14831629", "title": "", "text": "Patent ductus arteriosus: lack of evidence forcommon treatments.Patent ductus arteriosus(PDA) is a common diagnosis among extremelypremature infants, especially in those with lungdisease. Treatments are often used to close thePDA. Despite nearly three decades of research,the question of whether the benefits oftreatments to prevent ductal patency or promoteclosure outweigh the risks of these treatmentsremains unanswered. The authors rarely usetreatments designed to close the PDA. Thisarticle reviews three considerations in support ofthis restrained approach: rates of spontaneousclosure of the ductus arteriosus; adverse effectof persistent ductal patency; and benefits andrisks of treatments for closure.", "metadata": {}}
+{"_id": "14834714", "title": "", "text": "Gene therapy of arthritis with TCR isolated fromthe inflamed paw.In recent years, the treatmentof autoimmune diseases has been significantlyadvanced by the use of biological agents.However, some biologics are accompanied withsevere side effects, including tuberculosis andother types of infection. There is thus a criticalneed for nonsystemic and lesion-specificmethods of delivering these therapeutic agents.We attempted to treat a mouse model of arthritisby using T cells that expressed a regulatorymolecule and were specifically directed to theinflamed paw. To this end, we first identified theTCR alphabeta genes accumulating in theinflamed paw of mice with collagen-inducedarthritis (CIA) by a combination of single-strandchain polymorphism analysis of TCR andsingle-cell sorting. We identified an expandedclone B47 which is autoreactive but is notspecific to type II collagen. In vivo, TCR genesfrom B47-transduced T cells accumulated in theinflamed paw. Injection of cells cotransduced", "metadata": {}}
+{"_id": "14835068", "title": "", "text": "Melatonin: A Mitochondrial Targeting MoleculeInvolving Mitochondrial Protection andDynamicsMelatonin has been speculated to bemainly synthesized by mitochondria. Thisspeculation is supported by the recent discoverythat aralkylamine N-acetyltransferase/serotoninN-acetyltransferase (AANAT/SNAT) is localized inmitochondria of oocytes and the isolatedmitochondria generate melatonin. We have alsospeculated that melatonin is amitochondria-targeted antioxidant. Itaccumulates in mitochondria with highconcentration against a concentration gradient.This is probably achieved by an activetransportation via mitochondrial melatonintransporter(s). Melatonin protects mitochondriaby scavenging reactive oxygen species (ROS),inhibiting the mitochondrial permeabilitytransition pore (MPTP), and activating uncouplingproteins (UCPs). Thus, melatonin maintains theoptimal mitochondrial membrane potential andpreserves mitochondrial functions. In addition,", "metadata": {}}
+{"_id": "14843502", "title": "", "text": "Self-reported health status and access to healthservices in a sample of prisoners inItalyBACKGROUND Self-reported health status inunderserved population of prisoners has notbeen extensively explored. The purposes of thiscross-sectional study were to assessself-reported health, quality of life, and access tohealth services in a sample of male prisoners ofItaly. METHODS A total of 908 prisoners receiveda self-administered anonymous questionnairepertaining on demographic and detentioncharacteristics, self-reported health status andquality of life, access to health services,lifestyles, and participation to preventive, social,and rehabilitation programs. A total of 650prisoners agreed to participate in the study andreturned the questionnaire. RESULTSRespectively, 31.6% and 43.5% of prisonersreported a poor perceived health status and apoor quality of life, and 60% admitted that theirhealth was worsened or greatly worsened duringthe prison stay. Older age, lower education,", "metadata": {}}
+{"_id": "14848619", "title": "", "text": "BH3-only Protein Noxa Is a Mediator of HypoxicCell Death Induced by Hypoxia-inducible Factor1αHypoxia is a common cause of cell death andis implicated in many disease processes includingstroke and chronic degenerative disorders. Inresponse to hypoxia, cells express a variety ofgenes, which allow adaptation to alteredmetabolic demands, decreased oxygen demands,and the removal of irreversibly damaged cells.Using polymerase chain reaction–basedsuppression subtractive hybridization to findgenes that are differentially expressed inhypoxia, we identified the BH3-only Bcl-2 familyprotein Noxa. Noxa is a candidate moleculemediating p53-induced apoptosis. We show thatNoxa promoter responds directly to hypoxia viahypoxia-inducible factor (HIF)-1α. Suppressionof Noxa expression by antisense oligonucleotidesrescued cells from hypoxia-induced cell deathand decreased infarction volumes in an animalmodel of ischemia. Further, we show thatreactive oxygen species and resultant", "metadata": {}}
+{"_id": "14853989", "title": "", "text": "Neutrophil extracellular chromatin traps connectinnate immune response toautoimmunityAutoantibodies to DNA andhistones (chromatin) are the defining antigenspecificity in systemic lupus erythematosus (SLE)and related musculoskeletal disorders but themechanisms responsible for their inductionremain mysterious. That situation rapidlychanged once neutrophil extracellular chromatintraps (NETs) were discovered and observed toplay a conserved role in innate immuneresponses to a broad variety of microbialpathogens. At the center of an infectiousprocess, neutrophils exert various antimicrobialdefenses, including the release of nuclearchromatin into the extracellular space. Theexternalized NETs, a complex meshwork ofnuclear chromatin and antimicrobial proteins,serve to immobilize and degrade microbialpathogens. Here, we critically evaluate theevidence supporting NETs versus apoptoticbodies as a source for nuclear antigens in", "metadata": {}}
+{"_id": "14863011", "title": "", "text": "Bcl2 Regulation by the Melanocyte MasterRegulator Mitf Modulates Lineage Survival andMelanoma Cell ViabilityKit/SCF signaling andMitf-dependent transcription are both essentialfor melanocyte development and pigmentation.To identify Mitf-dependent Kit transcriptionaltargets in primary melanocytes, microarraystudies were undertaken. Among identifiedtargets was BCL2, whose germline deletionproduces melanocyte loss and which exhibitedphenotypic synergy with Mitf in mice. BCL2'sregulation by Mitf was verified in melanocytesand melanoma cells and by chromatinimmunoprecipitation of the BCL2 promoter. Mitfalso regulates BCL2 in osteoclasts, and bothMitf(mi/mi) and Bcl2(-/-) mice exhibit severeosteopetrosis. Disruption of Mitf in melanocytesor melanoma triggered profound apoptosissusceptible to rescue by BCL2 overexpression.Clinically, primary human melanoma expressionmicroarrays revealed tight nearest neighborlinkage for MITF and BCL2. This linkage helps", "metadata": {}}
+{"_id": "14864285", "title": "", "text": "YOKO HONDA AND SHUJI HONDA 1Longevity isregulated by the daf-2 gene network inCaenorhabditis elegans. Mutations in the daf-2gene, which encodes a member of the insulinreceptor family, confer the life extension (Age)phenotype and the constitutive dauer (agrowth-arrested larval form specialized fordispersal) formation phenotype. The Agephenotype is mutually potentiated by two lifeextension mutations in the daf-2 gene and theclk-1 gene, a homologue of yeast CAT5/COQ7known to regulate ubiquinone biosynthesis. Inthis study, we demonstrated that the daf-2mutation also conferred an oxidative stressresistance (Oxr) phenotype, which was alsoenhanced by the clk-1 mutation. Similar to theAge phenotype, the Oxr phenotype wasregulated by the genetic pathway of insulin-likesignaling from daf-2 to the daf-16 gene, ahomologue of the HNF-3/forkhead transcriptionfactor. These findings led us to examine whetherthe insulin-like signaling pathway regulates the", "metadata": {}}
+{"_id": "14865329", "title": "", "text": "Brown Fat and Browning for the Treatment ofObesity and Related Metabolic DisordersBrownfat is a specialized fat depot that can increaseenergy expenditure and produce heat. After therecent discovery of the presence of active brownfat in human adults and novel transcriptionfactors controlling brown adipocytedifferentiation, the field of the study of brown fathas gained great interest and is rapidly growing.Brown fat expansion and/or activation results inincreased energy expenditure and a negativeenergy balance in mice and limits weight gain.Brown fat is also able to utilize blood glucose andlipid and results in improved glucose metabolismand blood lipid independent of weight loss.Prolonged cold exposure and beta adrenergicagonists can induce browning of white adiposetissue. The inducible brown adipocyte, beigeadipocyte evolving by thermogenic activation ofwhite adipose tissue have different origin andmolecular signature from classical brownadipocytes but share the characteristics of high", "metadata": {}}
+{"_id": "14874811", "title": "", "text": "Hypoxia-induced energy stress regulates mRNAtranslation and cell growth.Oxygen (O2)deprivation, or hypoxia, has profound effects oncell metabolism and growth. Cells can adapt tolow O2 in part through activation ofhypoxia-inducible factor (HIF). We report herethat hypoxia inhibits mRNA translation bysuppressing multiple key regulators, includingeIF2alpha, eEF2, and the mammalian target ofrapamycin (mTOR) effectors 4EBP1, p70S6K,and rpS6, independent of HIF. Hypoxia results inenergy starvation and activation of theAMPK/TSC2/Rheb/mTOR pathway. HypoxicAMP-activated protein kinase (AMPK) activationalso leads to eEF2 inhibition. Moreover, hypoxiceffects on cellular bioenergetics and mTORinhibition increase over time. Mutation of theTSC2 tumor suppressor gene confers a growthadvantage to cells by repressing hypoxic mTORinhibition and hypoxia-induced G1 arrest.Together, eIF2alpha, eEF2, and mTOR inhibitionrepresent important HIF-independent", "metadata": {}}
+{"_id": "14893425", "title": "", "text": "The dystonia-associated protein torsinAmodulates synaptic vesicle recycling.The loss ofa glutamic acid residue in the AAA-ATPase(ATPases associated with diverse cellularactivities) torsinA is responsible for most cases ofearly onset autosomal dominant primarydystonia. In this study, we found that snapin,which binds SNAP-25 (synaptosome-associatedprotein of 25,000 Da) and enhances theassociation of the SNARE complex withsynaptotagmin, is an interacting partner for bothwild type and mutant torsinA. Snapinco-localized with endogenous torsinA on densecore granules in PC12 cells and was recruited toperinuclear inclusions containing mutantDeltaE-torsinA in neuroblastoma SH-SY5Y cells.In view of these observations, synaptic vesiclerecycling was analyzed using the lipophilic dyeFM1-43 and an antibody directed against anintravesicular epitope of synaptotagmin I. Wefound that overexpression of wild type torsinAnegatively affects synaptic vesicle endocytosis.", "metadata": {}}
+{"_id": "14893428", "title": "", "text": "In vivo electroporation in the embryonic mousecentral nervous systemThis protocol describes abasic method for in vivo electroporation in thenervous system of embryonic mice. Delivery ofelectric pulses following microinjection of DNAinto the brain ventricle or the spinal cord centralcanal enables efficient transfection of genes intothe nervous system. Transfection is facilitated byforceps-type electrodes, which hold the uterusand/or the yolk sac containing the embryo. Morethan ten embryos in a single pregnant mousecan be operated on within 30 min. More than90% of operated embryos survive and more than90% of these survivors express the transfectedgenes appropriately. Gene expression in neuronspersists for a long time, even at postnatalstages, after electroporation. Thus, this methodcould be used to analyze roles of genes not onlyin embryonic development but also in higherorder function of the nervous system, such aslearning.", "metadata": {}}
+{"_id": "14915566", "title": "", "text": "Hierarchical phylogenetic models for analyzingmultipartite sequence data.Debate exists overhow to incorporate information from multipartitesequence data in phylogenetic analyses. Strictcombined-data approaches argue forconcatenation of all partitions and estimation ofone evolutionary history, maximizing theexplanatory power of the data.Consensus/independence approaches endorse atwo-step procedure where partitions areanalyzed independently and then a consensus isdetermined from the multiple results. Mixturesacross the model space of a strict combined-dataapproach and a priori independent parametersare popular methods to integrate these methods.We propose an alternative middle ground byconstructing a Bayesian hierarchical phylogeneticmodel. Our hierarchical framework enablesresearchers to pool information across datapartitions to improve estimate precision inindividual partitions while permitting estimationand testing of tendencies in across-partition", "metadata": {}}
+{"_id": "14920021", "title": "", "text": "Up-to-date catalogues of yeast proteincomplexesGold standard datasets on proteincomplexes are key to inferring and validatingprotein-protein interactions. Despite muchprogress in characterizing protein complexes inthe yeast Saccharomyces cerevisiae, numerousresearchers still use as reference the manuallycurated complexes catalogued by the MunichInformation Center of Protein Sequencesdatabase. Although this catalogue has served thecommunity extremely well, it no longer reflectsthe current state of knowledge. Here, we reporttwo catalogues of yeast protein complexes asresults of systematic curation efforts. The firstone, denoted as CYC2008, is a comprehensivecatalogue of 408 manually curated heteromericprotein complexes reliably backed by small-scaleexperiments reported in the current literature.This catalogue represents an up-to-datereference set for biologists interested indiscovering protein interactions and proteincomplexes. The second catalogue, denoted as", "metadata": {}}
+{"_id": "14923462", "title": "", "text": "Synergistic Mechanisms of DNA Demethylationduring Transition to Ground-StatePluripotencyPluripotent stem cells (PSCs) occupya spectrum of reversible molecular statesranging from a naive ground-state in 2i, tometastable embryonic stem cells (ESCs) inserum, to lineage-primed epiblast stem cells(EpiSCs). To investigate the role of DNAmethylation (5mC) across distinct pluripotentstates, we mapped genome-wide 5mC and5-hydroxymethycytosine (5hmC) in multiplePSCs. Ground-state ESCs exhibit an altereddistribution of 5mC and 5hmC at regulatoryelements and dramatically lower absolute levelsrelative to ESCs in serum. By contrast, EpiSCsexhibit increased promoter 5mC coupled withreduced 5hmC, which contributes to theirdevelopmental restriction. Switch to 2i triggersrapid onset of both the ground-state geneexpression program and global DNAdemethylation. Mechanistically, repression of denovo methylases by PRDM14 drives DNA", "metadata": {}}
+{"_id": "14924526", "title": "", "text": "Febrile seizures in the developing brain result inpersistent modification of neuronal excitability inlimbic circuitsFebrile (fever-induced) seizuresaffect 3–5% of infants and young children.Despite the high incidence of febrile seizures,their contribution to the development of epilepsylater in life has remained controversial.Combining a new rat model of complex febrileseizures and patch clamp techniques, wedetermined that hyperthermia-induced seizuresin the immature rat cause a selective presynapticincrease in inhibitory synaptic transmission in thehippocampus that lasts into adulthood. Thelong-lasting nature of these potent alterations insynaptic communication after febrile seizuresdoes not support the prevalent view of the'benign' nature of early-life febrile convulsions.", "metadata": {}}
+{"_id": "14926162", "title": "", "text": "Identification of an allele of VAM3/SYP22 thatconfers a semi-dwarf phenotype in Arabidopsisthaliana.The short stem and midrib (ssm)mutants of Arabidopsis thaliana show bothsemi-dwarf and wavy leaf phenotypes due todefects in the elongation of the stem internodesand leaves. Moreover, these abnormalitiescannot be recovered by exogenousphytohormones. ssm was originally identified asa single recessive mutant of the ecotypeColumbia (Col-0), but genetic crossingexperiments have revealed that this mutantphenotype is restored by another gene that isfunctional in the ecotype Landsberg erecta (Ler)and not in Col-0. Map-based cloning of the genethat is defective in ssm mutants has uncovered asmall deletion in the sixth intron of a geneencoding a syntaxin, VAM3/SYP22, which hasbeen implicated in vesicle transport to thevacuole. This mutation appears to cause apeptide insertion in the deduced VAM3/SYP22polypeptide sequence due to defective splicing of", "metadata": {}}
+{"_id": "14934137", "title": "", "text": "Class Ia MHC-deficient BALB/c mice generateCD8+ T cell-mediated protective immunityagainst Listeria monocytogenes infection.CD8(+)T cells are required for protective immunityagainst intracellular pathogens such as Listeriamonocytogenes. In this study, we used class IaMHC-deficient mice, which have a severereduction in circulating CD8(+) T cells, todetermine the protective capacity of class IbMHC-restricted T cells during L. monocytogenesinfection. The K(b-/-)D(b-/-) mutation wasbackcrossed onto a C.B10 (BALB/c congenic atH-2 locus with C57BL/10) background, becauseBALB/c mice are more susceptible to Listeriainfection than other commonly studied mousestrains such as C57BL/6. C.B10 K(b-/-)D(b-/-)mice immunized with a sublethal dose of L.monocytogenes were fully protected against asubsequent lethal infection. Adoptive transfer ofListeria-immune splenocyte subsets into naiveK(b-/-)D(b-/-) mice indicated that CD8(+) T cellswere the major component of this protective", "metadata": {}}
+{"_id": "14938990", "title": "", "text": "Upregulated PD-1 Expression Is Associated withthe Development of Systemic LupusErythematosus, but Not the PD-1.1 Allele of thePDCD1 GeneSystemic lupus erythematosus(SLE) is a multisystem autoimmune disease withcomplicated genetic inheritance. Programmeddeath 1 (PD-1), a negative T cell regulator tomaintain peripheral tolerance, induces negativesignals to T cells during interaction with itsligands and is therefore a candidate gene in thedevelopment of SLE. In order to examinewhether expression levels of PD-1 contribute tothe pathogenesis of SLE, 30 patients with SLEand 30 controls were recruited and their PD-1expression levels in peripheral bloodmononuclear cells (PBMCs) were measured viaflow cytometry and quantitativereal-time-reverse transcription polymerase chainreaction (RT-PCR). Also, whether PD-1expression levels are associated with the variantof the SNP rs36084323 and the SLE DiseaseActivity Index (SLEDAI) was studied in this work.", "metadata": {}}
+{"_id": "14965508", "title": "", "text": "Endothelial cell membranes containpodocalyxin--the major sialoprotein of visceralglomerular epithelial cellsPodocalyxin is themajor sialoprotein in the glycocalyx ofglomerular podocytes. Here we report on itsextraglomerular localization, using amonospecific antibody which was obtained byaffinity purification of IgG on nitrocellulosetransfers of glomerular podocalyxin. By indirectimmunofluorescence, podocalyxin was found inthe blood vessels of several organs (lung, heart,kidney, small intestine, brain, pancreas, aorta,the periportal blood vessels in liver, and thecentral arteries of follicles of the spleen, but notin the endothelia that line the sinusoids of thelatter organs). By immunoelectronmicroscopy--using immunogold conjugates indiffusion (\"pre-embedding\") and surface(\"postembedding\") procedures--podocalyxin waslocalized on the luminal membrane domain ofendothelial cells, in a patchy distribution. Thepresence of podocalyxin was confirmed in SDS", "metadata": {}}
+{"_id": "14972169", "title": "", "text": "Teratogen-Induced Oxidative Stress TargetsGlyceraldehyde-3-Phosphate Dehydrogenase inthe Organogenesis Stage MouseEmbryoExposure during the organogenesis stageof the mouse embryo to the model teratogen,hydroxyurea (HU), induces curly tail and limbmalformations. Oxidative stress contributes tothe developmental toxicity of HU. Reactiveoxygen species (ROS) interact withpolyunsaturated bilipid membranes to formα,β-unsaturated reactive aldehydes;4-hydroxy-2-nonenal (4-HNE), one of the mostcytotoxic of these aldehydes, covalently adductswith proteins, lipids, and nucleic acids. The goalof the current study is to determine if HUexposure of CD1 mice on gestation day 9generates region-specific 4-HNE-protein adductsin the embryo and to identify the proteinstargeted. The formation of 4-HNE-proteinadducts was elevated in the caudal region ofcontrol embryos; HU exposure further increased4-HNE-protein adduct formation in this area.", "metadata": {}}
+{"_id": "14973286", "title": "", "text": "Recurrent venous thromboembolism andbleeding complications during anticoagulanttreatment in patients with cancer and venousthrombosis.A small proportion of patients withdeep vein thrombosis develop recurrent venousthromboembolic complications or bleeding duringanticoagulant treatment. These complicationsmay occur more frequently if these patients haveconcomitant cancer. This prospective follow-upstudy sought to determine whether in thrombosispatients those with cancer have a higher risk forrecurrent venous thromboembolism or bleedingduring anticoagulant treatment than thosewithout cancer. Of the 842 included patients,181 had known cancer at entry. The 12-monthcumulative incidence of recurrentthromboembolism in cancer patients was 20.7%(95% CI, 15.6%-25.8%) versus 6.8% (95% CI,3.9%- 9.7%) in patients without cancer, for ahazard ratio of 3.2 (95% CI, 1.9-5.4) The12-month cumulative incidence of majorbleeding was 12.4% (95% CI, 6.5%-18.2%) in", "metadata": {}}
+{"_id": "15040589", "title": "", "text": "Fitting multilevel models in complex survey datawith design weights:RecommendationsBACKGROUND Multilevelmodels (MLM) offer complex survey dataanalysts a unique approach to understandingindividual and contextual determinants of publichealth. However, little summarized guidanceexists with regard to fitting MLM in complexsurvey data with design weights. Simulationwork suggests that analysts should scale designweights using two methods and fit the MLM usingunweighted and scaled-weighted data. Thisarticle examines the performance ofscaled-weighted and unweighted analyses acrossa variety of MLM and software programs.METHODS Using data from the 2005-2006National Survey of Children with Special HealthCare Needs (NS-CSHCN: n = 40,723) thatcollected data from children clustered withinstates, I examine the performance of scalingmethods across outcome type (categorical vs.continuous), model type (level-1, level-2, or", "metadata": {}}
+{"_id": "15041758", "title": "", "text": "Functional outcomes of multi-conditioncollaborative care and successful ageing: resultsof randomised trialOBJECTIVE To evaluate theeffectiveness of integrated care for chronicphysical diseases and depression in reducingdisability and improving quality of life. DESIGN Arandomised controlled trial of multi-conditioncollaborative care for depression and poorlycontrolled diabetes and/or risk factors forcoronary heart disease compared with usual careamong middle aged and elderlypeople   SETTING Fourteen primary care clinicsin Seattle, Washington.   PARTICIPANTS Patientswith diabetes or coronary heart disease, or both,and blood pressure above 140/90 mm Hg, lowdensity lipoprotein concentration >3.37 mmol/L,or glycated haemoglobin 8.5% or higher, andPHQ-9 depression scores of ≥ 10.INTERVENTION A 12 month intervention toimprove depression, glycaemic control, bloodpressure, and lipid control by integrating a \"treatto target\" programme for diabetes and risk", "metadata": {}}
+{"_id": "15048300", "title": "", "text": "A Comparison of Cost Effectiveness Using Datafrom Randomized Trials or Actual ClinicalPractice: Selective Cox-2 Inhibitors as anExampleBACKGROUND Data on absolute risks ofoutcomes and patterns of drug use incost-effectiveness analyses are often based onrandomised clinical trials (RCTs). The objectiveof this study was to evaluate the external validityof published cost-effectiveness studies bycomparing the data used in these studies(typically based on RCTs) to observational datafrom actual clinical practice. Selective Cox-2inhibitors (coxibs) were used as an example.METHODS AND FINDINGS The UK GeneralPractice Research Database (GPRD) was used toestimate the exposure characteristics andindividual probabilities of upper gastrointestinal(GI) events during current exposure tononsteroidal anti-inflammatory drugs (NSAIDs)or coxibs. A basic cost-effectiveness model wasdeveloped evaluating two alternative strategies:prescription of a conventional NSAID or coxib.", "metadata": {}}
+{"_id": "15058155", "title": "", "text": "7α, 25-dihydroxycholesterol-mediated activationof EBI2 in immune regulation and diseasesEBI2,aka GPR183, is a G-couple receptor originallyidentified in 1993 as one of main genes inducedin Burkitt's lymphoma cell line BL41 byEpstein-Barr virus (EBV) infection. After it wasreported in 2009 that the receptor played a keyrole in regulating B cell migration and responses,we initiated an effort in looking for itsendogenous ligand. In 2011 we and anothergroup reported the identification of 7α,25-dihydroxyxcholesterol (7α, 25-OHC), anoxysterol, as the likely physiological ligand ofEBI2. A few subsequently published studiesfurther elucidated how 7α, 25-OHC bound toEBI2, and how a gradient of 7α, 25-OHC could begenerated in vivo and regulated migration,activation, and functions of B cells, T cells,dendritic cells (DCs), monocytes/macrophages,and astrocytes. The identification of 7α, 25-OHCas a G protein-coupled receptor ligand revealed apreviously unknown signaling system of", "metadata": {}}
+{"_id": "15077696", "title": "", "text": "PrimPol Bypasses UV Photoproducts duringEukaryotic Chromosomal DNA ReplicationDNAdamage can stall the DNA replication machinery,leading to genomic instability. Thus, numerousmechanisms exist to complete genomeduplication in the absence of a pristine DNAtemplate, but identification of the enzymesinvolved remains incomplete. Here, we establishthat Primase-Polymerase (PrimPol; CCDC111),an archaeal-eukaryotic primase (AEP) ineukaryotic cells, is involved in chromosomal DNAreplication. PrimPol is required for replicationfork progression on ultraviolet (UV)light-damaged DNA templates, possibly mediatedby its ability to catalyze translesion synthesis(TLS) of these lesions. This PrimPol UV lesionbypass pathway is not epistatic with the Polη-dependent pathway and, as a consequence,protects xeroderma pigmentosum variant (XP-V)patient cells from UV-induced cytotoxicity. Inaddition, we establish that PrimPol is alsorequired for efficient replication fork progression", "metadata": {}}
+{"_id": "15081770", "title": "", "text": "The novel immunosuppressive enzyme IL4I1 isexpressed by neoplastic cells of several B-celllymphomas and by tumor-associatedmacrophagesWe previously reported a strongIL4I1 gene expression in primary mediastinalB-cell lymphoma (PMBL) and recently identifiedthe protein as a secreted L-phenylalanineoxidase, physiologically expressed by myeloidcells, which inhibits T-cell proliferation in vitro.Here, we analyzed the pattern of IL4I1 proteinexpression in 315 human lymphoid andnon-lymphoid malignancies. Besides PMBL, IL4I1expression in tumors was very frequent. IL4I1was detected in tumor-associated macrophagesfrom most of the tumors and in neoplastic cellsfrom follicular lymphoma, classic and nodularlymphocyte predominant Hodgkin lymphomasand small lymphocytic lymphoma, three of whichare germinal center derived. IL4I1-positivetumor cells were also detected in rare cases ofsolid cancers, mainly mesothelioma. Theenzymatic activity paralleled protein expression,", "metadata": {}}
+{"_id": "15113221", "title": "", "text": "Poor prognosis in carcinoma is associated with agene expression signature of aberrant PTENtumor suppressor pathwayactivity.Pathway-specific therapy is the future ofcancer management. The oncogenicphosphatidylinositol 3-kinase (PI3K) pathway isfrequently activated in solid tumors; however,currently, no reliable test for PI3K pathwayactivation exists for human tumors. Takingadvantage of the observation that loss of PTEN,the negative regulator of PI3K, results in robustactivation of this pathway, we developed andvalidated a microarray gene expression signaturefor immunohistochemistry (IHC)-detectable PTENloss in breast cancer (BC). The most significantsignature gene was PTEN itself, indicating thatPTEN mRNA levels are the primary determinantof PTEN protein levels in BC. Some PTENIHC-positive BCs exhibited the signature of PTENloss, which was associated to moderatelyreduced PTEN mRNA levels cooperating withspecific types of PIK3CA mutations and/or", "metadata": {}}
+{"_id": "15121114", "title": "", "text": "Suppression of subtelomeric VSG switching byTrypanosoma brucei TRF requires its TTAGGGrepeat-binding activityTrypanosoma bruceicauses human African trypanosomiasis andregularly switches its major surface antigen,VSG, in the bloodstream of its mammalian hostto evade the host immune response. VSGs areexpressed exclusively from subtelomeric loci,and we have previously shown that telomereproteins TbTIF2 and TbRAP1 play important rolesin VSG switching and VSG silencing regulation,respectively. We now discover that the telomereduplex DNA-binding factor, TbTRF, also plays acritical role in VSG switching regulation, as atransient depletion of TbTRF leads to significantlymore VSG switching events. We solved the NMRstructure of the DNA-binding Myb domain ofTbTRF, which folds into a canonicalhelix-loop-helix structure that is conserved to theMyb domains of mammalian TRF proteins. TheTbTRF Myb domain tolerates well the bulky Jbase in T. brucei telomere DNA, and the", "metadata": {}}
+{"_id": "15128866", "title": "", "text": "CD4+ T cell-mediated cytotoxicity eliminatesprimary tumor cells in metastatic melanomathrough high MHC class II expression and can beenhanced by inhibitory receptorblockadeMetastatic melanoma is a rapidlyprogressing disease with high mortality rate andlimited treatment options. Immunotherapy basedon tumor-targeting cytotoxic T cell responsesrepresents a promising strategy. To assist in itsdevelopment, we examined the possibility andefficacy of using CD4+ cytotoxic T cells. Theregulatory mechanisms controlling CD4+ Tcell-mediated cytotoxicity were also investigated.We found that naturally occurring granzyme Band perforin-expressing CD4+ cytotoxic T cellscan be recovered from metastatic melanomapatients at significantly elevated frequenciescompared to those from healthy controls. TheseCD4+ cytotoxic T cells were also capable ofkilling autologous tumor cells harvested frommetastatic melanoma, independent of CD8+ Tcells or any other cell types. However, several", "metadata": {}}
+{"_id": "15129362", "title": "", "text": "The epidemiology and iatrogenic transmission ofhepatitis C virus in Egypt: a Bayesian coalescentapproach.Hepatitis C virus (HCV) is a leadingcause of liver cancer and cirrhosis, and Egypt haspossibly the highest HCV prevalence worldwide.In this article we use a newly developedBayesian inference framework to estimate thetransmission dynamics of HCV in Egypt fromsampled viral gene sequences, and to predict thepublic health impact of the virus. Our resultsindicate that the effective number of HCVinfections in Egypt underwent rapid exponentialgrowth between 1930 and 1955. The timing andspeed of this spread provides quantitativegenetic evidence that the Egyptian HCV epidemicwas initiated and propagated by extensiveantischistosomiasis injection campaigns.Although our results show that HCV transmissionhas since decreased, we conclude that HCV islikely to remain prevalent in Egypt for severaldecades. Our combined population genetic andepidemiological analysis provides detailed", "metadata": {}}
+{"_id": "15135001", "title": "", "text": "Improving population representation throughgeographic health information systems: mappingthe MURDOCK study.This paper highlightsmethods for using geospatial analysis to assess,enhance, and improve recruitment efforts toensure representativeness in study populations.We apply these methods to the Measurement toUnderstand Reclassification of Disease ofCabarrus/Kannapolis (MURDOCK) study, alongitudinal population health study focused onthe city of Kannapolis and Cabarrus County, NC.Although efforts have been made to recruit aparticipant registry that is representative of the18 ZIP code catchment region inclusive ofCabarrus County and Kannapolis, bias in suchrecruitment is inevitable. Participants in theMURDOCK study are geospatially referenced atentry, providing information that can be used tomonitor and guide recruitment efforts. MURDOCKparticipant population representativeness wasassessed using chi-squared tests to compare theMURDOCK population with 2010 Census data,", "metadata": {}}
+{"_id": "15153602", "title": "", "text": "Haplotype-based variant detection fromshort-read sequencingThe direct detection ofhaplotypes from short-read DNA sequencing datarequires changes to existing small-variantdetection methods. Here, we develop a Bayesianstatistical framework which is capable ofmodeling multiallelic loci in sets of individualswith non-uniform copy number. We thendescribe our implementation of this framework ina haplotype-based variant detector, FreeBayes.", "metadata": {}}
+{"_id": "15155862", "title": "", "text": "Longitudinal Genome-Wide Association ofCardiovascular Disease Risk Factors in theBogalusa Heart StudyCardiovascular disease(CVD) is the leading cause of death worldwide.Recent genome-wide association (GWA) studieshave pinpointed many loci associated with CVDrisk factors in adults. It is unclear, however, ifthese loci predict trait levels at all ages, if theyare associated with how a trait develops overtime, or if they could be used to screenindividuals who are pre-symptomatic to providethe opportunity for preventive measures beforedisease onset. We completed a genome-wideassociation study on participants in thelongitudinal Bogalusa Heart Study (BHS) andhave characterized the association betweengenetic factors and the development of CVD riskfactors from childhood to adulthood. We report 7genome-wide significant associations involvingCVD risk factors, two of which have beenpreviously reported. Top regions were tested forreplication in the Young Finns Study (YF) and two", "metadata": {}}
+{"_id": "15176526", "title": "", "text": "Actin and serum response factor transducephysical cues from the microenvironment toregulate epidermal stem cell fatedecisionsEpidermal homeostasis depends on abalance between stem cell renewal anddifferentiation and is regulated by extrinsicsignals from the extracellular matrix (ECM). Apowerful approach to analysing the pathwaysinvolved is to engineer single-cellmicroenvironments in which individual variablesare precisely and quantitatively controlled. Here,we employ micropatterned surfaces to identifythe signalling pathways by which restricted ECMcontact triggers human epidermal stem cells toinitiate terminal differentiation. On small (20 μmdiameter) circular islands, keratinocytesremained rounded, and differentiated at higherfrequency than cells that could spread on large(50 μm diameter) islands. Differentiation did notdepend on ECM composition or density. Rather,the actin cytoskeleton mediated shape-induceddifferentiation by regulating serum response", "metadata": {}}
+{"_id": "15194125", "title": "", "text": "Reproducibility and automatic measurement ofQT dispersion.This study investigatedinterobserver (two observers) and intrasubject(two measurements) reproducibility of QTdispersion from abnormal electrocardiograms inpatients with previous myocardial infarction, andcompared a user-interactive with an automaticmeasurement system. Standard 12-leadelectrocardiograms, recorded at 25 mm.s-1,were randomly chosen from 70 patients followingmyocardial infarction. These were scanned into apersonal computer, and specially designedsoftware skeletonized and joined each image.The images were then available foruser-interactive (mouse and computer screen),or automatic measurements using a speciallydesigned algorithm. For all methodsreproducibility of the RR interval was excellent(mean absolute errors 3-4 ms, relative errors0.3-0.5%). Reproducibility of the mean QTinterval was good; intrasubject error was 6 ms(relative error 1.4%), interobserver error was 7", "metadata": {}}
+{"_id": "15215393", "title": "", "text": "Inhibition of LSD1 sensitizes glioblastoma cells tohistone deacetylase inhibitors.Glioblastomamultiforme (GBM) is a particularly aggressivebrain tumor and remains a clinically devastatingdisease. Despite innovative therapies for thetreatment of GBM, there has been no significantincrease in patient survival over the past decade.Enzymes that control epigenetic alterations areof considerable interest as targets for cancertherapy because of their critical roles in cellularprocesses that lead to oncogenesis. Severalinhibitors of histone deacetylases (HDACs) havebeen developed and tested in GBM withmoderate success. We found that treatment ofGBM cells with HDAC inhibitors caused theaccumulation of histone methylation, amodification removed by the lysine specificdemethylase 1 (LSD1). This led us to examinethe effects of simultaneously inhibiting HDACsand LSD1 as a potential combination therapy.We evaluated induction of apoptosis in GBM celllines after combined inhibition of LSD1 and", "metadata": {}}
+{"_id": "15237660", "title": "", "text": "Challenges for malaria elimination in Zanzibar:pyrethroid resistance in malaria vectors and poorperformance of long-lasting insecticidenetsBACKGROUND Long-lasting insecticidetreated nets (LLINs) and indoor residual housespraying (IRS) are the main interventions for thecontrol of malaria vectors in Zanzibar. The aim ofthe present study was to assess the susceptibilitystatus of malaria vectors against the insecticidesused for LLINs and IRS and to determine thedurability and efficacy of LLINs on the island.METHODS Mosquitoes were sampled from Pembaand Unguja islands in 2010-2011 for use in WHOsusceptibility tests. One hundred and fifty LLINswere collected from households on Unguja, theirphysical state was recorded and then tested forefficacy as well as total insecticide content.RESULTS Species identification revealed thatover 90% of the Anopheles gambiae complexwas An. arabiensis with a small number of An.gambiae s.s. and An. merus being present.Susceptibility tests showed that An. arabiensis", "metadata": {}}
+{"_id": "15248287", "title": "", "text": "Proliferating cell nuclear antigen acts as acytoplasmic platform controlling humanneutrophil survivalNeutrophil apoptosis is ahighly regulated process essential forinflammation resolution, the molecularmechanisms of which are only partiallyelucidated. In this study, we describe a survivalpathway controlled by proliferating cell nuclearantigen (PCNA), a nuclear factor involved in DNAreplication and repairing of proliferating cells. Weshow that mature neutrophils, despite theirinability to proliferate, express high levels ofPCNA exclusively in their cytosol andconstitutively associated with procaspases,presumably to prevent their activation. Notably,cytosolic PCNA abundance decreased duringapoptosis, and increased during in vitro and invivo exposure to the survival factor granulocytecolony-stimulating factor (G-CSF). Peptidesderived from the cyclin-dependent kinaseinhibitor p21, which compete with procaspases tobind PCNA, triggered neutrophil apoptosis thus", "metadata": {}}
+{"_id": "15274349", "title": "", "text": "Development of the Human Infant IntestinalMicrobiotaAlmost immediately after a humanbeing is born, so too is a new microbialecosystem, one that resides in that person'sgastrointestinal tract. Although it is a universaland integral part of human biology, the temporalprogression of this process, the sources of themicrobes that make up the ecosystem, how andwhy it varies from one infant to another, andhow the composition of this ecosystem influenceshuman physiology, development, and diseaseare still poorly understood. As a step towardsystematically investigating these questions, wedesigned a microarray to detect and quantitatethe small subunit ribosomal RNA (SSU rRNA)gene sequences of most currently recognizedspecies and taxonomic groups of bacteria. Weused this microarray, along with sequencing ofcloned libraries of PCR-amplified SSU rDNA, toprofile the microbial communities in an averageof 26 stool samples each from 14 healthy,full-term human infants, including a pair of", "metadata": {}}
+{"_id": "15282056", "title": "", "text": "Combinatorial modulation of galP and glk geneexpression for improved alternative glucoseutilizationPhosphoenolpyruvate (PEP) is animportant precursor for anaerobic production ofsuccinate and malate. Although inactivatingPEP/carbohydrate phosphotransferase systems(PTS) could increase PEP supply, the resultingstrain had a low glucose utilization rate. In orderto improve anaerobic glucose utilization rate forefficient production of succinate and malate,combinatorial modulation of galactose permease(galP) and glucokinase (glk) gene expressionwas carried out in chromosome of an Escherichiacoli strain with inactivated PTS. Libraries ofartificial regulatory parts, including promoter andmessenger RNA stabilizing region (mRS), werefirstly constructed in front of β-galactosidasegene (lacZ) in E. coli chromosome through λ-Redrecombination. Most regulatory parts selectedfrom mRS library had constitutive strengthsunder different cultivation conditions. Aconvenient one-step recombination method was", "metadata": {}}
+{"_id": "15286783", "title": "", "text": "Matrix eQTL: Ultra fast eQTL analysis via largematrix operationsExpression quantitative traitloci (eQTL) mapping aims to determine genomicregions that regulate gene transcription.Expression QTL is used to study the regulatorystructure of normal tissues and to search forgenetic factors in complex diseases such ascancer, diabetes, and cystic fibrosis. A moderneQTL dataset contains millions of SNPs andthousands of transcripts measured for hundredsof samples. This makes the analysiscomputationally complex as it involvesindependent testing for association for everytranscript-SNP pair. The heavy computationalburden makes eQTL analysis less popular, oftenforces analysts to restrict their attention to just asubset of transcripts and SNPs. As largergenotype and gene expression datasets becomeavailable, the demand for fast tools for eQTLanalysis increases. We present a new method forfast eQTL analysis via linear models, calledMatrix eQTL. Matrix eQTL can model and test for", "metadata": {}}
+{"_id": "15305881", "title": "", "text": "The structure of DdrB from Deinococcus: a newfold for single-stranded DNA bindingproteinsDeinococcus spp. are renowned for theiramazing ability to recover rapidly from severegenomic fragmentation as a result of exposure toextreme levels of ionizing radiation ordesiccation. Despite having been originallycharacterized over 50 years ago, the mechanismunderlying this remarkable repair process is stillpoorly understood. Here, we report the 2.8 Astructure of DdrB, a single-stranded DNA(ssDNA) binding protein unique to Deinococcusspp. that is crucial for recovery following DNAdamage. DdrB forms a pentameric ring capableof binding single-stranded but notdouble-stranded DNA. Unexpectedly, the crystalstructure reveals that DdrB comprises a novelfold that is structurally and topologically distinctfrom all other single-stranded binding (SSB)proteins characterized to date. The need for aunique ssDNA binding function in response tosevere damage, suggests a distinct role for DdrB", "metadata": {}}
+{"_id": "15319019", "title": "", "text": "N348I in the Connection Domain of HIV-1Reverse Transcriptase Confers Zidovudine andNevirapine ResistanceBackground Thecatalytically active 66-kDa subunit of the humanimmunodeficiency virus type 1 (HIV-1) reversetranscriptase (RT) consists of DNA polymerase,connection, and ribonuclease H (RNase H)domains. Almost all known RT inhibitorresistance mutations identified to date map tothe polymerase domain of the enzyme. However,the connection and RNase H domains are notroutinely analysed in clinical samples and none ofthe genotyping assays available for patientmanagement sequence the entire RT codingregion. The British Columbia Centre forExcellence in HIV/AIDS (the Centre) genotypesclinical isolates up to codon 400 in RT, and ourretrospective statistical analyses of the Centre’sdatabase have identified an N348I mutation inthe RT connection domain intreatment-experienced individuals. The objectiveof this multidisciplinary study was to establish", "metadata": {}}
+{"_id": "15322518", "title": "", "text": "Dual Targeting of PDGFRα and FGFR1 DisplaysSynergistic Efficacy in Malignant RhabdoidTumorsSubunits of the SWI/SNF chromatinremodeling complex are mutated in a significantproportion of human cancers. Malignant rhabdoidtumors (MRTs) are lethal pediatric cancerscharacterized by a deficiency in the SWI/SNFsubunit SMARCB1. Here, we employ anintegrated molecular profiling and chemicalbiology approach to demonstrate that thereceptor tyrosine kinases (RTKs) PDGFRα andFGFR1 are coactivated in MRT cells and that dualblockade of these receptors has synergisticefficacy. Inhibitor combinations targeting bothreceptors and the dual inhibitor ponatinibsuppress the AKT and ERK1/2 pathways leadingto apoptosis. MRT cells that have acquiredresistance to the PDGFRα inhibitor pazopanib aresusceptible to FGFR inhibitors. We show thatPDGFRα levels are regulated by SMARCB1expression, and assessment of clinical specimensdocuments the expression of both PDGFRα and", "metadata": {}}
+{"_id": "15327601", "title": "", "text": "A nano-positioning system for macromolecularstructural analysisVery often, the positions offlexible domains within macromolecules as wellas within macromolecular complexes cannot bedetermined by standard structural biologymethods. To overcome this problem, wedeveloped a method that uses probabilistic dataanalysis to combine single-moleculemeasurements with X-ray crystallography data.The method determines not only the most likelyposition of a fluorescent dye molecule attachedto the domain but also the completethree-dimensional probability distributiondepicting the experimental uncertainty. With thisapproach, single-pair fluorescence resonanceenergy transfer measurements can now be usedas a quantitative tool for investigating theposition and dynamics of flexible domains withinmacromolecular complexes. We applied thismethod to find the position of the 5′ end of thenascent RNA exiting transcription elongationcomplexes of yeast (Saccharomyces cerevisiae)", "metadata": {}}
+{"_id": "15335331", "title": "", "text": "Tumor-associated macrophages correlate withthe clinicopathological features and pooroutcomes via inducing epithelial to mesenchymaltransition in oral squamous cellcarcinomaBACKGROUND Both tumor-associatedmacrophages (TAMs) and the epithelial tomesenchymal transition (EMT) of cancer cellsplay key roles in promoting tumor progression.However, whether TAMs could induce EMT in theprogression of oral squamous cell carcinoma(OSCC) remains undefined. RESULTS Here wedetected the expression of macrophages markersCD68 and CD163, epithelial marker E-cadherinand mesenchymal marker vimentin in 127 OSCCpatients by using semi-quantitativeimmunohistochemistry. CD68 and CD163expression was not confined to the infiltratingTAMs, but also detected in cancer cells. The highnumber of CD68-positive macrophages wascorrelated with poor overall survival. Meanwhile,the expression of CD163 both in macrophagesand in cancer cells was associated with poor", "metadata": {}}
+{"_id": "15337254", "title": "", "text": "Geometric cues for directing the differentiation ofmesenchymal stem cells.Significant efforts havebeen directed to understanding the factors thatinfluence the lineage commitment of stem cells.This paper demonstrates that cell shape,independent of soluble factors, has a stronginfluence on the differentiation of humanmesenchymal stem cells (MSCs) from bonemarrow. When exposed to competing solubledifferentiation signals, cells cultured inrectangles with increasing aspect ratio and inshapes with pentagonal symmetry but withdifferent subcellular curvature-and with eachoccupying the same area-display differentadipogenesis and osteogenesis profiles. Theresults reveal that geometric features thatincrease actomyosin contractility promoteosteogenesis and are consistent with in vivocharacteristics of the microenvironment of thedifferentiated cells. Cytoskeletal-disruptingpharmacological agents modulate shape-basedtrends in lineage commitment verifying the", "metadata": {}}
+{"_id": "15347087", "title": "", "text": "Amyloid accumulation is a late event in sporadicAlzheimer's disease-like pathology innontransgenic ratsThe amyloid cascadehypothesis posits that deposition of the amyloidβ (Aβ) peptide in the brain is a key event in theinitiation of Alzheimer's disease (AD).Nonetheless, it now seems increasingly unlikelythat amyloid toxicity is the cause of sporadic AD,which leads to cognitive decline. Here, usingaccelerated-senescence nontransgenic OXYSrats, we confirmed that aggregation of Aβ is alater event in AD-like pathology. We showed thatan age-dependent increase in the levels ofAβ\u0000\u0000\u0000\u0000 and extracellular Aβ deposits in thebrain of OXYS rats occur later than do synapticlosses, neuronal cell death, mitochondrialstructural abnormalities, andhyperphosphorylation of the tau protein. Weidentified the variants of the genes that arestrongly associated with the risk of eitherlate-onset or early-onset AD, including App,Apoe4, Bace1, Psen1, Psen2, and Picalm. We", "metadata": {}}
+{"_id": "15360986", "title": "", "text": "Estimating low-density lipoprotein cholesterol bythe Friedewald equation is adequate forclassifying patients on the basis of nationallyrecommended cutpoints.We comparedlow-density lipoprotein cholesterol (LDL) valuesobtained by the Friedewald formula--i.e., totalcholesterol minus high-density lipoprotein (HDL)cholesterol minus very-low-density lipoprotein(VLDL) cholesterol (estimated as triglyceridedivided by 5)--with those obtained by lipoproteinfractionation, using 4736 specimens. Whentriglycerides were less than 2.0 g/L, greater than90% of estimated LDL cholesterol values wereacceptable, within +/- 10% of measured values.At triglyceride concentrations of 2.0-4.0 g/L and4.0-6.0 g/L, only 72% and 39%, respectively, ofthe estimates were acceptable. LDL valuesderived from an alternative formula, estimatingVLDL as triglycerides divided by 6, were evenless accurate. Nevertheless, the use of estimatedLDL for risk classification based on the NationalCholesterol Education Program Adult Treatment", "metadata": {}}
+{"_id": "15365719", "title": "", "text": "Conditional Kif3a ablation causes abnormalhedgehog signaling topography, growth platedysfunction, and excessive bone and cartilageformation during mouse skeletogenesis.Themotor protein Kif3a and primary cilia regulateimportant developmental processes, but theirroles in skeletogenesis remain ill-defined. Herewe created mice deficient in Kif3a in cartilageand focused on the cranial base andsynchondroses. Kif3a deficiency caused cranialbase growth retardation and dysmorphogenesis,which were evident in neonatal animals byanatomical and micro-computed tomography(microCT) inspection. Kif3a deficiency alsochanged synchondrosis growth plate organizationand function, and the severity of these changesincreased over time. By postnatal day (P)7,mutant growth plates lacked typical zones ofchondrocyte proliferation and hypertrophy, andwere instead composed of chondrocytes with anunusual phenotype characterized by strongcollagen II (Col2a1) gene expression but barely", "metadata": {}}
+{"_id": "15381976", "title": "", "text": "Morin Attenuates Ovalbumin-Induced AirwayInflammation by Modulating OxidativeStress-Responsive MAPK Signaling.Asthma is oneof the most common inflammatory diseasescharacterized by airway hyperresponsiveness,inflammation, and remodeling. Morin, an activeingredient obtained from Moraceae plants, hasbeen demonstrated to have promisinganti-inflammatory activities in a range ofdisorders. However, its impacts on pulmonarydiseases, particularly on asthma, have not beenclarified. This study was designed to investigatewhether morin alleviates airway inflammation inchronic asthma with an emphasis on oxidativestress modulation. In vivo, ovalbumin- (OVA-)sensitized mice were administered with morin ordexamethasone before challenge.Bronchoalveolar lavage fluid (BALF) and lungtissues were obtained to perform cell counts,histological analysis, and enzyme-linkedimmunosorbent assay. In vitro, human bronchialepithelial cells (BECs) were challenged by tumor", "metadata": {}}
+{"_id": "15405204", "title": "", "text": "Spontaneous autoimmunity prevented by thymicexpression of a single self-antigenThe expressionof self-antigen in the thymus is believed to beresponsible for the deletion of autoreactive Tlymphocytes, a critical process in themaintenance of unresponsiveness to self. TheAutoimmune regulator (Aire) gene, which isdefective in the disorder autoimmunepolyglandular syndrome type 1, has been shownto promote the thymic expression ofself-antigens. A clear link, however, betweenspecific thymic self-antigens and a singleautoimmune phenotype in this model has beenlacking. We show that autoimmune eye diseasein aire-deficient mice develops as a result of lossof thymic expression of a single eye antigen,interphotoreceptor retinoid-binding protein(IRBP). In addition, lack of IRBP expressionsolely in the thymus, even in the presence of aireexpression, is sufficient to trigger spontaneouseye-specific autoimmunity. These results suggestthat failure of thymic expression of selective", "metadata": {}}
+{"_id": "15414628", "title": "", "text": "Preventing bacterial DNA release and absent inmelanoma 2 inflammasome activation by aLegionella effector functioning in membranetrafficking.Legionella pneumophila, the causativeagent of Legionnaires' pneumonia, resides in adistinct vacuole structure calledLegionella-containing vacuole (LCV). The LCVresists fusion with the lysosome and permitsefficient bacterial replication in hostmacrophages, which requires a Dot/Icm type IVBsecretion system. Dot/Icm-translocated effectorSdhA is critical for L. pneumophila intracellulargrowth and functions to prevent host cell death.Here, we show that the absence of SdhA resultedin elevated caspase-1 activation and IL-1βsecretion as well as macrophage pyroptosisduring Legionella infection. These inflammasomeactivation phenotypes were independent of theestablished flagellin-NAIP5-NLRC4 axis, butrelied on the DNA-sensing AIM2 inflammasome.We further demonstrate that Legionella DNA wasreleased into macrophage cytosol, and this effect", "metadata": {}}
+{"_id": "15419873", "title": "", "text": "Cytosolic viral sensor RIG-I is a5'-triphosphate-dependent translocase ondouble-stranded RNA.Retinoic acidinducible-gene I (RIG-I) is a cytosolicmultidomain protein that detects viral RNA andelicits an antiviral immune response. TwoN-terminal caspase activation and recruitmentdomains (CARDs) transmit the signal, and theregulatory domain prevents signaling in theabsence of viral RNA. 5'-triphosphate anddouble-stranded RNA (dsRNA) are two molecularpatterns that enable RIG-I to discriminatepathogenic from self-RNA. However, the functionof the DExH box helicase domain that is alsorequired for activity is less clear. Usingsingle-molecule protein-induced fluorescenceenhancement, we discovered a robust adenosine5'-triphosphate-powered dsRNA translocationactivity of RIG-I. The CARDs dramaticallysuppress translocation in the absence of5'-triphosphate, and the activation by5'-triphosphate triggers RIG-I to translocate", "metadata": {}}
+{"_id": "15425958", "title": "", "text": "Human Cytomegalovirus-Encoded Interleukin-10Homolog Inhibits Maturation of Dendritic Cellsand Alters Their FunctionalityInterleukin-10(IL-10) suppresses the maturation and cytokineproduction of dendritic cells (DCs), keyregulators of adaptive immunity, and preventsthe activation and polarization of naïve T cellstowards protective gamma interferon-producingeffectors. We hypothesized that humancytomegalovirus (HCMV) utilizes its viral IL-10homolog (cmvIL-10) to attenuate DCfunctionality, thereby subverting the efficientinduction of antiviral immune responses. RNAand protein analyses demonstrated that thecmvIL-10 gene was expressed with late genekinetics. Treatment of immature DCs (iDCs) withsupernatant from HCMV-infected culturesinhibited both the lipopolysaccharide-induced DCmaturation and proinflammatory cytokineproduction. These inhibitory effects werespecifically mediated through the IL-10 receptorand were not observed when DCs were treated", "metadata": {}}
+{"_id": "15426878", "title": "", "text": "Model for unidirectional movement of axonemaland cytoplasmic dynein moleculesA model for theunidirectional movement of dynein is presentedbased on structural observations and biochemicalexperimental results available. In this model, thebinding affinity of dynein for microtubule isindependent of its nucleotide state and thechange between strong and weakmicrotubule-binding is determined naturally bythe variation of relative orientation between thestalk and microtubule as the stalk rotatesfollowing nucleotide-state transition. Thus theenigmatic communication from the ATP bindingsite in the globular domain to the far MT-bindingsite in the tip of the stalk, which is prerequisite inconventional models, is not required. Using thepresent model, the previous experimental resultssuch as the effect of ATP and ADP bindings ondissociation of dynein from microtubule, theprocessive movement of single-headed axonemaldyneins at saturating ATP concentration, the loaddependence of step size for the processive", "metadata": {}}
+{"_id": "15435343", "title": "", "text": "The inflammasome component NLRP3 impairsantitumor vaccine by enhancing theaccumulation of tumor-associatedmyeloid-derived suppressor cells.Theinflammasome is a proteolysis complex thatgenerates the active forms of theproinflammatory cytokines interleukin (IL)-1βand IL-18. Inflammasome activation is mediatedby NLR proteins that respond to microbial andnonmicrobial stimuli. Among NLRs, NLRP3 sensesthe widest array of stimuli and enhancesadaptive immunity. However, its role inantitumor immunity is unknown. Therefore, weevaluated the function of the NLRP3inflammasome in the immune response usingdendritic cell vaccination against the poorlyimmunogenic melanoma cell line B16-F10.Vaccination of Nlrp3(-/-) mice led to a relative4-fold improvement in survival relative to controlanimals. Immunity depended on CD8(+) T cellsand exhibited immune specificity and memory.Increased vaccine efficacy in Nlrp3(-/-) hosts did", "metadata": {}}
+{"_id": "15462523", "title": "", "text": "Natural Killer Cells for Immunotherapy –Advantages of the NK-92 Cell Line over Blood NKCellsNatural killer (NK) cells are potent cytotoxiceffector cells for cancer therapy and potentiallyfor severe viral infections. However, there aretechnical challenges to obtain sufficient numbersof functionally active NK cells from a patient'sblood since they represent only 10% of thelymphocytes and are often dysfunctional. Thealternative is to obtain cells from a healthydonor, which requires depletion of the allogeneicT cells to prevent graft-versus-host reactions.Cytotoxic cell lines have been established frompatients with clonal NK-cell lymphoma. Thosecells can be expanded in culture in the presenceof IL-2. Except for the NK-92 cell line, though,none of the other six known NK cell lines hasconsistently and reproducibly shown highantitumor cytotoxicity. Only NK-92 cells caneasily be genetically manipulated to recognizespecific tumor antigens or to augmentmonoclonal antibody activity through", "metadata": {}}
+{"_id": "15472716", "title": "", "text": "Differential activation of DNA-PK based on DNAstrand orientation and sequence biasDNA-PKcsand Ku are essential components of the complexthat catalyzes non-homologous end joining(NHEJ) of DNA double-strand breaks (DSBs). Ku,a heterodimeric protein, binds to DNA ends andfacilitates recruitment of the catalytic subunit,DNA-PKcs. We have investigated the effect ofDNA strand orientation and sequence bias on theactivation of DNA-PK. In addition, we assessedthe effect of the position and strand orientationof cisplatin adducts on kinase activation. A seriesof duplex DNA substrates with site-specificcisplatin–DNA adducts placed in three differentorientations on the duplex DNA were prepared.Terminal biotin modification and streptavidin(SA) blocking was employed to direct DNA-PKbinding to the unblocked termini with a specificDNA strand orientation and cisplatin–DNA adductposition. DNA-PK kinase activity was measuredand the results reveal that DNA strandorientation and sequence bias dramatically", "metadata": {}}
+{"_id": "15473205", "title": "", "text": "Regulators of Trypanosoma brucei Cell CycleProgression and Differentiation Identified Using aKinome-Wide RNAi ScreenThe Africantrypanosome, Trypanosoma brucei, maintains anintegral link between cell cycle regulation anddifferentiation during its intricate life cycle.Whilst extensive changes in phosphorylationhave been documented between the mammalianbloodstream form and the insect procyclic form,relatively little is known about the parasite'sprotein kinases (PKs) involved in the control ofcellular proliferation and differentiation. Toaddress this, a T. brucei kinome-wide RNAi cellline library was generated, allowing independentinducible knockdown of each of the parasite's190 predicted protein kinases. Screening of thislibrary using a cell viability assay identified ≥42PKs that are required for normal bloodstreamform proliferation in culture. A secondary screenidentified 24 PKs whose RNAi-mediated depletionresulted in a variety of cell cycle defectsincluding in G1/S, kinetoplast", "metadata": {}}
+{"_id": "15476777", "title": "", "text": "Chemotherapy options in elderly and frailpatients with metastatic colorectal cancer (MRCFOCUS2): an open-label, randomised factorialtrialBACKGROUND Elderly and frail patients withcancer, although often treated withchemotherapy, are under-represented in clinicaltrials. We designed FOCUS2 to investigatereduced-dose chemotherapy options and to seekobjective predictors of outcome in frail patientswith advanced colorectal cancer. METHODS Weundertook an open, 2 × 2 factorial trial in 61 UKcentres for patients with previously untreatedadvanced colorectal cancer who were consideredunfit for full-dose chemotherapy. Aftercomprehensive health assessment (CHA),patients were randomly assigned byminimisation to: 48-h intravenous fluorouracilwith levofolinate (group A); oxaliplatin andfluorouracil (group B); capecitabine (group C); oroxaliplatin and capecitabine (group D).Treatment allocation was not masked. Startingdoses were 80% of standard doses, with", "metadata": {}}
+{"_id": "15478227", "title": "", "text": "Whole-genome sequencing of Oryza brachyanthareveals mechanisms underlying Oryza genomeevolutionThe wild species of the genus Oryzacontain a largely untapped reservoir ofagronomically important genes for riceimprovement. Here we report the 261-Mb denovo assembled genome sequence of Oryzabrachyantha. Low activity of long-terminal repeatretrotransposons and massive internal deletionsof ancient long-terminal repeat elements lead tothe compact genome of Oryza brachyantha. Wemodel 32,038 protein-coding genes in the Oryzabrachyantha genome, of which only 70% arelocated in collinear positions in comparison withthe rice genome. Analysing breakpoints ofnon-collinear genes suggests that double-strandbreak repair through non-homologous endjoining has an important role in gene movementand erosion of collinearity in the Oryza genomes.Transition of euchromatin to heterochromatin inthe rice genome is accompanied by segmentaland tandem duplications, further expanded by", "metadata": {}}
+{"_id": "15482274", "title": "", "text": "Ultrasound imaging for lumbar punctures andepidural catheterisations: systematic review andmeta-analysis.OBJECTIVE To determine whetherultrasound imaging can reduce the risk of failedlumbar punctures or epidural catheterisations,when compared with standard palpationmethods, and whether ultrasound imaging canreduce traumatic procedures, insertion attempts,and needle redirections. DESIGN Systematicreview and meta-analysis of randomisedcontrolled trials. DATA SOURCES Ovid Medline,Embase, and Cochrane Central Register ofControlled Trials up to May 2012, withoutrestriction by language or publication status.REVIEW METHODS Randomised trials thatcompared ultrasound imaging with standardmethods (no imaging) in the performance of alumbar puncture or epidural catheterisation wereidentified. RESULTS 14 studies with a total of1334 patients were included (674 patientsassigned to the ultrasound group, 660 to thecontrol group). Five studies evaluated lumbar", "metadata": {}}
+{"_id": "15488881", "title": "", "text": "Guidance of B cells by the orphan Gprotein-coupled receptor EBI2 shapes humoralimmune responses.Humoral immunity dependson both rapid and long-term antibody productionagainst invading pathogens. This is achieved bythe generation of spatially distinct extrafollicularplasmablast and follicular germinal center (GC) Bcell populations, but the signals that guideresponding B cells to these alternativecompartments have not been fully elucidated.Here, we show that expression of the orphan Gprotein-coupled receptor Epstein-Barrvirus-induced gene 2 (EBI2, also known asGPR183) by activated B cells was essential fortheir movement to extrafollicular sites andinduction of early plasmablast responses.Conversely, downregulation of EBI2 enabled Bcells to access the center of follicles andpromoted efficient GC formation. EBI2 thereforeprovides a previously uncharacterized dimensionto B cell migration that is crucial for coordinatingrapid versus long-term antibody responses.", "metadata": {}}
+{"_id": "15491308", "title": "", "text": "SIRT1 is required for long-term growth of humanmesenchymal stem cellsHuman mesenchymalstem cells (MSCs) have therapeutic potentialbecause of their ability to self-renew anddifferentiate into multiple tissues. However,senescence often occurs in MSCs when they arecultured in vitro and the molecular mechanismsunderlying this effect remain unclear. In thisstudy, we found that NAD-dependent proteindeacetylase SIRT1 is differentially expressed inboth human bone marrow-derived MSCs(B-MSCs) and adipose tissue-derived MSCs afterincreasing passages of cell culture. Usinglentiviral shRNA we demonstrated that selectiveknockdown of SIRT1 in human MSCs at earlypassage slows down cell growth and acceleratescellular senescence. Conversely, overexpressionof SIRT1 delays senescence in B-MSCs that haveundergone prolonged in vitro culturing and thecells do not lose adipogenic and osteogenicpotential. In addition, we found that the delayedaccumulation of the protein p16 is involved in the", "metadata": {}}
+{"_id": "15491404", "title": "", "text": "Rapid and persistent modulation of actindynamics regulates postsynaptic reorganizationunderlying bidirectional plasticityThe synapse isa highly organized cellular specialization whosestructure and composition are reorganized, bothpositively and negatively, depending on thestrength of input signals. The mechanismsorchestrating these changes are not wellunderstood. A plausible locus for thereorganization of synapse components andstructure is actin, because it serves as bothcytoskeleton and scaffold for synapses and existsin a dynamic equilibrium between F-actin andG-actin that is modulated bidirectionally bycellular signaling. Using a new FRET-basedimaging technique to monitor F-actin/G-actinequilibrium, we show here that tetanicstimulation causes a rapid, persistent shift ofactin equilibrium toward F-actin in the dendriticspines of rat hippocampal neurons. This enlargesthe spines and increases postsynaptic bindingcapacity. In contrast, prolonged low-frequency", "metadata": {}}
+{"_id": "15493354", "title": "", "text": "Sublime Microglia: Expanding Roles for theGuardians of the CNSRecent findings challengethe concept that microglia solely function indisease states in the central nervous system(CNS). Rather than simply reacting to CNSinjury, infection, or pathology, emerging lines ofevidence indicate that microglia sculpt thestructure of the CNS, refine neuronal circuitryand network connectivity, and contribute toplasticity. These physiological functions ofmicroglia in the normal CNS begin duringdevelopment and persist into maturity. Here, wedevelop a conceptual framework for functions ofmicroglia beyond neuroinflammation and discussthe rich repertoire of signaling andcommunication motifs in microglia that arecritical both in pathology and for the normalphysiology of the CNS.", "metadata": {}}
+{"_id": "15512462", "title": "", "text": "Cancer after pre-eclampsia: follow up of theJerusalem perinatal study cohort.OBJECTIVE Tocompare the incidence of cancer among womenwith and without a history of pre-eclampsia.DESIGN Cohort study. SETTING Jerusalemperinatal study of women who delivered in threelarge hospitals in West Jerusalem during1964-76. PARTICIPANTS 37 033 women. MAINOUTCOME MEASURES Age adjusted andmultivariable adjusted hazard ratios for cancerincidence for the entire cohort and for womenwho were primiparous at study entry. RESULTSCancer developed in 91 women who hadpre-eclampsia and 2204 who did not (hazardratio 1.27, 95% confidence interval 1.03 to1.57). The risk of site specific cancers wasincreased, particularly of the stomach, ovaryepithelium, breast, and lung or larynx. Theincidence of cancer of the stomach, breast,ovary, kidney, and lung or larynx was increasedin primiparous women at study entry who had ahistory pre-eclampsia. CONCLUSIONS A history", "metadata": {}}
+{"_id": "15521377", "title": "", "text": "Keeping your senescent cells undercontrolCellular senescence is a stable form ofcell-cycle arrest which is thought to limit theproliferative potential of premalignant cells [1].The senescence phenotype was initially describedby Hayflick and Moorhead in 1961 on humanfibroblasts undergoing replicative exhaustion inculture [2]. It has been shown that senescencecan be triggered in different cell types inresponse to diverse forms of cellular damage orstress (for review see [1]). Importantly, whilesenescence was denounced as a tissue culturephenomenon for many years, recent in vivostudies demonstrated that cellular senescencerepresents a potent failsafe mechanism againsttumorigenesis and contributes to the cytotoxicityof certain anticancer agents (see for example[3-7]). Interestingly, senescent cells have alsobeen observed in certain aged or damagedtissues and there is growing evidence thatsenescence checkpoints can affect theregenerative reserve of tissues and organismal", "metadata": {}}
+{"_id": "15535511", "title": "", "text": "Role for insulin signaling in catecholaminergicneurons in control of energyhomeostasis.Dopaminergic midbrain neuronsintegrate signals on food palatability andfood-associated reward into the complex controlof energy homeostasis. To define the role ofinsulin receptor (IR) signaling in this circuitry, weinactivated IR signaling in tyrosine hydroxylase(Th)-expressing cells of mice (IR(ΔTh)). IRinactivation in Th-expressing cells of miceresulted in increased body weight, increased fatmass, and hyperphagia. While insulin acutelystimulated firing frequency in 50% ofdopaminergic VTA/SN neurons, this responsewas abolished in IR(ΔTh) mice. Moreover, thesemice exhibited an altered response to cocaineunder food-restricted conditions. Taken together,these data provide in vivo evidence for a criticalrole of insulin signaling in catecholaminergicneurons to control food intake and energyhomeostasis.", "metadata": {}}
+{"_id": "15541119", "title": "", "text": "[New guidelines to evaluate the response totreatment in solid tumors].Anticancer agents gothrough a process by which their antitumoractivity, on the basis of the amount of tumorshrinkage they could generate, has beeninvestigated. In the late 1970s, the InternationalUnion Against Cancer and the World HealthOrganization (WHO) introduced specific criteriafor the codification of tumor response evaluation.In 1994, several organizations involved in clinicalcancer research joined together to undertake thereview of these response evaluation criteria onthe basis of their experience and knowledge.After several years of intensive discussions, newguidelines are ready and will replace the previousWHO criteria. In parallel to this initiative, one ofthe participating groups developed a model bywhich response rates could be derived fromunidimensional measurement of tumor lesionsinstead of the usual bidimensional approach. Thisnew concept has been largely validated by theResponse Evaluation Criteria in Solid Tumors", "metadata": {}}
+{"_id": "15548965", "title": "", "text": "Structural Rearrangements of NR1/NR2A NMDAReceptors during Allosteric InhibitionIonotropicglutamate receptor (iGluR) subunits contain alarge N-terminal domain (NTD) that precedes theagonist-binding domain (ABD) and participates insubunit oligomerization. In NMDA receptors(NMDARs), the NTDs of NR2A and NR2B subunitsalso form binding sites for the endogenousinhibitor Zn(2+) ion. Although these allostericsites have been characterized in detail, themolecular mechanisms by which the NTDscommunicate with the rest of the receptor topromote its inhibition remain unknown. Here, weidentify the ABD dimer interface as a majorstructural determinant that permits couplingbetween the NTDs and the channel gate. Thestrength of this interface also controls protoninhibition, another form of allosteric modulationof NMDARs. Conformational rearrangements atthe ABD dimer interface thus appear to be a keymechanism conserved in all iGluR subfamilies,but have evolved to fulfill different functions: fast", "metadata": {}}
+{"_id": "15551129", "title": "", "text": "The role of iron in Mycobacterium smegmatisbiofilm formation: the exochelin siderophore isessential in limiting iron conditions for biofilmformation but not for planktonic growthManyspecies of mycobacteria form structured biofilmcommunities at liquid–air interfaces and on solidsurfaces. Full development of Mycobacteriumsmegmatis biofilms requires addition ofsupplemental iron above 1 μM ferrous sulphate,although addition of iron is not needed forplanktonic growth. Microarray analysis of the M.smegmatis transcriptome shows thatiron-responsive genes – especially those involvedin siderophore synthesis and iron uptake – arestrongly induced during biofilm formationreflecting a response to iron deprivation, evenwhen 2 μM iron is present. The acquisition of ironunder these conditions is specifically dependenton the exochelin synthesis and uptake pathways,and the strong defect of an iron–exochelinuptake mutant suggests a regulatory role of ironin the transition to biofilm growth. In contrast,", "metadata": {}}
+{"_id": "15559582", "title": "", "text": "Plasma lipids and prolactin in patients withbreast cancer.In a comparative study of pre- andpostmenopausal women with benign andmalignant breast disease, a number ofdifferences were observed in circulating plasmaprolactin and lipid concentrations. Plasma lipids,phospholipids, triglycerides, cholesterol and freefatty acids were all higher in blood obtained frombreast cancer patients prior to surgery.HDL-Cholesterol levels were significantly lower inthese patients. These differences remained whenthe patient groups were sub-divided according tomenopausal status. Plasma prolactinconcentrations were also found to be higher incancer compared with non-cancer patients, thiseffect being more marked in premenopausal thanin postmenopausal patients. Premenopausalpatients with invasive or poorly differentiateddisease had significantly higher prolactin levelsthan those with non-invasive disease. Nocorrelations were found between plasmaprolactin and any of the lipid fractions.", "metadata": {}}
+{"_id": "15561961", "title": "", "text": "expression by oxidizedlinoleicHypercholesterolemia is associated withimpairments in endothelium-dependent vascularrelaxations. Paradoxically, endothelial productionof nitrogen oxides is increased in early stages ofhypercholesterolemia. Prior work has shown thatoxidized low density lipoprotein (LDL) has bothstimulatory and inhibitory effects on endothelialnitric oxide synthase expression (eNOS) and hasfocused on lysophosphatidyl choline (LPC) as acomponent of oxidized LDL which may modulatethis effect. Another biologically active componentof oxidized LDL is13-hydroperoxyoctadecadienoic acid(13-HPODE), an oxidized form of linoleic acid.The purpose of this study was to determine theeffect of HPODE on the expression of eNOS inbovine aortic endothelial cells (BAECs). Twentyfour hour treatment of endothelial cells withHPODE caused a dose-dependent increase ineNOS mRNA levels as assessed by Northernanalysis. The time response studies show that", "metadata": {}}
+{"_id": "15563864", "title": "", "text": "Specific killing of multiple myeloma cells by(-)-epigallocatechin-3-gallate extracted fromgreen tea: biologic activity and therapeuticimplications.Epigallocatechin-3-gallate (EGCG), apolyphenol extracted from green tea, is anantioxidant with chemopreventive andchemotherapeutic actions. Based on its ability tomodulate growth factor-mediated cellproliferation, we evaluated its efficacy in multiplemyeloma (MM). EGCG induced both dose- andtime-dependent growth arrest and subsequentapoptotic cell death in MM cell lines includingIL-6-dependent cells and primary patient cells,without significant effect on the growth ofperipheral blood mononuclear cells (PBMCs) andnormal fibroblasts. Treatment with EGCG also ledto significant apoptosis in human myeloma cellsgrown as tumors in SCID mice. EGCG interactswith the 67-kDa laminin receptor 1 (LR1), whichis significantly elevated in myeloma cell lines andpatient samples relative to normal PBMCs.RNAi-mediated inhibition of LR1 resulted in", "metadata": {}}
+{"_id": "15570691", "title": "", "text": "Pharmacologic inhibition of cyclin-dependentkinases 4 and 6 arrests the growth ofglioblastoma multiforme intracranialxenografts.Activation of cyclin-dependentkinases 4 and 6 (cdk4/6) occurs in the majorityof glioblastoma multiforme (GBM) tumors, andrepresents a promising molecular target for thedevelopment of small molecule inhibitors. In thecurrent study, we investigated the moleculardeterminants and in vivo response of diverseGBM cell lines and xenografts to PD-0332991, acdk4/6-specific inhibitor. In vitro testing ofPD-0332991 against a panel of GBM cell linesrevealed a potent G(1) cell cycle arrest andinduction of senescence in each of 16retinoblastoma protein (Rb)-proficient cell linesregardless of other genetic lesions, whereas 5cell lines with homozygous inactivation of Rbwere completely resistant to treatment. Shorthairpin RNA depletion of Rb expression conferredresistance of GBM cells to PD-0332991, furtherdemonstrating a requirement of Rb for sensitivity", "metadata": {}}
+{"_id": "15570962", "title": "", "text": "Choosing Haplotype-Tagging SNPS Based onUnphased Genotype Data Using a PreliminarySample of Unrelated Subjects with an Examplefrom the Multiethnic Cohort StudyWe describe anapproach for picking haplotype-tagging singlenucleotide polymorphisms (htSNPs) that ispresently being taken in two large nestedcase-control studies within a multiethnic cohort(MEC), which are engaged in a search forassociations between risk of prostate and breastcancer and common genetic variations incandidate genes. Based on a preliminary sampleof 70 control subjects chosen at random fromeach of the 5 ethnic groups in the MEC weestimate haplotype frequencies using a variant ofthe Excoffier-Slatkin E-M algorithm aftergenotyping a high density of SNPs selected every3–5 kb in and surrounding a candidate gene. Inorder to evaluate the performance of a candidateset of htSNPS (which will be genotyped in themuch larger case-control sample) we treat thehaplotype frequencies estimate above as known,", "metadata": {}}
+{"_id": "15578265", "title": "", "text": "A model for the role of gut bacteria in thedevelopment of autoimmunity for type 1diabetesSeveral lines of evidence suggest a rolefor the gut microbiome in type 1 diabetes.Treating diabetes-prone rodents with probioticsor antibiotics prevents the development of thedisorder. Diabetes-prone rodents also have adistinctly different gut microbiome comparedwith healthy rodents. Recent studies in childrenwith a high genetic risk for type 1 diabetesdemonstrate significant differences in the gutmicrobiome between children who developautoimmunity for the disease and those whoremain healthy. However, the differences inmicrobiome composition between autoimmuneand healthy children are not consistent across allstudies because of the strong environmentalinfluences on microbiome composition,particularly diet and geography. Controllingconfounding factors of microbiome compositionuncovers bacterial associations with disease. Forexample, in a human cohort from a single Finnish", "metadata": {}}
+{"_id": "15588516", "title": "", "text": "METHODS AND RESULTSCytoscape is an opensource software project for integratingbiomolecular interaction networks withhigh-throughput expression data and othermolecular states into a unified conceptualframework. Although applicable to any system ofmolecular components and interactions,Cytoscape is most powerful when used inconjunction with large databases ofprotein-protein, protein-DNA, and geneticinteractions that are increasingly available forhumans and model organisms. Cytoscape'ssoftware Core provides basic functionality tolayout and query the network; to visuallyintegrate the network with expression profiles,phenotypes, and other molecular states; and tolink the network to databases of functionalannotations. The Core is extensible through astraightforward plug-in architecture, allowingrapid development of additional computationalanalyses and features. Several case studies ofCytoscape plug-ins are surveyed, including a", "metadata": {}}
+{"_id": "15590539", "title": "", "text": "Dual Regulation of miRNA Biogenesis GeneratesTarget Specificity in Neurotrophin-InducedProtein SynthesisControl of translation is afundamental source of regulation in geneexpression. The induction of protein synthesis bybrain-derived neurotrophic factor (BDNF)critically contributes to enduring modifications ofsynaptic function, but how BDNF selectivelyaffects only a minority of expressed mRNAs ispoorly understood. We report that BDNF rapidlyelevates Dicer, increasing mature miRNA levelsand inducing RNA processing bodies in neurons.BDNF also rapidly induces Lin28, causingselective loss of Lin28-regulated miRNAs and acorresponding upregulation in translation of theirtarget mRNAs. Binding sites for Lin28-regulatedmiRNAs are necessary and sufficient to conferBDNF responsiveness to a transcript. Lin28deficiency, or expression of a Lin28-resistantLet-7 precursor miRNA, inhibits BDNF translationspecificity and BDNF-dependent dendritearborization. Our data establish that specificity in", "metadata": {}}
+{"_id": "15593561", "title": "", "text": "A Viral microRNA Cluster Strongly Potentiates theTransforming Properties of a HumanHerpesvirusEpstein-Barr virus (EBV), anoncogenic human herpesvirus, induces cellproliferation after infection of resting Blymphocytes, its reservoir in vivo. The virallatent proteins are necessary for permanent Bcell growth, but it is unknown whether they aresufficient. EBV was recently found to encodemicroRNAs (miRNAs) that are expressed ininfected B cells and in some EBV-associatedlymphomas. EBV miRNAs are grouped into twoclusters located either adjacent to the BHRF1gene or in introns contained within the viralBART transcripts. To understand the role of theBHRF1 miRNA cluster, we have constructed avirus mutant that lacks all its three members(Δ123) and a revertant virus. Here we show thatthe B cell transforming capacity of the Δ123 EBVmutant is reduced by more than 20-fold, relativeto wild type or revertant viruses. B cells exposedto the knock-out virus displayed slower growth,", "metadata": {}}
+{"_id": "15600979", "title": "", "text": "EMSY overexpression disrupts the BRCA2/RAD51pathway in the DNA-damage response:implications for chromosomalinstability/recombination syndromes ascheckpoint diseasesEMSY links the BRCA2pathway to sporadic breast/ovarian cancer. Itencodes a nuclear protein that binds to theBRCA2 N-terminal domain implicated inchromatin/transcription regulation, but whensporadically amplified/overexpressed, increasedEMSY level represses BRCA2 transactivationpotential and induces chromosomal instability,mimicking the activity of BRCA2 mutations in thedevelopment of hereditary breast/ovariancancer. In addition to chromatin/transcriptionregulation, EMSY may also play a role in theDNA-damage response, suggested by its abilityto localize at chromatin sites of DNAdamage/repair. This implies that EMSYoverexpression may also repress BRCA2 inDNA-damage replication/checkpoint andrecombination/repair, coordinated processes that", "metadata": {}}
+{"_id": "15615957", "title": "", "text": "Original ArticleUNLABELLED Fruit and vegetableconsumption has been inversely associated withthe risk of chronic diseases including cancer andcardiovascular disease, with the beneficial effectsattributed to a variety of protective antioxidants,carotenoids and phytonutrients. The objective ofthe present study was to determine the effect ofsupplementation with dehydrated concentratesfrom mixed fruit and vegetable juices (JuicePlus+R) on serum antioxidant and folate status,plasma homocysteine levels and markers foroxidative stress and DNA damage. Japanesesubjects (n=60; age 27.8 yrs; BMI 22.1) wererecruited to participate in a double-blind placebocontrolled study and were randomized into 2groups of 30, matched for sex, age, BMI andsmoking status (39 males, 22 smokers; 21females, 13 smokers). Subjects were givenencapsulated supplements containing mixed fruitand vegetable juice concentrates or a matchingplacebo for 28 days, with blood and urinesamples collected at baseline, day 14 and day 28", "metadata": {}}
+{"_id": "15617300", "title": "", "text": "NCBI GEO: archive for functional genomics datasets—updateThe Gene Expression Omnibus(GEO, http://www.ncbi.nlm.nih.gov/geo/) is aninternational public repository forhigh-throughput microarray and next-generationsequence functional genomic data sets submittedby the research community. The resourcesupports archiving of raw data, processed dataand metadata which are indexed, cross-linkedand searchable. All data are freely available fordownload in a variety of formats. GEO alsoprovides several web-based tools and strategiesto assist users to query, analyse and visualizedata. This article reports current status andrecent database developments, including therelease of GEO2R, an R-based web applicationthat helps users analyse GEO data.", "metadata": {}}
+{"_id": "15617866", "title": "", "text": "Viral Paratransgenesis in the Malaria VectorAnopheles gambiaeParatransgenesis, the geneticmanipulation of insect symbiotic microorganisms,is being considered as a potential method tocontrol vector-borne diseases such as malaria.The feasibility of paratransgenic malaria controlhas been hampered by the lack of candidatesymbiotic microorganisms for the major vectorAnopheles gambiae. In other systems,densonucleosis viruses (DNVs) are attractiveagents for viral paratransgenesis because theyinfect important vector insects, can begenetically manipulated and are transmitted tosubsequent generations. However, An. gambiaehas been shown to be refractory to DNVdissemination. We discovered, cloned andcharacterized the first known DNV (AgDNV)capable of infection and dissemination in An.gambiae. We developed a flexible AgDNV-basedexpression vector to express any gene of interestin An. gambiae using a two-plasmidhelper-transducer system. To demonstrate", "metadata": {}}
+{"_id": "15635366", "title": "", "text": "The polycomb group protein L3mbtl2 assemblesan atypical PRC1-family complex that is essentialin pluripotent stem cells and earlydevelopment.L3mbtl2 has been implicated intranscriptional repression and chromatincompaction but its biological function has notbeen defined. Here we show that disruption ofL3mbtl2 results in embryonic lethality withfailure of gastrulation. This correlates withcompromised proliferation and abnormaldifferentiation of L3mbtl2(-/-) embryonic stem(ES) cells. L3mbtl2 regulates genes by recruitinga Polycomb Repressive Complex1 (PRC1)-relatedcomplex, resembling the previously describedE2F6-complex, and including G9A, Hdac1, andRing1b. The presence of L3mbtl2 at target genesis associated with H3K9 dimethylation, lowhistone acetylation, and H2AK119 ubiquitination,but the latter is neither dependent on L3mbtl2nor sufficient for repression. Genome-widestudies revealed that the L3mbtl2-dependentcomplex predominantly regulates genes not", "metadata": {}}
+{"_id": "15648443", "title": "", "text": "Long-term effect of aspirin on cancer risk incarriers of hereditary colorectal cancer: ananalysis from the CAPP2 randomised controlledtrialBACKGROUND Observational studies reportreduced colorectal cancer in regular aspirinconsumers. Randomised controlled trials haveshown reduced risk of adenomas but none haveemployed prevention of colorectal cancer as aprimary endpoint. The CAPP2 trial aimed toinvestigate the antineoplastic effects of aspirinand a resistant starch in carriers of Lynchsyndrome, the major form of hereditarycolorectal cancer; we now report long-termfollow-up of participants randomly assigned toaspirin or placebo. METHODS In the CAPP2randomised trial, carriers of Lynch syndromewere randomly assigned in a two-by-two factorialdesign to 600 mg aspirin or aspirin placebo or 30g resistant starch or starch placebo, for up to 4years. Randomisation was in blocks of 16 withprovision for optional single-agent randomisationand extended postintervention double-blind", "metadata": {}}
+{"_id": "15655418", "title": "", "text": "Drosophila CPEB Orb2A Mediates MemoryIndependent of Its RNA-BindingDomainLong-term memory and synapticplasticity are thought to require the synthesis ofnew proteins at activated synapses. The CPEBfamily of RNA binding proteins, includingDrosophila Orb2, has been implicated in thisprocess. The precise mechanism by which thesemolecules regulate memory formation ishowever poorly understood. We used genetargeting and site-specific transgenesis tospecifically modify the endogenous orb2 gene inorder to investigate its role in long-term memoryformation. We show that the Orb2A and Orb2Bisoforms, while both essential, have distinctfunctions in memory formation. These twoisoforms have common glutamine-rich andRNA-binding domains, yet Orb2A uniquelyrequires the former and Orb2B the latter. Wefurther show that Orb2A induces Orb2 complexesin a manner dependent upon both itsglutamine-rich region and neuronal activity. We", "metadata": {}}
+{"_id": "15657779", "title": "", "text": "Functional hemichannels in astrocytes: a novelmechanism of glutamate release.Little is knownabout the expression and possible functions ofunopposed gap junction hemichannels in thebrain. Emerging evidence suggests that gapjunction hemichannels can act as stand-alonefunctional channels in astrocytes. Withimmunocytochemistry, dye uptake, and HPLCmeasurements, we show that astrocytes in vitroexpress functional hemichannels that canmediate robust efflux of glutamate andaspartate. Functional hemichannels wereconfirmed by passage of extracellular luciferyellow (LY) into astrocytes in nominal divalentcation-free solution (DCFS) and the ability toblock this passage with gap junction blockingagents. Glutamate/aspartate release (or LYloading) in DCFS was blocked by multivalentcations (Ca2+, Ba2+, Sr2+, Mg2+, and La3+)and by gap junction blocking agents(carbenoxolone, octanol, heptanol, flufenamicacid, and 18alpha-glycyrrhetinic acid) with", "metadata": {}}
+{"_id": "15659108", "title": "", "text": "Human Rad52 binds and wraps single-strandedDNA and mediates annealing via twohRad52–ssDNA complexesRad52 promotes theannealing of complementary strands of DNAbound by replication protein A (RPA) duringdiscrete repair pathways. Here, we used afluorescence resonance energy transfer (FRET)between two fluorescent dyes incorporated intoDNA substrates to probe the mechanism bywhich human Rad52 (hRad52) interacts with andmediates annealing of ssDNA-hRPA complexes.Human Rad52 bound ssDNA or ssDNA-hRPAcomplex in two, concentration-dependentmodes. At low hRad52 concentrations, ssDNAwas wrapped around the circumference of theprotein ring, while at higher proteinconcentrations, ssDNA was stretched betweenmultiple hRad52 rings. Annealing by hRad52occurred most efficiently when eachcomplementary DNA strand or each ssDNA-hRPAcomplex was bound by hRad52 in a wrappedconfiguration, suggesting homology search and", "metadata": {}}
+{"_id": "15663829", "title": "", "text": "Mendelian Randomization Study of B-TypeNatriuretic Peptide and Type 2 Diabetes:Evidence of Causal Association from PopulationStudiesBACKGROUND Genetic andepidemiological evidence suggests an inverseassociation between B-type natriuretic peptide(BNP) levels in blood and risk of type 2 diabetes(T2D), but the prospective association of BNPwith T2D is uncertain, and it is unclear whetherthe association is confounded. METHODS ANDFINDINGS We analysed the association betweenlevels of the N-terminal fragment of pro-BNP(NT-pro-BNP) in blood and risk of incident T2D ina prospective case-cohort study and genotypedthe variant rs198389 within the BNP locus inthree T2D case-control studies. We combined ourresults with existing data in a meta-analysis of11 case-control studies. Using a Mendelianrandomization approach, we compared theobserved association between rs198389 and T2Dto that expected from the NT-pro-BNP level toT2D association and the NT-pro-BNP difference", "metadata": {}}
+{"_id": "15669393", "title": "", "text": "brain organizationTransient activation ofestrogen receptors (ER) in the developing brainduring a limited perinatal \"window of time\" isrecognized as a key mechanism ofdefeminization of neural control of reproductivefunction and sexual behavior. Two major ERisoforms, alpha and beta, are present in neuralcircuits that govern ovarian cycle and sexualbehavior. Using highly selective ER agonists, thisstudy provides the first evidence for distinctcontribution of individual ER isoforms to theprocess of estrogen dependent defeminization.Neonatal activation of the ERalpha in female ratsresulted in abrogation of cyclic ovarian activityand female sexual behavior in adulthood. Theseeffects are associated with male-like alterationsin the morphology of the anteroventralperiventricular (AVPV) and sexually dimorphicnucleus of the preoptic area (SDN-POA), as wellas refractoriness to estrogen-mediated inductionof sexual receptivity. Exposure to anERbeta-selective agonist induced persistent", "metadata": {}}
+{"_id": "15670968", "title": "", "text": "Thresholds for the cost–effectiveness ofinterventions: alternative approachesManycountries use the cost-effectiveness thresholdsrecommended by the World HealthOrganization's Choosing Interventions that areCost-Effective project (WHO-CHOICE) whenevaluating health interventions. This project setsthe threshold for cost-effectiveness as the cost ofthe intervention per disability-adjusted life-year(DALY) averted less than three times thecountry's annual gross domestic product (GDP)per capita. Highly cost-effective interventions aredefined as meeting a threshold per DALY avertedof once the annual GDP per capita. We arguethat reliance on these thresholds reduces thevalue of cost-effectiveness analyses and makessuch analyses too blunt to be useful for mostdecision-making in the field of public health. Useof these thresholds has little theoreticaljustification, skirts the difficult but necessaryranking of the relative values oflocally-applicable interventions and omits any", "metadata": {}}
+{"_id": "15678772", "title": "", "text": "Effect of low doses of ionising radiation in infancyon cognitive function in adulthood: Swedishpopulation based cohort study.OBJECTIVE Todetermine whether exposure to low doses ofionising radiation in infancy affects cognitivefunction in adulthood. DESIGN Population basedcohort study. SETTING Sweden. PARTICIPANTS3094 men who had received radiation forcutaneous haemangioma before age 18 monthsduring 1930-59. MAIN OUTCOME MEASURESRadiation dose to frontal and posterior parts ofthe brain, and association between dose andintellectual capacity at age 18 or 19 years basedon cognitive tests (learning ability, logicalreasoning, spatial recognition) and high schoolattendance. RESULTS The proportion of boyswho attended high school decreased withincreasing doses of radiation to both the frontaland the posterior parts of the brain from about32% among those not exposed to around 17% inthose who received > 250 mGy. For the frontaldose, the multivariate odds ratio was 0.47 (95%", "metadata": {}}
+{"_id": "15685921", "title": "", "text": "Differential effects of charybdotoxin on theactivity of retinal ganglion cells in the dark- andlight-adapted mouse retinaPatch-clamprecordings were made from retinal ganglion cellsin the mouse retina. Under dark adaptation,blockage of BK(Ca) channels increases thespontaneous excitatory postsynaptic currents(EPSCs) and light-evoked On-EPSCs, while itdecreases the light-evoked Off inhibitorypostsynaptic currents (IPSCs). However, underlight adaptation it decreases the light-evokedOn-EPSCs, the spontaneous IPSCs and thelight-evoked On- and Off-IPSCs. Blockage ofBK(Ca) channels significantly altered the outputsof RGCs by changing their light-evokedresponses into a bursting pattern and increasingthe light-evoked depolarization of the membranepotentials, while it did not significantly changethe peak firing rates of light-evoked responses.", "metadata": {}}
+{"_id": "15692098", "title": "", "text": "Hutchinson-Gilford progeria syndrome: review ofthe phenotypeHutchinson-Gilford progeriasyndrome (HGPS) is a rare but well known entitycharacterized by extreme short stature, low bodyweight, early loss of hair, lipodystrophy,scleroderma, decreased joint mobility, osteolysis,and facial features that resemble aged persons.Cardiovascular compromise leads to earlydemise. Cognitive development is normal. Dataon 10 of our own cases and 132 cases fromliterature are presented. The incidence in the lastcentury in the Netherlands was 1:4,000,000. Sexratio was 1.2:1. Main first symptoms were failureto thrive (55%), hair loss (40%), skin problems(28%), and lipodystrophy (20%). Mean age atdiagnosis was 2.9 years. Growth in weight wasmore disturbed than growth in height, andgrowth delay started already prenatally. Meanheight > 13 years was 109.0 cm, mean weightwas 14.5 kg. Osteolysis was wide-spread but notexpressed, except in the viscerocranium, andremained limited to membranous formed bone.", "metadata": {}}
+{"_id": "15707049", "title": "", "text": "Identification of an autoantigen demonstrates alink between interstitial lung disease and a defectin central tolerance.Interstitial lung disease (ILD)is a common manifestation of systemicautoimmunity characterized by progressiveinflammation or scarring of the lungs. Patientswho develop these complications can exhibitsignificantly impaired gas exchange that mayresult in hypoxemia, pulmonary hypertension,and even death. Unfortunately, little isunderstood about how these diseases arise,including the role of specific defects in immunetolerance. Another key question is whetherautoimmune responses targeting the lungparenchyma are critical to ILD pathogenesis,including that of isolated idiopathic forms. Weshow that a specific defect in central tolerancebrought about by mutations in the autoimmuneregulator gene (Aire) leads to an autoreactive Tcell response to a lung antigen namedvomeromodulin and the development of ILD. Wefound that a human patient and mice with", "metadata": {}}
+{"_id": "15716328", "title": "", "text": "In vivo role of ER-associated peptidase activity intailoring peptides for presentation by MHC classIa and class Ib moleculesEndoplasmic reticulum(ER)-associated aminopeptidase (ERAP)1 hasbeen implicated in the final proteolyticprocessing of peptides presented by majorhistocompatibility complex (MHC) class Imolecules. To evaluate the in vivo role of ERAP1,we have generated ERAP1-deficient mice. Cellsurface expression of the class Ia moleculesH-2Kb and H-2Db and of the class Ib moleculeQa-2 was significantly reduced in these animals.Although cells from mutant animals exhibitedreduced capacity to present several self- andforeign antigens to Kb-, Db-, or Qa-1b–restrictedCD8+ cytotoxic T cells, presentation of someantigens was unaffected or significantlyenhanced. Consistent with these findings, micegenerated defective CD8+ T cell responsesagainst class I–presented antigens. Thesefindings reveal an important in vivo role ofER-associated peptidase activity in tailoring", "metadata": {}}
+{"_id": "15721252", "title": "", "text": "PD 0332991, a selective cyclin D kinase 4/6inhibitor, preferentially inhibits proliferation ofluminal estrogen receptor-positive human breastcancer cell lines in vitroINTRODUCTIONAlterations in cell cycle regulators have beenimplicated in human malignancies includingbreast cancer. PD 0332991 is an orally active,highly selective inhibitor of the cyclin D kinases(CDK)4 and CDK6 with ability to blockretinoblastoma (Rb) phosphorylation in the lownanomolar range. To identify predictors ofresponse, we determined the in vitro sensitivityto PD 0332991 across a panel of molecularlycharacterized human breast cancer cell lines.METHODS Forty-seven human breast cancer andimmortalized cell lines representing the knownmolecular subgroups of breast cancer weretreated with PD 0332991 to determine IC50values. These data were analyzed againstbaseline gene expression data to identify genesassociated with PD 0332991 response. RESULTSCell lines representing luminal estrogen", "metadata": {}}
+{"_id": "15727984", "title": "", "text": "Identification of secreted proteins that mediatecell-cell interactions in an in vitro model of thelung cancer microenvironment.Non-small celllung cancer (NSCLC) cells with somaticmutations in K-ras recruit to the tumor a varietyof cell types (hereafter collectively termed\"stromal cells\") that can promote or inhibittumorigenesis by mechanisms that have notbeen fully elucidated. Here, we postulated thatstromal cells in the tumor microenvironmentalter the tumor cell secretome, including thoseproteins required for tumor growth anddissemination, and we developed an in vitromodel to test this hypothesis. Coculturing amurine K-ras mutant lung adenocarcinoma cellline (LKR-13) with a murine lung stromal cell(macrophage, endothelial cell, or fibroblast)enhanced stromal cell migration, inducedendothelial tube formation, increased LKR-13 cellproliferation, and regulated the secretion ofproteins involved in angiogenesis, inflammation,cell proliferation, and epithelial-to-mesenchymal", "metadata": {}}
+{"_id": "15728433", "title": "", "text": "Tightrope act: autophagy in stem cell renewal,differentiation, proliferation, and agingAutophagyis a constitutive lysosomal catabolic pathwaythat degrades damaged organelles and proteinaggregates. Stem cells are characterized byself-renewal, pluripotency, and quiescence; theirlong life span, limited capacity to dilute cellularwaste and spent organelles due to quiescence,along with their requirement for remodeling inorder to differentiate, all suggest that theyrequire autophagy more than other cell types.Here, we review the current literature on the roleof autophagy in embryonic and adult stem cells,including hematopoietic, mesenchymal, andneuronal stem cells, highlighting the diverse andcontrasting roles autophagy plays in theirbiology. Furthermore, we review the few studieson stem cells, lysosomal activity, and autophagy.Novel techniques to detect autophagy in primarycells are required to study autophagy in differentstem cell types. These will help to elucidate theimportance of autophagy in stem cells during", "metadata": {}}
+{"_id": "15778034", "title": "", "text": "Variant Histone H2A.Z Is Globally Localized tothe Promoters of Inactive Yeast Genes andRegulates Nucleosome PositioningH2A.Z is anevolutionary conserved histone variant involvedin transcriptional regulation, antisilencing,silencing, and genome stability. Themechanism(s) by which H2A.Z regulates thesevarious biological functions remains poorlydefined, in part due to the lack of knowledgeregarding its physical location alongchromosomes and the bearing it has inregulating chromatin structure. Here we mappedH2A.Z across the yeast genome at anapproximately 300-bp resolution, usingchromatin immunoprecipitation combined withtiling microarrays. We have identified 4,862small regions—typically one or two nucleosomeswide—decorated with H2A.Z. Those “Z loci” arepredominantly found within specific nucleosomesin the promoter of inactive genes all across thegenome. Furthermore, we have shown thatH2A.Z can regulate nucleosome positioning at", "metadata": {}}
+{"_id": "15780826", "title": "", "text": "Collective trauma in northern Sri Lanka: aqualitative psychosocial-ecologicalstudyBACKGROUND Complex situations thatfollow war and natural disasters have apsychosocial impact on not only the individualbut also on the family, community and society.Just as the mental health effects on theindividual psyche can result in non pathologicaldistress as well as a variety of psychiatricdisorders; massive and widespread trauma andloss can impact on family and social processescausing changes at the family, community andsocietal levels. METHOD This qualitative,ecological study is a naturalistic, psychosocialethnography in Northern Sri Lanka, whileactively involved in psychosocial and communitymental health programmes among the Tamilcommunity. Participatory observation, keyinformant interviews and focus group discussionwith community level relief and rehabilitationworkers and government and non-governmentalofficials were used to gather data. The effects on", "metadata": {}}
+{"_id": "15790930", "title": "", "text": "Guidelines for the selection of highly effectivesiRNA sequences for mammalian and chick RNAinterference.In the present study, therelationship between short interfering RNA(siRNA) sequence and RNA interference (RNAi)effect was extensively analyzed using 62 targetsof four exogenous and two endogenous genesand three mammalian and Drosophila cells. Wepresent the rules that may govern siRNAsequence preference and in accordance withwhich highly effective siRNAs essential forsystematic mammalian functional genomics canbe readily designed. These rules indicate thatsiRNAs which simultaneously satisfy all four ofthe following sequence conditions are capable ofinducing highly effective gene silencing inmammalian cells: (i) A/U at the 5' end of theantisense strand; (ii) G/C at the 5' end of thesense strand; (iii) at least five A/U residues inthe 5' terminal one-third of the antisense strand;and (iv) the absence of any GC stretch of morethan 9 nt in length. siRNAs opposite in features", "metadata": {}}
+{"_id": "15795880", "title": "", "text": "Overview of the CCP4 suite and currentdevelopmentsThe CCP4 (CollaborativeComputational Project, Number 4) software suiteis a collection of programs and associated dataand software libraries which can be used formacromolecular structure determination byX-ray crystallography. The suite is designed tobe flexible, allowing users a number of methodsof achieving their aims. The programs are from awide variety of sources but are connected by acommon infrastructure provided by standard fileformats, data objects and graphical interfaces.Structure solution by macromolecularcrystallography is becoming increasinglyautomated and the CCP4 suite includes severalautomation pipelines. After giving a briefdescription of the evolution of CCP4 over the last30 years, an overview of the current suite isgiven. While detailed descriptions are given inthe accompanying articles, here it is shown howthe individual programs contribute to a completesoftware package.", "metadata": {}}
+{"_id": "15803282", "title": "", "text": "Histone Demethylase Expression EnhancesHuman Somatic Cell Nuclear Transfer Efficiencyand Promotes Derivation of Pluripotent StemCells.The extremely low efficiency of humanembryonic stem cell (hESC) derivation usingsomatic cell nuclear transfer (SCNT) limits itspotential application. Blastocyst formation fromhuman SCNT embryos occurs at a low rate andwith only some oocyte donors. We previouslyshowed in mice that reduction of histone H3lysine 9 trimethylation (H3K9me3) throughectopic expression of the H3K9me3 demethylaseKdm4d greatly improves SCNT embryodevelopment. Here we show that overexpressionof a related H3K9me3 demethylase KDM4Aimproves human SCNT, and that, as in mice,H3K9me3 in the human somatic cell genome isan SCNT reprogramming barrier. Overexpressionof KDM4A significantly improves the blastocystformation rate in human SCNT embryos byfacilitating transcriptional reprogramming,allowing efficient derivation of SCNT-derived", "metadata": {}}
+{"_id": "15816729", "title": "", "text": "Interface Contractility between Differently FatedCells Drives Cell Elimination and CystFormationAlthough cellular tumor-suppressionmechanisms are widely studied, little is knownabout mechanisms that act at the level of tissuesto suppress the occurrence of aberrant cells inepithelia. We find that ectopic expression oftranscription factors that specify cell fates causesabnormal epithelial cysts in Drosophila imaginaldiscs. Cysts do not form cell autonomously butresult from the juxtaposition of two cellpopulations with divergent fates. Juxtaposition ofwild-type and aberrantly specified cells inducesenrichment of actomyosin at their entire sharedinterface, both at adherens junctions as well asalong basolateral interfaces. Experimentalvalidation of 3D vertex model simulationsdemonstrates that enhanced interfacecontractility is sufficient to explain manymorphogenetic behaviors, which depend on cellcluster size. These range from cyst formation byintermediate-sized clusters to segregation of", "metadata": {}}
+{"_id": "15830352", "title": "", "text": "Resonating circadian clocks enhance fitness incyanobacteria.In some organisms longevity,growth, and developmental rate are improvedwhen they are maintained on a light/dark cycle,the period of which \"resonates\" optimally withthe period of the endogenous circadian clock.However, to our knowledge no studies havedemonstrated that reproductive fitness per se isimproved by resonance between the endogenousclock and the environmental cycle. We tested theadaptive significance of circadian programmingby measuring the relative fitness undercompetition between various strains ofcyanobacteria expressing different circadianperiods. Strains that had a circadian periodsimilar to that of the light/dark cycle werefavored under competition in a manner thatindicates the action of soft selection.", "metadata": {}}
+{"_id": "15832146", "title": "", "text": "Stromal Fibroblasts Present in Invasive HumanBreast Carcinomas Promote Tumor Growth andAngiogenesis through Elevated SDF-1/CXCL12SecretionFibroblasts often constitute the majorityof the stromal cells within a breast carcinoma,yet the functional contributions of these cells totumorigenesis are poorly understood. Using acoimplantation tumor xenograft model, wedemonstrate that carcinoma-associatedfibroblasts (CAFs) extracted from human breastcarcinomas promote the growth of admixedbreast carcinoma cells significantly more than donormal mammary fibroblasts derived from thesame patients. The CAFs, which exhibit the traitsof myofibroblasts, play a central role inpromoting the growth of tumor cells throughtheir ability to secrete stromal cell-derived factor1 (SDF-1); CAFs promote angiogenesis byrecruiting endothelial progenitor cells (EPCs) intocarcinomas, an effect mediated in part by SDF-1.CAF-secreted SDF-1 also stimulates tumorgrowth directly, acting through the cognate", "metadata": {}}
+{"_id": "15833835", "title": "", "text": "Embryonic Origin of Postnatal Neural StemCellsAdult neural stem/progenitor (B1) cellswithin the walls of the lateral ventricles generatedifferent types of neurons for the olfactory bulb(OB). The location of B1 cells determines thetypes of OB neurons they generate. Here weshow that the majority of mouse B1 cellprecursors are produced between embryonicdays (E) 13.5 and 15.5 and remain largelyquiescent until they become reactivatedpostnatally. Using a retroviral library carryingover 100,000 genetic tags, we found that B1cells share a common progenitor with embryoniccells of the cortex, striatum, and septum, butthis lineage relationship is lost before E15.5. Theregional specification of B1 cells is evident asearly as E11.5 and is spatially linked to theproduction of neurons that populate differentareas of the forebrain. This study reveals anearly embryonic regional specification ofpostnatal neural stem cells and the lineagerelationship between them and embryonic", "metadata": {}}
+{"_id": "15836115", "title": "", "text": "The Opa1-Dependent Mitochondrial CristaeRemodeling Pathway Controls Atrophic,Apoptotic, and Ischemic TissueDamageMitochondrial morphological andultrastructural changes occur during apoptosisand autophagy, but whether they are relevant invivo for tissue response to damage is unclear.Here we investigate the role of the optic atrophy1 (OPA1)-dependent cristae remodeling pathwayin vivo and provide evidence that it regulates theresponse of multiple tissues to apoptotic,necrotic, and atrophic stimuli. Genetic inhibitionof the cristae remodeling pathway in vivo doesnot affect development, but protects mice fromdenervation-induced muscular atrophy, ischemicheart and brain damage, as well ashepatocellular apoptosis. Mechanistically,OPA1-dependent mitochondrial cristaestabilization increases mitochondrial respiratoryefficiency and blunts mitochondrial dysfunction,cytochrome c release, and reactive oxygenspecies production. Our results indicate that the", "metadata": {}}
+{"_id": "15856466", "title": "", "text": "First Proposal of Minimum Information About aCellular Assay for Regenerative Medicine:Advances in stem cell research have triggeredscores of studies in regenerative medicine in alarge number of institutions and companiesaround the world. However, reproducibility anddata exchange among laboratories or cell banksare constrained by the lack of a standardizedformat for experiments. To enhance informationflow in stem cell and derivative cell research,here we propose a minimum informationstandard to describe cellular assay data tofacilitate practical regenerative medicine. Basedon the existing Minimum Information About aCellular Assay, we developed MinimumInformation About a Cellular Assay forRegenerative Medicine (MIACARM), which allowsfor the description of advanced cellularexperiments with defined taxonomy of humancell types. By using controlled terms, such asontologies, MIACARM will provide a platform forcellular assay data exchange among cell banks", "metadata": {}}
+{"_id": "15868816", "title": "", "text": "The PAR proteins: fundamental players in animalcell polarization.The par genes were discoveredin genetic screens for regulators of cytoplasmicpartitioning in the early embryo of C. elegans,and encode six different proteins required forasymmetric cell division by the worm zygote.Some of the PAR proteins are localizedasymmetrically and form physical complexeswith one another. Strikingly, the PAR proteinshave been found to regulate cell polarization inmany different contexts in diverse animals,suggesting they form part of an ancient andfundamental mechanism for cell polarization.Although the picture of how the PAR proteinsfunction remains incomplete, cell biology andbiochemistry are beginning to explain how PARproteins polarize cells.", "metadata": {}}
+{"_id": "15879544", "title": "", "text": "Prions Adhere to Soil Minerals and RemainInfectiousAn unidentified environmental reservoirof infectivity contributes to the naturaltransmission of prion diseases (transmissiblespongiform encephalopathies [TSEs]) in sheep,deer, and elk. Prion infectivity may enter soilenvironments via shedding from diseasedanimals and decomposition of infected carcasses.Burial of TSE-infected cattle, sheep, and deer asa means of disposal has resulted in unintentionalintroduction of prions into subsurfaceenvironments. We examined the potential for soilto serve as a TSE reservoir by studying theinteraction of the disease-associated prionprotein (PrPSc) with common soil minerals. Inthis study, we demonstrated substantial PrPScadsorption to two clay minerals, quartz, and fourwhole soil samples. We quantified thePrPSc-binding capacities of each mineral.Furthermore, we observed that PrPSc desorbedfrom montmorillonite clay was cleaved at anN-terminal site and the interaction between", "metadata": {}}
+{"_id": "15879931", "title": "", "text": "Regulated Accumulation of DesmosterolIntegrates Macrophage Lipid Metabolism andInflammatory ResponsesInflammation andmacrophage foam cells are characteristicfeatures of atherosclerotic lesions, but themechanisms linking cholesterol accumulation toinflammation and LXR-dependent responsepathways are poorly understood. To investigatethis relationship, we utilized lipidomic andtranscriptomic methods to evaluate the effect ofdiet and LDL receptor genotype on macrophagefoam cell formation within the peritoneal cavitiesof mice. Foam cell formation was associated withsignificant changes in hundreds of lipid speciesand unexpected suppression, rather thanactivation, of inflammatory gene expression. Weprovide evidence that regulated accumulation ofdesmosterol underlies many of the homeostaticresponses, including activation of LXR targetgenes, inhibition of SREBP target genes,selective reprogramming of fatty acidmetabolism, and suppression of", "metadata": {}}
+{"_id": "15889329", "title": "", "text": "A JOURNAL OF NEUROLOGYBrain glial cells, fivetimes more prevalent than neurons, haverecently received attention for their potentialinvolvement in epileptic seizures. Microglia andastrocytes, associated with inflammatory innateimmune responses, are responsible forsurveillance of brain damage that frequentlyresults in seizures. Thus, an intriguingsuggestion has been put forward that seizuresmay be facilitated and perhaps triggered by brainimmune responses. Indeed, recent evidencestrongly implicates innate immune responses inlowering seizure threshold in experimentalmodels of epilepsy, yet, there is no proof thatthey can play an independent role in initiatingseizures in vivo. Here, we show that corticalinnate immune responses alone produceprofound increases of brain excitability resultingin focal seizures. We found that corticalapplication of lipopolysaccharide, binding totoll-like receptor 4 (TLR4), triples evoked fieldpotential amplitudes and produces focal", "metadata": {}}
+{"_id": "15893330", "title": "", "text": "Sequential domain assembly of ribosomal proteinS3 drives 40S subunit maturation.Eukaryoticribosomes assemble by association of ribosomalRNA with ribosomal proteins into nuclearprecursor particles, which undergo a complexmaturation pathway coordinated bynon-ribosomal assembly factors. Here, weprovide functional insights into how successivestructural re-arrangements in ribosomal proteinS3 promote maturation of the 40S ribosomalsubunit. We show that S3 dimerizes and isimported into the nucleus with its N-domain in arotated conformation and associated with thechaperone Yar1. Initial assembly of S3 with 40Sprecursors occurs via its C-domain, while theN-domain protrudes from the 40S surface. Yar1is replaced by the assembly factor Ltv1, therebyfixing the S3 N-domain in the rotated orientationand preventing its 40S association. Finally, Ltv1release, triggered by phosphorylation, andflipping of the S3 N-domain into its final positionresults in the stable integration of S3. Such a", "metadata": {}}
+{"_id": "15907458", "title": "", "text": "Assaying proliferation and differentiation capacityof stem cells using disaggregated adult mouseepidermisIn this protocol, we describe how toisolate keratinocytes from adult mouseepidermis, fractionate them into differentsub-populations on the basis of cell surfacemarkers and examine their function in an in vivoskin reconstitution assay with disaggregatedneonatal dermal cells. We also describe how theisolated keratinocytes can be subjected to clonalanalysis in vitro and in vivo and how to enrich forhair follicle-inducing dermal papilla cells in thedermal preparation. Using these approaches, it ispossible to compare the capacity of differentpopulations of adult epidermal stem cells toproliferate and to generate progeny thatdifferentiate along the different epidermallineages. Isolating, fractionating and graftingcells for the skin reconstitution assay is normallyspread over 2 d. Clonal growth in culture isassessed after 14 d, while evaluation of thegrafts is carried out after 4–5 weeks.", "metadata": {}}
+{"_id": "15913433", "title": "", "text": "Telomerase-negative immortalized human cellscontain a novel type of promyelocytic leukemia(PML) body.Telomerase-negative immortalizedhuman cells maintain their telomeres by amechanism known as alternative lengthening oftelomeres (ALT). We report here that ALT cellscontain a novel promyelocytic leukemia (PML)body (ALT-associated PML body, APB). APBs arelarge donut-shaped nuclear structures containingPML protein, telomeric DNA, and the telomerebinding proteins human telomere repeat bindingfactors 1 and 2. Immunostaining showed thatAPBs also contain replication factor A, RAD51,and RAD52, proteins involved in DNA synthesisand recombination. During immortalization, APBsappeared at exactly the same time as activationof ALT. APBs were found in ALT tumors and celllines but not in mortal cell strains or intelomerase-positive cell lines or tumors.", "metadata": {}}
+{"_id": "15925931", "title": "", "text": "Prediction of coronary artery disease by asystemic atherosclerosis score index derivedfrom whole-body MR angiographyBACKGROUNDWhole-body magnetic resonance angiography(WB-MRA) has shown its potential for thenon-invasive assessment of nearly the entirearterial vasculature within one examination.Since the presence of extra-cardiacatherosclerosis is associated with an increasedrisk of coronary events, our goal was to establishthe relationship between WB-MRA findings,including a systemic atherosclerosis score index,and the presence of significant coronary arterydisease (CAD). METHODS WB-MRA wasperformed on a 1.5T scanner in 50 patientsscheduled to undergo elective cardiaccatheterization for suspected CAD. In eachpatient, 40 extra-cardiac vessel segments wereevaluated and assigned scores according to theirluminal narrowing. The atherosclerosis scoreindex (ASI) was generated as the ratio ofsummed scores to analyzable segments.", "metadata": {}}
+{"_id": "15926408", "title": "", "text": "Analysis of re-replication from deregulated originlicensing by DNA fiber spreadingA majorchallenge each human cell-division cycle is toensure that DNA replication origins do not initiatemore than once, a phenomenon known asre-replication. Acute deregulation of replicationcontrol ultimately causes extensive DNAdamage, cell-cycle checkpoint activation and celldeath whereas moderate deregulation promotesgenome instability and tumorigenesis. In theabsence of detectable increases in cellular DNAcontent however, it has been difficult to directlydemonstrate re-replication or to determine if theability to re-replicate is restricted to a particularcell-cycle phase. Using an adaptation of DNAfiber spreading we report the direct detection ofre-replication on single DNA molecules fromhuman chromosomes. Using this method wedemonstrate substantial re-replication within 1 hof S phase entry in cells overproducing thereplication factor, Cdt1. Moreover, a comparisonof the HeLa cancer cell line to untransformed", "metadata": {}}
+{"_id": "15928989", "title": "", "text": "Liver receptor homolog-1 is essential forpregnancySuccessful pregnancy requirescoordination of an array of signals and factorsfrom multiple tissues. One such element, liverreceptor homolog-1 (Lrh-1), is an orphan nuclearreceptor that regulates metabolism and hormonesynthesis. It is strongly expressed in granulosacells of ovarian follicles and in the corpus luteumof rodents and humans. Germline ablation ofNr5a2 (also called Lrh-1), the gene coding forLrh-1, in mice is embryonically lethal atgastrulation. Depletion of Lrh-1 in the ovarianfollicle shows that it regulates genes required forboth steroid synthesis and ovulation. To studythe effects of Lrh-1 on mouse gestation, wegenetically disrupted its expression in the corpusluteum, resulting in luteal insufficiency. Hormonereplacement permitted embryo implantation butwas followed by gestational failure with impairedendometrial decidualization, compromisedplacental formation, fetal growth retardation andfetal death. Lrh-1 is also expressed in the mouse", "metadata": {}}
+{"_id": "15945975", "title": "", "text": "Transcriptional Signature and Memory Retentionof Human-Induced Pluripotent Stem CellsGeneticreprogramming of somatic cells to a pluripotentstate (induced pluripotent stem cells or iPSCs) byover-expression of specific genes has beenaccomplished using mouse and human cells.However, it is still unclear how similar humaniPSCs are to human Embryonic Stem Cells(hESCs). Here, we describe the transcriptionalprofile of human iPSCs generated without viralvectors or genomic insertions, revealing thatthese cells are in general similar to hESCs butwith significant differences. For the generation ofhuman iPSCs without viral vectors or genomicinsertions, pluripotent factors Oct4 and Nanogwere cloned in episomal vectors and transfectedinto human fetal neural progenitor cells. Thetransient expression of these two factors, orfrom Oct4 alone, resulted in efficient generationof human iPSCs. The reprogramming strategydescribed here revealed a potentialtranscriptional signature for human iPSCs yet", "metadata": {}}
+{"_id": "15946643", "title": "", "text": "A CXCL1 Paracrine Network Links CancerChemoresistance and MetastasisMetastasis andchemoresistance in cancer are linkedphenomena, but the molecular basis for this linkis unknown. We uncovered a network ofparacrine signals between carcinoma, myeloid,and endothelial cells that drives both processesin breast cancer. Cancer cells that overexpressCXCL1 and 2 by transcriptional hyperactivationor 4q21 amplification are primed for survival inmetastatic sites. CXCL1/2 attractCD11b(+)Gr1(+) myeloid cells into the tumor,which produce chemokines including S100A8/9that enhance cancer cell survival. Althoughchemotherapeutic agents kill cancer cells, thesetreatments trigger a parallel stromal reactionleading to TNF-α production by endothelial andother stromal cells. TNF-α via NF-kB heightensthe CXCL1/2 expression in cancer cells, thusamplifying the CXCL1/2-S100A8/9 loop andcausing chemoresistance. CXCR2 blockers breakthis cycle, augmenting the efficacy of", "metadata": {}}
+{"_id": "15948830", "title": "", "text": "Prophylaxis of postoperative vomiting in childrenundergoing tonsillectomy: a systematic reviewand meta-analysis.Postoperative vomiting (POV)remains one of the commonest causes ofsignificant morbidity after tonsillectomy inchildren. A variety of prophylactic anti-emeticinterventions have been reported, but there hasonly been a limited systematic review in thispatient group. A systematic search wasperformed by using Cochrane Controlled TrialsRegister, MEDLINE and EMBASE to identifydouble-blind, randomized, placebo-controlledtrials of prophylactic anti-emetic interventions inchildren undergoing tonsillectomy, with orwithout adenoidectomy. The outcome of interestwas POV in the first 24 h. Summary estimates ofthe effect of each prophylactic anti-emeticstrategy were derived using fixed effectmeta-analysis. Where appropriate,dose-response effects were estimated usinglogistic regression and 22 articles wereidentified. Good evidence was found for the", "metadata": {}}
+{"_id": "15953181", "title": "", "text": "A method of comparing the areas under receiveroperating characteristic curves derived from thesame cases.Receiver operating characteristic(ROC) curves are used to describe and comparethe performance of diagnostic technology anddiagnostic algorithms. This paper refines thestatistical comparison of the areas under twoROC curves derived from the same set ofpatients by taking into account the correlationbetween the areas that is induced by the pairednature of the data. The correspondence betweenthe area under an ROC curve and the Wilcoxonstatistic is used and underlying Gaussiandistributions (binormal) are assumed to providea table that converts the observed correlations inpaired ratings of images into a correlationbetween the two ROC areas. This between-areacorrelation can be used to reduce the standarderror (uncertainty) about the observed differencein areas. This correction for pairing, analogous tothat used in the paired t-test, can produce aconsiderable increase in the statistical sensitivity", "metadata": {}}
+{"_id": "15955172", "title": "", "text": "Transient inactivation of Rb and ARF yieldsregenerative cells from postmitotic mammalianmuscle.An outstanding biological question is whytissue regeneration in mammals is limited,whereas urodele amphibians and teleost fishregenerate major structures, largely by cell cyclereentry. Upon inactivation of Rb, proliferation ofpostmitotic urodele skeletal muscle is induced,whereas in mammalian muscle this mechanismdoes not exist. We postulated that a tumorsuppressor present in mammals but absent inregenerative vertebrates, the Ink4a product ARF(alternative reading frame), is a regenerationsuppressor. Concomitant inactivation of Arf andRb led to mammalian muscle cell cycle reentry,loss of differentiation properties, andupregulation of cytokinetic machinery. Singlepostmitotic myocytes were isolated by lasermicro-dissection-catapulting, and transientsuppression of Arf and Rb yielded myoblastcolonies that retained the ability to differentiateand fuse into myofibers upon transplantation in", "metadata": {}}
+{"_id": "15960670", "title": "", "text": "CENP-B Controls Centromere FormationDepending on the Chromatin ContextThecentromere is a chromatin region that serves asthe spindle attachment point and directsaccurate inheritance of eukaryotic chromosomesduring cell divisions. However, the mechanism bywhich the centromere assembles and stabilizesat a specific genomic region is not clear. The denovo formation of a human/mammalian artificialchromosome (HAC/MAC) with a functionalcentromere assembly requires the presence ofalpha-satellite DNA containing binding motifs forthe centromeric CENP-B protein. Wedemonstrate here that de novo centromereassembly on HAC/MAC is dependent on CENP-B.In contrast, centromere formation is suppressedin cells expressing CENP-B when alpha-satelliteDNA was integrated into a chromosomal site.Remarkably, on those integration sites CENP-Benhances histone H3-K9 trimethylation and DNAmethylation, thereby stimulatingheterochromatin formation. Thus, we propose", "metadata": {}}
+{"_id": "15966318", "title": "", "text": "Improved tools for biological sequencecomparison.We have developed three computerprograms for comparisons of protein and DNAsequences. They can be used to search sequencedata bases, evaluate similarity scores, andidentify periodic structures based on localsequence similarity. The FASTA program is amore sensitive derivative of the FASTP program,which can be used to search protein or DNAsequence data bases and can compare a proteinsequence to a DNA sequence data base bytranslating the DNA data base as it is searched.FASTA includes an additional step in thecalculation of the initial pairwise similarity scorethat allows multiple regions of similarity to bejoined to increase the score of relatedsequences. The RDF2 program can be used toevaluate the significance of similarity scoresusing a shuffling method that preserves localsequence composition. The LFASTA program candisplay all the regions of local similarity betweentwo sequences with scores greater than a", "metadata": {}}
+{"_id": "15968271", "title": "", "text": "The adverse consequences of unmet need amongolder persons living in the community:dual-eligible versus Medicare-onlybeneficiaries.OBJECTIVE Our objective is toestimate and compare the prevalence of selectedadverse consequences associated with unmetneed for assistance among a socioeconomicallyand medically vulnerable subgroup of the olderadult population, those who are dually eligible forMedicare and Medicaid, with those eligible forMedicare only. METHOD Using data from theNational Health and Aging Trends Study(NHATS), a representative survey of the olderMedicare population, we calculated theprevalence of disability-related need forassistance with self-care, household tasks, andmobility activities and the prevalence of adverseconsequences of unmet need by dually eligibleand Medicare only status. RESULTS Over 2million community-dwelling older personsexperienced an adverse consequence due tounmet need for assistance with self-care (e.g.,", "metadata": {}}
+{"_id": "15969637", "title": "", "text": "Supplementary information: ‘MesoRD User’sGuide ’ and otherUNLABELLED MesoRD is a toolfor stochastic simulation of chemical reactionsand diffusion. In particular, it is animplementation of the next subvolume method,which is an exact method to simulate the Markovprocess corresponding to the reaction-diffusionmaster equation. AVAILABILITY MesoRD is freesoftware, written in C++ and licensed under theGNU general public license (GPL). MesoRD runson Linux, Mac OS X, NetBSD, Solaris andWindows XP. It can be downloaded fromhttp://mesord.sourceforge.net. CONTACTjohan.elf@icm.uu.se; johan.hattne@embl-hamburg.de   SUPPLEMENTARY INFORMATION'MesoRD User's Guide' and other documents areavailable at http://mesord.sourceforge.net.", "metadata": {}}
+{"_id": "15972906", "title": "", "text": "Functional anatomy of T cell activation andsynapse formation.T cell activation and functionrequire a structured engagement ofantigen-presenting cells. These cell contacts arecharacterized by two distinct dynamics in vivo:transient contacts resulting from promigratoryjunctions called immunological kinapses orprolonged contacts from stable junctions calledimmunological synapses. Kinapses operate in thesteady state to allow referencing toself-peptide-MHC (pMHC) and searching forpathogen-derived pMHC. Synapses are inducedby T cell receptor (TCR) interactions with agonistpMHC under specific conditions and correlatewith robust immune responses that generateeffector and memory T cells. High-resolutionimaging has revealed that the synapse is highlycoordinated, integrating cell adhesion, TCRrecognition of pMHC complexes, and an array ofactivating and inhibitory ligands to promote orprevent T cell signaling. In this review, weexamine the molecular components, geometry,", "metadata": {}}
+{"_id": "15975146", "title": "", "text": "Modulation of Replicative Lifespan inCryptococcus neoformans: Implications forVirulenceThe fungal pathogen, Cryptococcusneoformans, has been shown to undergoreplicative aging. Old cells are characterized byadvanced generational age and phenotypicchanges that appear to mediate enhancedresistance to host and antifungal-based killing.As a consequence of this age-associatedresilience, old cells accumulate during chronicinfection. Based on these findings, wehypothesized that shifting the generational ageof a pathogenic yeast population would alter itsvulnerability to the host and affect its virulence.SIR2 is a well-conserved histone deacetylase,and a pivotal target for the development ofanti-aging drugs. We tested its effect on C.neoformans' replicative lifespan (RLS). First, amutant C. neoformans strain (sir2Δ) wasgenerated, and confirmed a predicted shortenedRLS in sir2Δ cells consistent with its known rolein aging. Next, RLS analysis showed that", "metadata": {}}
+{"_id": "15981174", "title": "", "text": "Pf4-Cre transgenic mice allow the generation oflineage-restricted gene knockouts for studyingmegakaryocyte and platelet function in vivo.Togenerate transgenic mice that expressCre-recombinase exclusively in themegakaryocytic lineage, we modified a mousebacterial artificial chromosome (BAC) clone byhomologous recombination and replaced the firstexon of the platelet factor 4 (Pf4), also calledCXCL4, with a codon-improved Cre cDNA.Several strains expressing the transgene wereobtained and one strain, Q3, was studied indetail. Crossing Q3 mice with the ROSA26-lacZreporter strain showed that Cre-recombinaseactivity was confined to megakaryocytes. Theseresults were further verified by crossing the Q3mice with a strain containing loxP-flankedintegrin beta1. Excision of this conditional allelein megakaryocytes was complete at the DNAlevel, and platelets were virtually devoid of theintegrin beta1 protein. The Pf4-Cre transgenicstrain will be a valuable tool to study", "metadata": {}}
+{"_id": "15983148", "title": "", "text": "LIN-44/Wnt Directs Dendrite Outgrowth throughLIN-17/Frizzled in C. elegans NeuronsNervoussystem function requires proper development oftwo functional and morphological domains ofneurons, axons and dendrites. Although boththese domains are equally important for signaltransmission, our understanding of dendritedevelopment remains relatively poor. Here, weshow that in C. elegans the Wnt ligand, LIN-44,and its Frizzled receptor, LIN-17, regulatedendrite development of the PQR oxygen sensoryneuron. In lin-44 and lin-17 mutants, PQRdendrites fail to form, display stunted growth, orare misrouted. Manipulation of temporal andspatial expression of LIN-44, combined withcell-ablation experiments, indicates that thismolecule is patterned during embryogenesis andacts as an attractive cue to define the site fromwhich the dendrite emerges. Genetic interactionbetween lin-44 and lin-17 suggests that theLIN-44 signal is transmitted through the LIN-17receptor, which acts cell autonomously in PQR.", "metadata": {}}
+{"_id": "15983982", "title": "", "text": "Why do general practitioners prescribe antibioticsfor upper respiratory tract infections to meetpatient expectations: a mixed methodsstudyOBJECTIVES To describe the role patientexpectations play in general practitioners (GPs)antibiotic prescribing for upper respiratory tractinfections (URTI). METHODS Concurrentexplanatory mixed methods approach using across-sectional survey and semistructuredinterviews. SETTINGS Primary care GPs inAustralia. PARTICIPANTS 584 GPs (response rateof 23.6%) completed the cross-sectional survey.32 GPs were interviewed individually. OUTCOMEMEASURE Prescribing of antibiotics for URTI.RESULTS More than half the GP respondents tothe survey in Australia self-reported that theywould prescribe antibiotics for an URTI to meetpatient expectations. Our qualitative findingssuggest that 'patient expectations' may be themain reason given for inappropriate prescribing,but it is an all-encompassing phrase thatincludes other reasons. These include limited", "metadata": {}}
+{"_id": "15984735", "title": "", "text": "Migraine and cardiovascular disease: systematicreview and meta-analysis.OBJECTIVE Toevaluate the association between migraine andcardiovascular disease, including stroke,myocardial infarction, and death due tocardiovascular disease. DESIGN Systematicreview and meta-analysis. DATA SOURCESElectronic databases (PubMed, Embase,Cochrane Library) and reference lists of includedstudies and reviews published until January2009. Selection criteria Case-control and cohortstudies investigating the association betweenany migraine or specific migraine subtypes andcardiovascular disease. Review methods Twoinvestigators independently assessed eligibility ofidentified studies in a two step approach.Disagreements were resolved by consensus.Studies were grouped according to a prioricategories on migraine and cardiovasculardisease. DATA EXTRACTION Two investigatorsextracted data. Pooled relative risks and 95%confidence intervals were calculated. RESULTS", "metadata": {}}
+{"_id": "15997009", "title": "", "text": "Effect of Duration and Intermittency of Rifampinon Tuberculosis Treatment Outcomes: ASystematic Review andMeta-AnalysisBACKGROUND Treatment regimensfor active tuberculosis (TB) that are intermittent,or use rifampin during only the initial phase,offer practical advantages, but their efficacy hasbeen questioned. We conducted a systematicreview of treatment regimens for active TB, toassess the effect of duration and intermittency ofrifampin use on TB treatment outcomes.METHODS AND FINDINGS PubMed, Embase, andthe Cochrane CENTRAL database for clinical trialswere searched for randomized controlled trials,published in English, French, or Spanish,between 1965 and June 2008. Selected studiesutilized standardized treatment withrifampin-containing regimens. Studies reportedbacteriologically confirmed failure and/or relapsein previously untreated patients withbacteriologically confirmed pulmonary TB. Pooledcumulative incidences of treatment outcomes", "metadata": {}}
+{"_id": "16016673", "title": "", "text": "A novel set of DNA methylation markers in urinesediments for sensitive/specific detection ofbladder cancer.PURPOSE This study aims toprovide a better set of DNA methylation markersin urine sediments for sensitive and specificdetection of bladder cancer. EXPERIMENTALDESIGN Fifty-nine tumor-associated genes wereprofiled in three bladder cancer cell lines, a smallcohort of cancer biopsies and urine sediments bymethylation-specific PCR. Twenty-one candidategenes were then profiled in urine sediments from132 bladder cancer patients (8 cases for stage0a; 68 cases for stage I; 50 cases for stage II; 4cases for stages III; and 2 cases for stage IV),23 age-matched patients with noncancerousurinary lesions, 6 neurologic diseases, and 7healthy volunteers. RESULTS Despite sixincidences of four genes reported in 3 of 23noncancerous urinary lesion patients analyzed,cancer-specific hypermethylation in urinesediments were reported for 15 genes (P <0.05). Methylation assessment of an 11-gene set", "metadata": {}}
+{"_id": "16056410", "title": "", "text": "Posttranslational Acetylation of α-TubulinConstrains Protofilament Number in NativeMicrotubulesBACKGROUND Microtubules are builtfrom linear polymers of α-β tubulin dimers(protofilaments) that form a tubular quinarystructure. Microtubules assembled from purifiedtubulin in vitro contain between 10 and 16protofilaments; however, such structuralpolymorphisms are not found in cells. Thisdiscrepancy implies that factors other thantubulin constrain microtubule protofilamentnumber, but the nature of these constraints isunknown. RESULTS Here, we show thatacetylation of MEC-12 α-tubulin constrainsprotofilament number in C. elegans touchreceptor neurons (TRNs). Whereas the sensorydendrite of wild-type TRNs is packed with across-linked bundle of long, 15-protofilamentmicrotubules, mec-17;atat-2 mutants lackingα-tubulin acetyltransferase activity have shortmicrotubules, rampant lattice defects, andvariable protofilament number both between and", "metadata": {}}
+{"_id": "16056514", "title": "", "text": "A KEY ROLE FOR OREXIN IN PANICANXIETYPanic disorder is a severe anxietydisorder with recurrent, debilitating panicattacks. In individuals with panic disorder thereis evidence of decreased centralgamma-aminobutyric acid (GABA) activity aswell as marked increases in autonomic andrespiratory responses after intravenous infusionsof hypertonic sodium lactate. In a rat model ofpanic disorder, chronic inhibition of GABAsynthesis in the dorsomedial-perifornicalhypothalamus of rats produces anxiety-likestates and a similar vulnerability to sodiumlactate-induced cardioexcitatory responses. Thedorsomedial-perifornical hypothalamus isenriched in neurons containing orexin (ORX, alsoknown as hypocretin), which have a crucial rolein arousal, vigilance and central autonomicmobilization, all of which are key components ofpanic. Here we show that activation ofORX-synthesizing neurons is necessary fordeveloping a panic-prone state in the rat panic", "metadata": {}}
+{"_id": "16057926", "title": "", "text": "Local Increases in Mechanical Tension ShapeCompartment Boundaries by Biasing CellIntercalationsMechanical forces play importantroles during tissue organization in developinganimals. Many tissues are organized intoadjacent, nonmixing groups of cells termedcompartments. Boundaries betweencompartments display a straight morphology andare associated with signaling centers that areimportant for tissue growth and patterning. Localincreases in mechanical tension at cell junctionsalong compartment boundaries have recentlybeen shown to prevent cell mixing and tomaintain straight boundaries. The cellularmechanisms by which local increases inmechanical tension prevent cell mixing atcompartment boundaries, however, remainpoorly understood. Here, we have used liveimaging and quantitative image analysis todetermine cellular dynamics at and near theanteroposterior compartment boundaries of theDrosophila pupal abdominal epidermis. We show", "metadata": {}}
+{"_id": "16058322", "title": "", "text": "MDA5 and PTPN2, two candidate genes for type1 diabetes, modify pancreatic β-cell responses tothe viral by-product double-strandedRNAbeta-Cell destruction in type 1 diabetes(T1D) is at least in part consequence of a 'dialog'between beta-cells and immune system. Thisdialog may be affected by the individual's geneticbackground. We presently evaluated whethermodulation of MDA5 and PTPN2, two candidategenes for T1D, affects beta-cell responses todouble-stranded RNA (dsRNA), a by-product ofviral replication. These genes were selectedfollowing comparison between known candidategenes for T1D and genes expressed in pancreaticbeta-cells, as identified in previous arrayanalysis. INS-1E cells and primaryfluorescence-activated cell sorting-purified ratbeta-cells were transfected with smallinterference RNAs (siRNAs) targeting MDA5 orPTPN2 and subsequently exposed to intracellularsynthetic dsRNA (polyinosinic-polycitidilicacid-PIC). Real-time RT-PCR, western blot and", "metadata": {}}
+{"_id": "16066726", "title": "", "text": "Tumor necrosis factor signaling mediatesresistance to mycobacteria by inhibiting bacterialgrowth and macrophage death.Tumor necrosisfactor (TNF), a key effector in controllingtuberculosis, is thought to exert protection bydirecting formation of granulomas, organizedaggregates of macrophages and other immunecells. Loss of TNF signaling causes progression oftuberculosis in humans, and the increasedmortality of Mycobacterium tuberculosis-infectedmice is associated with disorganized necroticgranulomas, although the precise roles of TNFsignaling preceding this endpoint remainundefined. We monitored transparentMycobacterium marinum-infected zebrafish liveto conduct a stepwise dissection of how TNFsignaling operates in mycobacterialpathogenesis. We found that loss of TNFsignaling caused increased mortality even whenonly innate immunity was operant. In theabsence of TNF, intracellular bacterial growthand granuloma formation were accelerated and", "metadata": {}}
+{"_id": "16086778", "title": "", "text": "Loss of negative regulation by Numb over Notchis relevant to human breast carcinogenesisThebiological antagonism between Notch and Numbcontrols the proliferative/differentiative balancein development and homeostasis. Althoughaltered Notch signaling has been linked to humandiseases, including cancer, evidence for asubstantial involvement of Notch in humantumors has remained elusive. Here, we showthat Numb-mediated control on Notch signalingis lost in \u000050% of human mammary carcinomas,due to specific Numb ubiquitination andproteasomal degradation. Mechanistically, Numboperates as an oncosuppressor, as its ectopicexpression in Numb-negative, but not inNumb-positive, tumor cells inhibits proliferation.Increased Notch signaling is observed inNumb-negative tumors, but reverts to basallevels after enforced expression of Numb.Conversely, Numb silencing increases Notchsignaling in normal breast cells and inNumb-positive breast tumors. Finally, growth", "metadata": {}}
+{"_id": "16090672", "title": "", "text": "Cortical Dynein Controls Microtubule Dynamics toGenerate Pulling Forces that Position MicrotubuleAstersDynein at the cortex contributes tomicrotubule-based positioning processes such asspindle positioning during embryonic cell divisionand centrosome positioning during fibroblastmigration. To investigate how cortical dyneininteracts with microtubule ends to generate forceand how this functional association impactspositioning, we have reconstituted the 'cortical'interaction between dynein and dynamicmicrotubule ends in an in vitro system usingmicrofabricated barriers. We show thatbarrier-attached dynein captures microtubuleends, inhibits growth, and triggers microtubulecatastrophes, thereby controlling microtubulelength. The subsequent interaction with shrinkingmicrotubule ends generates pulling forces up toseveral pN. By combining experiments inmicrochambers with a theoretical description ofaster mechanics, we show that dynein-mediatedpulling forces lead to the reliable centering of", "metadata": {}}
+{"_id": "16098747", "title": "", "text": "Breast cancer risk factors in relation to breastdensity (United States)Evaluate known breastcancer risk factors in relation to breast density.We examined factors in relation to breast densityin 144,018 New Hampshire (NH) women with atleast one mammogram recorded in a statewidemammography registry. Mammographic breastdensity was measured by radiologists using theBI-RADS classification; risk factors of interestwere obtained from patient intake forms andquestionnaires. Initial analyses showed a stronginverse influence of age and body mass index(BMI) on breast density. In addition, women withlate age at menarche, late age at first birth,premenopausal women, and those currentlyusing hormone therapy (HT) tended to havehigher breast density, while those with greaterparity tended to have less dense breasts.Analyses stratified on age and BMI suggestedinteractions, which were formally assessed in amultivariable model. The impact of current HTuse, relative to nonuse, differed across age", "metadata": {}}
+{"_id": "16108876", "title": "", "text": "Perspective: repression of competition and theevolution of cooperation.Repression ofcompetition within groups joins kin selection asthe second major force in the history of lifeshaping the evolution of cooperation. Whenopportunities for competition against neighborsare limited within groups, individuals canincrease their own success only by enhancing theefficiency and productivity of their group. Thus,characters that repress competition withingroups promote cooperation and enhance groupsuccess. Leigh first expressed this idea in thecontext of fair meiosis, in which eachchromosome has an equal chance oftransmission via gametes. Randomized successmeans that each part of the genome canincrease its own success only by enhancing thetotal number of progeny and thus increasing thesuccess of the group. Alexander used this insightabout repression of competition in fair meiosis todevelop his theories for the evolution of humansociality. Alexander argued that human social", "metadata": {}}
+{"_id": "16119973", "title": "", "text": "ArticleIBD is characterized by uncontrolledimmune responses in inflamed mucosa, withdominance of IL-17-producing cells anddeficiency of Treg cells. The aim of this studywas to explore the effect and mechanisms of RA,the ligand of RARalpha, on immune responses inhuman and murine colitis. Colonic biopsies frompatients with UC were cultured and treated withRA as the agonist of RARalpha or LE135 as theantagonist of RARalpha. Expressions of IL-17 andFOXP3 were detected by immunohistochemistry.Murine colitis was induced by intrarectaladministration with TNBS at Day 1. Mice werethen i.p.-treated with RA or LE135 daily for 7days. Cytokine levels in the cultures of mouseLPMCs were measured. Expressions of FOXP3and IL-17 in colon tissues or MLN were detectedby immunohistological analysis. Body weight andcolon inflammation were evaluated. RAtreatment up-regulated FOXP3 expression anddown-regulated IL-17 expression in colonbiopsies of patients and in colon tissues and MLN", "metadata": {}}
+{"_id": "16120395", "title": "", "text": "Multiple RNA surveillance pathways limitaberrant expression of iron uptake mRNAs andprevent iron toxicity in S. cerevisiae.Tightregulation of the expression of mRNAs encodingiron uptake proteins is essential to control ironhomeostasis and avoid intracellular iron toxicity.We show that many mRNAs encoding iron uptakeor iron mobilization proteins are expressed iniron-replete conditions in the absence of the S.cerevisiae RNase III ortholog Rnt1p or of thenuclear exosome component Rrp6p. Extendedforms of these mRNAs accumulate in theabsence of Rnt1p or of the 5'-->3' exonucleasesXrn1p and Rat1p, showing that multipledegradative pathways contribute to thesurveillance of aberrant forms of thesetranscripts. RNase III-deficient cells arehypersensitive to high iron concentrations,suggesting that Rnt1p-mediated RNAsurveillance is required to prevent iron toxicity.These results show that RNA surveillancethrough multiple ribonucleolytic pathways plays", "metadata": {}}
+{"_id": "16128711", "title": "", "text": "Differential regulation of adherens junctiondynamics during apical-basalpolarization.Adherens junctions (AJs) in epithelialcells are constantly turning over to modulateadhesion properties under various physiologicaland developmental contexts, but how such AJdynamics are regulated during the apical-basalpolarization of primary epithelia remains unclear.Here, we used new and genetically validated GFPmarkers of Drosophila E-cadherin (DE-cadherin,hereafter referred to as DE-Cad) and β-catenin(Armadillo, Arm) to quantitatively assay the invivo dynamics of biosynthetic turnover andmembrane redistribution by fluorescencerecovery after photobleaching (FRAP) assays.Our data showed that membrane DE-Cad andArm in AJs of polarizing epithelial cells had muchfaster biosynthetic turnover than in polarizedcells. Fast biosynthetic turnover of membraneDE-Cad is independent of actin- anddynamin-based trafficking, but ismicrotubule-dependent. Furthermore, Arm in AJs", "metadata": {}}
+{"_id": "16167746", "title": "", "text": "Phylogenetic analysis of mRNA polyadenylationsites reveals a role of transposable elements inevolution of the 3′-end of genesmRNApolyadenylation is an essential step for thematuration of almost all eukaryotic mRNAs, andis tightly coupled with termination oftranscription in defining the 3'-end of genes.Large numbers of human and mouse genesharbor alternative polyadenylation sites [poly(A)sites] that lead to mRNA variants containingdifferent 3'-untranslated regions (UTRs) and/orencoding distinct protein sequences. Here, weexamined the conservation and divergence ofdifferent types of alternative poly(A) sites acrosshuman, mouse, rat and chicken. We found thatthe 3'-most poly(A) sites tend to be moreconserved than upstream ones, whereas poly(A)sites located upstream of the 3'-most exon, alsotermed intronic poly(A) sites, tend to be muchless conserved. Genes with longer evolutionaryhistory are more likely to have alternativepolyadenylation, suggesting gain of poly(A) sites", "metadata": {}}
+{"_id": "16172576", "title": "", "text": "Inter- and Intra-Host Viral Diversity in a LargeSeasonal DENV2 OutbreakBACKGROUND Highgenetic diversity at both inter- and intra-hostlevel are hallmarks of RNA viruses due to theerror-prone nature of their genome replication.Several groups have evaluated the extent of viralvariability using different RNA virus deepsequencing methods. Although much of thiseffort has been dedicated to pathogens thatcause chronic infections in humans, few studiesinvestigated arthropod-borne, acute viralinfections. METHODS AND PRINCIPAL FINDINGSWe deep sequenced the complete genome of tenDENV2 isolates from representative classical andsevere cases sampled in a large outbreak inBrazil using two different approaches. Analysis ofthe consensus genomes confirmed the largerextent of the 2010 epidemic in comparison to aprevious epidemic caused by the same viruses inanother city two years before (genetic distance =0.002 and 0.0008 respectively). Analysis of viralpopulations within the host revealed a high level", "metadata": {}}
+{"_id": "16180601", "title": "", "text": "Serum Soluble Corin Deficiency Predicts MajorDisability within 3 Months after AcuteStrokeOBJECTIVE Serum soluble corin has beenassociated with stroke. However, whether it isassociated with stroke prognosis has not yetbeen studied. Therefore, we aimed to study theassociation of serum soluble corin with risk ofpoor outcomes within 3 months after stroke.METHODS We followed 522 stroke patients for 3months to identify major disability, death andvascular events. Serum soluble corin wasmeasured at baseline for all participants. Logisticregression was used to examine the associationsof baseline serum soluble corin with outcomes ofstroke, adjusting for age, sex, baseline NIHSSscore, hours from onset to hospitalization,smoking, drinking, hypertension, diabetes,coronary heart disease, atrial fibrillation, familyhistory of stroke, and stroke subtype. RESULTSPatients with high corin had a significantly lowercrude risk for the composite outcome of majordisability or death (OR = 0.64, 95%CI:", "metadata": {}}
+{"_id": "16201748", "title": "", "text": "Altered PTEN expression; a diagnostic marker fordifferentiating normal, hyperplastic andneoplastic endometriumBACKGROUND Differentmolecular alterations have been described inendometrioid endometrial carcinoma (EECA).Among them the most frequently altered is lossof the PTEN protein, a tumor suppressor gene.The purpose of this study was to evaluate theexpression pattern of PTEN gene in normal,hyperplastic and neoplastic endometrium.METHODS In a study in a referral gynecologichospital in Tehran, Iran, immunohistochemical(IHC) evaluation of PTEN was performed on 87consecutive specimens to the following threegroups; group A- normal proliferativeendometrium(n = 29); group B- hyperplasticendometrium [including simple hyperplasiawithout atypia(n = 21) and complex hyperplasiawith atypia (n = 8)] and group C- EECA(n = 29).Immunostaining of cells was analyzed byarbitrary quantitative methods according to bothslide's area staining and intensity of color", "metadata": {}}
+{"_id": "16204011", "title": "", "text": "Care Seeking for Neonatal Illness in Low- andMiddle-Income Countries: A SystematicReviewBACKGROUND Despite recentachievements to reduce child mortality, neonataldeaths continue to remain high, accounting for41% of all deaths in children under five years ofage worldwide, of which over 90% occur in low-and middle-income countries (LMICs). Infectionsare a leading cause of death and limitations incare seeking for ill neonates contribute to highmortality rates. As estimates for care-seekingbehaviors in LMICs have not been studied, thisreview describes care seeking for neonatalillnesses in LMICs, with particular attention totype of care sought. METHODS AND FINDINGSWe conducted a systematic literature review ofstudies that reported the proportion of caregiversthat sought care for ill or suspected ill neonatesin LMICs. The initial search yielded 784 studies,of which 22 studies described relevant data fromcommunity household surveys, facility-basedsurveys, and intervention trials. The majority of", "metadata": {}}
+{"_id": "16208091", "title": "", "text": "Synaptic Incorporation of AMPA Receptors duringLTP Is Controlled by a PKC Phosphorylation Siteon GluR1Incorporation of GluR1-containing AMPAreceptors into synapses is essential to severalforms of neural plasticity, including long-termpotentiation (LTP). Numerous signaling pathwaysthat trigger this process have been identified, butthe direct modifications of GluR1 that control itsincorporation into synapses are unclear. Here,we show that phosphorylation of GluR1 by PKCat a highly conserved serine 818 residue isincreased during LTP and critical for LTPexpression. GluR1 is phosphorylated by PKC atthis site in vitro and in vivo. In addition, acutephosphorylation at GluR1 S818 by PKC, as wellas a phosphomimetic mutation, promotes GluR1synaptic incorporation. Conversely, preventingGluR1 S818 phosphorylation reduces LTP andblocks PKC-driven synaptic incorporation ofGluR1. We conclude that the phosphorylation ofGluR1 S818 by PKC is a critical event in theplasticity-driven synaptic incorporation of AMPA", "metadata": {}}
+{"_id": "16217855", "title": "", "text": "The Bloom's syndrome helicase promotes theannealing of complementary single-strandedDNAThe product of the gene mutated in Bloom'ssyndrome, BLM, is a 3′–5′ DNA helicasebelonging to the highly conserved RecQ family.In addition to a conventional DNA strandseparation activity, BLM catalyzes both thedisruption of non-B-form DNA, such asG-quadruplexes, and the branch migration ofHolliday junctions. Here, we have characterized anew activity for BLM: the promotion ofsingle-stranded DNA (ssDNA) annealing. Thisactivity does not require Mg2+, is inhibited byssDNA binding proteins and ATP, and isdependent on DNA length. Through analysis ofvarious truncation mutants of BLM, we show thatthe C-terminal domain is essential for strandannealing and identify a 60 amino acid stretch ofthis domain as being important for both ssDNAbinding and strand annealing. We present amodel in which the ssDNA annealing activity ofBLM facilitates its role in the processing of DNA", "metadata": {}}
+{"_id": "16232581", "title": "", "text": "Bayesian selection of continuous-time Markovchain evolutionary models.We develop areversible jump Markov chain Monte Carloapproach to estimating the posterior distributionof phylogenies based on aligned DNA/RNAsequences under several hierarchicalevolutionary models. Using a proper, yetnontruncated and uninformative prior, wedemonstrate the advantages of the Bayesianapproach to hypothesis testing and estimation inphylogenetics by comparing different models forthe infinitesimal rates of change amongnucleotides, for the number of rate classes, andfor the relationships among branch lengths. Wecompare the relative probabilities of thesemodels and the appropriateness of a molecularclock using Bayes factors. Our most generalmodel, first proposed by Tamura and Nei,parameterizes the infinitesimal changeprobabilities among nucleotides (A, G, C, T/U)into six parameters, consisting of threeparameters for the nucleotide stationary", "metadata": {}}
+{"_id": "16233471", "title": "", "text": "The intersection between aging andcardiovascular disease.The average lifespan ofhumans is increasing, and with it the percentageof people entering the 65 and older age group isgrowing rapidly and will continue to do so in thenext 20 years. Within this age group,cardiovascular disease will remain the leadingcause of death, and the cost associated withtreatment will continue to increase. Aging is aninevitable part of life and unfortunately poses thelargest risk factor for cardiovascular disease.Although numerous studies in the cardiovascularfield have considered both young and agedhumans, there are still many unansweredquestions as to how the genetic pathways thatregulate aging in model organisms influencecardiovascular aging. Likewise, in the molecularbiology of aging field, few studies fully assess therole of these aging pathways in cardiovascularhealth. Fortunately, this gap is beginning toclose, and these two fields are merging together.We provide an overview of some of the key", "metadata": {}}
+{"_id": "16237005", "title": "", "text": "Single-RNA counting reveals alternative modesof gene expression in yeastProper execution oftranscriptional programs is a key requirement ofgene expression regulation, demanding accuratecontrol of timing and amplitude. How preciselythe transcription machinery fulfills this task is notknown. Using an in situ hybridization approachthat detects single mRNA molecules, wemeasured mRNA abundance and transcriptionalactivity within single Saccharomyces cerevisiaecells. We found that expression levels forparticular genes are higher than initially reportedand can vary substantially among cells.However, variability for most constitutivelyexpressed genes is unexpectedly small.Combining single-transcript measurements withcomputational modeling indicates that lowexpression variation is achieved by transcribinggenes using single transcription-initiation eventsthat are clearly separated in time, rather than bytranscriptional bursts. In contrast, PDR5, a generegulated by the transcription coactivator", "metadata": {}}
+{"_id": "16242975", "title": "", "text": "A complete landscape of post-transcriptionalmodifications in mammalian mitochondrialtRNAsIn mammalian mitochondria, 22 species oftRNAs encoded in mitochondrial DNA play crucialroles in the translation of 13 essential subunits ofthe respiratory chain complexes involved inoxidative phosphorylation. Followingtranscription, mitochondrial tRNAs are modifiedby nuclear-encoded tRNA-modifying enzymes.These modifications are required for the properfunctioning of mitochondrial tRNAs (mt tRNAs),and the absence of these modifications can causepathological consequences. To date, however,the information available about thesemodifications has been incomplete. To addressthis issue, we isolated all 22 species of mt tRNAsfrom bovine liver and comprehensivelydetermined the post-transcriptional modificationsin each tRNA by mass spectrometry. Here, wedescribe the primary structures withpost-transcriptional modifications of sevenspecies of mt tRNAs which were previously", "metadata": {}}
+{"_id": "16252863", "title": "", "text": "Preventing coronary heart disease: B vitaminsand homocysteine.The list of preventable andreversible risk factors for atheroscleroticcardiovascular disease continues to grow.Cigarette smoking, high blood pressure, physicalinactivity, elevated cholesterol, underlyinglipoprotein abnormalities, lipoprotein(a),diabetes, overweight, male gender, and age arewell-established risk factors. During the 1990s,there have been many reports associatingelevated plasma homocysteine levels witharteriosclerotic cardiovascular disease andconsistent evidence that dietary andsupplemental folic acid can reduce homocysteinelevels.1 2   The article by Robinson andcolleagues3 in this issue of Circulation presentsfurther evidence of the importance ofhomocysteine and suggestive evidence thatplasma folate and plasma pyrixodal-l-phosphate(vitamin B6) are protective factors. Their study ispart of the European Concerted Action Project,4which examined 750 patients younger than age", "metadata": {}}
+{"_id": "16256507", "title": "", "text": "Relationship between serum parathyroidhormone levels, vitamin D sufficiency, andcalcium intake.CONTEXT Adequate vitamin Dstatus for optimum bone health has receivedincreased recognition in recent years; however,the ideal intake is not known. Serum25-hydroxyvitamin D is the generally acceptedindicator of vitamin D status, but no universalreference level has been reached. OBJECTIVE Toinvestigate the relative importance of highcalcium intake and serum 25-hydroxyvitamin Dfor calcium homeostasis, as determined byserum intact parathyroid hormone (PTH).DESIGN, SETTING, AND PARTICIPANTSCross-sectional study of 2310 healthy Icelandicadults who were divided equally into 3 agegroups (30-45 years, 50-65 years, or 70-85years) and recruited from February 2001 toJanuary 2003. They were administered asemi-quantitative food frequency questionnaire,which assessed vitamin D and calcium intake.Participants were further divided into groups", "metadata": {}}
+{"_id": "16267205", "title": "", "text": "Sex-specific effects of the DAF-12 steroidreceptor on aging in Caenorhabditis elegans.Sexdifferences in longevity and aging are seenthroughout the animal kingdom. These are likelyto result, in part, from sex differences inendocrinology. In the nematode Caenorhabditiselegans, males are the longer-lived sex. Here weexplore the possibility that sex differences ininsulin/insulin-like growth factor 1 (IGF-1) andsteroid endocrinology contribute to this sexdifference in aging by studying C. eleganspopulations in liquid culture. We report that inhermaphrodite populations, mutational loss ofthe DAF-12 steroid receptor affected life span asin previous plate-culture studies: mutantlongevity is suppressed in a weak daf-2insulin/IGF-1 receptor mutant but enhanced in astronger daf-2 mutant. However, in males,mutation of daf-12 had little effect on aging ineither weak or strong daf-2 mutants. Moreover,while mutation of daf-12 marginally reduced lifespan in daf-2(+) hermaphrodites, as in", "metadata": {}}
+{"_id": "16270577", "title": "", "text": "Nonclassical binding of formylated peptide incrystal structure of the MHC class lb moleculeH2-M3H2-M3 is a class Ib MHC molecule of themouse with a 10(4)-fold preference for bindingN-formylated peptides. To elucidate the basis ofthis unusual specificity, we expressed andcrystallized a soluble form of M3 with aformylated nonamer peptide, fMYFINILTL, anddetermined the structure by X-raycrystallography. M3, refined at 2.1 A resolution,resembles class la MHC molecules in its overallstructure, but differs in the peptide-bindinggroove. The A pocket, which usuallyaccommodates the free N-terminus of a boundpeptide, is closed, and the peptide is shifted oneresidue, such that the P1 side chain is lodged inthe B pocket. The formyl group is coordinated byHis-9 and a bound water on the floor of thegroove.", "metadata": {}}
+{"_id": "16280642", "title": "", "text": "Sequential signals toward podosome formation inNIH-src cellsPodosomes (also termedinvadopodia in cancer cells) are actin-richadhesion structures with matrix degradationactivity that develop in various cell types.Despite their significant physiologicalimportance, the molecular mechanism ofpodosome formation is largely unknown. In thisstudy, we investigated the molecularmechanisms of podosome formation. Theexpression of various phosphoinositide-bindingdomains revealed that the podosomes inSrc-transformed NIH3T3 (NIH-src) cells areenriched with PtdIns(3,4)P2, suggesting animportant role of this phosphoinositide inpodosome formation. Live-cell imaging analysisrevealed that Src-expression stimulatedpodosome formation at focal adhesions ofNIH3T3 cells after PtdIns(3,4)P2 accumulation.The adaptor protein Tks5/FISH, which isessential for podosome formation, was found toform a complex with Grb2 at adhesion sites in an", "metadata": {}}
+{"_id": "16284655", "title": "", "text": "Forebrain engraftment by human glial progenitorcells enhances synaptic plasticity and learning inadult mice.Human astrocytes are larger andmore complex than those of infraprimatemammals, suggesting that their role in neuralprocessing has expanded with evolution. Toassess the cell-autonomous andspecies-selective properties of human glia, weengrafted human glial progenitor cells (GPCs)into neonatal immunodeficient mice. Uponmaturation, the recipient brains exhibited largenumbers and high proportions of both humanglial progenitors and astrocytes. The engraftedhuman glia were gap-junction-coupled to hostastroglia, yet retained the size andpleomorphism of hominid astroglia, andpropagated Ca2+ signals 3-fold faster than theirhosts. Long-term potentiation (LTP) was sharplyenhanced in the human glial chimeric mice, aswas their learning, as assessed by Barnes mazenavigation, object-location memory, and bothcontextual and tone fear conditioning. Mice", "metadata": {}}
+{"_id": "16287725", "title": "", "text": "Reprogramming of human fibroblasts topluripotency with lineage specifiers.Since theinitial discovery that OCT4, SOX2, KLF4, andc-MYC overexpression sufficed for the inductionof pluripotency in somatic cells, methodologiesreplacing the original factors have enhanced ourunderstanding of the reprogramming process.However, unlike in mouse, OCT4 has not beenreplaced successfully during reprogramming ofhuman cells. Here we report on a strategy toaccomplish this replacement. Through acombination of transcriptome and bioinformaticanalysis we have identified factors previouslycharacterized as being lineage specifiers that areable to replace OCT4 and SOX2 in thereprogramming of human fibroblasts. Our resultsshow that it is possible to replace OCT4 andSOX2 simultaneously with alternative lineagespecifiers in the reprogramming of human cells.At a broader level, they also support a model inwhich counteracting lineage specificationnetworks underlies the induction of pluripotency.", "metadata": {}}
+{"_id": "16319097", "title": "", "text": "Mechanisms of endocytosis.Endocyticmechanisms control the lipid and proteincomposition of the plasma membrane, therebyregulating how cells interact with theirenvironments. Here, we review what is knownabout mammalian endocytic mechanisms, withfocus on the cellular proteins that control theseevents. We discuss the well-studiedclathrin-mediated endocytic mechanisms anddissect endocytic pathways that proceedindependently of clathrin. Theseclathrin-independent pathways include theCLIC/GEEC endocytic pathway, arf6-dependentendocytosis, flotillin-dependent endocytosis,macropinocytosis, circular doral ruffles,phagocytosis, and trans-endocytosis. We alsocritically review the role of caveolae andcaveolin1 in endocytosis. We highlight the rolesof lipids, membrane curvature-modulatingproteins, small G proteins, actin, and dynamin inendocytic pathways. We discuss the functionalrelevance of distinct endocytic pathways and", "metadata": {}}
+{"_id": "16322674", "title": "", "text": "Birth Size and Breast Cancer Risk: Re-analysis ofIndividual Participant Data from 32StudiesBACKGROUND Birth size, perhaps a proxyfor prenatal environment, might be a correlate ofsubsequent breast cancer risk, but findings fromepidemiological studies have been inconsistent.We re-analysed individual participant data frompublished and unpublished studies to obtainmore precise estimates of the magnitude andshape of the birth size-breast cancer association.METHODS AND FINDINGS Studies wereidentified through computer-assisted and manualsearches, and personal communication withinvestigators. Individual participant data from 32studies, comprising 22,058 breast cancer cases,were obtained. Random effect models were used,if appropriate, to combine study-specificestimates of effect. Birth weight was positivelyassociated with breast cancer risk in studiesbased on birth records (pooled relative risk [RR]per one standard deviation [SD] [= 0.5 kg]increment in birth weight: 1.06; 95% confidence", "metadata": {}}
+{"_id": "16346504", "title": "", "text": "LncRNA-GAS5 induces PTEN expression throughinhibiting miR-103 in endometrial cancercellsBACKGROUND Growth arrest-specific 5(GAS5) was reported to be implicated andaberrantly express in multiple cancers. However,the expression and mechanism of action of GAS5were largely poor understood in endometrialcarcinoma. RESULTS According to the result ofreal-time reverse-transcriptase polymerase chainreaction (RT-PCR) and flow cytometry analysis,we identified that GAS5 was down-regulated inendometrial cancer cells and stimulated theapoptosis of endometrial cancer cells. Toinvestigate the expression of GAS5, PTEN andmiR-103, RT-PCR was performed. And we foundthat the expression of PTEN was up-regulatedwhen endometrial cancer cells overexpressedGAS5. The prediction of bioinformatics onlinerevealed that GAS5 could bind to miR-103, whichwas further found to be regulated by GAS5.Finally, we found that miR-103 mimic coulddecrease the mRNA and protein levels of PTEN", "metadata": {}}
+{"_id": "16355392", "title": "", "text": "Modification of kidney barrier function by theurokinase receptorPodocyte dysfunction,represented by foot process effacement andproteinuria, is often the starting point forprogressive kidney disease. Therapies aimed atthe cellular level of the disease are currently notavailable. Here we show that induction ofurokinase receptor (uPAR) signaling in podocytesleads to foot process effacement and urinaryprotein loss via a mechanism that includeslipid-dependent activation of αvβ3 integrin. Micelacking uPAR (Plaur−/−) are protected fromlipopolysaccharide (LPS)-mediated proteinuriabut develop disease after expression of aconstitutively active β3 integrin. Gene transferstudies reveal a prerequisite for uPAR expressionin podocytes, but not in endothelial cells, for thedevelopment of LPS-mediated proteinuria.Mechanistically, uPAR is required to activateαvβ3 integrin in podocytes, promoting cellmotility and activation of the small GTPasesCdc42 and Rac1. Blockade of αvβ3 integrin", "metadata": {}}
+{"_id": "16361581", "title": "", "text": "Jagged1-induced Notch signaling drivesproliferation of multiple myeloma cells.Notchreceptors expressed on hematopoietic stem cellsinteract with their ligands on bone marrowstromal cells and thereby control cell fatedecisions and survival. We recentlydemonstrated that Notch signaling is involved inproliferation and survival of B cell-derived tumorcells of classic Hodgkin disease and described anovel mechanism for the oncogenic capacity ofNotch. In this study we investigated whetherNotch signaling is involved in the tightinteractions between neoplastic plasma cells andtheir bone marrow microenvironment, which areessential for tumor cell growth in multiplemyeloma (MM). Here we demonstrate that Notchreceptors and their ligand Jagged1 are highlyexpressed in cultured and primary MM cells,whereas nonneoplastic counterparts show low toundetectable levels of Notch. Functional dataindicate that ligand-induced Notch signaling is agrowth factor for MM cells and suggest that these", "metadata": {}}
+{"_id": "16364639", "title": "", "text": "An Extensive MicroRNA-Mediated Network ofRNA-RNA Interactions Regulates EstablishedOncogenic Pathways in GlioblastomaBy analyzinggene expression data in glioblastoma incombination with matched microRNA profiles, wehave uncovered a posttranscriptional regulationlayer of surprising magnitude, comprising morethan 248,000 microRNA (miR)-mediatedinteractions. These include \u00007,000 genes whosetranscripts act as miR \"sponges\" and 148 genesthat act through alternative, nonspongeinteractions. Biochemical analyses in cell linesconfirmed that this network regulatesestablished drivers of tumor initiation andsubtype implementation, including PTEN,PDGFRA, RB1, VEGFA, STAT3, and RUNX1,suggesting that these interactions mediatecrosstalk between canonical oncogenic pathways.siRNA silencing of 13 miR-mediated PTENregulators, whose locus deletions are predictiveof PTEN expression variability, was sufficient todownregulate PTEN in a 3'UTR-dependent", "metadata": {}}
+{"_id": "16375102", "title": "", "text": "Direct reprogramming of mouse fibroblasts toneural progenitors.The simple yet powerfultechnique of induced pluripotency mayeventually supply a wide range of differentiatedcells for cell therapy and drug development.However, making the appropriate cells viainduced pluripotent stem cells (iPSCs) requiresreprogramming of somatic cells and subsequentredifferentiation. Given how arduous and lengthythis process can be, we sought to determinewhether it might be possible to convert somaticcells into lineage-specific stem/progenitor cells ofanother germ layer in one step, bypassing theintermediate pluripotent stage. Here we showthat transient induction of the fourreprogramming factors (Oct4, Sox2, Klf4, andc-Myc) can efficiently transdifferentiatefibroblasts into functional neural stem/progenitorcells (NPCs) with appropriate signaling inputs.Compared with induced neurons (or iN cells,which are directly converted from fibroblasts),transdifferentiated NPCs have the distinct", "metadata": {}}
+{"_id": "16389141", "title": "", "text": "Tissue-Specific Knockout of the Insulin Receptorin Pancreatic β Cells Creates an Insulin SecretoryDefect Similar to that in Type 2DiabetesDysfunction of the pancreatic beta cell isan important defect in the pathogenesis of type 2diabetes, although its exact relationship to theinsulin resistance is unclear. To determinewhether insulin signaling has a functional role inthe beta cell we have used the Cre-loxP systemto specifically inactivate the insulin receptor genein the beta cells. The resultant mice exhibit aselective loss of insulin secretion in response toglucose and a progressive impairment of glucosetolerance. These data indicate an importantfunctional role for the insulin receptor in glucosesensing by the pancreatic beta cell and suggestthat defects in insulin signaling at the level of thebeta cell may contribute to the observedalterations in insulin secretion in type 2 diabetes.", "metadata": {}}
+{"_id": "16390264", "title": "", "text": "Social variations in access to hospital care forpatients with colorectal, breast, and lung cancerbetween 1999 and 2006: retrospective analysisof hospital episode statisticsOBJECTIVES Todetermine the extent to which type of hospitaladmission (emergency compared with elective)and surgical procedure varied by socioeconomiccircumstances, age, sex, and year of admissionfor colorectal, breast, and lung cancer. DESIGNRepeated cross sectional study with data fromindividual patients, 1 April 1999 to 31 March2006. SETTING Hospital episode statistics (HES)dataset. PARTICIPANTS 564 821 patients aged50 and over admitted with a diagnosis ofcolorectal, breast, or lung cancer. MAINOUTCOME MEASURES Proportion of patientsadmitted as emergencies, and the proportionreceiving the recommended surgical treatment.RESULTS Patients from deprived areas, olderpeople, and women were more likely to beadmitted as emergencies. For example, theadjusted odds ratio for patients with breast", "metadata": {}}
+{"_id": "16398049", "title": "", "text": "Identification of Gene Positioning Factors UsingHigh-Throughput Imaging MappingGenomes arearranged non-randomly in the 3D space of thecell nucleus. Here, we have developed HIPMap, ahigh-precision, high-throughput, automatedfluorescent in situ hybridization imaging pipeline,for mapping of the spatial location of genomeregions at large scale. High-throughput imagingposition mapping (HIPMap) enabled an unbiasedsiRNA screen for factors involved in genomeorganization in human cells. We identify 50cellular factors required for proper positioning ofa set of functionally diverse genomic loci.Positioning factors include chromatin remodelers,histone modifiers, and nuclear envelope and poreproteins. Components of the replication andpost-replication chromatin re-assemblymachinery are prominently represented amongpositioning factors, and timely progression ofcells through replication, but not mitosis, isrequired for correct gene positioning. Our resultsestablish a method for the large-scale mapping", "metadata": {}}
+{"_id": "16398827", "title": "", "text": "Astrocyte-Mediated Distributed Plasticity atHypothalamic Glutamate SynapsesAfferentactivity can induce fast, feed-forward changes insynaptic efficacy that are synapse specific. Usingcombined electrophysiology, caged moleculephotolysis, and Ca(2+) imaging, we describe aplasticity in which the recruitment of astrocytesin response to afferent activity causes a fast andfeed-forward, yet distributed increase in theamplitude of quantal synaptic currents atmultiple glutamate synapses on magnocellularneurosecretory cells in the hypothalamicparaventricular nucleus. The plasticity is largelymultiplicative, consistent with a proportionalincrease or \"scaling\" in the strength of allsynapses on the neuron. This effect requires ametabotropic glutamate receptor-mediated risein Ca(2+) in the astrocyte processes surroundingthe neuron and the release of the gliotransmitterATP, which acts on postsynaptic purinergicreceptors. These data provide evidence for aform of distributed synaptic plasticity that is", "metadata": {}}
+{"_id": "16422880", "title": "", "text": "Effect of smoking reduction on lung cancerrisk.CONTEXT Many smokers are unable orunwilling to completely quit smoking. A proposedmeans of harm reduction is to reduce thenumber of cigarettes smoked per day. However,it is not clear whether this strategy decreases therisk for tobacco-related diseases. OBJECTIVE Toassess the effects of smoking reduction on lungcancer incidence. DESIGN, SETTING, ANDPARTICIPANTS Observational population-basedcohort study with up to 31 years of follow-upfrom the Copenhagen Centre for ProspectivePopulation Studies, which administrates datafrom 3 longitudinal studies conducted inCopenhagen and suburbs, the Copenhagen CityHeart Study, the Copenhagen Male Study, andthe Glostrup Population Studies, Denmark.Participants were 11,151 men and 8563 women(N = 19,714) aged 20 to 93 years, who attended2 consecutive examinations with a 5- to 10-yearinterval between 1964 and 1988. Participantsunderwent a physical examination and", "metadata": {}}
+{"_id": "16427454", "title": "", "text": "Facilities for macromolecular crystallography atthe Helmholtz-Zentrum BerlinThreemacromolecular crystallography (MX) beamlinesat the Helmholtz-Zentrum Berlin (HZB) areavailable for the regional, national andinternational structural biology user community.The state-of-the-art synchrotron beamlines forMX BL14.1, BL14.2 and BL14.3 are locatedwithin the low-β section of the BESSY II electronstorage ring. All beamlines are fed from asuperconducting 7 T wavelength-shifter insertiondevice. BL14.1 and BL14.2 are energy tunable inthe range 5-16 keV, while BL14.3 is afixed-energy side station operated at 13.8 keV.All three beamlines are equipped with CCDdetectors. BL14.1 and BL14.2 are in regular useroperation providing about 200 beam days peryear and about 600 user shifts to approximately50 research groups across Europe. BL14.3 hasinitially been used as a test facility and wasbrought into regular user mode operation duringthe year 2010. BL14.1 has recently been", "metadata": {}}
+{"_id": "16461149", "title": "", "text": "PHENIX: a comprehensive Python-based systemfor macromolecular structuresolutionMacromolecular X-ray crystallography isroutinely applied to understand biologicalprocesses at a molecular level. However,significant time and effort are still required tosolve and complete many of these structuresbecause of the need for manual interpretation ofcomplex numerical data using many softwarepackages and the repeated use of interactivethree-dimensional graphics. PHENIX has beendeveloped to provide a comprehensive systemfor macromolecular crystallographic structuresolution with an emphasis on the automation ofall procedures. This has relied on thedevelopment of algorithms that minimize oreliminate subjective input, the development ofalgorithms that automate procedures that aretraditionally performed by hand and, finally, thedevelopment of a framework that allows a tightintegration between the algorithms.", "metadata": {}}
+{"_id": "16465895", "title": "", "text": "Telomeric 3′ Overhangs Derive from Resectionby Exo1 and Apollo and Fill-In byPOT1b-Associated CSTA 3' overhang is critical forthe protection and maintenance of mammaliantelomeres, but its synthesis must be regulated toavoid excessive resection of the 5' end, whichcould cause telomere shortening. How thisbalance is achieved in mammals has not beenresolved. Here, we determine the mechanism for3' overhang synthesis in mouse cells byevaluating changes in telomeric overhangsthroughout the cell cycle and at leading- andlagging-end telomeres. Apollo, a nuclease boundto the shelterin subunit TRF2, initiates formationof the 3' overhang at leading-, but notlagging-end telomeres. Hyperresection by Apollois blocked at both ends by the shelterin proteinPOT1b. Exo1 extensively resects both telomereends, generating transient long 3' overhangs inS/G2. CST/AAF, a DNA polα.primase accessoryfactor, binds POT1b and shortens the extendedoverhangs produced by Exo1, likely through", "metadata": {}}
+{"_id": "16472469", "title": "", "text": "Targeting BRCA1 and BRCA2 Deficiencies withG-Quadruplex-InteractingCompoundsG-quadruplex (G4)-forming genomicsequences, including telomeres, representnatural replication fork barriers. Stalledreplication forks can be stabilized and restartedby homologous recombination (HR), which alsorepairs DNA double-strand breaks (DSBs) arisingat collapsed forks. We have previously shownthat HR facilitates telomere replication. Here, wedemonstrate that the replication efficiency ofguanine-rich (G-rich) telomeric repeats isdecreased significantly in cells lacking HR.Treatment with the G4-stabilizing compoundpyridostatin (PDS) increases telomere fragility inBRCA2-deficient cells, suggesting that G4formation drives telomere instability.Remarkably, PDS reduces proliferation ofHR-defective cells by inducing DSBaccumulation, checkpoint activation, andderegulated G2/M progression and by enhancingthe replication defect intrinsic to HR deficiency.", "metadata": {}}
+{"_id": "16488405", "title": "", "text": "Downloaded fromPhysical activity induces asubclinical inflammatory response, mediated inpart by leukocytes, and manifested by elevatedconcentrations of circulating proinflammatorycytokines, including interleukin (IL)-1β, IL-6, andtumor necrosis factor-α (TNF-α). However, thesource of the cytokines that appear duringexercise remains unknown. In this study, weexamined exercise-induced changes in plasmacytokine concentrations and their correspondingmRNA expression in peripheral bloodmononuclear cells. Ten healthy [peak oxygenuptake = 48.8 ± 6.5 (SD) ml · kg−1 · min−1]but untrained men [age = 25 ± 5 (SD) yr]undertook 3 h of exercise (cycling and inclinedwalking) at 60–65% peak oxygen uptake.Circulating leukocyte subset counts wereelevated during and 2 h postexercise butreturned to normal within 24 h. Plasmaconcentrations of IL-1β, IL-6, and TNF-α peakedat the end of exercise and remained elevated at2 h (IL-6) and up to 24 h (IL-1β and TNF-α)", "metadata": {}}
+{"_id": "16494316", "title": "", "text": "Receptor tyrosine kinases endocytosis inendothelium: biology and signaling.Receptortyrosine kinases are involved in regulation of keyprocesses in endothelial biology, includingproliferation, migration, and angiogenesis. It isnow generally accepted that receptor tyrosinekinase signaling occurs intracellularly and on theplasma membrane, although many importantdetails remain to be worked out. Endocytosis andsubsequent intracellular traffickingspatiotemporally regulate receptor tyrosinekinase signaling, whereas signaling endosomesprovide a platform for the compartmentalizationof signaling events. This review summarizesrecent advances in our understanding ofendothelial receptor tyrosine kinase endocytosisand signaling using vascular endothelial growthfactor receptor-2 as a paradigm.", "metadata": {}}
+{"_id": "16495649", "title": "", "text": "Ethnographic study of incidence and severity ofintravenous drug errors.OBJECTIVES Todetermine the incidence and clinical importanceof errors in the preparation and administration ofintravenous drugs and the stages of the processin which errors occur. DESIGN Prospectiveethnographic study using disguised observation.PARTICIPANTS Nurses who prepared andadministered intravenous drugs. SETTING 10wards in a teaching and non-teaching hospital inthe United Kingdom. MAIN OUTCOME MEASURESNumber, type, and clinical importance of errors.RESULTS 249 errors were identified. At least oneerror occurred in 212 out of 430 intravenousdrug doses (49%, 95% confidence interval 45%to 54%). Three doses (1%) had potentiallysevere errors, 126 (29%) potentially moderateerrors, and 83 (19%) potentially minor errors.Most errors occurred when giving bolus doses ormaking up drugs that required multiple steppreparation. CONCLUSIONS The rate ofintravenous drug errors was high. Although most", "metadata": {}}
+{"_id": "16510361", "title": "", "text": "Feature Selection with the Boruta PackageThisarticle describes a R package Boruta,implementing a novel feature selection algorithmfor finding emph{all relevant variables}. Thealgorithm is designed as a wrapper around aRandom Forest classification algorithm. Ititeratively removes the features which areproved by a statistical test to be less relevantthan random probes. The Boruta packageprovides a convenient interface to the algorithm.The short description of the algorithm andexamples of its application are presented.", "metadata": {}}
+{"_id": "16511863", "title": "", "text": "Integrin-linked kinase expression is elevated inhuman cardiac hypertrophy and induceshypertrophy in transgenic mice.BACKGROUNDAlthough numerous signaling pathways areknown to be activated in experimental cardiachypertrophy, the molecular basis of thehypertrophic response inherent in human heartdiseases remains largely unknown.Integrin-linked kinase (ILK) is a multifunctionalprotein kinase that physically links beta-integrinswith the actin cytoskeleton, suggesting apotential mechanoreceptor role. METHODS ANDRESULTS Here, we show a marked increase inILK protein levels in hypertrophic ventricles ofpatients with congenital and acquired outflowtract obstruction. This increase in ILK wasassociated with activation of the Rho familyguanine triphosphatases, Rac1 and Cdc42, andknown hypertrophic signaling kinases, includingextracellular signal-related kinases (ERK1/2) andp70 S6 kinase. Transgenic mice withcardiac-specific expression of a constitutively", "metadata": {}}
+{"_id": "16527698", "title": "", "text": "Functional and molecular defects of pancreaticislets in human type 2 diabetes.To shed furtherlight on the primary alterations of insulinsecretion in type 2 diabetes and the possiblemechanisms involved, we studied severalfunctional and molecular properties of isletsisolated from the pancreata of 13 type 2 diabeticand 13 matched nondiabetic cadaveric organdonors. Glucose-stimulated insulin secretionfrom type 2 diabetic islets was significantly lowerthan from control islets, whereas arginine- andglibenclamide-stimulated insulin release was lessmarkedly affected. The defects wereaccompanied by reduced mRNA expression ofGLUT1 and -2 and glucokinase and by diminishedglucose oxidation. In addition, AMP-activatedprotein kinase activation was reduced.Furthermore, the expression of insulin wasdecreased, and that of pancreatic duodenalhomeobox-1 (PDX-1) and forkhead box O1(Foxo-1) was increased. Nitrotyrosine and8-hydroxy-2'-deoxyguanosine concentrations,", "metadata": {}}
+{"_id": "16532419", "title": "", "text": "Induction of stem-like cells with malignantproperties by chronic exposure of human lungepithelial cells to single-walled carbonnanotubesBACKGROUND Carbon nanotubes(CNT) hold great promise to create new andbetter products for commercial and biomedicalapplications, but their long-term adverse healtheffects are a major concern. The objective of thisstudy was to address human lung cancer risksassociated with chronic pulmonary exposure tosingle-walled (SW) CNT through the fundamentalunderstanding of cellular and molecularprocesses leading to carcinogenesis. Wehypothesized that the acquisition of cancer stemcells (CSC), a subpopulation that drive tumorinitiation and progression, may contribute to CNTcarcinogenesis. METHODS Non-tumorigenichuman lung epithelial cells were chronicallyexposed to well-dispersed SWCNT for a period of6 months at the physiologically relevantconcentration of 0.02 μg/cm2 surface area dose.Chronic SWCNT-exposed cells were evaluated for", "metadata": {}}
+{"_id": "16541762", "title": "", "text": "Reprogramming factor stoichiometry influencesthe epigenetic state and biological properties ofinduced pluripotent stem cells.We compared twogenetically highly defined transgenic systems toidentify parameters affecting reprogramming ofsomatic cells to a pluripotent state. Our resultsdemonstrate that the level and stoichiometry ofreprogramming factors during thereprogramming process strongly influence theresulting pluripotency of iPS cells. Highexpression of Oct4 and Klf4 combined with lowerexpression of c-Myc and Sox2 produced iPS cellsthat efficiently generated \"all-iPSC mice\" bytetraploid (4n) complementation, maintainednormal imprinting at the Dlk1-Dio3 locus, anddid not create mice with tumors. Loss ofimprinting (LOI) at the Dlk1-Dio3 locus did notstrictly correlate with reduced pluripotencythough the efficiency of generating \"all-iPSCmice\" was diminished. Our data indicate thatstoichiometry of reprogramming factors caninfluence epigenetic and biological properties of", "metadata": {}}
+{"_id": "16546131", "title": "", "text": "Activator protein-1 (AP-1) DNA binding activity isinduced by hydroxyurea in organogenesis stagemouse embryosHydroxyurea is a potentteratogen; free radical scavengers orantioxidants reduce its teratogenicity. ActivatorProtein-1 (AP-1) and NF-kappaB areredox-sensitive transcription factors withimportant roles in normal development and thestress response. This study was designed todetermine if exposure to teratogenic doses ofhydroxyurea induces oxidative stress and altersgene expression by activating these transcriptionfactors. Pregnant mice were treated with salineor hydroxyurea (400, 500, or 600 mg/kg) ongestation day 9 (GD 9) and killed either on GD 9,0.5, 3, or 6 h after treatment, to assess oxidativestress and transcription factor activities, or onGD 18, to assess fetal development. Exposure to400 mg/kg hydroxyurea did not affect theprogeny, whereas exposure to 500 or 600 mg/kgresulted in dose-dependent increases in fetalresorptions and malformations, including curly", "metadata": {}}
+{"_id": "16550075", "title": "", "text": "BCL-6 represses genes that function inlymphocyte differentiation, inflammation, andcell cycle control.BCL-6, a transcriptionalrepressor frequently translocated in lymphomas,regulates germinal center B cell differentiationand inflammation. DNA microarray screeningidentified genes repressed by BCL-6, includingmany lymphocyte activation genes, suggestingthat BCL-6 modulates B cell receptor signals.BCL-6 repression of two chemokine genes,MIP-1alpha and IP-10, may also attenuateinflammatory responses. Blimp-1, another BCL-6target, is important for plasmacyticdifferentiation. Since BCL-6 expression issilenced in plasma cells, repression of blimp-1 byBCL-6 may control plasmacytic differentiation.Indeed, inhibition of BCL-6 function initiatedchanges indicative of plasmacytic differentiation,including decreased expression of c-Myc andincreased expression of the cell cycle inhibitorp27kip1. These data suggest that malignanttransformation by BCL-6 involves inhibition of", "metadata": {}}
+{"_id": "16557565", "title": "", "text": "Local, Efflux-Dependent Auxin Gradients as aCommon Module for Plant OrganFormationPlants, compared to animals, exhibitan amazing adaptability and plasticity in theirdevelopment. This is largely dependent on theability of plants to form new organs, such aslateral roots, leaves, and flowers duringpostembryonic development. Organ primordiadevelop from founder cell populations intoorgans by coordinated cell division anddifferentiation. Here, we show that organformation in Arabidopsis involves dynamicgradients of the signaling molecule auxin withmaxima at the primordia tips. These gradientsare mediated by cellular efflux requiringasymmetrically localized PIN proteins, whichrepresent a functionally redundant network forauxin distribution in both aerial and undergroundorgans. PIN1 polar localization undergoes adynamic rearrangement, which correlates withestablishment of auxin gradients and primordiumdevelopment. Our results suggest that", "metadata": {}}
+{"_id": "16562534", "title": "", "text": "Drosophila MICAL regulates myofilamentorganization and synaptic structureThe overallsize and structure of a synaptic terminal is animportant determinant of its function. In alarge-scale mutagenesis screen, designed toidentify Drosophila mutants with abnormallystructured neuromuscular junctions (NMJs), wediscovered mutations in Drosophila mical, aconserved gene encoding a multi-domain proteinwith a N-terminal monooxygenase domain. Inmical mutants, synaptic boutons do not sproutnormally over the muscle surface and tend toform clusters along synaptic branches and atnerve entry sites. Consistent with highexpression of MICAL in somatic muscles,immunohistochemical stainings reveal that thesubcellular localization and architecture ofcontractile muscle filaments are dramaticallydisturbed in mical mutants. Instead of beingintegrated into a regular sarcomeric pattern,actin and myosin filaments are disorganized andaccumulate beneath the plasmamembrane.", "metadata": {}}
+{"_id": "16572581", "title": "", "text": "Viral Infection of Engrafted Human Islets Leadsto DiabetesType 1 diabetes (T1D) ischaracterized by the destruction of theinsulin-producing β-cells of pancreatic islets.Genetic and environmental factors bothcontribute to T1D development. Viral infectionwith enteroviruses is a suspected trigger for T1D,but a causal role remains unproven andcontroversial. Studies in animals are problematicbecause of species-specific differences in hostcell susceptibility and immune responses tocandidate viral pathogens such as coxsackievirusB (CVB). In order to resolve the controversialrole of viruses in human T1D, we developed aviral infection model in immunodeficient micebearing human islet grafts. Hyperglycemia wasinduced in mice by specific ablation of nativeβ-cells. Human islets, which are naturallysusceptible to CVB infection, were transplantedto restore normoglycemia. Transplanted micewere infected with CVB4 and monitored forhyperglycemia. Forty-seven percent of", "metadata": {}}
+{"_id": "16605494", "title": "", "text": "MicroRNA-22 (miR-22) Overexpression IsNeuroprotective via General Anti-ApoptoticEffects and May also Target Specific Huntington’sDisease-Related MechanismsBACKGROUNDWhereas many causes and mechanisms ofneurodegenerative diseases have beenidentified, very few therapeutic strategies haveemerged in parallel. One possible explanation isthat successful treatment strategy may requiresimultaneous targeting of more than onemolecule of pathway. A new therapeuticapproach to have emerged recently is theengagement of microRNAs (miRNAs), whichaffords the opportunity to target multiple cellularpathways simultaneously using a singlesequence. METHODOLOGY/PRINCIPAL FINDINGSWe identified miR-22 as a potentiallyneuroprotective miRNA based on its predictedregulation of several targets implicated inHuntington's disease (histone deacetylase 4(HDAC4), REST corepresor 1 (Rcor1) andregulator of G-protein signaling 2 (Rgs2)) and its", "metadata": {}}
+{"_id": "16625620", "title": "", "text": "Research in cardiovascular care: a positionstatement of the Council on CardiovascularNursing and Allied Professionals of the EuropeanSociety of Cardiology.To deliver optimal patientcare, evidence-based care is advocated andresearch is needed to support health care staff ofall disciplines in deciding which options to use intheir daily practice. Due to the increasingcomplexity of cardiac care across the life span ofpatients combined with the increasingopportunities and challenges in multidisciplinaryresearch, the Science Committee of the Councilon Cardiovascular Nursing and AlliedProfessionals (CCNAP) recognised the need for aposition statement to guide researchers,policymakers and funding bodies to contribute tothe advancement of the body of knowledge thatis needed to further improve cardiovascular care.In this paper, knowledge gaps in currentresearch related to cardiovascular patient careare identified, upcoming challenges are exploredand recommendations for future research are", "metadata": {}}
+{"_id": "16626264", "title": "", "text": "Genome-Wide Dynamics of Htz1, a Histone H2AVariant that Poises Repressed/Basal Promotersfor Activation through Histone LossHistonevariants help specialize chromatin regions;however, their impact on transcriptionalregulation is largely unknown. Here, wedetermined the genome-wide localization anddynamics of Htz1, the yeast histone H2A variant.Htz1 localizes to hundreds of repressed/basal PolII promoters and prefers TATA-less promoters.Specific Htz1 deposition requires the SWR1complex, which largely colocalizes with Htz1.Htz1 occupancy correlates with particular histonemodifications, and Htz1 deposition is partiallyreliant on Gcn5 (a histone acetyltransferase) andBdf1, an SWR1 complex member that bindsacetylated histones. Changes in growthconditions cause a striking redistribution of Htz1from activated to repressed/basal promoters.Furthermore, Htz1 promotes full gene activationbut does not generally impact repression.Importantly, Htz1 releases from purified", "metadata": {}}
+{"_id": "16626846", "title": "", "text": "Metagenomic analysis of microbial consortiumfrom natural crude oil that seeps into the marineecosystem offshore Southern CaliforniaCrude oilscan be major contaminants of the marineecosystem and microorganisms play a significantrole in the degradation of its main constituents.To increase our understanding of the microbialhydrocarbon degradation process in the marineecosystem, we collected crude oil from an activeseep area located in the Santa Barbara Channel(SBC) and generated a total of about 52 Gb ofraw metagenomic sequence data. The assembleddata comprised ~500 Mb, representing ~1.1million genes derived primarily fromchemolithoautotrophic bacteria. Members ofOceanospirillales, a bacterial order belonging tothe Deltaproteobacteria, recruited less than 2%of the assembled genes within the SBCmetagenome. In contrast, the microbialcommunity associated with the oil plume thatdeveloped in the aftermath of the DeepwaterHorizon (DWH) blowout in 2010, was dominated", "metadata": {}}
+{"_id": "16627684", "title": "", "text": "Hmga2 Promotes Neural Stem Cell Self-Renewalin Young but Not Old Mice by Reducing p16Ink4aand p19Arf ExpressionStem cells persistthroughout life in diverse tissues by undergoingself-renewing divisions. Self-renewal capacitydeclines with age, partly because of increasingexpression of the tumor suppressor p16(Ink4a).We discovered that the Hmga2 transcriptionalregulator is highly expressed in fetal neural stemcells but that expression declines with age. Thisdecrease is partly caused by the increasingexpression of let-7b microRNA, which is knownto target HMGA2. Hmga2-deficient mice showreduced stem cell numbers and self-renewalthroughout the central and peripheral nervoussystems of fetal and young-adult mice but notold-adult mice. Furthermore, p16(Ink4a) andp19(Arf) expression were increased inHmga2-deficient fetal and young-adult stemcells, and deletion of p16(Ink4a) and/or p19(Arf)partially restored self-renewal capacity. let-7boverexpression reduced Hmga2 and increased", "metadata": {}}
+{"_id": "16630060", "title": "", "text": "Genotoxic Stress Abrogates Renewal ofMelanocyte Stem Cells by Triggering TheirDifferentiationSomatic stem cell depletion due tothe accumulation of DNA damage has beenimplicated in the appearance of aging-relatedphenotypes. Hair graying, a typical sign of agingin mammals, is caused by the incompletemaintenance of melanocyte stem cells (MSCs)with age. Here, we report that irreparable DNAdamage, as caused by ionizing radiation,abrogates renewal of MSCs in mice. Surprisingly,the DNA-damage response triggers MSCdifferentiation into mature melanocytes in theniche, rather than inducing their apoptosis orsenescence. The resulting MSC depletion leads toirreversible hair graying. Furthermore, deficiencyof Ataxia-telangiectasia mutated (ATM), a centraltransducer kinase of the DNA-damage response,sensitizes MSCs to ectopic differentiation,demonstrating that the kinase protects MSCsfrom their premature differentiation byfunctioning as a \"stemness checkpoint\" to", "metadata": {}}
+{"_id": "16630996", "title": "", "text": "Gemcitabine chemoresistance and molecularmarkers associated with gemcitabine transportand metabolism in human pancreatic cancercellsTo identify predictive molecular markers forgemcitabine resistance, we investigated changesin the expression of four genes associated withgemcitabine transport and metabolism duringthe development of acquired gemcitabineresistance of pancreatic cancer cell lines. Theexpression levels of human equilibrativenucleoside transporter-1 (hENT1), deoxycytidinekinase (dCK), RRM1, and RRM2 mRNA wereanalysed by real-time light cycler-PCR in varioussubclones during the development of acquiredresistance to gemcitabine. Real-time lightcycler-PCR demonstrated that the expressionlevels of either RRM1 or RRM2 progressivelyincreased during the development of gemcitabineresistance. Expression of dCK was slightlyincreased in cells resistant to lowerconcentrations of gemcitabine, but wasdecreased below the undetectable level in higher", "metadata": {}}
+{"_id": "16644043", "title": "", "text": "The DNA Damage Machinery and HomologousRecombination Pathway Act Consecutively toProtect Human TelomeresTelomeres protectchromosome ends from being detected as lesionsand from triggering DNA damage checkpoints.Paradoxically, telomere function depends oncheckpoint proteins such as ATM and ATR, but amolecular model explaining this seeminglycontradictory relationship has been missing sofar. Here we show that the DNA damagemachinery acts on telomeres in at least twoindependent steps. First, the ATR-dependentmachinery is recruited to telomeres beforetelomere replication is completed, likely inresponse to single-stranded DNA resulting fromreplication fork stalling. Second, after replication,telomeres attract ATM and the homologousrecombination (HR) machinery. In vivo and invitro results suggest that the HR machinery isrequired for formation of a telomere-specificstructure at chromosome ends after replication.Our results suggest that telomere ends need to", "metadata": {}}
+{"_id": "16660256", "title": "", "text": "Sprouty1 Regulates Reversible Quiescence of aSelf-Renewing Adult Muscle Stem Cell Poolduring RegenerationSatellite cells are skeletalmuscle stem cells capable of self-renewal anddifferentiation after transplantation, but whetherthey contribute to endogenous muscle fiberrepair has been unclear. The transcription factorPax7 marks satellite cells and is critical forestablishing the adult satellite cell pool. By usinga lineage tracing approach, we show that afterinjury, quiescent adult Pax7(+) cells enter thecell cycle; a subpopulation returns to quiescenceto replenish the satellite cell compartment, whileothers contribute to muscle fiber formation. Wedemonstrate that Sprouty1 (Spry1), a receptortyrosine kinase signaling inhibitor, is expressedin quiescent Pax7(+) satellite cells in uninjuredmuscle, downregulated in proliferating myogeniccells after injury, and reinduced as Pax7(+) cellsre-enter quiescence. We show that Spry1 isrequired for the return to quiescence andhomeostasis of the satellite cell pool during", "metadata": {}}
+{"_id": "16669757", "title": "", "text": "Mechanosensitivity in the enteric nervoussystemThe enteric nervous system (ENS)autonomously controls gut muscle activity.Mechanosensitive enteric neurons (MEN) initiatereflex activity by responding to mechanicaldeformation of the gastrointestinal wall. MENthroughout the gut primarily respond tocompression or stretch rather than to shearforce. Some MEN are multimodal as theyrespond to compression and stretch. Dependingon the region up to 60% of the entire ENSpopulation responds to mechanical stress. MENfire action potentials after mechanical stimulationof processes or soma although they are moresensitive to process deformation. There are atleast two populations of MEN based on theirsensitivity to different modalities of mechanicalstress and on their firing pattern. (1) Rapidly,slowly and ultra-slowly adapting neurons whichencode compressive forces. (2) Ultra-slowlyadapting stretch-sensitive neurons encodingtensile forces. Rapid adaptation of firing is", "metadata": {}}
+{"_id": "16686383", "title": "", "text": "Phosphorylation of centromeric histone H3variant regulates chromosome segregation inSaccharomyces cerevisiaeThe centromerichistone H3 variant (CenH3) is essential forchromosome segregation in eukaryotes. Weidentify posttranslational modifications ofSaccharomyces cerevisiae CenH3, Cse4.Functional characterization of cse4phosphorylation mutants shows growth andchromosome segregation defects when combinedwith kinetochore mutants okp1 and ame1. Usinga phosphoserine-specific antibody, we show thatthe association of phosphorylated Cse4 withcentromeres increases in response to defectivemicrotubule attachment or reduced cohesion. Wedetermine that evolutionarily conservedIpl1/Aurora B contributes to phosphorylation ofCse4, as levels of phosphorylated Cse4 arereduced at centromeres in ipl1 strains in vivo,and in vitro assays show phosphorylation of Cse4by Ipl1. Consistent with these results, weobserve that a phosphomimetic cse4-4SD", "metadata": {}}
+{"_id": "16691520", "title": "", "text": "Genome-wide analysis of estrogen receptorbinding sitesThe estrogen receptor is the mastertranscriptional regulator of breast cancerphenotype and the archetype of a moleculartherapeutic target. We mapped all estrogenreceptor and RNA polymerase II binding sites ona genome-wide scale, identifying the authenticcis binding sites and target genes, in breastcancer cells. Combining this unique resource withgene expression data demonstrates distincttemporal mechanisms of estrogen-mediatedgene regulation, particularly in the case ofestrogen-suppressed genes. Furthermore, thisresource has allowed the identification ofcis-regulatory sites in previously unexploredregions of the genome and the cooperatingtranscription factors underlying estrogensignaling in breast cancer.", "metadata": {}}
+{"_id": "16693950", "title": "", "text": "Replicative aging in yeast: the means to theend.Progress in aging research is now rapid, andsurprisingly, studies in a single-celled eukaryoteare a driving force. The genetic modulators ofreplicative life span in yeast are being identified,the molecular events that accompany aging arebeing discovered, and the extent to whichlongevity pathways are conserved between yeastand multicellular eukaryotes is being tested. Inthis review, we provide a brief retrospective viewon the development of yeast as a model foraging and then turn to recent discoveries thathave pushed aging research into novel directionsand also linked aging in yeast to well-developedhypotheses in mammals. Although the questionof what causes aging still cannot be answereddefinitively, that day may be rapidlyapproaching.", "metadata": {}}
+{"_id": "16701509", "title": "", "text": "Serum high-density lipoprotein cholesterol,metabolic profile, and breast cancerrisk.BACKGROUND The prevalence of metabolicsyndrome (obesity, glucose intolerance, lowserum high-density lipoprotein cholesterol[HDL-C], high serum triglycerides, hypertension)is high and increasing in parallel with anincreasing breast cancer incidence worldwide.HDL-C represents an important aspect of thesyndrome, yet its role in breast cancer is stillundefined. METHODS In two population-basedscreening surveys during 1977-1983 and1985-1987, serum HDL-C was assayedenzymatically among 38,823 Norwegian womenaged 17-54 years at entry. Height, weight, bloodpressure, serum lipids, fat and energy intake,physical activity, parity, oral contraceptive use,hormone therapy use, alcohol intake, andtobacco use were also assessed. We used Coxproportional hazards modeling to estimate therelative risk (RR) of breast cancer associatedwith serum HDL-C levels and to adjust for", "metadata": {}}
+{"_id": "16705338", "title": "", "text": "Prediction of Chemical-Protein InteractionsNetwork with Weighted Network-Based InferenceMethodChemical-protein interaction (CPI) is thecentral topic of target identification and drugdiscovery. However, large scale determination ofCPI is a big challenge for in vitro or in vivoexperiments, while in silico prediction showsgreat advantages due to low cost and highaccuracy. On the basis of our previousdrug-target interaction prediction vianetwork-based inference (NBI) method, wefurther developed node- and edge-weighted NBImethods for CPI prediction here. Twocomprehensive CPI bipartite networks extractedfrom ChEMBL database were used to evaluatethe methods, one containing 17,111 CPI pairsbetween 4,741 compounds and 97 Gprotein-coupled receptors, the other including13,648 CPI pairs between 2,827 compounds and206 kinases. The range of the area underreceiver operating characteristic curves was 0.73to 0.83 for the external validation sets, which", "metadata": {}}
+{"_id": "16712164", "title": "", "text": "Exploiting the yeast stress-activated signalingnetwork to inform on stress biology and diseasesignalingHealthy cells utilize intricate systems tomonitor their environment and mount robustresponses in the event of cellular stress.Whether stress arises from external insults ordefects due to mutation and disease, cells mustbe able to respond precisely to mount theappropriate defenses. Multi-faceted stressresponses are generally coupled with arrest ofgrowth and cell-cycle progression, which bothlimits the transmission of damaged materials andserves to reallocate limited cellular resourcestoward defense. Therefore, stress defense versusrapid growth represent competing interests inthe cell. How eukaryotic cells set the balancebetween defense versus proliferation, and inparticular knowledge of the regulatory networksthat control this decision, are poorly understood.In this perspective, we expand upon our recentwork inferring the stress-activated signalingnetwork in budding yeast, which captures", "metadata": {}}
+{"_id": "16728949", "title": "", "text": "Cell Stem Cell Review FoxO Transcription Factorsand Stem Cell Homeostasis: Insights from theHematopoietic SystemThe forkhead O (FoxO)family of transcription factors participates indiverse physiologic processes, includinginduction of cell-cycle arrest, stress resistance,differentiation, apoptosis, and metabolism.Several recent studies indicate thatFoxO-dependent signaling is required forlong-term regenerative potential of thehematopoietic stem cell (HSC) compartmentthrough regulation of HSC response tophysiologic oxidative stress, quiescence, andsurvival. These observations link FoxO functionin mammalian systems with the evolutionarilyconserved role of FoxO in promotion of stressresistance and longevity in lower phylogeneticsystems. Furthermore, these findings haveimplications for aging in higher organisms and inmalignant stem cell biology, and suggest thatFoxOs may play an important role in themaintenance and integrity of stem cell", "metadata": {}}
+{"_id": "16732790", "title": "", "text": "A Teratocarcinoma-Like Human Embryonic StemCell (hESC) Line and Four hESC Lines RevealPotentially Oncogenic Genomic ChangesThe firstSwiss human embryonic stem cell (hESC) line,CH-ES1, has shown features of a malignant cellline. It originated from the only singleblastomere that survived cryopreservation of anembryo, and it more closely resemblesteratocarcinoma lines than other hESC lines withrespect to its abnormal karyotype and itsformation of invasive tumors when injected intoSCID mice. The aim of this study was tocharacterize the molecular basis of theoncogenicity of CH-ES1 cells, we looked forabnormal chromosomal copy number (by arrayComparative Genomic Hybridization, aCGH) andsingle nucleotide polymorphisms (SNPs). To seehow unique these changes were, we comparedthese results to data collected from the 2102Epteratocarcinoma line and four hESC lines (H1,HS293, HS401 and SIVF-02) which displayednormal G-banding result. We identified genomic", "metadata": {}}
+{"_id": "16734530", "title": "", "text": "The Association between Single-NucleotidePolymorphisms of ORAI1 Gene and BreastCancer in a Taiwanese PopulationBACKGROUNDBreast cancer is the most common malignancy inwomen. There is increasing evidence suggestingthat ORAI1, components of store-operatedcalcium channel, play a pivotal role in breastcancer progression and metastasis. METHODS Atotal of 384 female patients with breast cancerwere included in this study. We selected fiverepresentative tagging ORAI1 SNPs from HapMapdatabase with minimum allele frequency (MAF)>10%. Genotyping was performed using TaqManallelic discrimination assay. Chi-square (χ²) testwas used to analyze statistical differences amongcontrol and patient groups in genotype and allelicfrequencies. RESULTS Two of the ORAI1 SNPs(rs12320939 and rs12313273) were associatedwith estrogen receptors positive in breast cancerpatients under the recessive model. When theBonferroni correction was performed, thesignificance still existed. In addition, rs12320939", "metadata": {}}
+{"_id": "16736872", "title": "", "text": "Noninvasive Imaging beyond the Diffraction Limitof 3D Dynamics in Thickly FluorescentSpecimensOptical imaging of the dynamics ofliving specimens involves tradeoffs betweenspatial resolution, temporal resolution, andphototoxicity, made more difficult in threedimensions. Here, however, we report that rapidthree-dimensional (3D) dynamics can be studiedbeyond the diffraction limit in thick or denselyfluorescent living specimens over many timepoints by combining ultrathin planar illuminationproduced by scanned Bessel beams withsuper-resolution structured illuminationmicroscopy. We demonstrate in vivo karyotypingof chromosomes during mitosis and identifydifferent dynamics for the actin cytoskeleton atthe dorsal and ventral surfaces of fibroblasts.Compared to spinning disk confocal microscopy,we demonstrate substantially reducedphotodamage when imaging rapid morphologicalchanges in D. discoideum cells, as well asimproved contrast and resolution at depth within", "metadata": {}}
+{"_id": "16736883", "title": "", "text": "The Ndc80 Kinetochore Complex FormsLoad-Bearing Attachments to DynamicMicrotubule Tips via Biased DiffusionKinetochorescouple chromosomes to the assembling anddisassembling tips of microtubules, a dynamicbehavior that is fundamental to mitosis in alleukaryotes but poorly understood. Genetic,biochemical, and structural studies implicate theNdc80 complex as a direct point of contactbetween kinetochores and microtubules, butthese approaches provide only a static view.Here, using techniques for manipulating andtracking individual molecules in vitro, wedemonstrate that the Ndc80 complex is capableof forming the dynamic, load-bearingattachments to assembling and disassemblingtips required for coupling in vivo. We alsoestablish that Ndc80-based coupling likely occursthrough a biased diffusion mechanism and thatthis activity is conserved from yeast to humans.Our findings demonstrate how an ensemble ofNdc80 complexes may provide the combination", "metadata": {}}
+{"_id": "16737163", "title": "", "text": "Myelin oligodendrocyte glycoprotein antibodiesare associated with a non-MS course inchildrenOBJECTIVE To determine whether myelinoligodendrocyte glycoprotein antibodies(MOG-Abs) were predictive of a demyelinationphenotype in children presenting with acquireddemyelinating syndrome (ADS). METHODSixty-five children with a first episode of ADS (12acute disseminated encephalomyelitis, 24 opticneuritis, 18 transverse myelitis, 11 otherclinically isolated syndrome) were identified from2 national demyelination programs in the UnitedKingdom and France. Acute serum samples weretested for MOG-Abs by cell-based assay.Antibodies were used to predict diagnosis ofmultiple sclerosis (MS) at 1 year. RESULTSTwenty-three of 65 (35%) children hadMOG-Abs. Antibody-positive andantibody-negative patients were not clinicallydifferent at presentation, but identification ofMOG-Abs predicted a non-MS course at 1-yearfollow-up: only 2/23 (9%) MOG-Ab-positive", "metadata": {}}
+{"_id": "16737210", "title": "", "text": "Kidney paired donation and optimizing the use oflive donor organs.CONTEXT Blood type andcrossmatch incompatibility will exclude at leastone third of patients in need from receiving a livedonor kidney transplant. Kidney paired donation(KPD) offers incompatible donor/recipient pairsthe opportunity to match for compatibletransplants. Despite its increasing popularity,very few transplants have resulted from KPD.OBJECTIVE To determine the potential impact ofimproved matching schemes on the number andquality of transplants achievable with KPD.DESIGN, SETTING, AND POPULATION Wedeveloped a model that simulates pools ofincompatible donor/recipient pairs. We designeda mathematically verifiable optimized matchingalgorithm and compared it with the schemecurrently used in some centers and regions.Simulated patients from the general communitywith characteristics drawn from distributionsdescribing end-stage renal disease patientseligible for renal transplantation and their willing", "metadata": {}}
+{"_id": "16745747", "title": "", "text": "Genetic Interaction between Mutations in c-Myband the KIX Domains of CBP and p300 AffectsMultiple Blood Cell Lineages and Influences BothGene Activation and RepressionAdult blood cellproduction or definitive hematopoiesis requiresthe transcription factor c-Myb. The closelyrelated KAT3 histone acetyltransferases CBP(CREBBP) and p300 (EP300) bind c-Myb throughtheir KIX domains and mice homozygous for ap300 KIX domain mutation exhibit multiple blooddefects. Perplexingly, mice homozygous for thesame KIX domain mutation in CBP have normalblood. Here we test the hypothesis that the CBPKIX domain contributes subordinately tohematopoiesis via a genetic interaction withc-Myb. We assessed hematopoiesis in micebearing compound mutations of c-Myb and/orthe KIX domains of CBP and p300, and measuredthe effect of KIX domain mutations onc-Myb-dependent gene expression. We foundthat in the context of a p300 KIX mutation, theCBP KIX domain mutation affects platelets, B", "metadata": {}}
+{"_id": "16760369", "title": "", "text": "Comparative determinants of 4-yearcardiovascular event rates in stable outpatientsat risk of or with atherothrombosis.CONTEXTClinicians and trialists have difficulty withidentifying which patients are highest risk forcardiovascular events. Prior ischemic events,polyvascular disease, and diabetes mellitus haveall been identified as predictors of ischemicevents, but their comparative contributions tofuture risk remain unclear. OBJECTIVE Tocategorize the risk of cardiovascular events instable outpatients with various initialmanifestations of atherothrombosis using simpleclinical descriptors. DESIGN, SETTING, ANDPATIENTS Outpatients with coronary arterydisease, cerebrovascular disease, or peripheralarterial disease or with multiple risk factors foratherothrombosis were enrolled in the globalReduction of Atherothrombosis for ContinuedHealth (REACH) Registry and were followed upfor as long as 4 years. Patients from 3647centers in 29 countries were enrolled between", "metadata": {}}
+{"_id": "16787954", "title": "", "text": "The association between sterilizing activity anddrug distribution into tuberculosis lesionsFindingnew treatment-shortening antibiotics to improvecure rates and curb the alarming emergence ofdrug resistance is the major objective oftuberculosis (TB) drug development. Using amatrix-assisted laser desorption/ionization(MALDI) mass spectrometry imaging suite in abiosafety containment facility, we show that thekey sterilizing drugs rifampicin and pyrazinamideefficiently penetrate the sites of TB infection inlung lesions. Rifampicin even accumulates innecrotic caseum, a critical lesion site wherepersisting tubercle bacilli reside. In contrast,moxifloxacin, which is active in vitro against asubpopulation of Mycobacterium tuberculosisthat persists in specific niches under drugpressure and has achieved treatment shorteningin mice, does not diffuse well in caseum,concordant with its failure to shorten therapy inrecent clinical trials. We suggest that suchdifferential spatial distribution and kinetics of", "metadata": {}}
+{"_id": "16790253", "title": "", "text": "Notch signaling: cell fate control and signalintegration in development.Notch signalingdefines an evolutionarily ancient cell interactionmechanism, which plays a fundamental role inmetazoan development. Signals exchangedbetween neighboring cells through the Notchreceptor can amplify and consolidate moleculardifferences, which eventually dictate cell fates.Thus, Notch signals control how cells respond tointrinsic or extrinsic developmental cues that arenecessary to unfold specific developmentalprograms. Notch activity affects theimplementation of differentiation, proliferation,and apoptotic programs, providing a generaldevelopmental tool to influence organ formationand morphogenesis.", "metadata": {}}
+{"_id": "16806763", "title": "", "text": "A long non-coding RNA signature to improveprognosis prediction of colorectalcancerIncreasing evidence suggests longnon-coding RNAs (lncRNAs) are frequentlyaberrantly expressed in cancers, however, fewrelated lncRNA signatures have been establishedfor prediction of cancer prognosis. We aimed todevelop a lncRNA signature to improve prognosisprediction of colorectal cancer (CRC). Using alncRNA-mining approach, we performed lncRNAexpression profiling in large CRC cohorts fromGene Expression Ominus (GEO), includingGSE39582 test series(N=436), internalvalidation series (N=117); and two independentvalidation series GSE14333 (N=197) andGSE17536(N=145). We established a set of sixlncRNAs that were significantly correlated withthe disease free survival (DFS) in the test series.Based on this six-lncRNA signature, the testseries patients could be classified into high-riskand low-risk subgroups with significantlydifferent DFS (HR=2.670; P<0.0001). The", "metadata": {}}
+{"_id": "16812091", "title": "", "text": "Clinical use of bone densitometry: scientificreview.CONTEXT Osteoporosis causes substantialmorbidity and costs $13.8 billion annually in theUnited States. Measurement of bone mass bydensitometry is a primary part of diagnosingosteoporosis and deciding a preventivetreatment course. Bone mineral densitometryhas become more widely available andcommonly used in practice. OBJECTIVE Toreview evidence about the value of variousclinical applications of bone densitometry. DATASOURCES A MEDLINE search was performed toupdate previous meta-analyses of therelationship between various measurements ofbone density and risk of vertebral and hipfracture. We used data from the prospectiveStudy of Osteoporotic Fractures to estimate riskof fracture from bone density and age inpostmenopausal women. STUDY SELECTIONAND DATA EXTRACTION When available,meta-analyses and systematic reviews areemphasized in the review. DATA SYNTHESIS", "metadata": {}}
+{"_id": "16826810", "title": "", "text": "Vascular Calcifying Progenitor Cells PossessBidirectional Differentiation PotentialsVascularcalcification is an advanced feature ofatherosclerosis for which no effective therapy isavailable. To investigate the modulation orreversal of calcification, we identified calcifyingprogenitor cells and investigated theircalcifying/decalcifying potentials. Cells from theaortas of mice were sorted into four groups usingSca-1 and PDGFRα markers. Sca-1(+)(Sca-1(+)/PDGFRα(+) and Sca-1(+)/PDGFRα(-))progenitor cells exhibited greater osteoblasticdifferentiation potentials than Sca-1(-)(Sca-1(-)/PDGFRα(+) and Sca-1(-)/PDGFRα(-))progenitor cells. Among Sca-1(+) progenitorpopulations, Sca-1(+)/PDGFRα(-) cellspossessed bidirectional differentiation potentialstowards both osteoblastic and osteoclasticlineages, whereas Sca-1(+)/PDGFRα(+) cellsdifferentiated into an osteoblastic lineageunidirectionally. When treated with a peroxisomeproliferator activated receptor γ (PPARγ) agonist,", "metadata": {}}
+{"_id": "16839245", "title": "", "text": "Physiological relevance of cell cycle kinases.Thebasic biology of the cell division cycle and itscontrol by protein kinases was originally studiedthrough genetic and biochemical studies in yeastand other model organisms. The majorregulatory mechanisms identified in this pioneerwork are conserved in mammals. However,recent studies in different cell types or geneticmodels are now providing a new perspective onthe function of these major cell cycle regulatorsin different tissues. Here, we review thephysiological relevance of mammalian cell cyclekinases such as cyclin-dependent kinases (Cdks),Aurora and Polo-like kinases, and mitoticcheckpoint regulators (Bub1, BubR1, and Mps1)as well as other less-studied enzymes such asCdc7, Nek proteins, or Mastl and theirimplications in development, tissue homeostasis,and human disease. Among these functions, thecontrol of self-renewal or asymmetric celldivision in stem/progenitor cells and the abilityto regenerate injured tissues is a central issue in", "metadata": {}}
+{"_id": "16853734", "title": "", "text": "Matrix Metalloproteinase 1 Is Necessary for theMigration of Human Bone Marrow-DerivedMesenchymal Stem Cells Toward HumanGliomaHuman mesenchymal stem cells (MSCs)have increasingly been used as cellular vectorsfor the delivery of therapeutic genes to tumors.However, the precise mechanism of mobilizationremains poorly defined. In this study, MSCs thatexpressed similar cell surface markers andexhibited multilineage differentiation potentialswere isolated from various donors. Interestingly,different MSC isolates displayed differentialmigration ability toward human glioma cells. Wehypothesized that distinct molecular signals maybe involved in the varied tumor tropismsexhibited by different MSC isolates. To test thishypothesis, gene expression profiles oftumor-trophic MSCs were compared with thoseof non-tumor-trophic MSCs. Among the variousdifferentially regulated genes, matrixmetalloproteinase one (MMP1) gene expressionand its protein activities were enhanced by", "metadata": {}}
+{"_id": "16855829", "title": "", "text": "Bullying in school: are short pupils at risk?Questionnaire study in a cohort.Bullying is stillprevalent in schools and is clearly stressful forvictims. 1 2 It may also have undesirableconsequences for bullies, with antisocialbehaviour persisting into adulthood. Victims aregenerally reported to be weaker than the bullies.2 3 This would suggest that very short pupils aremore likely to be victims and less likely to be theaggressors. The Wessex growth study allowed usto examine the prevalence of bullying, asexperienced or perpetrated by pupils of differentheights. Ninety two short normal adolescentswho had been below the third centile for heightat school entry4 and 117 controls matched forage and sex completed a bullying questionnaire,derived from work by Whitney and Smith.5 Therewere no refusals or any significant differences insex or social class between the groups. Mean age(range) was 14.7 (13.4-15.7) years. Mean heightSD scores were: short pupils −1.90 (−3.53 to−0.01), controls 0.31 (−1.41 …", "metadata": {}}
+{"_id": "16863359", "title": "", "text": "Inflammasome-induced IL-1β secretion inmicroglia is characterized by delayed kineticsand is only partially dependent on inflammatorycaspases.Inflammasomes are multiproteincomplexes that link pathogen recognition andcellular stress to the processing of theproinflammatory cytokine interleukin-1β (IL-1β).Whereas inflammasome-mediated activation isheavily studied in hematopoietic macrophagesand dendritic cells, much less is known aboutmicroglia, resident tissue macrophages of thebrain that originate from a distinct progenitor. Todirectly compare inflammasome-mediatedactivation in different types of macrophages, weisolated primary microglia and hematopoieticmacrophages from adult, healthy rhesusmacaques. We analyzed the expression profile ofNOD (nucleotide-binding oligomerizationdomain)-like receptors, adaptor proteins, andcaspases and characterized inflammasomeactivation and regulation in detail. We heredemonstrate that primary microglia can respond", "metadata": {}}
+{"_id": "16882895", "title": "", "text": "microRNA-29a suppresses cell proliferation bytargeting SPARC in hepatocellular carcinoma.Inthe present study, we constructed a lentivirusvector encoding the miR-29a             precursorand established two stably infected cell lines,PLC-29a and 97L-29a. The overexpression ofmiR-29a was confirmed by TaqMan RT-PCR andsignificantly             suppressed the growth ofthe hepatocellular carcinoma cell lines MHCC-97Land             PLC. Dual-luciferase reporter assaysindicated that the SPARC mRNA 3'UTR wasdirectly             targeted by miR-29a since themutated 3'UTR was not affected. SilencingSPARC             expression by RNAi knockdownresulted in a similar effect as miR-29aoverexpression             on hepatocellularcarcinoma (HCC) cell growth regulation.Anti-miR-29a oligonucleotides             (AMOs)upregulated the levels of SPARC in the HCC cells.The phosphorylation of             AKT/mTORdownstream of SPARC was inhibited inmiR-29a-overexpressing HCC cells. We further", "metadata": {}}
+{"_id": "16905344", "title": "", "text": "Another Barrier to Regeneration in the CNS:Activated Macrophages Induce ExtensiveRetraction of Dystrophic Axons through DirectPhysical InteractionsInjured axons of the adultCNS undergo lengthy retraction from the initialsite of axotomy after spinal cord injury.Macrophage infiltration correlatesspatiotemporally with this deleteriousphenomenon, but the direct involvement of theseinflammatory cells has not been demonstrated.In the present study, we examined the role ofmacrophages in axonal retraction within thedorsal columns after spinal cord injury in vivoand found that retraction occurred between days2 and 28 after lesion and that the ends of injuredaxons were associated with ED-1+ cells.Clodronate liposome-mediated depletion ofinfiltrating macrophages resulted in a significantreduction in axonal retraction; however, we sawno evidence of regeneration. We used time-lapseimaging of adult dorsal root ganglion neurons inan in vitro model of the glial scar to examine", "metadata": {}}
+{"_id": "16927286", "title": "", "text": "Large-Scale Movements of IF3 and tRNA duringBacterial Translation InitiationIn bacterialtranslational initiation, three initiation factors(IFs 1-3) enable the selection of initiator tRNAand the start codon in the P site of the 30Sribosomal subunit. Here, we report 11single-particle cryo-electron microscopy(cryoEM) reconstructions of the complex ofbacterial 30S subunit with initiator tRNA, mRNA,and IFs 1-3, representing different steps alongthe initiation pathway. IF1 provides keyanchoring points for IF2 and IF3, therebyenhancing their activities. IF2 positions a domainin an extended conformation appropriate forcapturing the formylmethionyl moiety chargedon tRNA. IF3 and tRNA undergo largeconformational changes to facilitate theaccommodation of the formylmethionyl-tRNA(fMet-tRNA(fMet)) into the P site for start codonrecognition.", "metadata": {}}
+{"_id": "16929739", "title": "", "text": "Corresponding Author:In higher eukaryotes,introns are spliced out of protein-coding mRNAsby the spliceosome, a massive complexcomprising five non-coding RNAs (ncRNAs) andabout 200 proteins. By comparing the differencesbetween spliceosomal proteins from many basaleukaryotic lineages, it is possible to inferproperties of the splicing system in the lastcommon ancestor of extant eukaryotes, theeukaryotic ancestor. We begin with thehypothesis that, similar to intron length (thatappears to have increased in multicellulareukaryotes), the spliceosome has increased incomplexity throughout eukaryotic evolution.However, examination of the distribution ofspliceosomal components indicates that not onlywas a spliceosome present in the eukaryoticancestor but it also contained most of the keycomponents found in today's eukaryotes. All thesmall nuclear ribonucleoproteins (snRNPs)protein components are likely to have beenpresent, as well as many splicing-related", "metadata": {}}
+{"_id": "16939583", "title": "", "text": "2D and 3D Stem Cell Models of Primate CorticalDevelopment Identify Species-SpecificDifferences in Progenitor Behavior Contributingto Brain Size.Variation in cerebral cortex size andcomplexity is thought to contribute to differencesin cognitive ability between humans and otheranimals. Here we compare cortical progenitor celloutput in humans and three nonhuman primatesusing directed differentiation of pluripotent stemcells (PSCs) in adherent two-dimensional (2D)and organoid three-dimensional (3D) culturesystems. Clonal lineage analysis showed thatprimate cortical progenitors proliferate for aprotracted period of time, during which theygenerate early-born neurons, in contrast torodents, where this expansion phase largelyceases before neurogenesis begins. The extent ofthis additional cortical progenitor expansiondiffers among primates, leading to differences inthe number of neurons generated by eachprogenitor cell. We found that this mechanismfor controlling cortical size is regulated cell", "metadata": {}}
+{"_id": "16962732", "title": "", "text": "Multicolor “DiOlistic” Labeling of the NervousSystem Using Lipophilic Dye CombinationsWedescribe a technique for rapid labeling of a largenumber of cells in the nervous system with manydifferent colors. By delivering lipophilicdye-coated particles to neuronal preparationswith a \"gene gun,\" individual neurons and gliawhose membranes are contacted by the particlesare quickly labeled. Using particles that are eachcoated with different combinations of variouslipophilic dyes, many cells within a complexneuronal network can be simultaneously labeledwith a wide variety of colors. This approach ismost effective in living material but also labelspreviously fixed material. In living material,labeled neurons continue to show normalsynaptic responses and undergo dendriticremodeling. This technique is thus useful forstudying structural plasticity of neuronal circuitsin living preparations. In addition, the Golgi-likelabeling of neurons with many different colorsprovides a novel way to study neuronal", "metadata": {}}
+{"_id": "16963081", "title": "", "text": "A DNA test to sex most birds.Birds are difficult tosex. Nestlings rarely show sex-linkedmorphology and we estimate that adult femalesappear identical to males in over 50% of theworld's bird species. This problem can hinderboth evolutionary studies and human-assistedbreeding of birds. DNA-based sex identificationprovides a solution. We describe a test based ontwo conserved CHD(chromo-helicase-DNA-binding) genes that arelocated on the avian sex chromosomes of allbirds, with the possible exception of the ratites(ostriches, etc.; Struthioniformes). The CHD-Wgene is located on the W chromosome; thereforeit is unique to females. The other gene, CHD-Z,is found on the Z chromosome and thereforeoccurs in both sexes (female, ZW; male, ZZ).The test employs PCR with a single set ofprimers. It amplifies homologous sections of bothgenes and incorporates introns whose lengthsusually differ. When examined on a gel there is asingle CHD-Z band in males but females have a", "metadata": {}}
+{"_id": "16964262", "title": "", "text": "Evidence that Embryonic Neurons Regulate theOnset of Cortical Gliogenesis viaCardiotrophin-1Precursor cells of the embryoniccortex sequentially generate neurons and thenglial cells, but the mechanisms regulating thisneurogenic-to-gliogenic transition are unclear.Using cortical precursor cultures, whichtemporally mimic this in vivo differentiationpattern, we demonstrate that cortical neuronssynthesize and secrete the neurotrophic cytokinecardiotrophin-1, which activates thegp130-JAK-STAT pathway and is essential for thetimed genesis of astrocytes in vitro. Our dataindicate that a similar phenomenon also occursin vivo. In utero electroporation of neurotrophiccytokines in the environment of embryoniccortical precursors causes premature gliogenesis,while acute perturbation of gp130 in corticalprecursors delays the normal timed appearanceof astrocytes. Moreover, the neonatalcardiotrophin-1-/- cortex contains fewerastrocytes. Together, these results describe a", "metadata": {}}
+{"_id": "16966326", "title": "", "text": "The Inhibition of TDP-43 MitochondrialLocalization Blocks Its Neuronal ToxicityGeneticmutations in TAR DNA-binding protein 43(TARDBP, also known as TDP-43) causeamyotrophic lateral sclerosis (ALS), and anincrease in the presence of TDP-43 (encoded byTARDBP) in the cytoplasm is a prominenthistopathological feature of degeneratingneurons in various neurodegenerative diseases.However, the molecular mechanisms by whichTDP-43 contributes to ALS pathophysiologyremain elusive. Here we have found that TDP-43accumulates in the mitochondria of neurons insubjects with ALS or frontotemporal dementia(FTD). Disease-associated mutations increaseTDP-43 mitochondrial localization. Inmitochondria, wild-type (WT) and mutantTDP-43 preferentially bindmitochondria-transcribed messenger RNAs(mRNAs) encoding respiratory complex Isubunits ND3 and ND6, impair their expressionand specifically cause complex I disassembly.", "metadata": {}}
+{"_id": "16979690", "title": "", "text": "Effect on the quality of peer review of blindingreviewers and asking them to sign their reports:a randomized controlled trial.CONTEXT Anxietyabout bias, lack of accountability, and poorquality of peer review has led to questions aboutthe imbalance in anonymity between reviewersand authors. OBJECTIVE To evaluate the effecton the quality of peer review of blindingreviewers to the authors' identities and requiringreviewers to sign their reports. DESIGNRandomized controlled trial. SETTING A generalmedical journal. PARTICIPANTS A total of 420reviewers from the journal's database.INTERVENTION We modified a paper acceptedfor publication introducing 8 areas of weakness.Reviewers were randomly allocated to 5 groups.Groups 1 and 2 received manuscripts from whichthe authors' names and affiliations had beenremoved, while groups 3 and 4 were aware ofthe authors' identities. Groups 1 and 3 wereasked to sign their reports, while groups 2 and 4were asked to return their reports unsigned. The", "metadata": {}}
+{"_id": "16980892", "title": "", "text": "2001. Comparison of three managementstrategies for patients with atypical squamouscells of undetermined significance. Baselineresults from a randomized trialBACKGROUNDMore than 2 million U.S. women receive anequivocal cervical cytologic diagnosis (atypicalsquamous cells of undetermined significance[ASCUS]) each year. Effective colposcopy triagestrategies are needed to identify the minority ofwomen who have clinically significant diseasewhile avoiding excessive follow-up evaluation forothers. METHODS The ASCUS/LSIL (i.e.,low-grade squamous intraepithelial lesion) TriageStudy (ALTS) is a multicenter, randomized trialcomparing the sensitivity and specificity of thefollowing three management strategies to detectcervical intraepithelial neoplasia grade 3 (CIN3):1) immediate colposcopy (considered to be thereference standard), 2) triage to colposcopybased on human papillomavirus (HPV) resultsfrom Hybrid Capture 2(TM) (HC 2) and thin-layercytology results, or 3) triage based on cytology", "metadata": {}}
+{"_id": "16999023", "title": "", "text": "Cell Stem Cell Article In Vivo Fate AnalysisReveals the Multipotent and Self-RenewalCapacities of Sox2 + Neural Stem Cells in theAdult HippocampusTo characterize the propertiesof adult neural stem cells (NSCs), we generatedand analyzed Sox2-GFP transgenic mice.Sox2-GFP cells in the subgranular zone (SGZ)express markers specific for progenitors, butthey represent two morphologically distinctpopulations that differ in proliferation levels.Lentivirus- and retrovirus-mediated fate-tracingstudies showed that Sox2+ cells in the SGZ havepotential to give rise to neurons and astrocytes,revealing their multipotency at the population aswell as at a single-cell level. A subpopulation ofSox2+ cells gives rise to cells that retain Sox2,highlighting Sox2+ cells as a primary source foradult NSCs. In response to mitotic signals,increased proliferation of Sox2+ cells is coupledwith the generation of Sox2+ NSCs as well asneuronal precursors. An asymmetric contributionof Sox2+ NSCs may play an important role in", "metadata": {}}
+{"_id": "17000834", "title": "", "text": "Past exposure to sun, skin phenotype, and risk ofmultiple sclerosis: case-control study.OBJECTIVETo examine whether past high sun exposure isassociated with a reduced risk of multiplesclerosis. DESIGN Population based case-controlstudy. SETTING Tasmania, latitudes 41-3degrees S.   PARTICIPANTS 136 cases withmultiple sclerosis and 272 controls randomlydrawn from the community and matched on sexand year of birth. MAIN OUTCOME MEASUREMultiple sclerosis defined by both clinical andmagnetic resonance imaging criteria. RESULTSHigher sun exposure when aged 6-15 years(average 2-3 hours or more a day in summerduring weekends and holidays) was associatedwith a decreased risk of multiple sclerosis(adjusted odds ratio 0.31, 95% confidenceinterval 0.16 to 0.59). Higher exposure in winterseemed more important than higher exposure insummer. Greater actinic damage was alsoindependently associated with a decreased riskof multiple sclerosis (0.32, 0.11 to 0.88 for", "metadata": {}}
+{"_id": "17017465", "title": "", "text": "Endocytic Trafficking of Rac Is Required for theSpatial Restriction of Signaling in CellMigrationThe small GTPases, Rab5 and Rac, areessential for endocytosis and actin remodeling,respectively. Coordination of these processes iscritical to achieve spatial restriction ofintracellular signaling, which is essential for avariety of polarized functions. Here, we showthat clathrin- and Rab5-mediated endocytosisare required for the activation of Rac induced bymotogenic stimuli. Rac activation occurs on earlyendosomes, where the RacGEF Tiam1 is alsorecruited. Subsequent recycling of Rac to theplasma membrane ensures localized signaling,leading to the formation of actin-based migratoryprotrusions. Thus, membrane trafficking of Rac isrequired for the spatial resolution ofRac-dependent motogenic signals. We furtherdemonstrate that a Rab5-to-Rac circuitrycontrols the morphology of motile mammaliantumor cells and primordial germinal cells duringzebrafish development, suggesting that this", "metadata": {}}
+{"_id": "17021845", "title": "", "text": "Significance of stem cell marker Nanog gene inthe diagnosis and prognosis of lung cancerTheaim of the present study was to analyze the stemcell marker, Nanog gene, for the diagnosis andprognosis of lung cancer cases, and to study itsapplication in the diagnosis of lung cancer. Intotal, 100 patients diagnosed with lung cancerbetween April, 2013 and May, 2015 wereincluded in the present study. The patients wererandomly divided into group A (lung cancer) andgroup B (squamous cell lung carcinoma). RT-PCRwas used to detect the cancer and adjacenttissues, and Nanog gene expression wasdetected in groups A and B in cells. The resultsshowed that, analysis of Nanog gene expressionin the two groups of patients varied to differentdegrees. There was no significant differencebetween the two groups with regard to age,gender, disease stage and lymph nodemetastasis. Nanog gene expression in patientswith carcinoma were significantly higher thanthat in the adjacent tissues (p<0.05). By", "metadata": {}}
+{"_id": "17023584", "title": "", "text": "Current knowledge and future directions of TLRand NOD signaling in sepsisThe incidence ofsepsis is increasing over time, along with anincreased risk of dying from the condition. Sepsiscare costs billions annually in the United States.Death from sepsis is understood to be a complexprocess, driven by a lack of normal immunehomeostatic functions and excessive productionof proinflammatory cytokines, which leads tomulti-organ failure. The Toll-like receptor (TLR)family, one of whose members was initiallydiscovered in Drosophila, performs an importantrole in the recognition of microbial pathogens.These pattern recognition receptors (PRRs), uponsensing invading microorganisms, activateintracellular signal transduction pathways. NODsignaling is also involved in the recognition ofbacteria and acts synergistically with the TLRfamily in initiating an efficient immune responsefor the eradication of invading microbialpathogens. TLRs and NOD1/NOD2 respond todifferent pathogen-associated molecular patterns", "metadata": {}}
+{"_id": "17049436", "title": "", "text": "Concentration Sensing by the Moving Nucleus inCell Fate Determination: A ComputationalAnalysisDuring development of the vertebrateneuroepithelium, the nucleus in neuralprogenitor cells (NPCs) moves from the apextoward the base and returns to the apex (calledinterkinetic nuclear migration) at which point thecell divides. The fate of the resulting daughtercells is thought to depend on the sampling by themoving nucleus of a spatial concentration profileof the cytoplasmic Notch intracellular domain(NICD). However, the nucleus executes complexstochastic motions including random waiting andback and forth motions, which can expose thenucleus to randomly varying levels ofcytoplasmic NICD. How nuclear position candetermine daughter cell fate despite thestochastic nature of nuclear migration is notclear. Here we derived a mathematical model forreaction, diffusion, and nuclear accumulation ofNICD in NPCs during interkinetic nuclearmigration (INM). Using experimentally measured", "metadata": {}}
+{"_id": "17050065", "title": "", "text": "Odorant-specific adaptation pathways generateolfactory plasticity in C. elegansFollowingprolonged exposure to an odorant, C. elegansexhibits a diminished response to the odorant forseveral hours. This olfactory adaptation isodorant selective; animals can adaptindependently to different odorants sensed by asingle pair of olfactory neurons, the AWCneurons. The mechanism of olfactory adaptationis genetically complex, with different genesrequired for adaptation to different odorants.Animals mutant for the gene adp-1 fail to adaptto a subset of AWC-sensed odorants; adp-1affects a calcium-dependent process required foradaptation. Mutations in another gene, osm-9,affect adaptation to a different but overlappingsubset of AWC-sensed odorants. Mutations inadp-1 and osm-9 do not diminish the ability ofunadapted animals to respond to odorants,indicating that odorant sensation and odorantadaptation are distinct processes.", "metadata": {}}
+{"_id": "17055665", "title": "", "text": "Genome-wide dFOXO targets and topology of thetranscriptomic response to stress and insulinsignallingFoxO transcription factors, inhibited byinsulin/insulin-like growth factor signalling (IIS),are crucial players in numerous organismalprocesses including lifespan. Using genomictools, we uncover over 700 direct dFOXO targetsin adult female Drosophila. dFOXO is directlyrequired for transcription of several IIScomponents and interacting pathways, such asTOR, in the wild-type fly. The genomic locationsoccupied by dFOXO in adults are different fromthose observed in larvae or cultured cells. Theselocations remain unchanged upon activation bystresses or reduced IIS, but the binding isincreased and additional targets activated upongenetic reduction in IIS. We identify the part ofthe IIS transcriptional response directlycontrolled by dFOXO and the indirect effects andshow that parts of the transcriptional response toIIS reduction do not require dfoxo. Promoteranalyses revealed GATA and other forkhead", "metadata": {}}
+{"_id": "17077004", "title": "", "text": "Stable partnership and progression to AIDS ordeath in HIV infected patients receiving highlyactive antiretroviral therapy: Swiss HIV cohortstudy.OBJECTIVES To explore the associationbetween a stable partnership and clinicaloutcome in HIV infected patients receiving highlyactive antiretroviral therapy (HAART). DESIGNProspective cohort study of adults with HIV(Swiss HIV cohort study). SETTING Sevenoutpatient clinics throughout Switzerland.PARTICIPANTS The 3736 patients in the cohortwho started HAART before 2002 (median age 36years, 29% female, median follow up 3.6 years).MAIN OUTCOME MEASURES Time to AIDS ordeath (primary endpoint), death alone, increasesin CD4 cell count of at least 50 and 100 abovebaseline, optimal viral suppression (a viral loadbelow 400 copies/ml), and viral rebound.RESULTS During follow up 2985 (80%)participants reported a stable partnership on atleast one occasion. When starting HAART, 52%(545/1042) of participants reported a stable", "metadata": {}}
+{"_id": "17081238", "title": "", "text": "Specific deficit of the ON response in visualtransmission by targeted disruption of themGIuR6 geneTaking advantage of the restrictedexpression of metabotropic glutamate receptorsubtype 6 (mGluR6) in retinal ON bipolar cells,we generated knockout mice lacking mGluR6expression. The homozygous mutant miceshowed a loss of ON responses but unchangedOFF responses to light. The mutant micedisplayed no obvious changes in retinal cellorganization nor in the projection of optic fibersto the brain. Furthermore, the mGluR6-deficientmice showed visual behavioral responses to lightstimulation as examined by shuttle boxavoidance behavior experiments using lightexposure as a conditioned stimulus. The resultsdemonstrate that mGluR6 is essential in synaptictransmission to the ON bipolar cell and that theOFF response provides an important means fortransmitting visual information.", "metadata": {}}
+{"_id": "17088791", "title": "", "text": "Common BRCA1 variants and susceptibility tobreast and ovarian cancer in the generalpopulation.Most multiple case families of youngonset breast cancer and ovarian cancer arethought to be due to highly penetrant mutationsin the predisposing genes BRCA1 and BRCA2.However, these mutations are uncommon in thepopulation and they probably account for only afew percent of all breast cancer incidence. Amuch larger fraction of breast cancer might, inprinciple, be due to common variants whichconfer more modest individual risks. There areseveral common polymorphisms in the BRCA1gene which generate amino acid substitutions.We have examined the frequency of four of thesepolymorphisms: Gln356Arg, Pro871Leu,Glu1038Gly and Ser1613Gly in large series ofbreast and ovarian cancer cases and matchedcontrols. Due to strong linkage disequilibrium,these four sites generate only three haplotypeswith a frequency > 1.3%. The most commonhaplotypes, defined by the alleles", "metadata": {}}
+{"_id": "17097974", "title": "", "text": "Exercise causes a tissue-specific change of NOproduction in the kidney and lung.Nitric oxide(NO) is produced in the vascular endotheliumand is a potent vasodilator substance thatparticipates in the regulation of local vasculartone. Exercise causes peculiar changes insystemic and regional blood flow, i.e., anincrease of systemic blood flow and aredistribution of local tissue blood flow, by whichthe blood flow is greatly increased in the workingmuscles, whereas it is decreased in some organssuch as the kidney and intestine. Thus wehypothesized that exercise causes atissue-specific change of NO production in someinternal organs. We studied whether exerciseaffects expression of NO synthase (NOS) mRNAand protein, NOS activity, and tissue level ofnitrite/nitrate (stable end products of NO) in thekidneys (in which blood flow during exercise isdecreased) and lungs (in which blood flow duringexercise is increased with the increase of cardiacoutput) of rat. Rats ran on a treadmill for 45 min", "metadata": {}}
+{"_id": "17101262", "title": "", "text": "Ballistic labeling and dynamic imaging ofastrocytes in organotypic hippocampal sliceculturesProtoplasmic astrocytes in mammalianCNS tissues in vivo have a highly complex 3Dmorphology, but in dissociated cell cultures theyoften assume a flattened, fibroblast-likemorphology bearing only a few, simpleprocesses. By fluorescent labeling and confocalreconstruction we show that many astrocytes inorganotypic hippocampal slice cultures exhibit amore native complex cytoarchitecture. Althoughastrocytes at the surface of slice cultures show areactive form with several thick glial fibrillaryacidic protein (GFAP)-positive processes,astrocytes situated in deeper portions of tissueslices retain a highly complex 3D morphologywith many fine spine- or veil-like protrusions.Dozens of astrocytes can be labeled in singleslice cultures by gene gun-mediated ballisticdelivery of gold or tungsten particles carryingcDNAs (Biolistics), lipophilic dyes (DiOlistics), orfluorescent intracellular calcium indicators", "metadata": {}}
+{"_id": "17119869", "title": "", "text": "A bipotential precursor population for pancreasand liver within the embryonic endoderm.Thepancreas emerges independently from dorsal andventral domains of embryonic gut endoderm.Gene inactivation experiments in mice haveidentified factors required for dorsal pancreasdevelopment, but factors that initiate the ventralpancreas have remained elusive. In this study,we investigated the hypothesis that theemergence of the ventral pancreas is related tothe emergence of the liver. We find that the liverand ventral pancreas are specified at the sametime and in the same general domain of cells.Using embryo tissue explantation experiments,we find that the default fate of the ventralforegut endoderm is to activate the pancreasgene program. FGF signalling from the cardiacmesoderm diverts this endoderm to expressgenes for liver instead of those for pancreas. Noevidence was found to indicate that the cell typechoice for pancreas or liver involves a selectionfor growth or viability. Cardiac mesoderm or FGF", "metadata": {}}
+{"_id": "17123316", "title": "", "text": "ErbB4-neuregulin signaling modulates synapsedevelopment and dendritic arborization throughdistinct mechanisms.Perturbations inneuregulin-1 (NRG1)/ErbB4 function have beenassociated with schizophrenia. Affected patientsexhibit altered levels of these proteins anddisplay hypofunction of glutamatergic synapsesas well as altered neuronal circuitry. However,the role of NRG1/ErbB4 in regulating synapsematuration and neuronal process formation hasnot been extensively examined. Here wedemonstrate that ErbB4 is expressed ininhibitory interneurons at both excitatory andinhibitory postsynaptic sites. Overexpression ofErbB4 postsynaptically enhances size but notnumber of presynaptic inputs. Conversely,knockdown of ErbB4 using shRNA decreases thesize of presynaptic inputs, demonstrating aspecific role for endogenous ErbB4 in synapsematuration. Using ErbB4 mutant constructs, wedemonstrate that ErbB4-mediated synapsematuration requires its extracellular domain,", "metadata": {}}
+{"_id": "17123657", "title": "", "text": "Dynamic Helix Interactions in TransmembraneSignalingStudying how protein transmembranedomains transmit signals across membranes isbeset by unique challenges. Here, we discuss thecircumstances that have led to success andreflect on what has been learned from theseexamples. Such efforts suggest that some of themost interesting properties of transmembranehelix interactions may be the least amenable tostudy by current techniques.", "metadata": {}}
+{"_id": "17124832", "title": "", "text": "Association between smoking and risk of bladdercancer among men and women.CONTEXTPrevious studies indicate that the populationattributable risk (PAR) of bladder cancer fortobacco smoking is 50% to 65% in men and20% to 30% in women and that current cigarettesmoking triples bladder cancer risk relative tonever smoking. During the last 30 years,incidence rates have remained stable in theUnited States in men (123.8 per 100,000person-years to 142.2 per 100,000person-years) and women (32.5 per 100,000person-years to 33.2 per 100,000 person-years);however, changing smoking prevalence andcigarette composition warrant revisiting riskestimates for smoking and bladder cancer.OBJECTIVE To evaluate the association betweentobacco smoking and bladder cancer. DESIGN,SETTING, AND PARTICIPANTS Men (n =281,394) and women (n = 186,134) of theNational Institutes of Health-AARP (NIH-AARP)Diet and Health Study cohort completed a", "metadata": {}}
+{"_id": "17150648", "title": "", "text": "Leptin regulates glutamate and glucosetransporters in hypothalamic astrocytes.Glialcells perform critical functions that alter themetabolism and activity of neurons, and there isincreasing interest in their role in appetite andenergy balance. Leptin, a key regulator ofappetite and metabolism, has previously beenreported to influence glial structural proteins andmorphology. Here, we demonstrate thatmetabolic status and leptin also modifyastrocyte-specific glutamate and glucosetransporters, indicating that metabolic signalsinfluence synaptic efficacy and glucose uptakeand, ultimately, neuronal function. We found thatbasal and glucose-stimulated electrical activity ofhypothalamic proopiomelanocortin (POMC)neurons in mice were altered in the offspring ofmothers fed a high-fat diet. In adulthood,increased body weight and fasting also alteredthe expression of glucose and glutamatetransporters. These results demonstrate thatwhole-organism metabolism alters hypothalamic", "metadata": {}}
+{"_id": "17163294", "title": "", "text": "Metabolic phenotyping of human blood plasma: apowerful tool to discriminate between cancertypes?BACKGROUND Accumulating evidence hasshown that cancer cell metabolism differs fromthat of normal cells. However, up to now it is notclear whether different cancer types arecharacterized by a specific metabolite profile.Therefore, this study aims to evaluate whetherthe plasma metabolic phenotype allows todiscriminate between lung and breast cancer.PATIENTS AND METHODS The proton nuclearmagnetic resonance spectrum of plasma isdivided into 110 integration regions,representing the metabolic phenotype. Theseintegration regions reflect the relative metaboliteconcentrations and were used to train aclassification model in discriminating between 80female breast cancer patients and 54 femalelung cancer patients, all with anadenocarcinoma. The validity of the model wasexamined by permutation testing and byclassifying an independent validation cohort of", "metadata": {}}
+{"_id": "17168045", "title": "", "text": "Direct in vivo assessment of microcirculatorydysfunction in severe falciparummalaria.BACKGROUND This study sought todescribe and quantify microcirculatory changesin the mucosal surfaces of patients with severemalaria, by direct in vivo observation usingorthogonal polarization spectral (OPS) imaging.METHODS The microcirculation in the rectalmucosa of adult patients with severe malaria wasassessed by use of OPS imaging, at admissionand then daily. Comparison groups comprisedpatients with uncomplicated falciparum malaria,patients with bacterial sepsis, and healthyindividuals. RESULTS Erythrocyte velocities weremeasured directly in 43 adult patients withsevere falciparum malaria, of whom 20 died.Microcirculatory blood flow was markedlydisturbed, with heterogeneous obstruction thatwas proportional to severity of disease. Blockedcapillaries were found in 29 patients (67%) andwere associated with concurrent hyperdynamicblood flow (erythrocyte velocity, >750 mm/s) in", "metadata": {}}
+{"_id": "17173492", "title": "", "text": "Multiple archaeal groups mediate methaneoxidation in anoxic cold seep sediments.Nomicroorganism capable of anaerobic growth onmethane as the sole carbon source has yet beencultivated. Consequently, information aboutthese microbes has been inferred fromgeochemical and microbiological observations offield samples. Stable isotope analysis of lipidbiomarkers and rRNA gene surveys haveimplicated specific microbes in the anaerobicoxidation of methane (AOM). Here we usecombined fluorescent in situ hybridization andsecondary ion mass spectrometry analyses, toidentify anaerobic methanotrophs in marinemethane-seep sediments. The results providedirect evidence for the involvement of at leasttwo distinct archaeal groups (ANME-1 andANME-2) in AOM at methane seeps. Althoughboth archaeal groups often occurred in directphysical association with bacteria, they also wereobserved as monospecific aggregations and assingle cells. The ANME-1 archaeal group more", "metadata": {}}
+{"_id": "17188921", "title": "", "text": "N-cadherin in the spotlight of cell-cell adhesion,differentiation, embryogenesis, invasion andsignalling.Cell migration is a process which isessential during embryonic development,throughout adult life and in some pathologicalconditions. Cadherins, and more specifically theneural cell adhesion molecule N-cadherin, playan important role in migration. Inembryogenesis, N-cadherin is the key moleculeduring gastrulation and neural crestdevelopment. N-cadherin mediated contactsactivate several pathways like Rho GTPases andfunction in tyrosine kinase signalling (forexample via the fibroblast growth factorreceptor). In cancer, cadherins control thebalance between suppression and promotion ofinvasion. E-cadherin functions as an invasionsuppressor and is downregulated in mostcarcinomas, while N-cadherin, as an invasionpromoter, is frequently upregulated. Expressionof N-cadherin in epithelial cells induces changesin morphology to a fibroblastic phenotype,", "metadata": {}}
+{"_id": "17194716", "title": "", "text": "Role of fascin in filopodial protrusionIn thisstudy, the mechanisms of actin-bundling infilopodia were examined. Analysis of cellularlocalization of known actin cross-linking proteinsin mouse melanoma B16F1 cells revealed thatfascin was specifically localized along the entirelength of all filopodia, whereas other actincross-linkers were not. RNA interference of fascinreduced the number of filopodia, and remainingfilopodia had abnormal morphology with wavyand loosely bundled actin organization.Dephosphorylation of serine 39 likely determinedcellular filopodia frequency. The constitutivelyactive fascin mutant S39A increased the numberand length of filopodia, whereas the inactivefascin mutant S39E reduced filopodia frequency.Fluorescence recovery after photobleaching ofGFP-tagged wild-type and S39A fascin showedthat dephosphorylated fascin underwent rapidcycles of association to and dissociation fromactin filaments in filopodia, with t1/2 < 10 s. Wepropose that fascin is a key specific actin", "metadata": {}}
+{"_id": "17195001", "title": "", "text": "TOR Signaling in Growth and MetabolismThetarget of rapamycin (TOR) is a conservedSer/Thr kinase that regulates cell growth andmetabolism in response to environmental cues.Here, highlighting contributions from studies inmodel organisms, we review mammalian TORcomplexes and the signaling branches theymediate. TOR is part of two distinct multiproteincomplexes, TOR complex 1 (TORC1), which issensitive to rapamycin, and TORC2, which is not.The physiological consequences of mammalianTORC1 dysregulation suggest that inhibitors ofmammalian TOR may be useful in the treatmentof cancer, cardiovascular disease, autoimmunity,and metabolic disorders.", "metadata": {}}
+{"_id": "17208742", "title": "", "text": "Self-Organization of the Escherichia coliChemotaxis Network Imaged withSuper-Resolution Light MicroscopyTheEscherichia coli chemotaxis network is a modelsystem for biological signal processing. In E. coli,transmembrane receptors responsible for signaltransduction assemble into large clusterscontaining several thousand proteins. Thesesensory clusters have been observed at cell polesand future division sites. Despite extensivestudy, it remains unclear how chemotaxisclusters form, what controls cluster size anddensity, and how the cellular location of clustersis robustly maintained in growing and dividingcells. Here, we use photoactivated localizationmicroscopy (PALM) to map the cellular locationsof three proteins central to bacterial chemotaxis(the Tar receptor, CheY, and CheW) with aprecision of 15 nm. We find that cluster sizes areapproximately exponentially distributed, with nocharacteristic cluster size. One-third of Tarreceptors are part of smaller lateral clusters and", "metadata": {}}
+{"_id": "17209919", "title": "", "text": "Ciliary Extracellular Vesicles: Txt MsgOrganellesCilia are sensory organelles thatprotrude from cell surfaces to monitor thesurrounding environment. In addition to its roleas sensory receiver, the cilium also releasesextracellular vesicles (EVs). The release ofsub-micron sized EVs is a conserved form ofintercellular communication used by all threekingdoms of life. These extracellular organellesplay important roles in both short and long rangesignaling between donor and target cells andmay coordinate systemic responses within anorganism in normal and diseased states. EVshedding from ciliated cells and EV–ciliainteractions are evolutionarily conservedphenomena, yet remarkably little is known aboutthe relationship between the cilia and EVs andthe fundamental biology of EVs. Studies in themodel organisms Chlamydomonas andCaenorhabditis elegans have begun to shed lighton ciliary EVs. Chlamydomonas EVs are shedfrom tips of flagella and are bioactive.", "metadata": {}}
+{"_id": "17223891", "title": "", "text": "The NOD-like receptor NLRP12 attenuates coloninflammation and tumorigenesis.NLRP12 is amember of the intracellular Nod-like receptor(NLR) family that has been suggested todownregulate the production of inflammatorycytokines, but its physiological role in regulatinginflammation has not been characterized. Weanalyzed mice deficient in Nlrp12 to study its rolein inflammatory diseases such as colitis andcolorectal tumorigenesis. We show thatNlrp12-deficient mice are highly susceptible tocolon inflammation and tumorigenesis, which isassociated with increased production ofinflammatory cytokines, chemokines, andtumorigenic factors. Enhanced coloninflammation and colorectal tumor developmentin Nlrp12-deficient mice are due to a failure todampen NF-κB and ERK activation inmacrophages. These results reveal a critical rolefor NLRP12 in maintaining intestinal homeostasisand providing protection against colorectaltumorigenesis.", "metadata": {}}
+{"_id": "17231273", "title": "", "text": "Ionic mechanism of ouabain-induced concurrentapoptosis and necrosis in individual culturedcortical neuronsEnergy deficiency anddysfunction of the Na+, K+-ATPase are commonconsequences of many pathological insults. Thenature and mechanism of cell injury induced byimpaired Na+, K+-ATPase, however, are not welldefined. We used cultured cortical neurons toexamine the hypothesis that blocking the Na+,K+-ATPase induces apoptosis by depletingcellular K+ and, concurrently, induces necroticinjury in the same cells by increasingintracellular Ca2+ and Na+. The Na+,K+-ATPase inhibitor ouabain inducedconcentration-dependent neuronal death.Ouabain triggered transient neuronal cellswelling followed by cell shrinkage, accompaniedby intracellular Ca2+ and Na+ increase, K+decrease, cytochrome c release, caspase-3activation, and DNA laddering. Electronmicroscopy revealed the coexistence ofultrastructural features of both apoptosis and", "metadata": {}}
+{"_id": "17236106", "title": "", "text": "Potential consequences of replacing a retailalcohol monopoly with a private licence system:results from Sweden.AIM To examine thepotential effects of replacing the Swedish alcoholretail system with a private licensing system onalcohol consumption and alcohol-related harm.DESIGN Two possible scenarios were analysed:(1) replacing the current alcohol retail monopolywith private licensed stores that specialize inalcohol sales or (2) making all alcohol availablein grocery stores. We utilized a multiplicativemodel that projected effects of changes in a setof key factors including hours of sale, retailprices, promotion and advertising and outletdensity. Next, we estimated the effect of theprojected consumption increase on a set of harmindicators. Values for the model parameters wereobtained from the research literature.MEASUREMENTS Measures of alcohol-relatedharm included explicitly alcohol-relatedmortality, accident mortality, suicide, homicide,assaults, drinking driving and sickness absence.", "metadata": {}}
+{"_id": "17240457", "title": "", "text": "A comprehensive genomic binding map of geneand chromatin regulatory proteins inSaccharomyces.Hundreds of different proteinsregulate and implement transcription inSaccharomyces. Yet their interrelationships havenot been investigated on a comprehensive scale.Here we determined the genome-wide bindinglocations of 200 transcription-related proteins,under normal and acute heat-shock conditions.This study distinguishes binding between distalversus proximal promoter regions as well as the3' ends of genes for nearly all mRNA and tRNAgenes. This study reveals (1) a greater diversityand specialization of regulation associated withthe SAGA transcription pathway compared to theTFIID pathway, (2) new regulators enriched attRNA genes, (3) a global co-occupancy networkof >20,000 unique regulator combinations thatshow a high degree of regulatoryinterconnections among lowly expressed genes,(4) regulators of the SAGA pathway locatedlargely distal to the core promoter and regulators", "metadata": {}}
+{"_id": "17271462", "title": "", "text": "Tie2/Angiopoietin-1 Signaling RegulatesHematopoietic Stem Cell Quiescence in the BoneMarrow NicheThe quiescent state is thought tobe an indispensable property for themaintenance of hematopoietic stem cells (HSCs).Interaction of HSCs with their particularmicroenvironments, known as the stem cellniches, is critical for adult hematopoiesis in thebone marrow (BM). Here, we demonstrate thatHSCs expressing the receptor tyrosine kinaseTie2 are quiescent and antiapoptotic, andcomprise a side-population (SP) of HSCs, whichadhere to osteoblasts (OBs) in the BM niche. Theinteraction of Tie2 with its ligand Angiopoietin-1(Ang-1) induced cobblestone formation of HSCsin vitro and maintained in vivo long-termrepopulating activity of HSCs. Furthermore,Ang-1 enhanced the ability of HSCs to becomequiescent and induced adhesion to bone,resulting in protection of the HSC compartmentfrom myelosuppressive stress. These datasuggest that the Tie2/Ang-1 signaling pathway", "metadata": {}}
+{"_id": "17324544", "title": "", "text": "Thirty-One Novel Biomarkers as Predictors forClinically Incident DiabetesBACKGROUND Theprevalence of diabetes is increasing in allindustrialized countries and its prevention hasbecome a public health priority. However, thepredictors of diabetes risk are insufficientlyunderstood. We evaluated, whether 31 novelbiomarkers could help to predict the risk ofincident diabetes. METHODS AND FINDINGS Thebiomarkers were evaluated primarily in theFINRISK97 cohort (n = 7,827; 417 cases ofclinically incident diabetes during the follow-up).The findings were replicated in the Health 2000cohort (n = 4,977; 179 cases of clinicallyincident diabetes during the follow-up). We usedCox proportional hazards models to calculate therelative risk of diabetes, after adjusting for theclassic risk factors, separately for eachbiomarker. Next, we assessed the discriminatoryability of single biomarkers using receiveroperating characteristic curves and C-statistics,integrated discrimination improvement (IDI) and", "metadata": {}}
+{"_id": "17327939", "title": "", "text": "Exploiting lymphatic transport and complementactivation in nanoparticle vaccinesAntigentargeting and adjuvancy schemes thatrespectively facilitate delivery of antigen todendritic cells and elicit their activation havebeen explored in vaccine development. Here weinvestigate whether nanoparticles can be used asa vaccine platform by targeting lymphnode–residing dendritic cells via interstitial flowand activating these cells by in situ complementactivation. After intradermal injection, interstitialflow transported ultra-small nanoparticles (25nm) highly efficiently into lymphatic capillariesand their draining lymph nodes, targeting half ofthe lymph node–residing dendritic cells, whereas100-nm nanoparticles were only 10% asefficient. The surface chemistry of thesenanoparticles activated the complement cascade,generating a danger signal in situ and potentlyactivating dendritic cells. Using nanoparticlesconjugated to the model antigen ovalbumin, wedemonstrate generation of humoral and cellular", "metadata": {}}
+{"_id": "17333231", "title": "", "text": "The sheddase ADAM10 is a potent modulator ofprion diseaseThe prion protein (PrP(C)) is highlyexpressed in the nervous system and criticallyinvolved in prion diseases where it misfolds intopathogenic PrP(Sc). Moreover, it has beensuggested as a receptor mediating neurotoxicityin common neurodegenerative proteinopathiessuch as Alzheimer's disease. PrP(C) is shed atthe plasma membrane by the metalloproteaseADAM10, yet the impact of this on prion diseaseremains enigmatic. Employing conditionalknockout mice, we show that depletion ofADAM10 in forebrain neurons leads toposttranslational increase of PrP(C) levels. Uponprion infection of these mice, clinical,biochemical, and morphological data reveal thatlack of ADAM10 significantly reduces incubationtimes and increases PrP(Sc) formation. Incontrast, spatiotemporal analysis indicates thatabsence of shedding impairs spread of prionpathology. Our data support a dual role forADAM10-mediated shedding and highlight the", "metadata": {}}
+{"_id": "17338543", "title": "", "text": "High-affinity zinc inhibition of NMDA NR1-NR2AreceptorsMicromolar concentrations ofextracellular Zn2+ are known to antagonizenative NMDA receptors via a dual mechanisminvolving both a voltage-independent and avoltage-dependent inhibition. We have tried toevaluate the relative importance of these twoeffects and their subunit specificity onrecombinant NMDA receptors expressed in HEK293 cells and Xenopus oocytes. The comparisonof NR1a-NR2A and NR1a-NR2B receptors showsthat the voltage-dependent inhibition is similar inboth types of receptors but that thevoltage-independent inhibition occurs at muchlower Zn2+ concentrations in NR1a-NR2Areceptors (IC50 in the nanomolar range) than inNR1a-NR2B receptors (IC50 in the micromolarrange). The high affinity of the effect observedwith NR1a-NR2A receptors was found to beattributable mostly to the slow dissociation ofZn2+ from its binding site. By analyzing theeffects of Zn2+ on varied combinations of NR1", "metadata": {}}
+{"_id": "17368516", "title": "", "text": "PrimPol, an Archaic Primase/PolymeraseOperating in Human CellsWe describe a secondprimase in human cells, PrimPol, which has theability to start DNA chains with deoxynucleotidesunlike regular primases, which use exclusivelyribonucleotides. Moreover, PrimPol is also a DNApolymerase tailored to bypass the most commonoxidative lesions in DNA, such as abasic sites and8-oxoguanine. Subcellular fractionation andimmunodetection studies indicated that PrimPolis present in both nuclear and mitochondrial DNAcompartments. PrimPol activity is detectable inmitochondrial lysates from human and mousecells but is absent from mitochondria derivedfrom PRIMPOL knockout mice. PRIMPOL genesilencing or ablation in human and mouse cellsimpaired mitochondrial DNA replication. On thebasis of the synergy observed with replicativeDNA polymerases Polγ and Polε, PrimPol isproposed to facilitate replication fork progressionby acting as a translesion DNA polymerase or asa specific DNA primase reinitiating downstream", "metadata": {}}
+{"_id": "17374970", "title": "", "text": "Predictors of Attrition and Academic Success ofMedical Students: A 30-Year RetrospectiveStudyAIM To determine attrition and predictorsof academic success among medical students atUniversity of Split, Croatia. METHODS Weanalysed academic records of 2054 studentsenrolled during 1979-2008 period. RESULTS Wefound that 26% (533/2054) of enrolled studentsdid not graduate. The most common reasons forattrition were 'personal' (36.4%), transfer toanother medical school (35.6%), and dismissaldue to unsatisfactory academic record (21.2%).Grade point average (GPA) and study duration ofattrition students were significantly associatedwith parental education. There were 1126graduates, 395 men and 731 women. Theiraverage graduation GPA was 3.67±0.53 andstudy duration 7.6±2.44 years. During 5-yearcurriculum only 6.4% (42/654) of studentsgraduated in time, and 55% (240/472) ofstudents graduated in time after curriculum wasextended to 6 years. Variables predicting", "metadata": {}}
+{"_id": "17388232", "title": "", "text": "Mechanical regulation of cell function withgeometrically modulated elastomericsubstratesWe report the establishment of alibrary of micromolded elastomeric micropostarrays to modulate substrate rigidityindependently of effects on adhesive and othermaterial surface properties. We demonstratedthat micropost rigidity impacts cell morphology,focal adhesions, cytoskeletal contractility andstem cell differentiation. Furthermore, earlychanges in cytoskeletal contractility predictedlater stem cell fate decisions in single cells.", "metadata": {}}
+{"_id": "17402386", "title": "", "text": "THE EMBO JOURNALGlutamate-gated ionchannels (ionotropic glutamate receptors,iGluRs) sense the extracellular milieu via anextensive extracellular portion, comprised of twoclamshell-shaped segments. The distal,N-terminal domain (NTD) has allosteric potentialin NMDA-type iGluRs, which has not beenascribed to the analogous domain in AMPAreceptors (AMPARs). In this study, we presentnew structural data uncovering dynamicproperties of the GluA2 and GluA3 AMPAR NTDs.GluA3 features a zipped-open dimer interfacewith unconstrained lower clamshell lobes,reminiscent of metabotropic GluRs (mGluRs).The resulting labile interface supportsinterprotomer rotations, which can betransmitted to downstream receptor segments.Normal mode analysis reveals two dominantmechanisms of AMPAR NTD motion:intraprotomer clamshell motions andinterprotomer counter-rotations, as well asaccessible interconversion between AMPAR and", "metadata": {}}
+{"_id": "17412260", "title": "", "text": "A complex secretory program orchestrated bythe inflammasome controls paracrinesenescenceOncogene-induced senescence (OIS)is crucial for tumour suppression. Senescent cellsimplement a complex pro-inflammatory responsetermed the senescence-associated secretoryphenotype (SASP). The SASP reinforcessenescence, activates immune surveillance andparadoxically also has pro-tumorigenicproperties. Here, we present evidence that theSASP can also induce paracrine senescence innormal cells both in culture and in human andmouse models of OIS in vivo. Couplingquantitative proteomics with small-moleculescreens, we identified multiple SASP componentsmediating paracrine senescence, including TGF-βfamily ligands, VEGF, CCL2 and CCL20. Amongstthem, TGF-β ligands play a major role byregulating p15(INK4b) and p21(CIP1).Expression of the SASP is controlled byinflammasome-mediated IL-1 signalling. Theinflammasome and IL-1 signalling are activated", "metadata": {}}
+{"_id": "17415081", "title": "", "text": "Prospective Study of One Million Deaths in India:Rationale, Design, and Validation ResultsOver75% of the annual estimated 9.5 million deathsin India occur in the home, and the largemajority of these do not have a certified cause.India and other developing countries urgentlyneed reliable quantification of the causes ofdeath. They also need better epidemiologicalevidence about the relevance of physical (suchas blood pressure and obesity), behavioral (suchas smoking, alcohol, HIV-1 risk taking, andimmunization history), and biological (such asblood lipids and gene polymorphisms)measurements to the development of disease inindividuals or disease rates in populations. Thisreport here is on the rationale, design, andimplementation of the world’s largestprospective study of the causes and correlates ofmortality. Nearly 14 million people in 2.4 millionnationally representative Indian households willbe monitored (for vital status and, if dead, thecauses of death through a well-validated verbal", "metadata": {}}
+{"_id": "17416520", "title": "", "text": "Genome-wide identification of genes directlyregulated by the pleiotropic transcription factorSpx in Bacillus subtilisThe transcriptionalregulator Spx plays a key role in maintaining theredox homeostasis of Bacillus subtilis cellsexposed to disulfide stress. Defects in Spx werepreviously shown to lead to differentialexpression of numerous genes but direct andindirect regulatory effects could not bedistinguished. Here we identified 283 discretechromosomal sites potentially bound by theSpx-RNA polymerase (Spx-RNAP) complex usingchromatin immunoprecipitation of Spx. Threequarters of these sites were located nearSigma(A)-dependent promoters, and upondiamide treatment, the fraction of the Spx-RNAPcomplex increased in parallel with the numberand occupancy of DNA sites. Correlation ofSpx-RNAP-binding sites with gene differentialexpression in wild-type and Δspx strains exposedor not to diamide revealed that 144 transcriptionunits comprising 275 genes were potentially", "metadata": {}}
+{"_id": "17421851", "title": "", "text": "Expression of interleukin-18 in humanatherosclerotic plaques and relation to plaqueinstability.BACKGROUND Interleukin (IL)-18 is apotent proinflammatory cytokine with potentialatherogenic properties. Its expression and role inatherosclerosis, however, are unknown.METHODS AND RESULTS In the present study,we examined stable and unstable human carotidatherosclerotic plaques retrieved byendarterectomy for the presence of IL-18 usingreverse transcription-polymerase chain reaction(PCR), Western blot, and immunohistochemicaltechniques. IL-18 was highly expressed in theatherosclerotic plaques compared with controlnormal arteries and was localized mainly inplaque macrophages. IL-18 receptor was alsoupregulated in plaque macrophages andendothelial cells, suggesting potential biologicaleffects. To examine the role of IL-18 inatherosclerosis, we determined the relationbetween IL-18 mRNA expression and signs ofplaque instability using real-time quantitative", "metadata": {}}
+{"_id": "17422777", "title": "", "text": "US-SOMO HPLC-SAXS module: dealing withcapillary fouling and extraction of purecomponent patterns from poorly resolvedSEC-SAXS dataSize-exclusion chromatographycoupled with SAXS (small-angle X-rayscattering), often performed using aflow-through capillary, should allow directcollection of monodisperse sample data.However, capillary fouling issues andnon-baseline-resolved peaks can hamper itsefficacy. The UltraScan solution modeler(US-SOMO) HPLC-SAXS (high-performance liquidchromatography coupled with SAXS) moduleprovides a comprehensive framework to analyzesuch data, starting with a simple linear baselinecorrection and symmetrical Gaussiandecomposition tools [Brookes, Pérez, Cardinali,Profumo, Vachette & Rocco (2013 \u0000). J. Appl.Cryst.46, 1823-1833]. In addition to several newfeatures, substantial improvements to bothroutines have now been implemented,comprising the evaluation of outcomes by", "metadata": {}}
+{"_id": "17433284", "title": "", "text": "Determination of Malaria Epidemiological Statusin Iran’s Malarious Areas as Baseline Informationfor Implementation of Malaria EliminationProgram in IranBACKGROUND According towillingness of the Ministry of Health, Iran andpresence of appropriate conditions for diseaseelimination, national malaria control programdecided to conduct a research to clarify malariastatus in 2007 and to provide requiredinformation to perform the elimination program.This review is comprised of the basis of nationalmalaria elimination program in vision of 2025,which was started in 2010. METHODS In thisdescriptive study, data were analyzed byapplications of different variables at district level.All districts in the three south eastern provinces,in which malaria has local transmission, wereconsidered. Malaria cases has been determinedand studied based on the national malariasurveillance system. RESULTS Since vivaxmalaria is predominant in Sistan & BaluchestanProvince, number of vivax cases is equal to", "metadata": {}}
+{"_id": "17438862", "title": "", "text": "Local neuroinflammation and the progression ofAlzheimer’s diseasePostmortemimmunohistochemical studies have revealed astate of chronic inflammation limited to lesionedareas of brain in Alzheimer’s disease. Some keyactors in this inflammation are activatedmicroglia (brain macrophages), proteins of theclassical complement cascade, the pentraxins,cytokines, and chemokines. The inflammationdoes not involve the adaptive immune system orperipheral organs, but is rather due to thephylogenetically much older innate immunesystem, which appears to operate in most tissuesof the body. Chronic inflammation can damagehost tissue and the brain may be particularlyvulnerable because of the postmitotic nature ofneurons. Many of the inflammatory mediatorshave been shown to be locally produced andselectively elevated in affected regions ofAlzheimer’s brain. Moreover, studies of tissue insuch degenerative processes as atherosclerosisand infarcted heart suggest a similar local innate", "metadata": {}}
+{"_id": "17447653", "title": "", "text": "BLAST+: architecture andapplicationsBACKGROUND Sequence similaritysearching is a very important bioinformaticstask. While Basic Local Alignment Search Tool(BLAST) outperforms exact methods through itsuse of heuristics, the speed of the current BLASTsoftware is suboptimal for very long queries ordatabase sequences. There are also someshortcomings in the user-interface of the currentcommand-line applications. RESULTS Wedescribe features and improvements of rewrittenBLAST software and introduce newcommand-line applications. Long querysequences are broken into chunks for processing,in some cases leading to dramatically shorter runtimes. For long database sequences, it is possibleto retrieve only the relevant parts of thesequence, reducing CPU time and memory usagefor searches of short queries against databasesof contigs or chromosomes. The program cannow retrieve masking information for databasesequences from the BLAST databases. A new", "metadata": {}}
+{"_id": "17450673", "title": "", "text": "Intrauterine environments and breast cancerrisk: meta-analysis and systematicreviewINTRODUCTION Various perinatal factors,including birth weight, birth order, maternal age,gestational age, twin status, and parentalsmoking, have been postulated to affect breastcancer risk in daughters by altering the hormonalenvironment of the developing fetal mammaryglands. Despite ample biologic plausibility,epidemiologic studies to date have yieldedconflicting results. We investigated theassociations between perinatal factors andsubsequent breast cancer risk throughmeta-analyses. METHODS We reviewed breastcancer studies published from January 1966 toFebruary 2007 that included data on birthweight, birth order, maternal age, gestationalage, twin status, and maternal or paternalsmoking. Meta-analyses using random effectmodels were employed to summarize the results.RESULTS We found that heavier birth weightswere associated with increased breast cancer", "metadata": {}}
+{"_id": "17454301", "title": "", "text": "Epidemiologic studies on Dengue in Santiago deCuba, 1997.A small, isolated outbreak of denguehemorrhagic fever/dengue shock syndrome(DHF/DSS) due to dengue virus type 2 (DEN-2)was documented in Santiago de Cuba on theisland of Cuba beginning in January 1997. Therewere 205 DHF/DSS cases, all in persons olderthan age 15 years. All but three had evidence ofa prior dengue infection, with the only knownopportunity being the islandwide dengue virustype 1 (DEN-1) epidemic of 1977-1979. Virtuallycomplete clinical and laboratory surveillance ofovert disease was achieved. From December1997 to January 1998, a random, age-stratifiedserum sample was obtained from 1,151 personsin 40 residential clusters in Santiago. Sera weretested for DEN-1 and DEN-2 neutralizingantibodies. The prevalence of DEN-2 antibodiesin children age 15 years and under, born afterthe 1981 DEN-2 epidemic, was taken as the1997 DEN-2 infection rate. This was adjustedslightly to accommodate observed cases,", "metadata": {}}
+{"_id": "17462437", "title": "", "text": "Prognostic and Predictive Value of KRASMutations in Advanced Non-Small Cell LungCancerClinical implications of KRAS mutations inadvanced non-small cell lung cancer remainunclear. We retrospectively evaluated theprognostic and predictive value of KRASmutations in patients with advanced NSCLC.Among 484 patients with available results forboth KRAS and EGFR mutations, 39 (8%) hadKRAS and 182 (38%) EGFR mutations, with twocases having both mutations. The median overallsurvivals for patients with KRAS mutations, EGFRmutations, or both wild types were 7.7, 38.0,and 15.0 months, respectively (P<0.001). TheKRAS mutation was an independent poorprognostic factor in the multivariate analysis(hazard ratio = 2.6, 95% CI: 1.8-3.7). Responserates and progression-free survival (PFS) for thepemetrexed-based regimen in the KRASmutation group were 14% and 2.1 months,inferior to those (28% and 3.9 months) in theKRAS wild type group. KRAS mutation tended to", "metadata": {}}
+{"_id": "17463469", "title": "", "text": "A Heteroskedasticity-Consistent CovarianceMatrix Estimator And A Direct Test ForHeteroskedasticityThis paper presents aparameter covariance matrix estimator which isconsistent even when the disturbances of a linearregression model are heteroskedastic. Thisestimator does not depend on a formal model ofthe structure of the heteroskedasticity. Bycomparing the elements of the new estimator tothose of the usual covariance estimator, oneobtains a direct test for heteroskedasticity, sincein the absence of heteroskedasticity, the twoestimators will be approximately equal, but willgenerally diverge otherwise. The test has anappealing least squares interpretation.", "metadata": {}}
+{"_id": "17463549", "title": "", "text": "Two Subsets of Naive T Helper Cells with DistinctT Cell Receptor Excision Circle Content in HumanAdult Peripheral BloodDuring ageing thymicfunction declines and is unable to meet thedemand for peripheral T helper (Th) cellreplenishment. Therefore, populationmaintenance of naive Th cells must be at leastpartly peripherally based. Such peripheralpostthymic expansion of recent thymic emigrants(RTEs) during ageing consequently should leadto loss or dilution of T cell receptor excisioncircles (TRECs) from a subset of naive T cells. Wehave identified two subsets of naive Th cells inhuman adult peripheral blood characterized by astriking unequal content of TRECs, indicatingdifferent peripheral proliferative histories. TRECsare highly enriched in peripheral naive CD45RA+Th cells coexpressing CD31 compared withperipheral naive CD45RA+ Th cells lacking CD31expression, in which TRECs can hardly bedetected. Furthermore we show thatCD31−CD45RA+ Th cells account for increasing", "metadata": {}}
+{"_id": "17464771", "title": "", "text": "A Role for the Vacuolating Cytotoxin, VacA, inColonization and Helicobacter pylori–InducedMetaplasia in the StomachCarriage ofHelicobacter pylori strains producing more active(s1/i1) forms of VacA is strongly associated withgastric adenocarcinoma. To our knowledge, weare the first to determine effects of differentpolymorphic forms of VacA on inflammation andmetaplasia in the mouse stomach. Bacteriaproducing the less active s2/i2 form of VacAcolonized mice more efficiently than mutants nullfor VacA or producing more active forms of it,providing the first evidence of a positive role forthe minimally active s2/i2 toxin. Strainsproducing more active toxin forms induced moresevere and extensive metaplasia andinflammation in the mouse stomach than strainsproducing weakly active (s2/i2) toxin. We alsoexamined the association in humans, controllingfor cagPAI status. In human gastric biopsyspecimens, the vacA i1 allele was stronglyassociated with precancerous intestinal", "metadata": {}}
+{"_id": "17482507", "title": "", "text": "Systematic review of role of bisphosphonates onskeletal morbidity in metastaticcancer.OBJECTIVE To review the evidence for theuse of bisphosphonates to reduce skeletalmorbidity in cancer patients with bonemetastases. DATA SOURCES Electronicdatabases, scanning reference lists, andconsultation with experts and pharmaceuticalcompanies. Foreign language papers wereincluded. STUDY SELECTION Included trials wererandomised controlled trials of patients withmalignant disease and bone metastases whowere treated with oral or intravenousbisphosphonate compared with anotherbisphosphonate, placebo, or standard care. Alltrials measured at least one outcome of skeletalmorbidity. RESULTS 95 articles were identified;30 studies fulfilled inclusion criteria. In studiesthat lasted > or = 6 months, compared withplacebo bisphosphonates significantly reducedthe odds ratio for fractures (vertebral 0.69, 95%confidence interval 0.57 to 0.84, P < 0.0001;", "metadata": {}}
+{"_id": "17506075", "title": "", "text": "Rodent Models of Depression: Neurotrophic andNeuroinflammatory BiomarkersRodent modelsare an indispensable tool for studying etiologyand progress of depression. Since interrelatedsystems of neurotrophic factors and cytokinescomprise major regulatory mechanismscontrolling normal brain plasticity, impairmentsof these systems form the basis for developmentof cerebral pathologies, including mentaldiseases. The present review focuses on thenumerous experimental rodent models ofdepression induced by different stress factors(exteroceptive and interoceptive) during earlylife (including prenatal period) or adulthood,giving emphasis to the data on the changes ofneurotrophic factors and neuroinflammatoryindices in the brain. These parameters areclosely related to behavioral depression-likesymptoms and impairments of neuronal plasticityand are both gender- and genotype-dependent.Stress-related changes in expression ofneurotrophins and cytokines in rodent brain are", "metadata": {}}
+{"_id": "17518195", "title": "", "text": "The docking domain of histone H2A is requiredfor H1 binding and RSC-mediated nucleosomeremodelingHistone variants within the H2Afamily show high divergences in their C-terminalregions. In this work, we have studied how thesedivergences and in particular, how a part of theH2A COOH-terminus, the docking domain, isimplicated in both structural and functionalproperties of the nucleosome. Using biochemicalmethods in combination with Atomic ForceMicroscopy and Electron Cryo-Microscopy, weshow that the H2A-docking domain is a keystructural feature within the nucleosome.Deletion of this domain or replacement with theincomplete docking domain from the variantH2A.Bbd results in significant structuralalterations in the nucleosome, including anincrease in overall accessibility to nucleases,un-wrapping of \u000010 bp of DNA from each end ofthe nucleosome and associated changes in theentry/exit angle of DNA ends. These structuralalterations are associated with a reduced ability", "metadata": {}}
+{"_id": "17539488", "title": "", "text": "Regulation of poly(A) site choice of several yeastmRNAsSeveral yeast genes produce multipletranscripts with different 3'-ends. Of these, fourgenes are known to produce truncatedtranscripts that end within the coding sequenceof longer transcripts: CBP1 , AEP2 / ATP13 ,RNA14 and SIR1 . It has been shown that thelevel of the truncated CBP1 transcript increasesduring the switch to respiratory growth whilethat of the full-length transcript decreases. Todetermine whether this phenomenon is unique toCBP1 , northern analysis was used to determinewhether the levels of other truncated transcriptsare regulated similarly by carbon source. Thelevels of the shortest transcripts of AEP2 / ATP13and RNA14 increased during respiration while theshortest SIR1 transcript remained constant.However, two longer SIR1 transcripts wereregulated reciprocally by carbon source. Mappingthe 3'-ends of each transcript by sequencingpartial cDNA clones revealed multiple 3'-ends foreach transcript. Examination of the sequences", "metadata": {}}
+{"_id": "17544977", "title": "", "text": "Circular RNA and miR-7 in cancer.MicroRNAs(miRNA) play important roles in fine-tuning geneexpression and are often deregulated in cancer.The identification of competing endogenous RNAand circular RNA (circRNA) as importantregulators of miRNA activity underscores theincreasing complexity of ncRNA-mediatedregulatory networks. Particularly, the recentlyidentified circular RNA, ciRS-7, which acts as adesignated miR-7 inhibitor/sponge, hasconceptually changed the mechanisticunderstanding of miRNA networks. As miR-7modulates the expression of several oncogenes,disclosing the regulation of miR-7 activity willlikely advance the understanding of variouscancer etiologies. Here, we review the currentknowledge about the ciRS-7/miR-7 axis incancer-related pathways and discuss possiblemodels explaining the relevance of coexpressingmiR-7 along with a circRNA inhibitor.", "metadata": {}}
+{"_id": "17546486", "title": "", "text": "Angiotensin II Evokes Angiogenic Signals withinSkeletal Muscle through Co-ordinated Effects onSkeletal Myocytes and Endothelial CellsSkeletalmuscle overload induces the expression ofangiogenic factors such as vascular endothelialgrowth factor (VEGF) and matrixmetalloproteinase (MMP)-2, leading to newcapillary growth. We found that theoverload-induced increase in angiogenesis, aswell as increases in VEGF, MMP-2 and MT1-MMPtranscripts were abrogated in muscle VEGF KOmice, highlighting the critical role ofmyocyte-derived VEGF in controlling thisprocess. The upstream mediators that contributeto overload-induced expression of VEGF have yetto be ascertained. We found that muscleoverload increased angiotensinogen expression,a precursor of angiotensin (Ang) II, and that AngII signaling played an important role in basalVEGF production in C2C12 cells. Furthermore,matrix-bound VEGF released from myoblastsinduced the activation of endothelial cells, as", "metadata": {}}
+{"_id": "17553026", "title": "", "text": "A specific loop in human DNA polymerase muallows switching between creative andDNA-instructed synthesisHuman DNApolymerase mu (Polμ) is a family X member thathas terminal transferase activity but, in spite of anon-orthodox selection of the templateinformation, displays its maximal catalyticefficiency in DNA-templated reactions. Asterminal deoxynucleotidyl transferase (TdT), Polμhas a specific loop (loop1) that could provide thisenzyme with its terminal transferase activity.When loop1 was deleted, human Polμ lacked TdTactivity but improved DNA-binding and DNAtemplate-dependent polymerization.Interestingly, when loop1 from TdT was insertedin Polμ (substituting its cognate loop1), theresulting chimaera displayed TdT activity,preferentially inserting dGTP residues, but had astrongly reduced template-dependentpolymerization activity. Therefore, a specializedloop in Polμ, that could adopt alternativeconformations, appears to provide this enzyme", "metadata": {}}
+{"_id": "17587795", "title": "", "text": "Dnmt1-Independent CG Methylation Contributesto Nucleosome Positioning in DiverseEukaryotesDnmt1 epigenetically propagatessymmetrical CG methylation in many eukaryotes.Their genomes are typically depleted of CGdinucleotides because of imperfect repair ofdeaminated methylcytosines. Here, weextensively survey diverse species lackingDnmt1 and show that, surprisingly, symmetricalCG methylation is nonetheless frequently presentand catalyzed by a different DNAmethyltransferase family, Dnmt5. NumerousDnmt5-containing organisms that diverged morethan a billion years ago exhibit clusteredmethylation, specifically in nucleosome linkers.Clustered methylation occurs at unprecedenteddensities and directly disfavors nucleosomes,contributing to nucleosome positioning betweenclusters. Dense methylation is enabled by aregime of genomic sequence evolution thatenriches CG dinucleotides and drives the highestCG frequencies known. Species with linker", "metadata": {}}
+{"_id": "17591478", "title": "", "text": "The Immunogenicity and Safety of theLive-attenuated SA 14-14-2 JapaneseEncephalitis Vaccine Given with a Two-dosePrimary Schedule in ChildrenEffective andtolerable vaccination is an essential strategy toprevent Japanese encephalitis (JE) in endemicareas. Although the live attenuated SA 14-14-2JE vaccine (LAJEV) has been widely used sinceits introduction, the systemic data of LAJEV wasvery rarely available in Korea. We conducted theopen-label, prospective cohort study to assessthe immunogenicity and safety of this vaccine.Ninety subjects were enrolled, and LAJEV in a2-dose primary series was given with a12-month interval. Neutralizing antibody titerswere measured before and after eachvaccination, and active monitoring for adverseevents was performed. After the first dose,91.1% of subjects had seroprotection with ageometric mean titer (GMT) of 40.9.Seroprotection rate after the second dose was97%, and GMT showed an increase of 6.5-fold.", "metadata": {}}
+{"_id": "17601006", "title": "", "text": "Centrosome-dependent asymmetric inheritanceof the midbody ring in Drosophila germline stemcell divisionMany stem cells, including Drosophilagermline stem cells (GSCs), divideasymmetrically, producing one stem cell and onedifferentiating daughter. Cytokinesis is oftenasymmetric, in that only one daughter cellinherits the midbody ring (MR) upon completionof abscission even in apparently symmetricallydividing cells. However, whether the asymmetryin cytokinesis correlates with cell fate or hasfunctional relevance has been poorly explored.Here we show that the MR is asymmetricallysegregated during GSC divisions in a centrosomeage-dependent manner: male GSCs, whichinherit the mother centrosome, exclude the MR,whereas female GSCs, which we here showinherit the daughter centrosome, inherit the MR.We further show that stem cell identity correlateswith the mode of MR inheritance. Together ourdata suggest that the MR does not inherentlydictate stem cell identity, although its", "metadata": {}}
+{"_id": "17625068", "title": "", "text": "Penile Curvature Incidence in Hypospadias: CanIt Be Determined?The aim was to retrospectivelydetermine the real incidence of congenital penilecurvature in various forms of hypospadias, inorder to indicate intraoperative assessment andcorrection of curvature. We analyzed 842patients with hypospadias who underwentsurgery from 2003 to 2010, classified into twogroups. First group was intraoperatively checkedfor curvature as a routine procedure, while acurvature in the second group was assessedmostly in severe hypospadias. Results areanalyzed using Fisher's and chi-square tests. Intotal, 238 cases (28.3%) of associated curvaturewere confirmed. Curvature was significantlymore frequent in the first group, regardinghypospadias in general (P < 0.01), as well asdistal (P < 0.05) and midshaft forms (P < 0.01).Penile curvature is common figure inhypospadias, including distal types.Intraoperative testing for associated curvatureshould be considered as a routine procedure in", "metadata": {}}
+{"_id": "17626822", "title": "", "text": "Home birth and barriers to referring women withobstetric complications to hospitals: amixed-methods study in Zahedan, southeasternIranBACKGROUND One factor that contributes tohigh maternal mortality in developing countriesis the delayed use of Emergency Obstetric-Care(EmOC) facilities. The objective of this study wasto determine the factors that hinder midwivesand parturient women from using hospitals whencomplications occur during home birth in Sistanand Baluchestan province, Iran, where 23% ofall deliveries take place in non- hospital settings.METHODS In the study and data management, amixed-methods approach was used. In thequantitative phase, we compared the existinghealth-sector data with World HealthOrganization (WHO) standards for the availabilityand use of EmOC services. The qualitative phaseincluded collection and analysis of interviewswith midwives and traditional birth attendantsand twenty-one in-depth interviews withmothers. The data collected in this phase were", "metadata": {}}
+{"_id": "17628888", "title": "", "text": "ATPase-Dependent Control of the Mms21 SUMOLigase during DNA RepairModification of proteinsby SUMO is essential for the maintenance ofgenome integrity. During DNA replication, theMms21-branch of the SUMO pathwaycounteracts recombination intermediates atdamaged replication forks, thus facilitating sisterchromatid disjunction. The Mms21 SUMO ligasedocks to the arm region of the Smc5 protein inthe Smc5/6 complex; together, they cooperateduring recombinational DNA repair. Yet how theactivity of the SUMO ligase is controlled remainsunknown. Here we show that the SUMO ligaseand the chromosome disjunction functions ofMms21 depend on its docking to an intact andactive Smc5/6 complex, indicating that theSmc5/6-Mms21 complex operates as a largeSUMO ligase in vivo. In spite of the physicaldistance separating the E3 and thenucleotide-binding domains in Smc5/6,Mms21-dependent sumoylation requires bindingof ATP to Smc5, a step that is part of the ligase", "metadata": {}}
+{"_id": "17631671", "title": "", "text": "Cadherins in brain morphogenesis andwiring.Cadherins are Ca(2+)-dependent cell-celladhesion molecules that play critical roles inanimal morphogenesis. Various cadherin-relatedmolecules have also been identified, which showdiverse functions, not only for the regulation ofcell adhesion but also for that of cell proliferationand planar cell polarity. During the past decade,understanding of the roles of these molecules inthe nervous system has significantly progressed.They are important not only for the developmentof the nervous system but also for its functionsand, in turn, for neural disorders. In this review,we discuss the roles of cadherins and relatedmolecules in neural development and function inthe vertebrate brain.", "metadata": {}}
+{"_id": "17648235", "title": "", "text": "Autocrine WNT signaling contributes to breastcancer cell proliferation via the canonical WNTpathway and EGFR transactivationDe-regulationof the wingless and integration site growth factor(WNT) signaling pathway via mutations in APCand Axin, proteins that target β-catenin fordestruction, have been linked to various types ofhuman cancer. These genetic alterations rarely,if ever, are observed in breast tumors. However,various lines of evidence suggest that WNTsignaling may also be de-regulated in breastcancer. Most breast tumors showhypermethylation of the promoter region ofsecreted Frizzled-related protein 1 (sFRP1), anegative WNT pathway regulator, leading todownregulation of its expression. As aconsequence, WNT signaling is enhanced andmay contribute to proliferation of human breasttumor cells. We previously demonstrated that, inaddition to the canonical WNT/β-cateninpathway, WNT signaling activates theextracellular signal-regulated kinase 1/2", "metadata": {}}
+{"_id": "17656445", "title": "", "text": "Alternative Markers of Hyperglycemia and Risk ofDiabetesOBJECTIVE Fructosamine, glycatedalbumin, and 1,5-anhydroglucitol (1,5-AG) are ofinterest for monitoring short-term glycemiccontrol in patients with diabetes; however, theirassociations with diabetes risk areuncharacterized. RESEARCH DESIGN ANDMETHODS We used Cox proportional hazardsmodels to examine the associations offructosamine, glycated albumin, and 1,5-AG withincident diabetes in 1,299 participants, from theAtherosclerosis Risk in Communities (ARIC)Study (2005-2006), who had no history ofdiagnosed diabetes at baseline. Incident diabeteswas self-reported during annual telephone calls.RESULTS There were 119 new cases of diabetesduring a median follow-up of 3.3 years. Whencompared with the lowest quartile, the fourthquartiles of fructosamine and glycated albuminwere significantly associated with diabetes risk(hazard ratio [HR] 3.99 [95% CI 1.93-8.28] and5.22 [2.49-10.94], respectively). The fourth", "metadata": {}}
+{"_id": "17671145", "title": "", "text": "ROR-γ drives androgen receptor expression andrepresents a therapeutic target incastration-resistant prostate cancerThe androgenreceptor (AR) is overexpressed andhyperactivated in human castration-resistantprostate cancer (CRPC). However, thedeterminants of AR overexpression in CRPC arepoorly defined. Here we show that retinoic acidreceptor-related orphan receptor γ (ROR-γ) isoverexpressed and amplified in metastatic CRPCtumors, and that ROR-γ drives AR expression inthe tumors. ROR-γ recruits nuclear receptorcoactivator 1 and 3 (NCOA1 and NCOA3, alsoknown as SRC-1 and SRC-3) to an AR-RORresponse element (RORE) to stimulate AR genetranscription. ROR-γ antagonists suppress theexpression of both AR and its variant AR-V7 inprostate cancer (PCa) cell lines and tumors.ROR-γ antagonists also markedly diminishgenome-wide AR binding, H3K27ac abundanceand expression of the AR target gene network.Finally, ROR-γ antagonists suppressed tumor", "metadata": {}}
+{"_id": "17676273", "title": "", "text": "affy--analysis of Affymetrix GeneChip data at theprobe level.MOTIVATION The processing of theAffymetrix GeneChip data has been a recentfocus for data analysts. Alternatives to theoriginal procedure have been proposed and someof these new methods are widely used. RESULTSThe affy package is an R package of functionsand classes for the analysis of oligonucleotidearrays manufactured by Affymetrix. The packageis currently in its second release, affy providesthe user with extreme flexibility when carryingout an analysis and make it possible to accessand manipulate probe intensity data. In thispaper, we present the main classes and functionsin the package and demonstrate how they can beused to process probe-level data. We alsodemonstrate the importance of probe-levelanalysis when using the Affymetrix GeneChipplatform.", "metadata": {}}
+{"_id": "17682477", "title": "", "text": "Inducible caspase-9 suicide gene controlsadverse effects from alloreplete T cells afterhaploidentical stem cell transplantation.To testthe feasibility of a single T-cell manipulation toeliminate alloreactivity while sparing antiviraland antitumor T cells, we infused 12haploidentical hematopoietic stem cell transplantpatients with increasing numbers of allorepletehaploidentical T cells expressing the induciblecaspase 9 suicide gene (iC9-T cells). Wedetermined whether the iC9-T cells producedimmune reconstitution and if any resultantgraft-versus-host disease (GVHD) could becontrolled by administration of a chemicalinducer of dimerization (CID;AP1903/Rimiducid). All patients receiving >10(4)alloreplete iC9-T lymphocytes per kilogramachieved rapid reconstitution of immuneresponses toward 5 major pathogenic virusesand concomitant control of active infections. Fourpatients received a single AP1903 dose. CIDinfusion eliminated 85% to 95% of circulating", "metadata": {}}
+{"_id": "17685207", "title": "", "text": "Clonal analysis of epiblast fate during germ layerformation in the mouse embryo.The fate of cellsin the epiblast at prestreak and early primitivestreak stages has been studied by injectinghorseradish peroxidase (HRP) into single cells insitu of 6.7-day mouse embryos and identifyingthe labelled descendants at midstreak to neuralplate stages after one day of culture. Ectodermwas composed of descendants of epiblastprogenitors that had been located in theembryonic axis anterior to the primitive streak.Embryonic mesoderm was derived from all areasof the epiblast except the distal tip and theadjacent region anterior to it: the most anteriormesoderm cells originated posteriorly, traversingthe primitive streak early; labelled cells in theposterior part of the streak at the neural platestage were derived from extreme anterior axialand paraxial epiblast progenitors; head processcells were derived from epiblast at or near theanterior end of the primitive streak. Endodermdescendants were most frequently derived from", "metadata": {}}
+{"_id": "17691617", "title": "", "text": "Effects of a High-Intensity Functional ExerciseProgram on Dependence in Activities of DailyLiving and Balance in Older Adults withDementiaOBJECTIVES To investigate the effectsof a high-intensity functional exercise programon independence in activities of daily living(ADLs) and balance in older people withdementia and whether exercise effects differedbetween dementia types. DESIGNCluster-randomized controlled trial: UmeåDementia and Exercise (UMDEX) study. SETTINGResidential care facilities, Umeå, Sweden.PARTICIPANTS Individuals aged 65 and olderwith a dementia diagnosis, a Mini-Mental StateExamination score of 10 or greater, anddependence in ADLs (N=186). INTERVENTIONNinety-three participants each were allocated tothe high-intensity functional exercise program,comprising lower limb strength and balanceexercises, and 93 to a seated control activity.MEASUREMENTS Blinded assessors measuredADL independence using the Functional", "metadata": {}}
+{"_id": "17693849", "title": "", "text": "Effect of Health Literacy on Quality of Lifeamongst Patients with Ischaemic Heart Diseasein Australian General PracticeBACKGROUNDAppropriate understanding of health informationby patients with cardiovascular disease (CVD) isfundamental for better management of riskfactors and improved morbidity, which can alsobenefit their quality of life. OBJECTIVES Toassess the relationship between health literacyand health-related quality of life (HRQoL) inpatients with ischaemic heart disease (IHD), andto investigate the role of sociodemographic andclinical variables as possible confounders.METHODS Cross-sectional study of patients withIHD recruited from a stratified sample of generalpractices in two Australian states (Queenslandand South Australia) between 2007 and 2009.Health literacy was measured using a validatedquestionnaire and classified as inadequate,marginal, or adequate. Physical and mentalcomponents of HRQoL were assessed using theMedical Outcomes Study Short Form (SF12)", "metadata": {}}
+{"_id": "17695748", "title": "", "text": "inTransglutaminase 2 (TGase 2) is aCa+2-dependent enzyme that catalyzes bothintracellular and extracellular cross-linkingreactions by transamidation of specific glutamineresidues. TGase 2 is known to be involved in themembrane-mediated events required forglucose-stimulated insulin release from thepancreatic beta cells. Here we show thattargeted disruption of TGase 2 impairsglucose-stimulated insulin secretion. TGase 2-/-mice show glucose intolerance afterintraperitoneal glucose loading. TGase 2-/- micemanifest a tendency to develop hypoglycemiaafter administration of exogenous insulin as aconsequence of enhanced insulin receptorsubstrate 2 (IRS-2) phosphorylation. We suggestthat the increased peripheral sensitivity to insulinpartially compensates for the defective secretionin this animal model. TGase 2-/- mousephenotype resembles that of the maturity-onsetdiabetes of young (MODY) patients. In thecourse of screening for human TGase 2 gene in", "metadata": {}}
+{"_id": "17702490", "title": "", "text": "Chromatin structure and gene expressionprograms of human embryonic and inducedpluripotent stem cells.Knowledge of both theglobal chromatin structure and the geneexpression programs of human embryonic stemcells (ESCs) and induced pluripotent stem cells(iPSCs) should provide a robust means to assesswhether the genomes of these cells have similarpluripotent states. Recent studies havesuggested that ESCs and iPSCs representdifferent pluripotent states with substantiallydifferent gene expression profiles. We describehere a comparison of global chromatin structureand gene expression data for a panel of humanESCs and iPSCs. Genome-wide maps ofnucleosomes with histone H3K4me3 andH3K27me3 modifications indicate that there islittle difference between ESCs and iPSCs withrespect to these marks. Gene expression profilesconfirm that the transcriptional programs ofESCs and iPSCs show very few consistentdifferences. Although some variation in", "metadata": {}}
+{"_id": "17708753", "title": "", "text": "Myeloid Cells Expressing VEGF and Arginase-1Following Uptake of Damaged Retinal PigmentEpithelium Suggests Potential Mechanism ThatDrives the Onset of Choroidal Angiogenesis inMiceWhilst data recognise both myeloid cellaccumulation during choroidal neovascularisation(CNV) as well as complement activation, none ofthe data has presented a clear explanation forthe angiogenic drive that promotes pathologicalangiogenesis. One possibility that is apre-eminent drive is a specific and earlyconditioning and activation of the myeloid cellinfiltrate. Using a laser-induced CNV murinemodel, we have identified that disruption ofretinal pigment epithelium (RPE) and Bruch'smembrane resulted in an early recruitment ofmacrophages derived from monocytes andmicroglia, prior to angiogenesis andcontemporaneous with lesional complementactivation. Early recruited CD11b(+) cellsexpressed a definitive gene signature of selectiveinflammatory mediators particularly a", "metadata": {}}
+{"_id": "17717391", "title": "", "text": "Monitoring Tumorigenesis and Senescence InVivo with a p16INK4a-LuciferaseModelMonitoring cancer and aging in vivoremains experimentally challenging. Here, wedescribe a luciferase knockin mouse (p16(LUC)),which faithfully reports expression ofp16(INK4a), a tumor suppressor and agingbiomarker. Lifelong assessment of luminescencein p16(+/LUC) mice revealed an exponentialincrease with aging, which was highly variable ina cohort of contemporaneously housed,syngeneic mice. Expression of p16(INK4a) withaging did not predict cancer development,suggesting that the accumulation of senescentcells is not a principal determinant ofcancer-related death. In 14 of 14 tested tumormodels, expression of p16(LUC) was focallyactivated by early neoplastic events, enablingvisualization of tumors with sensitivity exceedingother imaging modalities. Activation ofp16(INK4a) was noted in the emerging neoplasmand surrounding stromal cells. This work", "metadata": {}}
+{"_id": "17731780", "title": "", "text": "The Bacteroides sp. 3_1_23 Pif1 protein is amultifunctional helicaseScPif1 DNA helicase is theprototypical member of a 5'-to-3' helicasesuperfamily conserved from bacteria to humanand plays various roles in the maintenance ofgenomic homeostasis. While many studies havebeen performed with eukaryotic Pif1 helicases,including yeast and human Pif1 proteins, thepotential functions and biochemical properties ofprokaryotic Pif1 helicases remain largelyunknown. Here, we report the expression,purification and biochemical analysis of Pif1helicase from Bacteroides sp. 3_1_23 (BsPif1).BsPif1 binds to a large panel of DNA substratesand, in particular, efficiently unwinds partialduplex DNAs with 5'-overhang, fork-likesubstrates, D-loop and flap-like substrates,suggesting that BsPif1 may act at stalled DNAreplication forks and enhance Okazaki fragmentmaturation. Like its eukaryotic homologues,BsPif1 resolves R-loop structures and unwindsDNA-RNA hybrids. Furthermore, BsPif1 efficiently", "metadata": {}}
+{"_id": "17741440", "title": "", "text": "Netting neutrophils in autoimmune small-vesselvasculitisSmall-vessel vasculitis (SVV) is achronic autoinflammatory condition linked toantineutrophil cytoplasm autoantibodies(ANCAs). Here we show that chromatin fibers,so-called neutrophil extracellular traps (NETs),are released by ANCA-stimulated neutrophils andcontain the targeted autoantigens proteinase-3(PR3) and myeloperoxidase (MPO). Deposition ofNETs in inflamed kidneys and circulatingMPO-DNA complexes suggest that NET formationtriggers vasculitis and promotes the autoimmuneresponse against neutrophil components inindividuals with SVV.", "metadata": {}}
+{"_id": "17755060", "title": "", "text": "Control of Nutrient Stress-Induced MetabolicReprogramming by PKCζ in TumorigenesisTumorcells have high-energetic and anabolic needs andare known to adapt their metabolism to be ableto survive and keep proliferating underconditions of nutrient stress. We show that PKCζdeficiency promotes the plasticity necessary forcancer cells to reprogram their metabolism toutilize glutamine through the serine biosyntheticpathway in the absence of glucose. PKCζrepresses the expression of two key enzymes ofthe pathway, PHGDH and PSAT1, andphosphorylates PHGDH at key residues to inhibitits enzymatic activity. Interestingly, the loss ofPKCζ in mice results in enhanced intestinaltumorigenesis and increased levels of these twometabolic enzymes, whereas patients with lowlevels of PKCζ have a poor prognosis.Furthermore, PKCζ and caspase-3 activities arecorrelated with PHGDH levels in human intestinaltumors. Taken together, this demonstrates thatPKCζ is a critical metabolic tumor suppressor in", "metadata": {}}
+{"_id": "17768946", "title": "", "text": "XRCC4's interaction with XLF is required forcoding (but not signal) end joiningXRCC4 andXLF are structurally related proteins importantfor DNA Ligase IV function. XRCC4 forms a tightcomplex with DNA Ligase IV while XLF interactsdirectly with XRCC4. Both XRCC4 and XLF formhomodimers that can polymerize as heterotypicfilaments independently of DNA Ligase IV.Emerging structural and in vitro biochemical datasuggest that XRCC4 and XLF together generate afilamentous structure that promotes bridgingbetween DNA molecules. Here, we show thatablating XRCC4's affinity for XLF results in DNArepair deficits including a surprising deficit in VDJcoding, but not signal end joining. These dataare consistent with a model whereby XRCC4/XLFcomplexes hold DNA ends together--stringentlyrequired for coding end joining, but dispensablefor signal end joining. Finally, DNA-PKphosphorylation of XRCC4/XLF complexes disruptDNA bridging in vitro, suggesting a regulatoryrole for DNA-PK's phosphorylation of XRCC4/XLF", "metadata": {}}
+{"_id": "17775228", "title": "", "text": "Loss of imprinting in colorectal cancer linked tohypomethylation of H19 and IGF2.Epigeneticalterations in human cancers include global DNAhypomethylation,gene hypomethylation andpromoter hypermethylation, and loss ofimprinting (LOI) of the insulin-like growthfactor-II gene (IGF2). A mechanism for LOIdescribed previously is hypermethylation of adifferentially methylated region (DMR) upstreamof the H19 gene, allowing activation of thenormally silent maternal allele of IGF2. Here weshow that this mechanism does not apply tocolorectal cancers, which show hypomethylationof the H19 DMR as well as a DMR upstream ofexon 3 of IGF2. This hypomethylation is found inboth colorectal cancers and normal mucosa fromthe same patients, and in cell lines with somaticcell knockout of DNA methyltransferases DNMT1and DNMT3B. These data suggest thathypomethylation is a mechanism for LOI, thatthe popular IGF2-H19 enhancer competitionmodel for IGF2 imprinting does not apply to the", "metadata": {}}
+{"_id": "17779800", "title": "", "text": "Management of patients with sore throats inrelation to guidelines: An interview study inSwedenOBJECTIVE To explore how a group ofSwedish general practitioners (GPs) managepatients with a sore throat in relation to currentguidelines as expressed in interviews. DESIGNQualitative content analysis was used to analysesemi-structured interviews. SETTING Swedishprimary care. SUBJECTS A strategic sample of 25GPs. MAIN OUTCOME MEASURES Perceivedmanagement of sore throat patients. RESULTS Itwas found that nine of the interviewed GPs wereadherent to current guidelines for sore throatand 16 were non-adherent. The two groupsdiffered in terms of guideline knowledge, whichwas shared within the team for adherent GPswhile idiosyncratic knowledge dominated for thenon-adherent GPs. Adherent GPs had no or lowconcerns for bacterial infections and differentialdiagnosis whilst non-adherent GPs believed thatin patients with a sore throat any bacterialinfection should be identified and treated with", "metadata": {}}
+{"_id": "17805221", "title": "", "text": "Catch and release: how do kinetochores hook theright microtubules during mitosis?Sportfishermen keep tension on their lines to preventhooked fish from releasing. A molecular versionof this angler's trick, operating at kinetochores,ensures accuracy during mitosis: the mitoticspindle attaches randomly to chromosomes andthen correctly bioriented attachments arestabilized due to the tension exerted on them byopposing microtubules. Incorrect attachments,which lack tension, are unstable and releasequickly, allowing another chance forbiorientation. Stabilization of molecularinteractions by tension also occurs in otherphysiological contexts, such as cell adhesion,motility, hemostasis, and tissue morphogenesis.Here, we review models for the stabilization ofkinetochore attachments with an eye towardemerging models for other force-activatedsystems. Although attention in the mitosis fieldhas focused mainly on one kinase-basedmechanism, multiple mechanisms may act", "metadata": {}}
+{"_id": "17814815", "title": "", "text": "Label-free in vivo imaging of myelinated axons inhealth and disease with spectral confocalreflectance microscopyWe report a newlydeveloped technique for high-resolution in vivoimaging of myelinated axons in the brain, spinalcord and peripheral nerve that requires nofluorescent labeling. This method, based onspectral confocal reflectance microscopy(SCoRe), uses a conventional laser-scanningconfocal system to generate images by mergingthe simultaneously reflected signals frommultiple lasers of different wavelengths. Strikingcolor patterns unique to individual myelinatedfibers are generated that facilitate their tracing indense axonal areas. These patterns highlightnodes of Ranvier and Schmidt-Lantermanincisures and can be used to detect variousmyelin pathologies. Using SCoRe we carried outchronic brain imaging up to 400 μm deep,capturing de novo myelination of mouse corticalaxons in vivo. We also established the feasibilityof imaging myelinated axons in the human", "metadata": {}}
+{"_id": "17821387", "title": "", "text": "Applicability of current staging/categorization ofα-synuclein pathology and their clinicalrelevanceIn Parkinson's disease (PD) anddementia with Lewy bodies (DLB)alpha-synuclein (alphaS) pathology is seen thatdisplays a predictable topographic distribution.There are two staging/categorization systems,i.e. Braak's and McKeith's, currently in use forthe assessment of alphaS pathology. The aim ofthese diagnostic strategies in pathology is, inaddition to assess the stage/severity ofpathology, to assess the probabilities of therelated clinical symptomatology i.e. dementiaand extrapyramidal symptoms (EPS). Herein, weassessed the applicability of these twostaging/categorization systems and thefrequency of dementia and EPS in a cohort of226 alphaS-positive-subjects. These subjectwere selected from a large autopsy sample (n =1,720), irrespective of the clinical presentation,based on the detection ofalphaS-immunoreactivity (IR) in one of the most", "metadata": {}}
+{"_id": "17829012", "title": "", "text": "Batf is important for IL-4 expression in Tfollicular helper cellsApart from T helper (Th)-2cells, T follicular helper (Tfh) cells are a majorclass of IL-4-producing T cells, required forregulation of type 2 humoral immunity; however,transcriptional control of IL-4 production in Tfhcells remains mainly unknown. Here, we showthat the basic leucine zipper transcription factorATF-like, Batf is important for IL-4 expression inTfh cells rather than in canonical Th2 cells.Functionally, Batf in cooperation with interferonregulatory factor (IRF) 4 along with Stat3 andStat6 trigger IL-4 production in Tfh cells bydirectly binding to and activation of the CNS2region in the IL-4 locus. In addition,Batf-to-c-Maf signalling is an importantdeterminant of IL-4 expression in Tfh cells. Batfdeficiency impairs the generation ofIL-4-producing Tfh cells that results in protectionagainst allergic asthma. Our results thus indicatea positive role of Batf in promoting thegeneration of pro-allergic IL-4-producing Tfh", "metadata": {}}
+{"_id": "17844478", "title": "", "text": "Autocrine VEGF Signaling Synergizes with EGFRin Tumor Cells to Promote Epithelial CancerDevelopmentIt is established that tumorcell-derived VEGF acts on endothelial cells topromote angiogenesis and tumor growth. Here,we demonstrate that in K5-SOS-dependentmouse skin tumors, autocrine VEGF is requiredfor tumor cell proliferation in a cell-autonomousand angiogenesis-independent manner. VEGF isupregulated in SOS-expressing tumors, and itsdeletion in epidermal cells delays tumorigenesisby suppressing angiogenesis and tumor cellproliferation. Epidermis-specific Flt1 deletion alsoimpairs tumorigenesis and proliferation.Surprisingly, complete tumor inhibition occurs inthe absence of VEGF in EGFR mutant mice,demonstrating that VEGFR and EGFR synergizein neoplastic cells to promote tumor growth.Mechanistically, K5-SOS upregulates VEGF, Flt1,and Neuropilin-1 in an Erk-dependent manner,thereby activating an autocrine proliferationloop, whereas EGFR prevents tumor cells from", "metadata": {}}
+{"_id": "17876040", "title": "", "text": "Discovery and development of the Polo-likekinase inhibitor volasertib in cancertherapyOwing to their integral involvement in cellcycle regulation, the Polo-like kinase (Plk) family,particularly Plk1, has emerged as an attractivetherapeutic target in oncology. In recent years,several Plk1 inhibitors have been developed, withsome agents showing encouraging results inearly-phase clinical trials. This review focuses onvolasertib (BI 6727; an investigational agent), apotent and selective Plk inhibitor. Volasertib hasshown promising activity in various cancer celllines and xenograft models of human cancer.Trials performed to date suggest that volasertibhas clinical efficacy in a range of malignancies,with the most promising results seen in patientswith acute myeloid leukemia (AML).Encouragingly, recent phase II data havedemonstrated that volasertib combined withlow-dose cytarabine (LDAC) was associated withhigher response rates and improved event-freesurvival than LDAC alone in patients with", "metadata": {}}
+{"_id": "17877537", "title": "", "text": "Babies driving robots: self-generated mobility invery young infantsSelf-generated mobility vialocomotion is a key for the cognitive, social andmotor development of young infants. For certainchildren with special needs, self-generatedmobility is only attained via assistive technologysuch as a power wheelchair. Up until recently,infants under 24 months of age were notconsidered candidates for training in powermobility. Recent work in our labs and otherssuggest that younger infants can utilize theirreaching and grasping ability to learn powermobility. This interdisciplinary study combinesour previous work in motor development andlearning in infants with special needs, and theapplication of robot technology for rehabilitationto determine whether young infants withoutstructured training, would drive a mobile robot,and if so, to determine how their driving wouldchange over multiple sessions. The two infantsthat were seen for the most sessions were thefocus of this pilot study. Both infants increased", "metadata": {}}
+{"_id": "17897801", "title": "", "text": "Effects of Abciximab on the architecture ofplatelet-rich clots in patients with acutemyocardial infarction undergoing primarycoronary intervention.BACKGROUND Abciximabplus aspirin improves the TIMI 3 flow rate of theinfarct-related artery in patients treated witheither percutaneous coronary intervention orthrombolysis. The present study investigatedwhether the reperfusion efficacy of abciximabrelates to modifications of clot architecture inpatients admitted for acute myocardial infarction(AMI). METHODS AND RESULTS A total of 23AMI patients in the Abciximab before Directangioplasty and stenting in Myocardial InfarctionRegarding Acute and Long term follow-up(ADMIRAL) trial received, in a double-blindfashion, either abciximab (n=13) or placebo(n=10) before primary stenting. Viscoelastic (G'in dyne/cm(2)) and morphological (mean plateletaggregate surface area [SAG] in micrometer(2))indexes of ex vivo platelet-rich clots (PRC) wereassessed in a double-blind fashion before and", "metadata": {}}
+{"_id": "17911973", "title": "", "text": "Natural Mutagenesis of Human Genomes byEndogenous RetrotransposonsTwo abundantclasses of mobile elements, namely Alu and L1elements, continue to generate newretrotransposon insertions in human genomes.Estimates suggest that these elements havegenerated millions of new germline insertions inindividual human genomes worldwide.Unfortunately, current technologies are notcapable of detecting most of these younginsertions, and the true extent of germlinemutagenesis by endogenous humanretrotransposons has been difficult to examine.Here, we describe technologies for detectingthese young retrotransposon insertions anddemonstrate that such insertions indeed areabundant in human populations. We also foundthat new somatic L1 insertions occur at highfrequencies in human lung cancer genomes.Genome-wide analysis suggests that altered DNAmethylation may be responsible for the highlevels of L1 mobilization observed in these", "metadata": {}}
+{"_id": "17914395", "title": "", "text": "Knowledge of young African American adultsabout heart disease: a cross-sectionalsurveyBACKGROUND African Americans havehigher rates of cardiovascular disease (CVD)mortality than other ethnic groups. Young adultsare prime targets for intervention strategies toprevent and reduce disease risk. The studypurpose was to determine the level of knowledgeof lifestyle risk factors for CVD among youngAfrican American adults in Phoenix. The resultswill be used to guide the development of CVDoutreach programs targeted to this population.The Health Belief Model was used as aconceptual framework. METHODS A conveniencesample of 172 African American men and womenaged 18-26 years completed a questionnaireadapted from the American Heart Associationnational surveys. Descriptive statistics werecompared by age, gender, education level, andhealth status variables including BMI, smokingstatus, and physical activity. RESULTS Someaspects of heart-disease were well known among", "metadata": {}}
+{"_id": "17917408", "title": "", "text": "Recent insights into the role of Notch signaling intumorigenesisMembers of the Notch family oftransmembrane receptors play an important rolein cell fate determination. Over the past decade,a role for Notch in the pathogenesis ofhematologic and solid malignancies has becomeapparent. Numerous cellular functions andmicroenvironmental cues associated withtumorigenesis are modulated by Notch signaling,including proliferation, apoptosis, adhesion,epithelial-to-mesenchymal transition, andangiogenesis. It is becoming increasingly evidentthat Notch signaling can be both oncogenic andtumor suppressive. This review highlights recentfindings regarding the molecular and functionalaspects of Notch-mediated neoplastictransformation. In addition, cellular mechanismsthat potentially explain the complex role of Notchin tumorigenesis are discussed.", "metadata": {}}
+{"_id": "17919731", "title": "", "text": "BRIEFINGS IN FUNCTIONAL GENOMICS ANDPROTEOMICS. VOL 5. NO 3. 209^221doi:10.1093/bfgp/ell028 Histone acetylation ingene regulationGenetic information is packagedin the highly dynamic nucleoprotein structurecalled chromatin. Many biological processes areregulated via post-translational modifications ofkey proteins. Acetylation of lysine residues at theN-terminal histone tails is one of the moststudied covalent modifications influencing generegulation in eukaryotic cells. This review focuseson the role of enzymes involved in controllingboth histone and non-histone proteinsacetylation levels in the cell, with particularemphasis on their effects on cancer.", "metadata": {}}
+{"_id": "17925632", "title": "", "text": "Efficacy of monthly tafenoquine for prophylaxisof Plasmodium vivax and multidrug-resistant P.falciparum malaria.We assessed monthly dosesof tafenoquine for preventing Plasmodium vivaxand multidrug-resistant P. falciparum malaria. Ina randomized, double-blind, placebo-controlledstudy, 205 Thai soldiers received either a loadingdose of tafenoquine 400 mg (base) daily for 3days, followed by single monthly 400-mg doses(n = 104), or placebo (n = 101), for up to 5consecutive months. In volunteers completingfollow-up (96 tafenoquine and 91 placeborecipients), there were 22 P. vivax, 8 P.falciparum, and 1 mixed infection. All infectionsexcept 1 P. vivax occurred in placebo recipients,giving tafenoquine a protective efficacy of 97%for all malaria (95% confidence interval [CI],82%-99%), 96% for P. vivax malaria (95% CI,76%-99%), and 100% for P. falciparum malaria(95% CI, 60%-100%). Monthly tafenoquine wassafe, well tolerated, and highly effective inpreventing P. vivax and multidrug-resistant P.", "metadata": {}}
+{"_id": "17930286", "title": "", "text": "Headache, migraine, and structural brain lesionsand function: population based Epidemiology ofVascular Ageing-MRI studyOBJECTIVE Toevaluate the association of overall and specificheadaches with volume of white matterhyperintensities, brain infarcts, and cognition.DESIGN Population based, cross sectional study.SETTING Epidemiology of Vascular Ageing study,Nantes, France. PARTICIPANTS 780 participants(mean age 69, 58.5% women) with detailedheadache assessment. MAIN OUTCOMEMEASURES Brain scans were evaluated forvolume of white matter hyperintensities (by fullyautomated imaging processing) and forclassification of infarcts (by visual reading with astandardised assessment grid). Cognitivefunction was assessed by a battery of testsincluding the mini-mental state examination.RESULTS 163 (20.9%) participants reported ahistory of severe headache and 116 hadmigraine, of whom 17 (14.7%) reported aurasymptoms. An association was found between", "metadata": {}}
+{"_id": "17933691", "title": "", "text": "Characterization of adipocytes derived fromfibro/adipogenic progenitors resident in humanskeletal muscleA population of fibro/adipogenicbut non-myogenic progenitors located betweenskeletal muscle fibers was recently discovered.The aim of this study was to determine theextent to which these progenitors differentiateinto fully functional adipocytes. Thecharacterization of muscle progenitor-derivedadipocytes is a central issue in understandingmuscle homeostasis. They are considered asbeing the cellular origin of intermuscular adiposetissue that develops in several pathophysiologicalsituations. Here fibro/adipogenic progenitorswere isolated from a panel of 15 human musclebiopsies on the basis of the specific cell-surfaceimmunophenotype CD15+/PDGFRα+CD56-. Thisallowed investigations of their differentiation intoadipocytes and the cellular functions ofterminally differentiated adipocytes. Adipogenicdifferentiation was found to be regulated by thesame effectors as those regulating differentiation", "metadata": {}}
+{"_id": "17934082", "title": "", "text": "Membrane lipids in invadopodia and podosomes:Key structures for cancer invasion andmetastasisInvadopodia are extracellular matrix(ECM)-degrading protrusions formed by invasivecancer cells. Podosomes are structuresfunctionally similar to invadopodia that are foundin oncogene-transformed fibroblasts andmonocyte-derived cells, including macrophagesand osteoclasts. These structures are thought toplay important roles in the pericellularremodeling of ECM during cancer invasion andmetastasis. Much effort has been directed towardidentification of the molecular components andregulators of invadopodia/podosomes, whichcould be therapeutic targets in the treatment ofmalignant cancers. However, it remains largelyunknown how these components are assembledinto invadopodia/podosomes and how theassembly process is spatially and temporallyregulated. This review will summarize recentprogress on the molecular mechanisms ofinvadopodia/podosome formation, with strong", "metadata": {}}
+{"_id": "17934603", "title": "", "text": "CCR2 and CXCR4 regulate peripheral bloodmonocyte pharmacodynamics and link to efficacyin experimental autoimmuneencephalomyelitisBACKGROUND CCR2 plays akey role in regulating monocyte trafficking tosites of inflammation and therefore has been thefocus of much interest as a target forinflammatory disease. METHODS Here weexamined the effects of CCR2 blockade with apotent small molecule antagonist to determinethe pharmacodynamic consequences on theperipheral blood monocyte compartment in thecontext of acute and chronic inflammatoryprocesses. RESULTS We demonstrate that CCR2antagonism in vivo led to a rapid decrease in thenumber of circulating Ly6Chi monocytes and thatthis decrease was largely due to theCXCR4-dependent sequestration of these cells inthe bone marrow, providing pharmacologicalevidence for a mechanism by which monocytedynamics are regulated in vivo. CCR2antagonism led to an accumulation of circulating", "metadata": {}}
+{"_id": "17939443", "title": "", "text": "Displacement of a DNA binding protein by DdahelicaseBacteriophage T4 Dda helicase hasrecently been shown to be active as a monomerfor unwinding of short duplex oligonucleotidesand for displacing streptavidin from3′-biotinylated oligonucleotides. However, itsactivity for streptavidin displacement and DNAunwinding has been shown to increase as thenumber of Dda molecules bound to the substratemolecule increases. A substrate was designed toaddress the ability of Dda to displace DNAbinding proteins. A DNA binding site for theEscherichia coli trp repressor was introduced intoan oligonucleotide substrate for Dda helicasecontaining single-stranded overhang. Here weshow that a Dda monomer is insufficient todisplace the E.coli trp repressor from dsDNAunder single turnover conditions, although thesubstrate is unwound and the repressordisplaced when the single-stranded overhang islong enough to accommodate two Ddamolecules. The quantity of product formed", "metadata": {}}
+{"_id": "17945638", "title": "", "text": "Control of Developmental Regulators byPolycomb in Human Embryonic StemCellsPolycomb group proteins are essential forearly development in metazoans, but theircontributions to human development are not wellunderstood. We have mapped the PolycombRepressive Complex 2 (PRC2) subunit SUZ12across the entire nonrepeat portion of thegenome in human embryonic stem (ES) cells. Wefound that SUZ12 is distributed across largeportions of over two hundred genes encoding keydevelopmental regulators. These genes areoccupied by nucleosomes trimethylated athistone H3K27, are transcriptionally repressed,and contain some of the most highly conservednoncoding elements in the genome. We foundthat PRC2 target genes are preferentiallyactivated during ES cell differentiation and thatthe ES cell regulators OCT4, SOX2, and NANOGcooccupy a significant subset of these genes.These results indicate that PRC2 occupies aspecial set of developmental genes in ES cells", "metadata": {}}
+{"_id": "17967608", "title": "", "text": "PAD4 is essential for antibacterial innateimmunity mediated by neutrophil extracellulartrapsNeutrophils trap and kill bacteria by forminghighly decondensed chromatin structures,termed neutrophil extracellular traps (NETs). Wepreviously reported that histonehypercitrullination catalyzed by peptidylargininedeiminase 4 (PAD4) correlates with chromatindecondensation during NET formation. However,the role of PAD4 in NET-mediated bacterialtrapping and killing has not been tested. Here,we use PAD4 knockout mice to show that PAD4is essential for NET-mediated antibacterialfunction. Unlike PAD4(+/+) neutrophils,PAD4(-/-) neutrophils cannot form NETs afterstimulation with chemokines or incubation withbacteria, and are deficient in bacterial killing byNETs. In a mouse infectious disease model ofnecrotizing fasciitis, PAD4(-/-) mice are moresusceptible to bacterial infection than PAD4(+/+)mice due to a lack of NET formation. Moreover,we found that citrullination decreased the", "metadata": {}}
+{"_id": "17973161", "title": "", "text": "Human ‘brite / beige’ adipocytes develop fromcapillary networks and their implantationimproves metabolic homeostasis inmiceUncoupling protein 1 (UCP1) is highlyexpressed in brown adipose tissue, where itgenerates heat by uncoupling electron transportfrom ATP production. UCP1 is also found outsideclassical brown adipose tissue depots, inadipocytes that are termed 'brite'(brown-in-white) or 'beige'. In humans, thepresence of brite or beige (brite/beige)adipocytes is correlated with a lean,metabolically healthy phenotype, but whether acausal relationship exists is not clear. Here wereport that human brite/beige adipocyteprogenitors proliferate in response topro-angiogenic factors, in association withexpanding capillary networks. Adipocytes formedfrom these progenitors transform in response toadenylate cyclase activation from being UCP1negative to being UCP1 positive, which is adefining feature of the beige/brite phenotype,", "metadata": {}}
+{"_id": "17973630", "title": "", "text": "Mindfulness meditation and improvement insleep quality and daytime impairment amongolder adults with sleep disturbances: arandomized clinical trial.IMPORTANCE Sleepdisturbances are most prevalent among olderadults and often go untreated. Treatment optionsfor sleep disturbances remain limited, and thereis a need for community-accessible programsthat can improve sleep. OBJECTIVE To determinethe efficacy of a mind-body medicineintervention, called mindfulness meditation, topromote sleep quality in older adults withmoderate sleep disturbances. DESIGN, SETTING,AND PARTICIPANTS Randomized clinical trialwith 2 parallel groups conducted from January 1to December 31, 2012, at a medical researchcenter among an older adult sample (mean [SD]age, 66.3 [7.4] years) with moderate sleepdisturbances (Pittsburgh Sleep Quality Index[PSQI] >5). INTERVENTIONS A standardizedmindful awareness practices (MAPs) intervention(n = 24) or a sleep hygiene education (SHE)", "metadata": {}}
+{"_id": "17991818", "title": "", "text": "THE ORIGIN AND DIFFERENTIATION OFMICROGLIAL CELLS DURINGDEVELOPMENTSome authors claim that microgliaoriginate from the neuroepithelium, althoughmost now believe that microglial cells are ofmesodermal origin, and probably belong to themonocyte/macrophage cell line. These cells mustenter the developing central nervous system(CNS) from the blood stream, the ventricularspace or the meninges. Afterward microglial cellsare distributed more or less homogeneouslythrough the entire nervous parenchyma.Stereotyped patterns of migration have beenrecognized during development, in whichlong-distance tangential migration precedesradial migration of individual cells. Microglial cellsmoving through the nervous parenchyma areameboid microglia, which apparentlydifferentiate into ramified microglia afterreaching their definitive location. This issupported by the presence of cells showingintermediate features between those of ameboid", "metadata": {}}
+{"_id": "17997584", "title": "", "text": "Integrin αvβ8-Mediated TGF-β Activation byEffector Regulatory T Cells Is Essential forSuppression of T-Cell-MediatedInflammationRegulatory T (Treg) cells play apivotal role in suppressing self-harmful T cellresponses, but how Treg cells mediatesuppression to maintain immune homeostasisand limit responses during inflammation isunclear. Here we show that effector Treg cellsexpress high amounts of the integrin αvβ8, whichenables them to activate latent transforminggrowth factor-β (TGF-β). Treg-cell-specificdeletion of integrin αvβ8 did not result in aspontaneous inflammatory phenotype,suggesting that this pathway is not important inTreg-cell-mediated maintenance of immunehomeostasis. However, Treg cells lackingexpression of integrin αvβ8 were unable tosuppress pathogenic T cell responses duringactive inflammation. Thus, our results identify amechanism by which Treg cells suppressexuberant immune responses, highlighting a key", "metadata": {}}
+{"_id": "18025240", "title": "", "text": "Effects of treatment for intestinal helminthinfection on growth and cognitive performance inchildren: systematic review of randomisedtrials.OBJECTIVE To summarise the effects ofanthelmintic drug treatment on growth andcognitive performance in children. DATASOURCES Electronic databases: CochraneInfectious Diseases Group controlled trialregister, Cochrane controlled trials register,Embase, and Medline. Citations of all identifiedtrials. Contact with the World HealthOrganization and field researchers. REVIEWMETHODS Systematic review of randomisedcontrolled trials in children aged 1-16 thatcompared anthelmintic treatment with placebo orno treatment. Assessment of validity and dataabstraction conducted independently by tworeviewers. MAIN OUTCOME MEASURES Growthand cognitive performance. RESULTS Thirtyrandomised controlled trials in more than 15 000children were identified. Effects on mean weightwere unremarkable, and heterogeneity was", "metadata": {}}
+{"_id": "18027063", "title": "", "text": "Choosing appropriate substitution models for thephylogenetic analysis of protein-codingsequences.Although phylogenetic inference ofprotein-coding sequences continues to dominatethe literature, few analyses incorporateevolutionary models that consider the geneticcode. This problem is exacerbated by theexclusion of codon-based models from commonlyemployed model selection techniques,presumably due to the computational costassociated with codon models. We investigatedan efficient alternative to standard nucleotidesubstitution models, in which codon position (CP)is incorporated into the model. We determinedthe most appropriate model for alignments of177 RNA virus genes and 106 yeast genes, using11 substitution models including one codonmodel and four CP models. The majority ofanalyzed gene alignments are best described byCP substitution models, rather than by standardnucleotide models, and without thecomputational cost of full codon models. These", "metadata": {}}
+{"_id": "18037805", "title": "", "text": "Polycomb Proteins Remain Bound to Chromatinand DNA during DNA Replication In VitroThetranscriptional status of a gene can bemaintained through multiple rounds of celldivision during development. This epigeneticeffect is believed to reflect heritable changes inchromatin folding and histone modifications orvariants at target genes, but little is known abouthow these chromatin features are inheritedthrough cell division. A particular challenge formaintaining transcription states is DNAreplication, which disrupts or diluteschromatin-associated proteins and histonemodifications. PRC1-class Polycomb groupprotein complexes are essential for developmentand are thought to heritably silence transcriptionby altering chromatin folding and histonemodifications. It is not known whether thesecomplexes and their effects are maintainedduring DNA replication or subsequentlyre-established. We find that when PRC1-classPolycomb complex-bound chromatin or DNA is", "metadata": {}}
+{"_id": "18038250", "title": "", "text": "Control of CNS Cell-Fate Decisions by SHP-2 andIts Dysregulation in Noonan SyndromeWithin thedeveloping mammalian CNS, growth factorsdirect multipotent precursors to generateneurons versus glia, a process that if perturbedmight lead to neural dysfunction. In this regard,genetic mutations resulting in constitutiveactivation of the protein tyrosine phosphataseSHP-2 cause Noonan Syndrome (NS), which isassociated with learning disabilities and mentalretardation. Here, we demonstrate that geneticknockdown of SHP-2 in cultured corticalprecursors or in the embryonic cortex inhibitedbasal neurogenesis and caused enhanced andprecocious astrocyte formation. Conversely,expression of an NS SHP-2 mutant promotedneurogenesis and inhibited astrogenesis. Neuralcell-fate decisions were similarly perturbed in amouse knockin model that phenocopies humanNS. Thus, SHP-2 instructs precursors to makeneurons and not astrocytes during theneurogenic period, and perturbations in the", "metadata": {}}
+{"_id": "18038955", "title": "", "text": "Global Regulation of H2A.Z Localization by theINO80 Chromatin-Remodeling Enzyme IsEssential for Genome IntegrityINO80 is anevolutionarily conserved, ATP-dependentchromatin-remodeling enzyme that plays roles intranscription, DNA repair, and replication. Here,we show that yeast INO80 facilitates thesediverse processes at least in part by controllinggenome-wide distribution of the histone variantH2A.Z. In the absence of INO80, H2A.Znucleosomes are mislocalized, and H2A.Z levelsat promoters show reduced responsiveness totranscriptional changes, suggesting that INO80controls H2A.Z dynamics. Additionally, wedemonstrate that INO80 has a histone-exchangeactivity in which the enzyme can replacenucleosomal H2A.Z/H2B with free H2A/H2Bdimers. Genetic interactions between ino80 andhtz1 support a model in which INO80 catalyzesthe removal of unacetylated H2A.Z fromchromatin as a mechanism to promote genomestability.", "metadata": {}}
+{"_id": "18041692", "title": "", "text": "Rho GTPase signalling in cell migrationCellsmigrate in multiple different ways depending ontheir environment, which includes theextracellular matrix composition, interactionswith other cells, and chemical stimuli. For alltypes of cell migration, Rho GTPases play acentral role, although the relative contribution ofeach Rho GTPase depends on the environmentand cell type. Here, I review recent advances inour understanding of how Rho GTPasescontribute to different types of migration,comparing lamellipodium-driven versusbleb-driven migration modes. I also describe howcells migrate across the endothelium. In additionto Rho, Rac and Cdc42, which are well known toregulate migration, I discuss the roles of otherless-well characterized members of the Rhofamily.", "metadata": {}}
+{"_id": "18042803", "title": "", "text": "A Novel Adaptor Protein Orchestrates ReceptorPatterning and Cytoskeletal Polarity in T-CellContactsRecognition of antigen by T cellsrequires the formation of a specialized junctionbetween the T cell and the antigen-presentingcell. This junction is generated by therecruitment and the exclusion of specific proteinsfrom the contact area. The mechanisms thatregulate these events are unknown. Here wedemonstrate that ligand engagement of theadhesion molecule, CD2, initiates a process ofprotein segregation, CD2 clustering, andcytoskeletal polarization. Although proteinsegregation was not dependent on thecytoplasmic domain of CD2, CD2 clustering andcytoskeletal polarization required an interactionof the CD2 cytoplasmic domain with a novelSH3-containing protein. This novel protein, calledCD2AP, is likely to facilitate receptor patterningin the contact area by linking specific adhesionreceptors to the cytoskeleton.", "metadata": {}}
+{"_id": "18062308", "title": "", "text": "Operable non-small cell lung cancer diagnosedby transpleural techniques : do they affectrelapse and prognosis?STUDY OBJECTIVE Weassessed whether transpleural methods fordiagnosing peripheral lung cancer, such asneedle aspiration or tumor excision, affectrelapse and prognosis, because these techniqueshave potential to spread malignant cells from thetumor. DESIGN A retrospective study. SETTINGNational referral hospital. PATIENTS Wereviewed 239 patients who underwent surgerybetween 1990 and 1998 and for whom non-smallcell lung cancer (NSCLC) of < 3 cm in maximumdiameter was completely resected. The durationof postoperative follow-up ranged from 12 to 105months, with a median period of 45 months.INTERVENTIONS We defined the transbronchialmethod as using a bronchoscope, and thetranspleural method as using needle aspirationcytology or tumor excision. Dichotomousvariables included gender, histologic type ofsquamous cell carcinoma or other type of", "metadata": {}}
+{"_id": "18064113", "title": "", "text": "Characterization of the adipocyte cellular lineagein vivoMature adipocytes are generated throughthe proliferation and differentiation of precursorcells. Our previous studies identified adipocyteprogenitors in white adipose tissue (WAT) asLin(-):CD29(+):CD34(+):Sca-1(+):CD24(+)(CD24(+)) cells that are capable of generatingfunctional WAT (ref.  ). Here, we employ severalCre recombinase mouse models to identify theadipocyte cellular lineage in vivo. Although it hasbeen proposed that white adipocytes are derivedfrom endothelial and haematopoietic lineages,we find that neither of these lineages label whiteadipocytes. However, platelet-derived growthfactor receptor α (PdgfRα)-Cre trace labels allwhite adipocytes. Analysis of WAT fromPdgfRα-Cre reporter mice identifies CD24(+) andLin(-):CD29(+):CD34(+):Sca-1(+): CD24(-)(CD24(-)) cells as adipocyte precursors. Weshow that CD24(+) cells generate the CD24(-)population in vivo and the CD24(-) cells expresslate markers of adipogenesis. From these data", "metadata": {}}
+{"_id": "18074797", "title": "", "text": "Reducing Plasmodium falciparum MalariaTransmission in Africa: A Model-Based Evaluationof Intervention StrategiesBACKGROUND Overthe past decade malaria intervention coveragehas been scaled up across Africa. However, itremains unclear what overall reduction intransmission is achievable using currentlyavailable tools. METHODS AND FINDINGS Wedeveloped an individual-based simulation modelfor Plasmodium falciparum transmission in anAfrican context incorporating the three majorvector species (Anopheles gambiae s.s., An.arabiensis, and An. funestus) with parametersobtained by fitting to parasite prevalence datafrom 34 transmission settings across Africa. Weincorporated the effect of the switch toartemisinin-combination therapy (ACT) andincreasing coverage of long-lasting insecticidetreated nets (LLINs) from the year 2000onwards. We then explored the impact ontransmission of continued roll-out of LLINs,additional rounds of indoor residual spraying", "metadata": {}}
+{"_id": "18078750", "title": "", "text": "Golgi Export of the Kir2.1 Channel Is Driven by aTrafficking Signal Located within Its TertiaryStructureMechanisms that are responsible forsorting newly synthesized proteins for traffic tothe cell surface from the Golgi are poorlyunderstood. Here, we show that the potassiumchannel Kir2.1, mutations in which areassociated with Andersen-Tawil syndrome, isselected as cargo into Golgi export carriers in anunusual signal-dependent manner. Unlikeconventional trafficking signals, which aretypically comprised of short linear peptidesequences, Golgi exit of Kir2.1 is dictated byresidues that are embedded within theconfluence of two separate domains. This signalpatch forms a recognition site for interaction withthe AP1 adaptor complex, thereby markingKir2.1 for incorporation into clathrin-coatedvesicles at the trans-Golgi. The identification of atrafficking signal in the tertiary structure ofKir2.1 reveals a quality control step that couplesprotein conformation to Golgi export and", "metadata": {}}
+{"_id": "18084826", "title": "", "text": "Characteristics of Body Fat, Body Fat Percentageand Other Body Composition for Koreans fromKNHANES IVAccurate measurement of fat masshas become increasingly important with theincreasing incidence of obesity. We assessed fatand muscle mass of Koreans with the KoreaNational Health and Nutrition ExaminationSurvey IV (KNHANES IV). We studied 10,456subjects (aged 20 to 85 yr; 4,476 men, 5,980women). Fat and muscle mass were measuredby dual-energy x-ray absorptiometry. Referencevalues of body compositions were obtained usingthe LMS method. The fat mass index (FMI, bodyfat mass/height(2); kg/m(2)) of Korean men didnot correlate with age (P = 0.452), but those ofKorean women (P < 0.001) did. The ratio ofpercentage of fat in the trunk and legs waspositively related with age in both the genders.The appendicular lean mass/height(2) (kg/m(2))of Korean men was negatively related to age (P< 0.001). In women, this ratio increased withage (P < 0.001). When we defined obesity", "metadata": {}}
+{"_id": "18098290", "title": "", "text": "The Evolution of Dominance in SporophyticSelf-Incompatibility Systems. II. MateAvailability and RecombinationSporophyticself-incompatibility (SSI) is a self-pollenrecognition system that enforces outcrossing inplants. Recognition in SSI systems is typicallycontrolled by a complex locus (5-locus) withseparate genes that determine pollen and stigmaspecificity. Experimental studies show thatS-alleles can be dominant, recessive, orcodominant, and that the dominance level of agiven S-allele can depend upon whether pollenor stigma specificity is examined. Here and in thecompanion paper by Llaurens and colleagues, theevolution of dominance in single-locus SSI isexplored using numerical models and simulation.Particular attention is directed at factors that cancause S-allele dominance to differ in pollenversus stigma. The effect of recombinationbetween the S-locus and modifier locus is alsoexamined. The models predict that limitation inthe number of compatible mates is required for", "metadata": {}}
+{"_id": "18104691", "title": "", "text": "Neurological outcomes of animal models ofuterine artery ligation and relevance to humanintrauterine growth restriction: a systematicreviewAIM This review explores the molecular,neurological, and behavioural outcomes inanimal models of uterine artery ligation. Weanalyse the relevance of this type of model tothe pathological and functional phenotypes thatare consistent with cerebral palsy and itsdevelopmental comorbidities in humans.METHOD A literature search of the PubMeddatabase was conducted for research using theuterine artery ligation model published between1990 and 2013. From the studies included, anyrelevant neuroanatomical and behaviouraldeficits were then summarized from eachdocument and used for further analysis.RESULTS There were 25 papers that met thecriteria included for review, and severaloutcomes were summarized from the results ofthese papers. Fetuses with growth restrictiondemonstrated a gradient of reduced body weight", "metadata": {}}
+{"_id": "18111172", "title": "", "text": "The fidelity of the ligation step determines howends are resolved during Nonhomologous endjoiningNonhomologous end joining (NHEJ) caneffectively resolve chromosome breaks despitediverse end structures; however, it is unclearhow the steps employed for resolution aredetermined. We sought to address this questionby analysing cellular NHEJ of ends withsystematically mispaired and damaged termini.We show NHEJ is uniquely proficient at bypassingsubtle terminal mispairs and radiomimeticdamage by direct ligation. Nevertheless, bypassability varies widely, with increases in mispairseverity gradually reducing bypass products from85 to 6%. End-processing by nucleases andpolymerases is increased to compensate,although paths with the fewest number of stepsto generate a substrate suitable for ligation arefavoured. Thus, both the frequency and nature ofend processing are tailored to meet the needs ofthe ligation step. We propose a model where theligase organizes all steps during NHEJ within the", "metadata": {}}
+{"_id": "18126445", "title": "", "text": "Laminin-based cell adhesion anchors microtubuleplus ends to the epithelial cell basal cortexthrough LL5α/βLL5beta has been identified as amicrotubule-anchoring factor that attachesEB1/CLIP-associating protein (CLASP)-boundmicrotubule plus ends to the cell cortex. In thisstudy, we show that LL5beta and its homologueLL5alpha (LL5s) colocalize with autocrinelaminin-5 and its receptors, integrinsalpha3beta1 and alpha6beta4, at the basal sideof fully polarized epithelial sheets. Depletion ofboth laminin receptor integrins abolishes thecortical localization of LL5s, whereas LL5depletion reduces the amount of integrin alpha3at the basal cell cortex. Activation of integrinalpha3 is sufficient to initiate LL5 accumulationat the cell cortex. LL5s form a complex with thecytoplasmic tails of these integrins, but theirinteraction might be indirect. Analysis of thethree-dimensional distribution of microtubulegrowth by visualizing EB1-GFP in epithelialsheets in combination with RNA interference", "metadata": {}}
+{"_id": "18144189", "title": "", "text": "DNA topoisomerases: structure, function, andmechanism.DNA topoisomerases solve thetopological problems associated with DNAreplication, transcription, recombination, andchromatin remodeling by introducing temporarysingle- or double-strand breaks in the DNA. Inaddition, these enzymes fine-tune thesteady-state level of DNA supercoiling both tofacilitate protein interactions with the DNA and toprevent excessive supercoiling that isdeleterious. In recent years, the crystalstructures of a number of topoisomerasefragments, representing nearly all the knownclasses of enzymes, have been solved. Thesestructures provide remarkable insights into themechanisms of these enzymes and complementprevious conclusions based on biochemicalanalyses. Surprisingly, despite little or nosequence homology, both type IA and type IIAtopoisomerases from prokaryotes and the typeIIA enzymes from eukaryotes share structuralfolds that appear to reflect functional motifs", "metadata": {}}
+{"_id": "18153456", "title": "", "text": "Pilot testing of dipsticks as point-of-care assaysfor rapid diagnosis of poor-quality artemisinindrugs in endemic settingsBACKGROUNDGood-quality artemisinin drugs are essential formalaria treatment, but increasing prevalence ofpoor-quality artemisinin drugs in many endemiccountries hinders effective management ofmalaria cases. METHODS To develop apoint-of-care assay for rapid identification ofcounterfeit and substandard artemisinin drugsfor resource-limited areas, we used specificmonoclonal antibodies against artesunate andartemether, and developed prototypes of lateralflow dipstick assays. In this pilot test, weevaluated the feasibility of these dipsticks underdifferent endemic settings and their performancein the hands of untrained personnel. RESULTSThe results showed that the dipstick tests can besuccessfully performed by different investigatorswith the included instruction sheet. None of theartemether and artesunate drugs collected frompublic pharmacies in different endemic countries", "metadata": {}}
+{"_id": "18174210", "title": "", "text": "Increased Microerythrocyte Count inHomozygous α+-Thalassaemia Contributes toProtection against Severe MalarialAnaemiaBACKGROUND The heritablehaemoglobinopathy alpha(+)-thalassaemia iscaused by the reduced synthesis of alpha-globinchains that form part of normal adulthaemoglobin (Hb). Individuals homozygous foralpha(+)-thalassaemia have microcytosis and anincreased erythrocyte count.Alpha(+)-thalassaemia homozygosity confersconsiderable protection against severe malaria,including severe malarial anaemia (SMA) (Hbconcentration < 50 g/l), but does not influenceparasite count. We tested the hypothesis thatthe erythrocyte indices associated withalpha(+)-thalassaemia homozygosity provide ahaematological benefit during acute malaria.METHODS AND FINDINGS Data from childrenliving on the north coast of Papua New Guineawho had participated in a case-control study ofthe protection afforded by", "metadata": {}}
+{"_id": "18188022", "title": "", "text": "Construction of Escherichia coli K-12 in-frame,single-gene knockout mutants: the KeiocollectionWe have systematically made a set ofprecisely defined, single\u0000gene deletions of allnonessential genes in Escherichia coli K\u000012.Open\u0000reading frame coding regions werereplaced with a kanamycin cassette flanked byFLP recognition target sites by using a one\u0000stepmethod for inactivation of chromosomal genesand primers designed to create in\u0000framedeletions upon excision of the resistancecassette. Of 4288 genes targeted, mutants wereobtained for 3985. To alleviate problemsencountered in high\u0000throughput studies, twoindependent mutants were saved for everydeleted gene. These mutants—the ‘Keiocollection’—provide a new resource not only forsystematic analyses of unknown gene functionsand gene regulatory networks but also forgenome\u0000wide testing of mutational effects in acommon strain background, E . coli K\u000012BW25113. We were unable to disrupt 303 genes,", "metadata": {}}
+{"_id": "18190552", "title": "", "text": "Validated RealTime reverse transcriptase PCRmethods for the diagnosis and pathotyping ofEurasian H7 avian influenzavirusesBACKGROUND Avian influenza (AI)caused by H7 AI viruses (AIVs) of both lowpathogenicity (LP) and high pathogenicity (HP)are notifiable poultry diseases. OBJECTIVESDesign and validate two RealTime reversetranscriptase polymerase chain reactions (RRTPCRs) for Eurasian H7 AIV detection andpathotyping. METHODS The H7 RRT PCRsamplified within the (i) HA2 and (ii) cleavage siteCS regions of the haemagglutinin gene. Bothwere validated against 65 H7 AIVs, 57 non-H7AIVs and 259 poultry swabs in comparison to Mgene (AI generic) RRT PCR and virus isolation(VI). An additional 38 swabs and 20 tissuespecimens extended validation against M geneRRT PCR. RESULTS Both H7 RRT PCRs amplifiedall 61 Eurasian lineage H7 AIVs and none of 57non-H7 AIVs. A total of 297 poultry swabs wereused to determine diagnostic sensitivity and", "metadata": {}}
+{"_id": "18199839", "title": "", "text": "Interleukin-6 receptor pathways in coronaryheart disease: a collaborative meta-analysis of82 studiesBACKGROUND Persistent inflammationhas been proposed to contribute to variousstages in the pathogenesis of cardiovasculardisease. Interleukin-6 receptor (IL6R) signallingpropagates downstream inflammation cascades.To assess whether this pathway is causallyrelevant to coronary heart disease, we studied afunctional genetic variant known to affect IL6Rsignalling. METHODS In a collaborativemeta-analysis, we studied Asp358Ala(rs2228145) in IL6R in relation to a panel ofconventional risk factors and inflammationbiomarkers in 125,222 participants. We alsocompared the frequency of Asp358Ala in 51,441patients with coronary heart disease and in136,226 controls. To gain insight into possiblemechanisms, we assessed Asp358Ala in relationto localised gene expression and topostlipopolysaccharide stimulation of interleukin6. FINDINGS The minor allele frequency of", "metadata": {}}
+{"_id": "18207615", "title": "", "text": "Plasma exosomes can deliver exogenous shortinterfering RNA to monocytes andlymphocytesDespite the promise of RNAinterference (RNAi) and its potential, e.g. for usein cancer therapy, several technical obstaclesmust first be overcome. The major hurdle ofRNAi-based therapeutics is to deliver nucleicacids across the cell's plasma membrane. Thisstudy demonstrates that exosome vesiclesderived from humans can deliver shortinterfering RNA (siRNA) to human mononuclearblood cells. Exosomes are nano-sized vesicles ofendocytic origin that are involved in cell-to-cellcommunication, i.e. antigen presentation,tolerance development and shuttle RNA (mainlymRNA and microRNA). Having tested differentstrategies, an optimized method(electroporation) was used to introduce siRNAinto human exosomes of various origins. Plasmaexosomes (exosomes from peripheral blood)were used as gene delivery vector (GDV) totransport exogenous siRNA to human blood cells.", "metadata": {}}
+{"_id": "18218379", "title": "", "text": "Quantitative analysis of tumor-derivedmethylated p16INK4a sequences in plasma,serum, and blood cells of hepatocellularcarcinoma patients.PURPOSE ANDEXPERIMENTAL DESIGN Using real-timequantitative methylation-specific PCR(RTQ-MSP), we quantified methylated p16INK4asequences and determined the fractionalconcentrations of circulating tumor DNA inplasma, serum, and peripheral blood cellscollected preoperatively, intraoperatively, andpostoperatively from 49 patients withhepatocellular carcinoma (HCC). RESULTSRTQ-MSP was sufficiently sensitive to detectdown to 10 genome-equivalents of methylatedp16INK4a sequences. Quantitative MSP datawere expressed in terms of the methylationindex, which was the percentage of bisulfiteconverted unmethylated and methylatedp16INK4a sequences that consisted ofmethylated p16INK4a sequences. Quantities ofmethylated p16INK4a sequences were detected", "metadata": {}}
+{"_id": "18231257", "title": "", "text": "Dynamic control of excitatory synapsedevelopment by a Rac1 GEF/GAP regulatorycomplex.The small GTPase Rac1 orchestratesactin-dependent remodeling essential fornumerous cellular processes including synapsedevelopment. While precise spatiotemporalregulation of Rac1 is necessary for its function,little is known about the mechanisms that enableRac1 activators (GEFs) and inhibitors (GAPs) toact in concert to regulate Rac1 signaling. Here,we identify a regulatory complex composed of aRac-GEF (Tiam1) and a Rac-GAP (Bcr) thatcooperate to control excitatory synapsedevelopment. Disruption of Bcr function withinthis complex increases Rac1 activity anddendritic spine remodeling, resulting in excessivesynaptic growth that is rescued by Tiam1inhibition. Notably, EphB receptors utilize theTiam1-Bcr complex to control synaptogenesis.Following EphB activation, Tiam1 inducesRac1-dependent spine formation, whereas Bcrprevents Rac1-mediated receptor internalization,", "metadata": {}}
+{"_id": "18231807", "title": "", "text": "4-1BB Costimulation Ameliorates T CellExhaustion Induced by Tonic Signaling ofChimeric Antigen ReceptorsChimeric antigenreceptors (CARs) targeting CD19 have mediateddramatic antitumor responses in hematologicmalignancies, but tumor regression has rarelyoccurred using CARs targeting other antigens. Itremains unknown whether the impressive effectsof CD19 CARs relate to greater susceptibility ofhematologic malignancies to CAR therapies, orsuperior functionality of the CD19 CAR itself. Weshow that tonic CAR CD3-ζ phosphorylation,triggered by antigen-independent clustering ofCAR single-chain variable fragments, can induceearly exhaustion of CAR T cells that limitsantitumor efficacy. Such activation is present tovarying degrees in all CARs studied, except thehighly effective CD19 CAR. We further determinethat CD28 costimulation augments, whereas4-1BB costimulation reduces, exhaustion inducedby persistent CAR signaling. Our results providebiological explanations for the antitumor effects", "metadata": {}}
+{"_id": "18236313", "title": "", "text": "Ultrafast Evolution and Loss of CRISPRsFollowing a Host Shift in a Novel WildlifePathogen, Mycoplasma gallisepticumMeasureablerates of genome evolution are well documentedin human pathogens but are less well understoodin bacterial pathogens in the wild, particularlyduring and after host switches. Mycoplasmagallisepticum (MG) is a pathogenic bacteriumthat has evolved predominantly in poultry andrecently jumped to wild house finches(Carpodacus mexicanus), a common NorthAmerican songbird. For the first time wecharacterize the genome and measure rates ofgenome evolution in House Finch isolates of MG,as well as in poultry outgroups. Usingwhole-genome sequences of 12 House Finchisolates across a 13-year serial sample and anadditional four newly sequenced poultry strains,we estimate a nucleotide diversity in House Finchisolates of only \u00002% of ancestral poultry strainsand a nucleotide substitution rate of0.8-1.2×10(-5) per site per year both in poultry", "metadata": {}}
+{"_id": "18237384", "title": "", "text": "Inducing Tumor Immunity through the SelectiveEngagement of Activating Fcγ Receptors onDendritic CellsInduction of tumor-specificimmunity requires that dendritic cells (DCs)efficiently capture and present tumor antigens toresult in the expansion and activation oftumor-specific cytotoxic T cells. The transitionfrom antigen capture to T cell stimulationrequires a maturation signal; in its absencetolerance, rather than immunity may develop.While immune complexes (ICs) are able toenhance antigen capture, they can be poor atinducing DC maturation, naive T cell activationand protective immunity. We now demonstratethat interfering with the inhibitory signaldelivered by FcγRIIB on DCs converts ICs topotent maturation agents and results in T cellactivation. Applying this approach toimmunization with DCs pulsed ex-vivo with ICs,we have generated antigen-specific CD8+ T cellsin vivo and achieved efficient protectiveimmunity in a murine melanoma model. These", "metadata": {}}
+{"_id": "18256197", "title": "", "text": "Homocysteine and the risk of ischemic stroke ina triethnic cohort: the NOrthern MAnhattanStudy.BACKGROUND AND PURPOSE The level oftotal homocysteine (tHcy) that confers a risk ofischemic stroke is unsettled, and no prospectivecohort studies have included sufficient elderlyminority subjects. We investigated theassociation between mild to moderate fastingtHcy level and the incidence of ischemic stroke,myocardial infarction, and vascular death in amultiethnic prospective study. METHODS Apopulation-based cohort was followed forvascular events (stroke, myocardial infarction,and vascular death). Baseline values of tHcy andmethylmalonic acid were measured among 2939subjects (mean age, 69+/-10; 61% women,53% Hispanics, 24% blacks, and 20% whites).Cox proportional models were used to calculatehazard ratios (HRs) and 95% CIs in tHcycategories after adjusting for age, race,education, renal insufficiency, B12 deficiency,and other risk factors. RESULTS The adjusted HR", "metadata": {}}
+{"_id": "18261004", "title": "", "text": "Expression and purification of recombinantmethylated HBHA in Mycobacteriumsmegmatis.The Heparin-Binding Haemagglutinin(HBHA) is a mycobacterial adhesin involved inthe dissemination of Mycobacterium tuberculosisfrom the site of primary infection and a potentialcandidate for the development of a new vaccineagainst tuberculosis. Methylation of HBHA is anovel post-translational event that impartsimportant immunological properties to theprotein. Since recombinant HBHA expressed inEscherichia coli is not methylated, weinvestigated the possibility of producingrecombinant methylated HBHA in fast growingmycobacteria for use in immunological andbiochemical studies. The complete codingsequence of HBHA was cloned in the plasmidpMV206, under the control of a strong promoter(hsp60) or its own promoter. The constructsgenerated were electroporated intoMycobacterium smegmatis and the recombinantstrains obtained were analyzed for the presence", "metadata": {}}
+{"_id": "18263406", "title": "", "text": "Detection of alternative lengthening of telomeresby telomere quantitative PCRAlternativelengthening of telomeres (ALT) is one of the twoknown telomere length maintenancemechanisms that are essential for the unlimitedproliferation potential of cancer cells. Existingmethods for detecting ALT in tumors requiresubstantial amounts of tumor material and arelabor intensive, making it difficult to studyprevalence and prognostic significance of ALT inlarge tumor cohorts. Here, we present a novelstrategy utilizing telomere quantitative PCR todiagnose ALT. The protocol is more rapid thanconventional methods and scrutinizes twodistinct characteristics of ALT cells concurrently:long telomeres and the presence of C-circles(partially double-stranded circles of telomericC-strand DNA). Requiring only 30 ng of genomicDNA, this protocol will facilitate large-scalestudies of ALT in tumors and can be readilyadopted by clinical laboratories.", "metadata": {}}
+{"_id": "18264714", "title": "", "text": "Noise and interlocking signaling pathwayspromote distinct transcription factor dynamics inresponse to different stressesAll cells perceiveand respond to environmental stresses throughelaborate stress-sensing networks. Yeast cellssense stress through diverse signaling pathwaysthat converge on the transcription factors Msn2and Msn4, which respond by initiating rapid,idiosyncratic cycles into and out of the nucleus.To understand the role of Msn2/4 nuclearlocalization dynamics, we combined time-lapsestudies of Msn2-GFP localization in living cellswith computational modeling of stress-sensingsignaling networks. We find that severalsignaling pathways, including Ras/protein kinaseA, AMP-activated kinase, the high-osmolarityresponse mitogen-activated protein kinasepathway, and protein phosphatase 1, regulateactivation of Msn2 in distinct ways in response todifferent stresses. Moreover, we find that burstsof nuclear localization elicit a more robusttranscriptional response than does sustained", "metadata": {}}
+{"_id": "18268012", "title": "", "text": "Long-term financing needs for HIV control insub-Saharan Africa in 2015-2050: a modellingstudy.OBJECTIVES To estimate the present valueof current and future funding needed for HIVtreatment and prevention in 9 sub-SaharanAfrican (SSA) countries that account for 70% ofHIV burden in Africa under different scenarios ofintervention scale-up. To analyse the gapsbetween current expenditures and fundingobligation, and discuss the policy implications offuture financing needs. DESIGN We used theGoals module from Spectrum, and applied themost up-to-date cost and coverage data toprovide a range of estimates for future financingobligations. The four different scale-up scenariosvary by treatment initiation threshold and servicecoverage level. We compared the modelprojections to current domestic and internationalfinancial sources available in selected SSAcountries. RESULTS In the 9 SSA countries, theestimated resources required for HIV preventionand treatment in 2015-2050 range from US$98", "metadata": {}}
+{"_id": "18275697", "title": "", "text": "Cell-mediated immunity and antibody responseselicited by attenuated Salmonella entericaSerovar Typhi strains used as live oral vaccinesin humans.The development of improved typhoidvaccines is a high global public health priority.However, their development has been hamperedby a lack of information regarding the specificdeterminants of protective immunity toSalmonella enterica serovar Typhi (S. Typhi)infection in humans. Although antibodies to S.Typhi O, H, and Vi appear to be involved inprotection against S. Typhi infection, it isunknown whether such antibodies mediateprotection, act in conjunction with other adaptiveresponses, or serve as a surrogate for thepresence of other, more dominant protectiveimmune responses (e.g., cell-mediated immunity[CMI]). CMI responses elicited by immunizationof subjects with attenuated S. Typhi oralvaccines include lymphoproliferation; productionof type 1 cytokines (e.g., interferon- gamma andtumor necrosis factor- alpha ); and classical", "metadata": {}}
+{"_id": "18276599", "title": "", "text": "Extensive Promoter-Centered ChromatinInteractions Provide a Topological Basis forTranscription RegulationHigher-orderchromosomal organization for transcriptionregulation is poorly understood in eukaryotes.Using genome-wide Chromatin InteractionAnalysis with Paired-End-Tag sequencing(ChIA-PET), we mapped long-range chromatininteractions associated with RNA polymerase IIin human cells and uncovered widespreadpromoter-centered intragenic, extragenic, andintergenic interactions. These interactions furtheraggregated into higher-order clusters, whereinproximal and distal genes were engaged throughpromoter-promoter interactions. Most genes withpromoter-promoter interactions were active andtranscribed cooperatively, and some interactingpromoters could influence each other implyingcombinatorial complexity of transcriptionalcontrols. Comparative analyses of different celllines showed that cell-specific chromatininteractions could provide structural frameworks", "metadata": {}}
+{"_id": "18321590", "title": "", "text": "Resazurin microtiter assay plate: simple andinexpensive method for detection of drugresistance in Mycobacterium tuberculosis.Amethod for detecting multidrug-resistantMycobacterium tuberculosis by using a reductionof resazurin is described. Eighty clinical isolateswere evaluated against isoniazid and rifampin;results at 7 days were compared with those ofthe proportion method. Specificity and sensitivitywere excellent. The method is simple,inexpensive, and rapid and might be used withother antituberculosis drugs.", "metadata": {}}
+{"_id": "18333304", "title": "", "text": "The pervasiveness and plasticity of circadianoscillations: the coupled circadian-oscillatorsframework.MOTIVATION Circadian oscillationshave been observed in animals, plants, fungi andcyanobacteria and play a fundamental role incoordinating the homeostasis and behavior ofbiological systems. Genetically encodedmolecular clocks found in nearly every cell,based on negative transcription/translationfeedback loops and involving only a dozen genes,play a central role in maintaining theseoscillations. However, high-throughput geneexpression experiments reveal that in a typicaltissue, a much larger fraction ([Formula: seetext]) of all transcripts oscillate with theday-night cycle and the oscillating species varywith tissue type suggesting that perhaps a muchlarger fraction of all transcripts, and perhaps alsoother molecular species, may bear the potentialfor circadian oscillations. RESULTS To betterquantify the pervasiveness and plasticity ofcircadian oscillations, we conduct the first", "metadata": {}}
+{"_id": "18340282", "title": "", "text": "Gene–environment interactions in 7610 womenwith breast cancer: prospective evidence fromthe Million Women StudyBACKGROUNDInformation is scarce about the combined effectson breast cancer incidence of low-penetrancegenetic susceptibility polymorphisms andenvironmental factors (reproductive,behavioural, and anthropometric risk factors forbreast cancer). To test for evidence ofgene-environment interactions, we comparedgenotypic relative risks for breast cancer acrossthe other risk factors in a large UK prospectivestudy. METHODS We tested gene-environmentinteractions in 7610 women who developedbreast cancer and 10 196 controls without thedisease, studying the effects of 12polymorphisms (FGFR2-rs2981582,TNRC9-rs3803662, 2q35-rs13387042,MAP3K1-rs889312, 8q24-rs13281615,2p-rs4666451, 5p12-rs981782,CASP8-rs1045485, LSP1-rs3817198,5q-rs30099, TGFB1-rs1982073, and", "metadata": {}}
+{"_id": "18344910", "title": "", "text": "Thrombocytopenia as an Indicator of Malaria inAdult PopulationObjectives. To evaluate thepredictive value of thrombocytopenia in malaria.Patients and Methods. It was a prospectiveobservational study on all febrile patients withthrombocytopenia presenting to the Medical Unitof Hayat Abad Medical Complex duringNovember 2008 to November 2010. Results. Ofthe total of 228 patients with fever andthrombocytopenia, 121 patients (53%) proved tobe suffering from malaria. Of them 82 patients(68%) had falciparum malaria while 39 patients(32%) had vivax infection. Of these 121patients, platelet counts ranged between 25,000and 150,000/dL with a mean value of101,000/dL (SD ± 47, 500) and a median of75,000/dL. Of the 107 patients who were notsuffering from malaria, the counts rangedbetween 10,000 and 150,000/dL with a meanvalue of 58,000/dL (SD ± 54, 000) and medianof 50,000/dL. Conclusions. The presence ofthrombocytopenia may be a predictor of malaria", "metadata": {}}
+{"_id": "18346333", "title": "", "text": "AMPA receptor ligand binding domain mobilityrevealed by functional cross linking.Glutamatereceptors mediate the majority of excitatorysynaptic transmission in the CNS. TheAMPA-subtype has rapid kinetics, with activation,deactivation and desensitization proceeding onthe millisecond timescale or faster.Crystallographic, biochemical, and functionalstudies suggest that GluR2 Cys mutants whichform intermolecular disulfide cross-links betweenthe lower D2 lobes of the ligand binding corescan be trapped in a conformation that representsthe desensitized state. We used multi-channelrapid perfusion techniques to examine the statedependence of cross-linking in these mutants.Under reducing conditions, both wild-type GluR2and the G725C and S729C mutants have normalactivation and desensitization kinetics, but theCys mutants can be efficiently trapped innonconducting states when oxidized. In contrastthe I664C mutant is only partially inactivatedunder oxidizing conditions. For S729C, disulfide", "metadata": {}}
+{"_id": "18348376", "title": "", "text": "Ncf1 (p47phox) Is Essential for Direct RegulatoryT Cell Mediated Suppression of CD4+ Effector TCellsBACKGROUND Multiple mechanisms havebeen advanced to account for CD4+FOXP3+regulatory T cell (Treg)-mediated suppression ofCD4+ effector T cells (Teffs) but none appear tocompletely explain suppression. Previous dataindicates that Tregs may affect themicroenvironment redox state. Given theinherent redox sensitivity of T cells, we testedthe hypothesis that oxidants may mediate thedirect suppression of Teffs by Tregs.METHODOLOGY/PRINCIPAL FINDINGS Tregs andTeffs were isolated from the spleens of wild type(WT) C57BL/6 mice or Ncf1(p47phox)-deficientC57BL/6 mice which lack NADPH oxidasefunction. Teffs were labeled with CFSE andco-cultured with unlabeled Tregs at varyingTreg:Teff ratios in the presence ofanti-CD3/CD28 coated beads for 3 days insuppression assays. Treg-mediated suppressionwas quantified by flow cytometric analysis of", "metadata": {}}
+{"_id": "18358026", "title": "", "text": "Oxidative damage targets complexes containingDNA methyltransferases, SIRT1, and polycombmembers to promoter CpG Islands.Cancer cellssimultaneously harbor global losses and gains inDNA methylation. We demonstrate that inducingcellular oxidative stress by hydrogen peroxidetreatment recruits DNA methyltransferase 1(DNMT1) to damaged chromatin. DNMT1becomes part of a complex(es) containingDNMT3B and members of the polycombrepressive complex 4. Hydrogen peroxidetreatment causes relocalization of these proteinsfrom non-GC-rich to GC-rich areas. Keycomponents are similarly enriched at genepromoters in an in vivo colitis model. Althoughhigh-expression genes enriched for members ofthe complex have histone mark and nascenttranscription changes, CpG island-containinglow-expression genes gain promoter DNAmethylation. Thus, oxidative damage inducesformation and relocalization of a silencingcomplex that may explain cancer-specific", "metadata": {}}
+{"_id": "18361917", "title": "", "text": "Expression profiles during dedifferentiation innewt lens regeneration revealed by expressedsequence tagsPURPOSE The adult newt canregenerate lens from pigmented epithelial cells(PECs) of the dorsal iris via dedifferentiation. Thepurpose of this research is to obtain sequenceresources for a newt lens regeneration study andto obtain insights of dedifferentiation at themolecular level. METHODS mRNA was purifiedfrom iris during dedifferentiation and its cDNAlibrary was constructed. From the cDNA library10,449 clones were sequenced and analyzed.RESULTS From 10,449 reads, 780 contigs and1,666 singlets were annotated. The presence ofseveral cancer- and apoptosis-related genesduring newt dedifferentiation was revealed.Moreover, several candidate genes, which mightparticipate in reprogramming duringdedifferentiation, were also found.CONCLUSIONS The expression of cancer- andapoptosis-related genes could be hallmarksduring dedifferentiation. The expression", "metadata": {}}
+{"_id": "18374364", "title": "", "text": "In vivo proliferation and cell cycle kinetics oflong-term self-renewing hematopoietic stemcells.A rare set of hematopoietic stem cells(HSC) must undergo a massive expansion toproduce mature blood cells. The phenotypicisolation of HSC from mice offers the opportunityto determine directly their proliferation kinetics.We analyzed the proliferation and cell cyclekinetics of long-term self-renewing HSC(LT-HSC) in normal adult mice. At any one time,approximately 5% of LT-HSC were in S/G2/Mphases of the cell cycle and another 20% were inG1 phase. BrdUrd incorporation was used todetermine the rate at which different cohorts ofHSC entered the cell cycle over time. About 50%of LT-HSC incorporated BrdUrd by 6 days and>90% incorporated BrdUrd by 30 days. By 6months, 99% of LT-HSC had incorporatedBrdUrd. We calculated that approximately 8% ofLT-HSC asynchronously entered the cell cycle perday. Nested reverse transcription-PCR analysisrevealed cyclin D2 expression in a high", "metadata": {}}
+{"_id": "18375089", "title": "", "text": "The role of the tissue omega-6/omega-3 fattyacid ratio in regulating tumorangiogenesisAngiogenesis is a necessary step intumor growth and metastasis. It is wellestablished that the metabolites of omega-6 andomega-3 fatty acids, which must be obtainedthrough the diet and cannot be synthesized denovo in mammals, have differential effects oncellular processes. Omega-6 fatty acid (n−6FA)-derived metabolites promote angiogenesisby increasing growth factor expression whereasomega-3 fatty acids (n−3 FA) haveanti-angiogenic and antitumor properties.However, most studies thus far have failed toaccount for the role of the n−6 FA/n−3 FA ratioin angiogenesis and instead examined theabsolute levels of n−6 and n−3 FA. This reviewhighlights the biochemical interactions betweenn−6 and n−3 FA and focuses on how then−6/n−3 FA ratio in tissues modulates tumorangiogenesis. We suggest that future workshould consider the n−6/n−3 FA ratio to be a", "metadata": {}}
+{"_id": "18379855", "title": "", "text": "The Natural Statistics of AudiovisualSpeechHumans, like other animals, are exposedto a continuous stream of signals, which aredynamic, multimodal, extended, and timevarying in nature. This complex input space mustbe transduced and sampled by our sensorysystems and transmitted to the brain where itcan guide the selection of appropriate actions. Tosimplify this process, it's been suggested thatthe brain exploits statistical regularities in thestimulus space. Tests of this idea have largelybeen confined to unimodal signals and naturalscenes. One important class of multisensorysignals for which a quantitative input spacecharacterization is unavailable is human speech.We do not understand what signals our brain hasto actively piece together from an audiovisualspeech stream to arrive at a percept versus whatis already embedded in the signal structure ofthe stream itself. In essence, we do not have aclear understanding of the natural statistics ofaudiovisual speech. In the present study, we", "metadata": {}}
+{"_id": "18399038", "title": "", "text": "Establishment of human iPSC-based models forthe study and targeting of glioma initiatingcellsGlioma tumour-initiating cells (GTICs) canoriginate upon the transformation of neuralprogenitor cells (NPCs). Studies on GTICs havefocused on primary tumours from which GTICscould be isolated and the use of humanembryonic material. Recently, the somaticgenomic landscape of human gliomas has beenreported. RTK (receptor tyrosine kinase) and p53signalling were found dysregulated in \u000090% and86% of all primary tumours analysed,respectively. Here we report on the use ofhuman-induced pluripotent stem cells (hiPSCs)for modelling gliomagenesis. Dysregulation ofRTK and p53 signalling in hiPSC-derived NPCs(iNPCs) recapitulates GTIC properties in vitro. Invivo transplantation of transformed iNPCs leadsto highly aggressive tumours containingundifferentiated stem cells and theirdifferentiated derivatives. Metabolic modulationcompromises GTIC viability. Last, screening of", "metadata": {}}
+{"_id": "18414462", "title": "", "text": "Thyroid Hormone Receptor Repression Linked toType I Pneumocyte Associated RespiratoryDistress SyndromeAlthough the lung is a definingfeature of air-breathing animals, the pathwaycontrolling the formation of type I pneumocytes,the cells that mediate gas exchange, is poorlyunderstood. In contrast, the glucocorticoidreceptor and its cognate ligand have long beenknown to promote type II pneumocytematuration; prenatal administration ofglucocorticoids is commonly used to attenuatethe severity of infant respiratory distresssyndrome (RDS). Here we show that knock-inmutations of the nuclear co-repressor SMRT(silencing mediator of retinoid and thyroidhormone receptors) in C57BL/6 mice(SMRTmRID) produces a previously unidentifiedrespiratory distress syndrome caused byprematurity of the type I pneumocyte. Thoughunresponsive to glucocorticoids, treatment withanti-thyroid hormone drugs (propylthiouracil ormethimazole) completely rescues SMRT-induced", "metadata": {}}
+{"_id": "18421962", "title": "", "text": "Assessing the ceRNA hypothesis withquantitative measurements of miRNA and targetabundance.Recent studies have reported thatcompetitive endogenous RNAs (ceRNAs) can actas sponges for a microRNA (miRNA) throughtheir binding sites and that changes in ceRNAabundances from individual genes can modulatethe activity of miRNAs. Consideration of thishypothesis would benefit from knowing thequantitative relationship between a miRNA andits endogenous target sites. Here, we alteredintracellular target site abundance throughexpression of an miR-122 target in hepatocytesand livers and analyzed the effects on miR-122target genes. Target repression was released in athreshold-like manner at high target siteabundance (≥1.5 × 10(5) added target sites percell), and this threshold was insensitive to theeffective levels of the miRNA. Furthermore, inresponse to extreme metabolic liver diseasemodels, global target site abundance ofhepatocytes did not change sufficiently to affect", "metadata": {}}
+{"_id": "18429416", "title": "", "text": "Immunological mechanisms for desensitizationand tolerance in food allergyFood allergy is amajor public health concern in westernizedcountries, estimated to affect 5 % of childrenand 3–4 % of adults. Allergen-specificimmunotherapy for food allergy is currentlybeing actively evaluated, but is stillexperimental. The optimal protocol, in terms ofthe route of administration of the food, targetmaintenance dose, and duration of maintenancetherapy, and the optimal patient for theseprocedures are still being worked out. Themechanisms underlying successful fooddesensitization are also unclear, in part, becausethere is no standard immunotherapy protocol.The mechanisms involved, however, may includemast cell and basophil suppression, developmentof food-specific IgG4 antibodies, reduction in thefood-specific IgE/IgG4 ratio, up-regulation andexpansion of natural or inducible regulatory Tcells, a skewing from a Th2 to a Th1 profile, andthe development of anergy and/or deletion in", "metadata": {}}
+{"_id": "18446525", "title": "", "text": "Prodromal non-motor symptoms of Parkinson’sdiseaseThe motor symptoms of Parkinson’sdisease (PD), bradykinesia, muscular rigidity,and tremor depend upon degeneration of thedopaminergic neurons in the substantia nigrapars compacta. Recent neuropathological studiesshow that the Lewy bodies, the intraneuronallandmark of PD, accumulate in several neuronalcell types in the brain. An ascending gradient ofpathological involvement, from the medullaoblongata to neocortical areas has beenreported. Thus the original view of PD as adisease characterized by selective damage of thedopaminergic neurons in the mesencephalonshould be updated into the concept of a severemultisystemic neurodegenerative disorder.Additionally, the neuropathological alterationsoutside the substantia nigra are soundlycorrelated with the non-motor symptoms of PD.As a result of these findings, interest is growingin the identification of prodromal non-motorsymptoms of PD. Indeed, data from the", "metadata": {}}
+{"_id": "18447487", "title": "", "text": "Erythroid Krüppel-Like Factor Directly Activatesthe Basic Krüppel-Like Factor Gene in ErythroidCells \u0000The Sp/Krüppel-like factor (Sp/Klf) familyis comprised of around 25 zinc fingertranscription factors that recognize CACCC boxesand GC-rich elements. We have investigatedbasic Krüppel-like factor (Bklf/Klf3) and showthat in erythroid tissues its expression is highlydependent on another family member, erythroidKrüppel-like factor (Eklf/Klf1). We observe thatBklf mRNA is significantly reduced in erythroidtissues from Eklf-null murine embryos. We findthat Bklf is driven primarily by two promoters, aubiquitously active GC-rich upstream promoter,1a, and an erythroid downstream promoter, 1b.Transcripts from the two promoters encodeidentical proteins. Interestingly, both theubiquitous and the erythroid promoter aredependent on Eklf in erythroid cells. Eklf alsoactivates both promoters in transient assays.Experiments utilizing an inducible form of Eklfdemonstrate activation of the endogenous Bklf", "metadata": {}}
+{"_id": "18450716", "title": "", "text": "Noncanonical Wnt Signaling PromotesObesity-Induced Adipose Tissue Inflammationand Metabolic Dysfunction Independent ofAdipose Tissue ExpansionAdipose tissuedysfunction plays a pivotal role in thedevelopment of insulin resistance in obeseindividuals. Cell culture studies andgain-of-function mouse models suggest thatcanonical Wnt proteins modulate adipose tissueexpansion. However, no genetic evidencesupports a role for endogenous Wnt proteins inadipose tissue dysfunction, and the role ofnoncanonical Wnt signaling remains largelyunexplored. Here we provide evidence fromhuman, mouse, and cell culture studies showingthat Wnt5a-mediated, noncanonical Wntsignaling contributes to obesity-associatedmetabolic dysfunction by increasing adiposetissue inflammation. Wnt5a expression issignificantly upregulated in human visceral fatcompared with subcutaneous fat in obeseindividuals. In obese mice, Wnt5a ablation", "metadata": {}}
+{"_id": "18467982", "title": "", "text": "A cluster of ribosome synthesis factors regulatepre-rRNA folding and 5.8S rRNA maturation bythe Rat1 exonucleaseThe 5'-exonuclease Rat1degrades pre-rRNA spacer fragments andprocesses the 5'-ends of the 5.8S and 25SrRNAs. UV crosslinking revealed multipleRat1-binding sites across the pre-rRNA,consistent with its known functions. The major5.8S 5'-end is generated by Rat1 digestion of theinternal transcribed spacer 1 (ITS1) spacer fromcleavage site A(3). Processing from A(3) requiresthe 'A(3)-cluster' proteins, including Cic1, Erb1,Nop7, Nop12 and Nop15, which showinterdependent pre-rRNA binding. Surprisingly,A(3)-cluster factors were not crosslinked close tosite A(3), but bound sites around the 5.8S 3'-and 25S 5'-regions, which are base paired inmature ribosomes, and in the ITS2 spacer thatseparates these rRNAs. In contrast, Nop4, aprotein required for endonucleolytic cleavage inITS1, binds the pre-rRNA near the 5'-end of5.8S. ITS2 was reported to undergo structural", "metadata": {}}
+{"_id": "18473550", "title": "", "text": "Synergistic activity of the histone deacetylaseinhibitor suberoylanilide hydroxamic acid and thebisphosphonate zoledronic acid against prostatecancer cells in vitro.Bisphosphonates are widelyused agents for the treatment of malignant bonedisease. They inhibit osteoclast-mediated boneresorption and can have direct effects on cancercells. In this study, we investigated whether theanticancer activity of the third-generationbisphosphonate zoledronic acid (ZOL) could beenhanced by combination with the histonedeacetylase inhibitor suberoylanilide hydroxamicacid (SAHA). We found that ZOL and SAHAcooperated to induce cell death in the prostatecancer cell lines LNCaP and PC-3. The effect wassynergistic, as evidenced by combination indexisobologram analysis. ZOL and SAHA synergizedto induce dissipation of the mitochondrialtransmembrane potential, to activate caspase-3,and to trigger DNA fragmentation, showing thatthe combination of ZOL and SAHA resulted in theinitiation of apoptosis. Because ZOL acts by", "metadata": {}}
+{"_id": "18488986", "title": "", "text": "The Immune Response to Melanoma Is Limitedby Thymic Selection of Self-AntigensTheexpression of melanoma-associated antigens(MAA) being limited to normal melanocytes andmelanomas, MAAs are ideal targets forimmunotherapy and melanoma vaccines. AsMAAs are derived from self, immune responsesto these may be limited by thymic tolerance. Theextent to which self-tolerance prevents efficientimmune responses to MAAs remains unknown.The autoimmune regulator (AIRE) controls theexpression of tissue-specific self-antigens inthymic epithelial cells (TECs). The level ofantigens expressed in the TECs determines thefate of auto-reactive thymocytes. Deficiency inAIRE leads in both humans (APECED patients)and mice to enlarged autoreactive immunerepertoires. Here we show increased IgG levelsto melanoma cells in APECED patients correlatingwith autoimmune skin features. Similarly, theenlarged T cell repertoire in AIRE(-/-) miceenables them to mount anti-MAA and", "metadata": {}}
+{"_id": "18489989", "title": "", "text": "Murine embryonic stem cell differentiation ispromoted by SOCS-3 and inhibited by the zincfinger transcription factor Klf4.Embryonic stem(ES) cells homozygous for a Shp-2 mutation(Shp-2(Delta46-110)) demonstrate leukemiainhibitory factor (LIF) hypersensitivity andincreased LIF-stimulated phosphorylation ofsignal transducer and activator of transcription(STAT3). We hypothesized that LIF-responsivegenes in Shp-2(Delta46-110) cells wouldrepresent potential candidates for molecules vitalfor ES cell self-renewal. Using microarrayanalysis, we detected 41 genes whoseexpression was modified by LIF inShp-2(Delta46-110) ES cells. Induction of 2significantly up-regulated genes, suppressor ofcytokine signaling-3 (SOCS-3) and Kruppel-likefactor 4 (Klf4), was verified using Northernblotting. ES cells overexpressing SOCS-3 had anincreased capacity to differentiate tohematopoietic progenitors, rather than toself-renew. In contrast, ES cells overexpressing", "metadata": {}}
+{"_id": "18494847", "title": "", "text": "MicroScope—an integrated microbial resource forthe curation and comparative analysis ofgenomic and metabolic dataMicroScope is anintegrated platform dedicated to both themethodical updating of microbial genomeannotation and to comparative analysis. Theresource provides data from completed andongoing genome projects (automatic and expertannotations), together with data sources frompost-genomic experiments (i.e. transcriptomics,mutant collections) allowing users to perfect andimprove the understanding of gene functions.MicroScope(http://www.genoscope.cns.fr/agc/microscope)combines tools and graphical interfaces toanalyse genomes and to perform the manualcuration of gene annotations in a comparativecontext. Since its first publication in January2006, the system (previously named MaGe forMagnifying Genomes) has been continuouslyextended both in terms of data content andanalysis tools. The last update of MicroScope was", "metadata": {}}
+{"_id": "18537148", "title": "", "text": "Comparison of Maximal Oxygen ConsumptionBetween Black and White Prepubertal andPubertal ChildrenThe purpose of thisinvestigation was to determine whether maximaloxygen consumption (VO2max) differed betweentwo selected groups of black and white childrenand whether a difference existed to determinewhether it was related to hematologic profiles,body composition, and/or physicalactivity/inactivity level. Forty-five prepubertaland 42 pubertal, clinically normal black andwhite children participated. Dual-energy x-rayabsorptiometry was used to determine bodycomposition. A computed tomography scan ofthe abdomen was used to determine visceraladipose tissue and s.c. adipose tissue. Dailyphysical activity/inactivity was assessed byquestionnaire. Black prepubertal and pubertalchildren had lower VO2max values whencompared with white children (28.8 ± 7.8 versus35.0 ± 6.5 mL · kg−1 · min−1, p < 0.01; 33.7 ±6.4 versus 40.4 ± 10.2 mL · kg−1 · min−1, p <", "metadata": {}}
+{"_id": "18546584", "title": "", "text": "Retinoic acid inhibits Th17 polarization andenhances FoxP3 expression through aStat-3/Stat-5 independent signalingpathway.CD4(+) helper T (Th) cells play a crucialrole in the delicate balance between host defenseand autoimmune disease. Two importantpopulations of helper T cells are theproinflammatory, interleukin-17(IL-17)-producing (Th17) cells and theanti-inflammatory forkhead box P3-positive(FoxP3(+)) T regulatory (Treg) cells. Here weshow that all-trans retinoic acid (ATRA) andother agonists of the retinoic acid receptor alpha(RARalpha) inhibit the formation of Th17 cellsand promote FoxP3 expression. Conversely,inhibition of retinoic acid signaling constrainstransforming growth factor beta (TGF-beta1)induction of FoxP3. The effect of ATRA ismediated independently of IL-2, signaltransducer and activator of transcription 5(Stat5) and Stat3, representing a novelmechanism for the induction of FoxP3 in CD4 T", "metadata": {}}
+{"_id": "18557974", "title": "", "text": "British Journal of Nutrition (2003), 89, 295–301q The Authors 2003 DOI: 10.1079/BJN2002776Plasma homocysteine concentration is decreasedby dietary intervention*High plasma totalhomocysteine (tHcy) concentration is reported tobe a risk factor for vascular diseases. Weinvestigated the extent to which serum folateand plasma tHcy respond to a high intake ofnatural folate from food. Thirty-seven healthyfemales volunteered t o participate in a crossoverdietary intervention. The study included abaseline period and two 5-week diet periods(low- and high-folate diets) with a 3-weekwashout in between. The low-folate dietcontained one serving of both vegetables andfruit/d, while during the high-folate diet thesubjects ate at least seven servings ofvegetables, berries, and citrus fruit/d. Serumand erythrocyte (RBC) folate, serum vitamin B(12), and plasma tHcy concentrations weremeasured at the base-line and at the end of eachdiet period. The mean concentrations of serum", "metadata": {}}
+{"_id": "18568804", "title": "", "text": "Achieving increased resolution and more pixelswith Superresolution Optical Fluctuation Imaging(SOFI)Superresolution Optical FluctuationImaging (SOFI) as initially demonstrated allowsfor a resolution enhancement in imaging by afactor of square-root of two. Here, wedemonstrate how to increase the resolution ofSOFI images by re-weighting the Optical TransferFunction (OTF). Furthermore, we demonstratehow cross-cumulants can be exploited to obtaina fair approximation of the underlyingPoint-Spread Function. We show a two-foldincrease of resolution (over the diffraction limit)of near-infrared quantum dot labeledtubulin-network of 3T3 fibroblasts.", "metadata": {}}
+{"_id": "18574146", "title": "", "text": "Evaluation of reagent strips in detectingasymptomatic bacteriuria in early pregnancy:prospective case series.OBJECTIVE To evaluatethe performance of reagent test strips inscreening pregnant women for asymptomaticbacteriuria at their first visit to an antenatalclinic. DESIGN Prospective case series. SETTINGAntenatal clinic of a large inner city maternityhospital. SUBJECTS All women attending for theirfirst antenatal clinic. Patients taking antibioticsfor any reason and those with urinary tractsymptoms were excluded. INTERVENTION Amidstream urine specimen was divided; half wassent for microscopy and formal bacteriologicalculture and the other half was tested with acommercial reagent strip test for the presence ofblood, protein, nitrite, and leucocyte esterase.MAIN OUTCOME MEASURES Sensitivity,specificity, and positive and negative predictivevalues of the reagent strips in diagnosingasymptomatic bacteriuria (defined as 10(5)colony forming units/ml urine). RESULTS", "metadata": {}}
+{"_id": "18575183", "title": "", "text": "Wnt5a functions in planar cell polarity regulationin mice.Planar cell polarity (PCP) refers to thepolarization of cells within the plane of a cellsheet. A distinctive epithelial PCP in vertebratesis the uniform orientation of stereociliary bundlesof the sensory hair cells in the mammaliancochlea. In addition to establishing epithelialPCP, planar polarization is also required forconvergent extension (CE); a polarized cellularmovement that occurs during neural tube closureand cochlear extension. Studies in Drosophilaand vertebrates have revealed a conserved PCPpathway, including Frizzled (Fz) receptors. Herewe use the cochlea as a model system to explorethe involvement of known ligands of Fz, Wntmorphogens, in PCP regulation. We show thatWnt5a forms a reciprocal expression pattern witha Wnt antagonist, the secreted frizzled-relatedprotein 3 (Sfrp3 or Frzb), along the axis of planarpolarization in the cochlear epithelium. Wefurther demonstrate that Wnt5a antagonizesFrzb in regulating cochlear extension and", "metadata": {}}
+{"_id": "18576103", "title": "", "text": "The RNA Polymerase “Switch Region” Is a Targetfor InhibitorsThe alpha-pyrone antibioticmyxopyronin (Myx) inhibits bacterial RNApolymerase (RNAP). Here, through acombination of genetic, biochemical, andstructural approaches, we show that Myxinteracts with the RNAP \"switch region\"--thehinge that mediates opening and closing of theRNAP active center cleft--to prevent interactionof RNAP with promoter DNA. We define thecontacts between Myx and RNAP and the effectsof Myx on RNAP conformation and propose thatMyx functions by interfering with opening of theRNAP active-center cleft during transcriptioninitiation. We further show that the structurallyrelated alpha-pyrone antibiotic corallopyronin(Cor) and the structurally unrelatedmacrocyclic-lactone antibiotic ripostatin (Rip)function analogously to Myx. The RNAP switchregion is distant from targets of previouslycharacterized RNAP inhibitors, and,correspondingly, Myx, Cor, and Rip do not exhibit", "metadata": {}}
+{"_id": "18592108", "title": "", "text": "How reliable are light traps in estimating bitingrates of adult Anopheles gambiae s.l. (Diptera:Culicidae) in the presence of treated bednets?The sampling efficiency of light trap catchesrelative to human bait catches in estimatingbiting rates of the mosquito Anopheles gambiaeGiles was investigated in two types of communityin southern Sierra Leone: (i) where most of theinhabitants slept under treated bed nets; and (ii)where most of the inhabitants slept without bednets. The number of female A. gambiaemosquitoes caught in these communities by lighttrap was strongly correlated (r > or = 0.72) withthose from corresponding human biting catchesperformed either on the same or adjacent nights.It was found that the relative sampling efficiencyof light traps varied slightly but significantly withmosquito abundance in villages with treated bednets, but not in those without them.Nevertheless, the relationship between relativesampling efficiency and mosquito abundance didnot differ significantly between the two types of", "metadata": {}}
+{"_id": "18600579", "title": "", "text": "Development of a novel mouse glioma modelusing lentiviral vectorsWe report thedevelopment of a new method to induceglioblastoma multiforme in adultimmunocompetent mice by injectingCre-loxP–controlled lentiviral vectors expressingoncogenes. Cell type- or region-specificexpression of activated forms of the oncoproteinsHarvey-Ras and AKT in fewer than 60 glialfibrillary acidic protein–positive cells in thehippocampus, subventricular zone or cortex ofmice heterozygous for the gene encoding thetumor suppressor Tp53 were tested. Micedeveloped glioblastoma multiforme whentransduced either in the subventricular zone orthe hippocampus. However, tumors were rarelydetected when the mice were transduced in thecortex. Transplantation of brain tumor cells intonaive recipient mouse brain resulted in theformation of glioblastoma multiforme–liketumors, which contained CD133+ cells, formedtumorspheres and could differentiate into", "metadata": {}}
+{"_id": "18617259", "title": "", "text": "Research LettersWe report a case of preclinicalvariant Creutzfeldt-Jakob disease (vCJD) in apatient who died from a non-neurologicaldisorder 5 years after receiving a bloodtransfusion from a donor who subsequentlydeveloped vCJD. Protease-resistant prion protein(PrP(res)) was detected by western blot,paraffin-embedded tissue blot, andimmunohistochemistry in the spleen, but not inthe brain. Immunohistochemistry for prionprotein was also positive in a cervical lymphnode. The patient was a heterozygote at codon129 of PRNP, suggesting that susceptibility tovCJD infection is not confined to the methioninehomozygous PRNP genotype. These findingshave major implications for future estimates andsurveillance of vCJD in the UK.", "metadata": {}}
+{"_id": "18639989", "title": "", "text": "Swi1Timeless Prevents Repeat Instability atFission Yeast TelomeresGenomic instabilityassociated with DNA replication stress is linkedto cancer and genetic pathologies in humans. Ifnot properly regulated, replication stress, suchas fork stalling and collapse, can be induced atnatural replication impediments presentthroughout the genome. The fork protectioncomplex (FPC) is thought to play a critical role instabilizing stalled replication forks at severalknown replication barriers including eukaryoticrDNA genes and the fission yeast mating-typelocus. However, little is known about the role ofthe FPC at other natural impediments includingtelomeres. Telomeres are considered to bedifficult to replicate due to the presence ofrepetitive GT-rich sequences andtelomere-binding proteins. However, theregulatory mechanism that ensures telomerereplication is not fully understood. Here, wereport the role of the fission yeastSwi1(Timeless), a subunit of the FPC, in", "metadata": {}}
+{"_id": "18654430", "title": "", "text": "Prediction of guide strand of microRNAs from itssequence and secondary structureBACKGROUNDMicroRNAs (miRNAs) are produced by thesequential processing of a long hairpin RNAtranscript by Drosha and Dicer, an RNase IIIenzymes, and form transitory small RNAduplexes. One strand of the duplex, whichincorporates into RNA-induced silencing complex(RISC) and silences the gene expression is calledguide strand, or miRNA; while the other strand ofduplex is degraded and called the passengerstrand, or miRNA*. Predicting the guide strand ofmiRNA is important for better understanding theRNA interference pathways. RESULTS This paperdescribes support vector machine (SVM) modelsdeveloped for predicting the guide strands ofmiRNAs. All models were trained and tested on adataset consisting of 329 miRNA and 329miRNA* pairs using five fold cross validationtechnique. Firstly, models were developed usingmono-, di-, and tri-nucleotide composition ofmiRNA strands and achieved the highest", "metadata": {}}
+{"_id": "18662787", "title": "", "text": "NIPBL, encoding a homolog of fungal Scc2-typesister chromatid cohesion proteins and flyNipped-B, is mutated in Cornelia de LangesyndromeCornelia de Lange syndrome (CdLS) isa multiple malformation disorder characterizedby dysmorphic facial features, mentalretardation, growth delay and limb reductiondefects. We indentified and characterized a newgene, NIPBL, that is mutated in individuals withCdLS and determined its structure and thestructures of mouse, rat and zebrafish homologs.We named its protein product delangin.Vertebrate delangins have substantial homologyto orthologs in flies, worms, plants and fungi,including Scc2-type sister chromatid cohesionproteins, and D. melanogaster Nipped-B. Wepropose that perturbed delangin function mayinappropriately activate DLX genes, therebycontributing to the proximodistal limb patterningdefects in CdLS. Genome analyses typicallyidentify individual delangin or Nipped-B-likeorthologs in diploid animal and plant genomes.", "metadata": {}}
+{"_id": "18676539", "title": "", "text": "Impaired FANCD2 monoubiquitination andhypersensitivity to camptothecin uniquelycharacterize Fanconi anemia complementationgroup M.FANCM is a component of the Fanconianemia (FA) core complex and one FA patient(EUFA867) with biallelic mutations in FANCM hasbeen described. Strikingly, we found thatEUFA867 also carries biallelic mutations inFANCA. After correcting the FANCA defect inEUFA867 lymphoblasts, a \"clean\" FA-M cell linewas generated. These cells were hypersensitiveto mitomycin C, but unlike cells defective inother core complex members, FANCM(-/-) cellswere proficient in monoubiquitinating FANCD2and were sensitive to the topoisomerase inhibitorcamptothecin, a feature shared only with the FAsubtype D1 and N. In addition, FANCM(-/-) cellswere sensitive to UV light. FANCM and aC-terminal deletion mutant rescued thecross-linker sensitivity of FANCM(-/-) cells,whereas a FANCM ATPase mutant did not.Because both mutants restored the formation of", "metadata": {}}
+{"_id": "18678095", "title": "", "text": "Vesicular Glycolysis Provides On-Board Energyfor Fast Axonal TransportFast axonal transport(FAT) requires consistent energy over longdistances to fuel the molecular motors thattransport vesicles. We demonstrate thatglycolysis provides ATP for the FAT of vesicles.Although inhibiting ATP production frommitochondria did not affect vesicles motility,pharmacological or genetic inhibition of theglycolytic enzyme GAPDH reduced transport incultured neurons and in Drosophila larvae.GAPDH localizes on vesicles via ahuntingtin-dependent mechanism and istransported on fast-moving vesicles withinaxons. Purified motile vesicles showed GAPDHenzymatic activity and produced ATP. Finally, weshow that vesicular GAPDH is necessary andsufficient to provide on-board energy for fastvesicular transport. Although detaching GAPDHfrom vesicles reduced transport, targetingGAPDH to vesicles was sufficient to promote FATin GAPDH deficient neurons. This specifically", "metadata": {}}
+{"_id": "18682109", "title": "", "text": "RB loss in resistant EGFR mutant lungadenocarcinomas that transform to small-celllung cancerTyrosine kinase inhibitors areeffective treatments for non-small-cell lungcancers (NSCLCs) with epidermal growth factorreceptor (EGFR) mutations. However, relapsetypically occurs after an average of 1 year ofcontinuous treatment. A fundamental histologicaltransformation from NSCLC to small-cell lungcancer (SCLC) is observed in a subset of theresistant cancers, but the molecular changesassociated with this transformation remainunknown. Analysis of tumour samples and celllines derived from resistant EGFR mutantpatients revealed that Retinoblastoma (RB) islost in 100% of these SCLC transformed cases,but rarely in those that remain NSCLC. Further,increased neuroendocrine marker and decreasedEGFR expression as well as greater sensitivity toBCL2 family inhibition are observed in resistantSCLC transformed cancers compared withresistant NSCLCs. Together, these findings", "metadata": {}}
+{"_id": "18691097", "title": "", "text": "Periostin Deficiency Increases Bone Damage andImpairs Injury Response to Fatigue Loading inAdult MiceBone damage removal and callusformation in response to fatigue loading areessential to prevent fractures. Periostin (Postn)is a matricellular protein that mediates adaptiveresponse of cortical bone to loading. Whetherand how periostin influences damage and theinjury response to fatigue remains unknown. Weinvestigated the skeletal response of Postn(-/-)and Postn(+/+) mice after fatigue stimulus byaxial compression of their tibia. In Postn(+/+)mice, cracks number and surface (CsNb, CsS)increased 1h after fatigue, with a decrease instrength compared to non-fatigued tibia. At 15days, CsNb had started to decline, while CtTVand CtBV increased in fatigued vs non-fatiguedtibia, reflecting a woven bone response that waspresent in 75% of the fatigued bones. Corticalporosity and remodelling also prominentlyincreased in the fatigued tibia of Postn(+/+)mice. At 30 days, paralleling a continuous", "metadata": {}}
+{"_id": "18694784", "title": "", "text": "Preferential occupancy of histone variant H2AZat inactive promoters influences local histonemodifications and chromatin remodeling.Theyeast histone variant H2AZ (Htz1) is implicatedin transcription activation, prevention of theectopic spread of heterochromatin, and genomeintegrity. Our genome-wide localization analysisrevealed that Htz1 is widely, but nonrandomly,distributed throughout the genome in anSWR1-dependent manner. We found that Htz1 isenriched in intergenic regions compared withcoding regions. Its occupancy is inverselyproportional to transcription rates and theenrichment of the RNA polymerase II underdifferent growth conditions. However, Htz1 doesnot seem to directly regulate transcriptionrepression genome-wide; instead, the presenceof Htz1 under the inactivated condition isessential for optimal activation of a subset ofgenes. In addition, Htz1 is not generallyresponsible for nucleosome positioning, even atthose promoters where Htz1 is highly enriched.", "metadata": {}}
+{"_id": "18695970", "title": "", "text": "Genomic organisation and transcriptioncharacterisation of the gene encodingLeishmania (Leishmania) amazonensis arginaseand its protein structure prediction.The genomicorganisation of the gene encoding Leishmania(Leishmania) amazonensis arginase as well as itsflanking regions were characterised. The size ofthe transcribed RNA was determined, allowing usto map the genomic sites signalling for RNAtrans-splicing and putative polyadenylationregions. The general organisation was comparedwith genes encoding other proteins alreadydescribed in organisms of the Trypanosomatidfamily. The complete nucleotide sequence of thearginase open reading frame was obtained andthe three-dimensional structure of the enzymewas inferred by a computational analysis of thededuced amino acid sequence, based on theestablished crystal structure described for Rattusnorvergicus arginase. The human liver arginasesequence was analysed in the same way and thecomparison of the presumed structure of both", "metadata": {}}
+{"_id": "18734652", "title": "", "text": "Endometrial carcinoma risk among womendiagnosed with endometrial hyperplasia: the34-year experience in a large healthplanClassifying endometrial hyperplasia (EH)according to the severity of glandular crowding(simple hyperplasia (SH) vs complex hyperplasia(CH)) and nuclear atypia (simple atypicalhyperplasia (SAH) vs complex atypicalhyperplasia (CAH)) should predict subsequentendometrial carcinoma risk, but data onprogression are lacking. Our nested case–controlstudy of EH progression included 138 cases, whowere diagnosed with EH and then with carcinoma(1970–2003) at least 1 year (median, 6.5 years)later, and 241 controls, who were individuallymatched on age, date, and follow-up durationand counter-matched on EH classification. Aftercentralised pathology panel and medical recordreview, we generated rate ratios (RRs) and 95%confidence intervals (CIs), adjusted fortreatment and repeat biopsies. With disorderedproliferative endometrium (DPEM) as the", "metadata": {}}
+{"_id": "18747744", "title": "", "text": "Redefining the Genetic Hierarchies ControllingSkeletal Myogenesis: Pax-3 and Myf-5 ActUpstream of MyoDWe analyzed Pax-3 (splotch),Myf-5 (targeted with nlacZ), and splotch/Myf-5homozygous mutant mice to investigate the rolesthat these genes play in programming skeletalmyogenesis. In splotch and Myf-5 homozygousembryos, myogenic progenitor cell perturbationsand early muscle defects are distinct.Remarkably, splotch/Myf-5 double homozygoteshave a dramatic phenotype not seen in theindividual mutants: body muscles are absent.MyoD does not rescue this double mutantphenotype since activation of this gene proves tobe dependent on either Pax-3 or Myf-5.Therefore, Pax-3 and Myf-5 define two distinctmyogenic pathways, and MyoD acts geneticallydownstream of these genes for myogenesis inthe body. This genetic hierarchy does not appearto operate for head muscle formation.", "metadata": {}}
+{"_id": "18750453", "title": "", "text": "Assessment of Volume Depletion in Children withMalariaBackground The degree of volumedepletion in severe malaria is currently unknown,although knowledge of fluid compartmentvolumes can guide therapy. To assistmanagement of severely ill children, and to testthe hypothesis that volume changes in fluidcompartments reflect disease severity, wemeasured body compartment volumes inGabonese children with malaria. Methods andFindings Total body water volume (TBW) andextracellular water volume (ECW) wereestimated in children with severe or moderatemalaria and in convalescence by tracer dilutionwith heavy water and bromide, respectively.Intracellular water volume (ICW) was derivedfrom these parameters. Bioelectrical impedanceanalysis estimates of TBW and ECW werecalibrated against dilution methods, andbioelectrical impedance analysis measurementswere taken daily until discharge. Sixteen childrenhad severe and 19 moderate malaria. Severe", "metadata": {}}
+{"_id": "18758057", "title": "", "text": "NSOM/QD-Based Direct Visualization ofCD3-Induced and CD28-Enhanced NanospatialCoclustering of TCR and Coreceptor inNanodomains in T Cell ActivationDirect molecularimaging of nano-spatial relationship between Tcell receptor (TCR)/CD3 and CD4 or CD8co-receptor before and after activation of aprimary T cell has not been reported. We haverecently innovated application of near-fieldscanning optical microscopy (NSOM) andimmune-labeling quantum dots (QD) to imageAg-specific TCR response during in vivo clonalexpansion, and now up-graded theNSOM/QD-based nanotechnology throughdipole-polarization and dual-color imaging. Usingthis imaging system scanning cell-membranemolecules at a best-optical lateral resolution, wedemonstrated that CD3, CD4 or CD8 moleculeswere distinctly distributed as single QD-boundmolecules or nano-clusters equivalent to 2-4 QDfluorescence-intensity/size on cell-membrane ofun-stimulated primary T cells, and approximately", "metadata": {}}
+{"_id": "18806488", "title": "", "text": "Hoxa9 transforms primary bone marrow cellsthrough specific collaboration with Meis1a butnot Pbx1b.Hoxa9, Meis1 and Pbx1 encodehomeodomaincontaining proteins implicated inleukemic transformation in both mice andhumans. Hoxa9, Meis1 and Pbx1 proteins havebeen shown to physically interact with eachother, as Hoxa9 cooperatively binds consensusDNA sequences with Meis1 and with Pbx1, whileMeis1 and Pbx1 form heterodimers in both thepresence and absence of DNA. In this study, wesought to determine if Hoxa9 could transformhemopoietic cells in collaboration with eitherPbx1 or Meis1. Primary bone marrow cells,retrovirally engineered to overexpress Hoxa9and Meis1a simultaneously, induced growthfactor-dependent oligoclonal acute myeloidleukemia in <3 months when transplanted intosyngenic mice. In contrast, overexpression ofHoxa9, Meis1a or Pbx1b alone, or thecombination of Hoxa9 and Pbx1b failed totransform these cells acutely within 6 months", "metadata": {}}
+{"_id": "18810195", "title": "", "text": "Tyr26 phosphorylation of PGAM1 provides ametabolic advantage to tumours by stabilizingthe active conformationHow oncogenic signallingcoordinates glycolysis and anabolic biosynthesisin cancer cells remains unclear. We recentlyreported that the glycolytic enzymephosphoglycerate mutase 1 (PGAM1) regulatesanabolic biosynthesis by controlling intracellularlevels of its substrate 3-phosphoglycerate andproduct 2-phosphoglycerate. Here we report anovel mechanism in which Y26 phosphorylationenhances PGAM1 activation through release ofinhibitory E19 that blocks the active site,stabilising cofactor 2,3-bisphosphoglyceratebinding and H11 phosphorylation. We also reportthe crystal structure of H11-phosphorylatedPGAM1 and find that phospho-H11 activatesPGAM1 at least in part by promoting substrate3-phosphoglycerate binding. Moreover, Y26phosphorylation of PGAM1 is common in humancancer cells and contributes to regulation of3-phosphoglycerate and 2-phosphoglycerate", "metadata": {}}
+{"_id": "18816720", "title": "", "text": "Spatial and Temporal Clustering of Dengue VirusTransmission in Thai VillagesBACKGROUNDTransmission of dengue viruses (DENV), theleading cause of arboviral disease worldwide, isknown to vary through time and space, likelyowing to a combination of factors related to thehuman host, virus, mosquito vector, andenvironment. An improved understanding ofvariation in transmission patterns is fundamentalto conducting surveillance and implementingdisease prevention strategies. To test thehypothesis that DENV transmission is spatiallyand temporally focal, we compared geographicand temporal characteristics within Thai villageswhere DENV are and are not being activelytransmitted. METHODS AND FINDINGS Clusterinvestigations were conducted within 100 m ofhomes where febrile index children with (positiveclusters) and without (negative clusters) acutedengue lived during two seasons of peak DENVtransmission. Data on human infection andmosquito infection/density were examined to", "metadata": {}}
+{"_id": "18834078", "title": "", "text": "Secondary T cell–T cell synaptic interactionsdrive the differentiation of protective CD8+ TcellsImmunization results in the differentiation ofCD8+ T cells, such that they acquire effectorabilities and convert into a memory pool. Primingof T cells takes place via an immunologicalsynapse formed with an antigen-presenting cell(APC). By disrupting synaptic stability atdifferent times, we found that the differentiationof CD8+ T cells required cell interactions beyondthose made with APCs. We identified a criticaldifferentiation period that required interactionsbetween primed T cells. We found that T cell–Tcell synapses had a major role in the generationof protective CD8+ T cell memory. T cell–T cellsynapses allowed T cells to polarize criticalsecretion of interferon-γ (IFN-γ) toward eachother. Collective activation and homotypicclustering drove cytokine sharing and acted asregulatory stimuli for T cell differentiation.", "metadata": {}}
+{"_id": "18841257", "title": "", "text": "The Histone H3 Lysine-27 Demethylase Jmjd3Links Inflammation to Inhibition ofPolycomb-Mediated Gene SilencingEpigeneticchromatin marks restrict the ability ofdifferentiated cells to change gene expressionprograms in response to environmental cues andto transdifferentiate. Polycomb group (PcG)proteins mediate gene silencing and represstransdifferentiation in a manner dependent onhistone H3 lysine 27 trimethylation (H3K27me3).However, macrophages migrated into inflamedtissues can transdifferentiate, but it is unknownwhether inflammation alters PcG-dependentsilencing. Here we show that the JmjC-domainprotein Jmjd3 is a H3K27me demethylaseexpressed in macrophages in response tobacterial products and inflammatory cytokines.Jmjd3 binds PcG target genes and regulates theirH3K27me3 levels and transcriptional activity.The discovery of an inducible enzyme that erasesa histone mark controlling differentiation and cellidentity provides a link between inflammation", "metadata": {}}
+{"_id": "18852643", "title": "", "text": "Apolipoprotein E and atherosclerosis: beyondlipid effect.In humans, apolipoprotein E (apoE) isa polymorphic multifunctional protein.1 It iscoded by three alleles (e2, e3, e4) of amodulator gene (level, variability, andsusceptibility gene) at the apoE locus onchromosome 19, determining six apoE genotypesand plasma phenotypes. Its pleiotropic effectsare exerted on plasma lipoprotein metabolism,coagulation, oxidative processes, macrophage,glial cell and neuronal cell homeostasis, adrenalfunction, central nervous system physiology,inflammation, and cell proliferation.2,3 ApoEpolymorphism modulates susceptibility to manydiseases. It is, however, particularly notoriousfor its role in neurodegenerative disorders4 andatherosclerotic arterial disease.5,6 The e4 allele(phenotypes E4/4 and E4/3) that is associatedwith higher low density lipoprotein cholesterol(LDL-C) is considered proatherogenic, whereasthe presence of the e2 allele (E3/2, E2/2), beingassociated with lower LDL-C levels, is deemed to", "metadata": {}}
+{"_id": "18855191", "title": "", "text": "Exploitative and Hierarchical Antagonism in aCooperative BacteriumSocial organisms thatcooperate with some members of their ownspecies, such as close relatives, may fail tocooperate with other genotypes of the samespecies. Such noncooperation may take the formof outright antagonism or social exploitation.Myxococcus xanthus is a highly social prokaryotethat cooperatively develops into spore-bearing,multicellular fruiting bodies in response tostarvation. Here we have characterized thenature of social interactions among ninedevelopmentally proficient strains of M. xanthusisolated from spatially distant locations. Strainswere competed against one another in allpossible pairwise combinations duringstarvation-induced development. In mostpairings, at least one competitor exhibited strongantagonism toward its partner and a majority ofmixes showed bidirectional antagonism thatdecreased total spore production, even to thepoint of driving whole populations to extinction.", "metadata": {}}
+{"_id": "18872233", "title": "", "text": "Mental Health Conditions Among PatientsSeeking and Undergoing Bariatric Surgery: AMeta-analysis.IMPORTANCE Bariatric surgery isassociated with sustained weight loss andimproved physical health status for severelyobese individuals. Mental health conditions maybe common among patients seeking bariatricsurgery; however, the prevalence of theseconditions and whether they are associated withpostoperative outcomes remains unknown.OBJECTIVE To determine the prevalence ofmental health conditions among bariatric surgerycandidates and recipients, to evaluate theassociation between preoperative mental healthconditions and health outcomes followingbariatric surgery, and to evaluate the associationbetween surgery and the clinical course ofmental health conditions. DATA SOURCES Wesearched PubMed, MEDLINE on OVID, andPsycINFO for studies published between January1988 and November 2015. Study quality wasassessed using an adapted tool for risk of bias;", "metadata": {}}
+{"_id": "18882947", "title": "", "text": "The Nuclear Effector of Wnt-Signaling, Tcf1,Functions as a T-Cell–Specific Tumor Suppressorfor Development of LymphomasThe HMG-boxfactor Tcf1 is required during T-cell developmentin the thymus and mediates the nuclear responseto Wnt signals. Tcf1(-/-) mice have previouslybeen characterized and show developmentalblocks at the CD4-CD8- double negative (DN) toCD4+CD8+ double positive transition. Due to theblocks in T-cell development, Tcf1(-/-) micenormally have a very small thymus.Unexpectedly, a large proportion of Tcf1(-/-)mice spontaneously develop thymic lymphomaswith 50% of mice developing a thymiclymphoma/leukemia at the age of 16 wk. Theselymphomas are clonal, highly metastatic, andparadoxically show high Wnt signaling whencrossed with Wnt reporter mice and have highexpression of Wnt target genes Lef1 and Axin2.In wild-type thymocytes, Tcf1 is higherexpressed than Lef1, with a predominance ofWnt inhibitory isoforms. Loss of Tcf1 as repressor", "metadata": {}}
+{"_id": "18895793", "title": "", "text": "Activator Control of Nucleosome Occupancy inActivation and Repression of TranscriptionTherelationship between chromatin structure andgene expression is a subject of intense study.The universal transcriptional activator Gal4removes promoter nucleosomes as it triggerstranscription, but how it does so has remainedobscure. The reverse process, repression oftranscription, has often been correlated with thepresence of nucleosomes. But it is not knownwhether nucleosomes are required for thateffect. A new quantitative assay describes, forany given location, the fraction of DNA moleculesin the population that bears a nucleosome at anygiven instant. This allows us to follow the timecourses of nucleosome removal and reformation,in wild-type and mutant cells, upon activation(by galactose) and repression (by glucose) of theGAL genes of yeast. We show that upon beingfreed of its inhibitor Gal80 by the action ofgalactose, Gal4 quickly recruits SWI/SNF to thegenes, and that nucleosome \"remodeler\" rapidly", "metadata": {}}
+{"_id": "18909530", "title": "", "text": "Contractile forces sustain and polarizehematopoiesis from stem and progenitorcells.Self-renewal and differentiation of stemcells depend on asymmetric division andpolarized motility processes that in other celltypes are modulated by nonmuscle myosin-II(MII) forces and matrix mechanics. Here, massspectrometry-calibrated intracellular flowcytometry of human hematopoiesis reveals MIIBto be a major isoform that is strongly polarized inhematopoietic stem cells and progenitors(HSC/Ps) and thereby downregulated indifferentiated cells via asymmetric division. MIIAis constitutive and activated bydephosphorylation during cytokine-triggereddifferentiation of cells grown on stiff,endosteum-like matrix, but not soft, marrow-likematrix. In vivo, MIIB is required for generation ofblood, while MIIA is required for sustained HSC/Pengraftment. Reversible inhibition of bothisoforms in culture with blebbistatin enriches forlong-term hematopoietic multilineage", "metadata": {}}
+{"_id": "18914652", "title": "", "text": "Critical Role of the Virus-Encoded MicroRNA-155Ortholog in the Induction of Marek's DiseaseLymphomasNotwithstanding thewell-characterised roles of a number ofoncogenes in neoplastic transformation,microRNAs (miRNAs) are increasingly implicatedin several human cancers. Discovery of miRNAsin several oncogenic herpesviruses such as KSHVhas further highlighted the potential ofvirus-encoded miRNAs to contribute to theironcogenic capabilities. Nevertheless, despite theidentification of several possible cancer-relatedgenes as their targets, the direct in vivo role ofvirus-encoded miRNAs in neoplastic diseasessuch as those induced by KSHV is difficult todemonstrate in the absence of suitable models.However, excellent natural disease models ofrapid-onset Marek's disease (MD) lymphomas inchickens allow examination of the oncogenicpotential of virus-encoded miRNAs. Using virusesmodified by reverse genetics of the infectiousBAC clone of the oncogenic RB-1B strain of MDV,", "metadata": {}}
+{"_id": "18924534", "title": "", "text": "Functional insights into the role ofnuclear-retained long noncoding RNAs in geneexpression control in mammalian cellsThemammalian genome harbors thousands of longnoncoding RNA (lncRNA) genes. Recent studieshave indicated the involvement of several ofthese lncRNAs in the regulation of geneexpression. lncRNAs play crucial roles in variousbiological processes ranging from epigeneticgene regulation, transcriptional control, topost-transcriptional regulation. lncRNAs arelocalized in various subcellular compartments,and major proportion of these are retained in thecell nucleus and could be broadly classified asnuclear-retained lncRNAs (nrRNAs). Based onthe identified functions, members of the nrRNAsexecute diverse roles, including providingarchitectural support to the hierarchicalsubnuclear organization and influencing therecruitment of chromatin modifier factors tospecific chromatin sites. In this review, we willsummarize the recently described roles of", "metadata": {}}
+{"_id": "18938992", "title": "", "text": "Downregulation of TAP1 in B lymphocytes bycellular and Epstein-Barr virus-encodedinterleukin-10.Virally infected cells degradeintracellular viral proteins proteolytically andpresent the resulting peptides in association withmajor histocompatibility complex (MHC) class Imolecules to CD8+ cytotoxic T lymphocytes(CTLs). These cells are normally prone toCTL-mediated elimination. However, severalviruses have evolved strategies to avoiddetection by the immune system that interferewith the pathway of antigen presentation.Epstein-Barr virus (EBV) expresses apredominantly late protein, the BCRF1 geneproduct vIL-10, that is similar in sequence to thehuman interleukin-10 (hIL-10). We show herethat vIL-10 affects the expression of one of thetwo transporter proteins (TAPs) associated withantigen presentation. Similarly, hIL-10 showedthe same activity. Expression of the LMP2 andTAP1 genes but not expression of TAP2 or LMP7is efficiently downregulated, indicating a specific", "metadata": {}}
+{"_id": "18949516", "title": "", "text": "TGF-β and Insulin Signaling RegulateReproductive Aging via Oocyte and GermlineQuality MaintenanceReproductive cessation isperhaps the earliest aging phenotype thathumans experience. Similarly, reproduction ofCaenorhabditis elegans ceases in mid-adulthood.Although somatic aging has been studied in bothworms and humans, mechanisms regulatingreproductive aging are not yet understood. Here,we show that TGF-β Sma/Mab and Insulin/IGF-1signaling regulate C. elegans reproductive agingby modulating multiple aspects of thereproductive process, including embryo integrity,oocyte fertilizability, chromosome segregationfidelity, DNA damage resistance, and oocyte andgermline morphology. TGF-β activity regulatesreproductive span and germline/oocyte qualitynoncell-autonomously and is temporally andtranscriptionally separable from its regulation ofgrowth. Chromosome segregation, cell cycle, andDNA damage response genes are upregulated inTGF-β mutant oocytes, decline in aged", "metadata": {}}
+{"_id": "18953920", "title": "", "text": "The Epithelial-Mesenchymal Transition GeneratesCells with Properties of Stem CellsTheepithelial-mesenchymal transition (EMT) is a keydevelopmental program that is often activatedduring cancer invasion and metastasis. We herereport that the induction of an EMT inimmortalized human mammary epithelial cells(HMLEs) results in the acquisition ofmesenchymal traits and in the expression ofstem-cell markers. Furthermore, we show thatthose cells have an increased ability to formmammospheres, a property associated withmammary epithelial stem cells. Independent ofthis, stem cell-like cells isolated from HMLEcultures form mammospheres and expressmarkers similar to those of HMLEs that haveundergone an EMT. Moreover, stem-like cellsisolated either from mouse or human mammaryglands or mammary carcinomas express EMTmarkers. Finally, transformed human mammaryepithelial cells that have undergone an EMT formmammospheres, soft agar colonies, and tumors", "metadata": {}}
+{"_id": "18956141", "title": "", "text": "NEMO Prevents RIP Kinase 1-Mediated EpithelialCell Death and Chronic Intestinal Inflammationby NF-κB-Dependent and -IndependentFunctionsIntestinal epithelial cells (IECs)regulate gut immune homeostasis, and impairedepithelial responses are implicated in thepathogenesis of inflammatory bowel diseases(IBD). IEC-specific ablation of nuclear factor κB(NF-κB) essential modulator (NEMO) causedPaneth cell apoptosis and impaired antimicrobialfactor expression in the ileum, as well ascolonocyte apoptosis and microbiota-drivenchronic inflammation in the colon. CombinedRelA, c-Rel, and RelB deficiency in IECs causedPaneth cell apoptosis but not colitis, suggestingthat NEMO prevents colon inflammation byNF-κB-independent functions. Inhibition ofreceptor-interacting protein kinase 1 (RIPK1)kinase activity or combined deficiency ofFas-associated via death domain protein (FADD)and RIPK3 prevented epithelial cell death, Panethcell loss, and colitis development in mice with", "metadata": {}}
+{"_id": "18987782", "title": "", "text": "Suppression of Myc oncogenic activity byribosomal protein haploinsufficiencyThe Myconcogene regulates the expression of severalcomponents of the protein synthetic machinery,including ribosomal proteins, initiation factors oftranslation, RNA polymerase III and ribosomalDNA. Whether and how increasing the cellularprotein synthesis capacity affects the multistepprocess leading to cancer remains to beaddressed. Here we use ribosomal proteinheterozygote mice as a genetic tool to restoreincreased protein synthesis in Emu-Myc/+transgenic mice to normal levels, and show thatthe oncogenic potential of Myc in this context issuppressed. Our findings demonstrate that theability of Myc to increase protein synthesisdirectly augments cell size and is sufficient toaccelerate cell cycle progression independently ofknown cell cycle targets transcriptionallyregulated by Myc. In addition, when proteinsynthesis is restored to normal levels,Myc-overexpressing precancerous cells are more", "metadata": {}}
+{"_id": "18988265", "title": "", "text": "Susceptibility to exacerbation in chronicobstructive pulmonary disease.BACKGROUNDAlthough we know that exacerbations are keyevents in chronic obstructive pulmonary disease(COPD), our understanding of their frequency,determinants, and effects is incomplete. In alarge observational cohort, we tested thehypothesis that there is a frequent-exacerbationphenotype of COPD that is independent ofdisease severity. METHODS We analyzed thefrequency and associations of exacerbation in2138 patients enrolled in the Evaluation of COPDLongitudinally to Identify Predictive SurrogateEndpoints (ECLIPSE) study. Exacerbations weredefined as events that led a care provider toprescribe antibiotics or corticosteroids (or both)or that led to hospitalization (severeexacerbations). Exacerbation frequency wasobserved over a period of 3 years. RESULTSExacerbations became more frequent (and moresevere) as the severity of COPD increased;exacerbation rates in the first year of follow-up", "metadata": {}}
+{"_id": "18997216", "title": "", "text": "Sympathetic baroreflex gain in normotensivepregnant women.Muscle sympathetic nerveactivity is increased during normotensivepregnancy while mean arterial pressure ismaintained or reduced, suggesting baroreflexresetting. We hypothesized spontaneoussympathetic baroreflex gain would be reduced innormotensive pregnant women relative tononpregnant matched controls. Integratedmuscle sympathetic burst incidence and totalsympathetic activity (microneurography), bloodpressure (Finometer), and R-R interval (ECG)were assessed at rest in 11 pregnant women (33± 1 wk gestation, 31 ± 1 yr, prepregnancy BMI:23.5 ± 0.9 kg/m(2)) and 11 nonpregnantcontrols (29 ± 1 yr; BMI: 25.2 ± 1.7 kg/m(2)).Pregnant women had elevated baselinesympathetic burst incidence (43 ± 2 vs. 33 ± 2bursts/100 heart beats, P = 0.01) and totalsympathetic activity (1,811 ± 148 vs. 1,140 ±55 au, P < 0.01) relative to controls. Both mean(88 ± 3 vs. 91 ± 2 mmHg, P = 0.4) and diastolic", "metadata": {}}
+{"_id": "18998807", "title": "", "text": "Facilitators and Impediments of the PluripotencyReprogramming Factors' Initial Engagement withthe GenomeThe ectopic expression oftranscription factors can reprogram cell fate, yetit is unknown how the initial binding of factors tothe genome relates functionally to the bindingseen in the minority of cells that becomereprogrammed. We report a map of Oct4, Sox2,Klf4, and c-Myc (O, S, K, and M) on the humangenome during the first 48 hr of reprogrammingfibroblasts to pluripotency. Three striking aspectsof the initial chromatin binding events include anunexpected role for c-Myc in facilitating OSKchromatin engagement, the primacy of O, S, andK as pioneer factors at enhancers of genes thatpromote reprogramming, and megabase-scalechromatin domains spanned by H3K9me3,including many genes required for pluripotency,that prevent initial OSKM binding and impede theefficiency of reprogramming. We find diverseaspects of initial factor binding that must beovercome in the minority of cells that become", "metadata": {}}
+{"_id": "19004126", "title": "", "text": "Fibrillar Collagen Inhibits Arterial Smooth MuscleProliferation through Regulation of Cdk2InhibitorsArterial smooth muscle cells (SMCs) arearrested in the G1 phase of the cell cycle onpolymerized type I collagen fibrils, whilemonomer collagen supports SMC proliferation.Cyclin E-associated kinase and cyclin-dependentkinase 2 (cdk2) phosphorylation are inhibited onpolymerized collagen, and levels of the cdk2inhibitors p27Kip1 and p21Cip1/Waf1 areincreased compared with SMCs on monomercollagen. p27Kip1 associates with the cyclinE-cdk2-p21Cip1/Waf1 complex in SMCs onpolymerized collagen. Monovalent blockingantibodies to alpha2 integrins, integrins thatmediate adhesion to both forms of collagen,mimic these effects on monomer collagen.Furthermore, polymerized collagen rapidlysuppresses p70 S6 kinase, a possible regulatorof p27Kip1. Thus, fibrillar collagen specificallyregulates early integrin signaling that may leadto up-regulation of cdk2 inhibitors and inhibition", "metadata": {}}
+{"_id": "19005293", "title": "", "text": "Memory CD4+ T cells induce innate responsesindependently of pathogenInflammation inducedby recognition of pathogen-associated molecularpatterns markedly affects subsequent adaptiveresponses. We asked whether the adaptiveimmune system can also affect the character andmagnitude of innate inflammatory responses. Wefound that the response of memory, but notnaive, CD4+ T cells enhances production ofmultiple innate inflammatory cytokines andchemokines (IICs) in the lung and that, duringinfluenza infection, this leads to early control ofvirus. Memory CD4+ T cell–induced IICs andviral control require cognate antigen recognitionand are optimal when memory cells are either Thelper type 1 (TH1) or TH17 polarized but areindependent of interferon-γ (IFN-γ) and tumornecrosis factor-α (TNF-α) production and do notrequire activation of conserved pathogenrecognition pathways. This represents apreviously undescribed mechanism by whichmemory CD4+ T cells induce an early innate", "metadata": {}}
+{"_id": "19047331", "title": "", "text": "Direct Upregulation of STAT3 byMicroRNA-551b-3p Deregulates Growth andMetastasis of Ovarian Cancer.3q26.2amplification in high-grade serous ovarian cancerleads to increased expression of maturemicroRNA miR551b-3p, which is associated withpoor clinical outcome. Importantly, miR551b-3pcontributes to resistance to apoptosis andincreased survival and proliferation of cancercells in vitro and in vivo. miR551b-3pupregulates STAT3 protein levels, and STAT3 isrequired for the effects of miR551b-3p on cellproliferation. Rather than decreasing levels oftarget mRNA as expected, we demonstrate thatmiR551b-3p binds a complementary sequenceon the STAT3 promoter, recruiting RNApolymerase II and the TWIST1 transcriptionfactor to activate STAT3 transcription, and thusdirectly upregulates STAT3 expression.Furthermore, anti-miR551b reduced STAT3expression in ovarian cancer cells in vitro and invivo and reduced ovarian cancer growth in vivo.", "metadata": {}}
+{"_id": "19052713", "title": "", "text": "Human albumin administration in critically illpatients: systematic review of randomisedcontrolled trials.OBJECTIVE To quantify effect onmortality of administering human albumin orplasma protein fraction during management ofcritically ill patients. DESIGN Systematic reviewof randomised controlled trials comparingadministration of albumin or plasma proteinfraction with no administration or withadministration of crystalloid solution in criticallyill patients with hypovolaemia, burns, orhypoalbuminaemia. SUBJECTS 30 randomisedcontrolled trials including 1419 randomisedpatients. MAIN OUTCOME MEASURE Mortalityfrom all causes at end of follow up for each trial.RESULTS For each patient category the risk ofdeath in the albumin treated group was higherthan in the comparison group. For hypovolaemiathe relative risk of death after albuminadministration was 1.46 (95% confidenceinterval 0.97 to 2.22), for burns the relative riskwas 2.40 (1.11 to 5.19), and for", "metadata": {}}
+{"_id": "19058822", "title": "", "text": "A fine-scale map of recombination rates andhotspots across the human genome.Geneticmaps, which document the way in whichrecombination rates vary over a genome, are anessential tool for many genetic analyses. Wepresent a high-resolution genetic map of thehuman genome, based on statistical analyses ofgenetic variation data, and identify more than25,000 recombination hotspots, together withmotifs and sequence contexts that play a role inhotspot activity. Differences between thebehavior of recombination rates over large(megabase) and small (kilobase) scales lead usto suggest a two-stage model for recombinationin which hotspots are stochastic features, withina framework in which large-scale rates areconstrained.", "metadata": {}}
+{"_id": "19071857", "title": "", "text": "Mental Health Support Provided Throughout theBariatric Surgery Clinical Pathway in FrenchSpecialized Care Centers forObesityPre-operative psychological assessmentis recommended by international guidelines forbariatric surgery candidates. Thereby, serviceteams caring for bariatric patients should includeat least one mental health provider (e.g., apsychologist or psychiatrist). The objective ofthis study was to evaluate the psychology andpsychiatry resources and practices in the 37specialized obesity centers (CSOs) created bythe French Ministry of Health. CSO coordinatorswere contacted by e-mail to collect generalinformation on the centers (e.g., number ofbariatric operations). Secondly, psychologistsand psychiatrists of each center completed ananonymous questionnaire assessing theirprofessional practices and their organization ofcare pathways. The vast majority of CSOcoordinators (81%, n = 26/32) answered oursurvey. These results show significant", "metadata": {}}
+{"_id": "19079491", "title": "", "text": "Calcium: Regulation of cell death: thecalcium–apoptosis linkTo live or to die? Thiscrucial question eloquently reflects the dual roleof Ca2+ in living organisms – survival factor orruthless killer. It has long been known that Ca2+signals govern a host of vital cell functions andso are necessary for cell survival. However, morerecently it has become clear that cellular Ca2+overload, or perturbation of intracellular Ca2+compartmentalization, can cause cytotoxicity andtrigger either apoptotic or necrotic cell death.", "metadata": {}}
+{"_id": "19099739", "title": "", "text": "Breaking the code of DNA binding specificity ofTAL-type III effectors.The pathogenicity of manybacteria depends on the injection of effectorproteins via type III secretion into eukaryoticcells in order to manipulate cellular processes.TAL (transcription activator-like) effectors fromplant pathogenic Xanthomonas are importantvirulence factors that act as transcriptionalactivators in the plant cell nucleus, where theydirectly bind to DNA via a central domain oftandem repeats. Here, we show how target DNAspecificity of TAL effectors is encoded. Twohypervariable amino acid residues in each repeatrecognize one base pair in the target DNA.Recognition sequences of TAL effectors werepredicted and experimentally confirmed. Themodular protein architecture enabled theconstruction of artificial effectors with newspecificities. Our study describes thefunctionality of a distinct type of DNA bindingdomain and allows the design of DNA bindingdomains for biotechnology.", "metadata": {}}
+{"_id": "19130782", "title": "", "text": "Interferon-Gamma at the Crossroads of TumorImmune Surveillance orEvasionInterferon-gamma (IFN-γ) is a pleiotropicmolecule with associated antiproliferative,pro-apoptotic and antitumor mechanisms. Thiseffector cytokine, often considered as a majoreffector of immunity, has been used in thetreatment of several diseases, despite itsadverse effects. Although broad evidenceimplicating IFN-γ in tumor immune surveillance,IFN-γ-based therapies undergoing clinical trialshave been of limited success. In fact, recentreports suggested that it may also play aprotumorigenic role, namely, through IFN-γsignaling insensitivity, downregulation of majorhistocompatibility complexes, and upregulationof indoleamine 2,3-dioxygenase and ofcheckpoint inhibitors, as programmed cell-deathligand 1. However, the IFN-γ-mediatedresponses are still positively associated withpatient's survival in several cancers.Consequently, major research efforts are", "metadata": {}}
+{"_id": "19132741", "title": "", "text": "Role of antioxidants in paraquattoxicity.Paraquat, a quarternary nitrogenherbicide, is a highly toxic compound for humansand animals and many cases of acute poisoningand death have been reported over the past fewdecades. The mechanisms of paraquat toxicityinvolve: the generation of the superoxide anion,which can lead to the formation of more toxicreactive oxygen species, such as hydrogenperoxide and hydroxyl radical; and the oxidationof the cellular NADPH, the major source ofreducing equivalents for the intracellularreduction of paraquat, which results in thedisruption of important NADPH-requiringbiochemical processes. The major cause of deathin paraquat poisoning is respiratory failure due toan oxidative insult to the alveolar epithelium withsubsequent obliterating fibrosis. Management ofparaquat poisoning has remained mostlysupportive and has been directed towards themodification of the toxicokinetics of the poison.Currently, there are no true pharmacological", "metadata": {}}
+{"_id": "19138874", "title": "", "text": "Nucleation of nuclear bodies by RNAThebiogenesis of the many functional compartmentscontained in the mammalian cell nucleus ispoorly understood. More specifically, little isknown regarding the initial nucleation steprequired for nuclear body formation. Here weshow that RNA can function as a structuralelement and a nucleator of nuclear bodies. Wefind that several types of coding and noncodingRNAs are sufficient to de novo assemble, and arephysiologically enriched in, histone locus bodies(with associated Cajal bodies), nuclear speckles,paraspeckles and nuclear stress bodies.Formation of nuclear bodies occurs throughrecruitment and accumulation of proteinsresident in the nuclear bodies by nucleating RNA.These results demonstrate that transcription is adriving force in nuclear body formation and RNAtranscripts can function as a scaffold in theformation of major nuclear bodies. Together,these data suggest that RNA-primed biogenesisof nuclear bodies is a general principle of nuclear", "metadata": {}}
+{"_id": "19140422", "title": "", "text": "Evaluation of human papillomavirus testing inprimary screening for cervical abnormalities:comparison of sensitivity, specificity, andfrequency of referral.CONTEXT Humanpapillomavirus (HPV) DNA testing of womenhaving Papanicolaou (Pap) smears showingatypical squamous cells of undeterminedsignificance (ASCUS) has clinical usefulness.Whether HPV DNA testing alone is useful inprimary screening remains to be determined.OBJECTIVE To determine the accuracy of HPVDNA testing for detecting cervical intraepithelialneoplasia (CIN) grade 3 or cancer (the criterionstandard). DESIGN, SETTING, ANDPARTICIPANTS Between December 1997 andOctober 2000, 4075 women who attendedPlanned Parenthood clinics in Washington Statewere screened simultaneously using thin-layerPap and HPV DNA testing by a polymerase chainreaction (PCR)-based method and by aliquid-based RNA-DNA hybridization capture withsignal amplification assay (signal amplification).", "metadata": {}}
+{"_id": "19149247", "title": "", "text": "Breaking the chains: structure and function ofthe deubiquitinasesUbiquitylation is a reversibleprotein modification that is implicated in manycellular functions. Recently, much progress hasbeen made in the characterization of asuperfamily of isopeptidases that removeubiquitin: the deubiquitinases (DUBs; also knownas deubiquitylating or deubiquitinatingenzymes). Far from being uniform in structureand function, these enzymes display a myriad ofdistinct mechanistic features. The small number(<100) of DUBs might at first suggest a lowdegree of selectivity; however, DUBs are subjectto multiple layers of regulation that modulateboth their activity and their specificity. Due totheir wide-ranging involvement in key regulatoryprocesses, these enzymes might provide newtherapeutic targets.", "metadata": {}}
+{"_id": "19165076", "title": "", "text": "Replication protein A: a heterotrimeric,single-stranded DNA-binding protein required foreukaryotic DNA metabolism.Replication protein A[RPA; also known as replication factor A (RFA)and human single-stranded DNA-binding protein]is a single-stranded DNA-binding protein that isrequired for multiple processes in eukaryoticDNA metabolism, including DNA replication, DNArepair, and recombination. RPA homologues havebeen identified in all eukaryotic organismsexamined and are all abundant heterotrimericproteins composed of subunits of approximately70, 30, and 14 kDa. Members of this family bindnonspecifically to single-stranded DNA andinteract with and/or modify the activities ofmultiple proteins. In cells, RPA is phosphorylatedby DNA-dependent protein kinase when RPA isbound to single-stranded DNA (during S phaseand after DNA damage). Phosphorylation of RPAmay play a role in coordinating DNA metabolismin the cell. RPA may also have a role inmodulating gene expression.", "metadata": {}}
+{"_id": "19182166", "title": "", "text": "Internal fixation versus nonoperative treatmentof displaced 3-part proximal humeral fractures inelderly patients: a randomized controlledtrial.BACKGROUND The aim of the study was toreport the 2-year outcome after a displaced3-part fracture of the proximal humerus inelderly patients randomized to treatment with alocking plate or nonoperative treatment.PATIENTS AND METHODS We included 60patients, mean age 74 years (range, 56-92),81% being women. The main outcome measureswere the Constant and Disabilities of the Arm,Shoulder and Hand (DASH) scores and thehealth-related quality of life (HRQoL) accordingto the EQ-5D. RESULTS At the final 2-yearfollow-up, the results for range of motion (ROM),function and HRQoL were all in favor of thelocking plate group. The mean flexion in thelocking plate group was 120° compared to 111°in the nonoperative group (P = .36) and themean abduction was 114° compared to 106° (P= .28). The corresponding values for the", "metadata": {}}
+{"_id": "19185192", "title": "", "text": "Good and bad consequences of altered fatty acidmetabolism in heart failure: evidence frommouse models.The shift in substrate preferenceaway from fatty acid oxidation (FAO) towardsincreased glucose utilization in heart failure haslong been interpreted as an oxygen-sparingmechanism. Inhibition of FAO has thereforeevolved as an accepted approach to treat heartfailure. However, recent data indicate thatincreased reliance on glucose might bedetrimental rather than beneficial for the failingheart. This review discusses new insights intometabolic adaptations in heart failure. Aparticular focus lies on data obtained frommouse models with modulations of cardiac FAmetabolism at different levels of the FAmetabolic pathway and how these differentlyaffect cardiac function. Based on studies in whichthese mouse models were exposed to ischaemicand non-ischaemic heart failure, we discusswhether and when modulations in FA metabolismare protective against heart failure.", "metadata": {}}
+{"_id": "19204979", "title": "", "text": "Pericytes of human skeletal muscle are myogenicprecursors distinct from satellite cellsCellsderived from blood vessels of human skeletalmuscle can regenerate skeletal muscle, similarlyto embryonic mesoangioblasts. However, adultcells do not express endothelial markers, butinstead express markers of pericytes, such asNG2 proteoglycan and alkaline phosphatase(ALP), and can be prospectively isolated fromfreshly dissociated ALP+ cells. Unlike canonicalmyogenic precursors (satellite cells),pericyte-derived cells express myogenic markersonly in differentiated myotubes, which they formspontaneously with high efficiency. Whentransplanted into severe combined immunedeficient–X-linked, mouse muscular dystrophy(scid–mdx) mice, pericyte-derived cells colonizehost muscle and generate numerous fibresexpressing human dystrophin. Similar cellsisolated from Duchenne patients, and engineeredto express human mini-dystrophin, also give riseto many dystrophin-positive fibres in vivo. These", "metadata": {}}
+{"_id": "19205326", "title": "", "text": "Ten years' experience with alendronate forosteoporosis in postmenopausalwomen.BACKGROUND Antiresorptive agents arewidely used to treat osteoporosis. We report theresults of a multinational randomized,double-blind study, in which postmenopausalwomen with osteoporosis were treated withalendronate for up to 10 years. METHODS Theinitial three-year phase of the study comparedthree daily doses of alendronate with placebo.Women in the original placebo group receivedalendronate in years 4 and 5 and then weredischarged. Women in the originalactive-treatment groups continued to receivealendronate during the initial extension (years 4and 5). In two further extensions (years 6 and 7,and 8 through 10), women who had received 5mg or 10 mg of alendronate daily continued onthe same treatment. Women in thediscontinuation group received 20 mg ofalendronate daily for two years and 5 mg daily inyears 3, 4, and 5, followed by five years of", "metadata": {}}
+{"_id": "19205437", "title": "", "text": "UCP1-independent signaling involvingSERCA2b-mediated calcium cycling regulatesbeige fat thermogenesis and systemic glucosehomeostasisUncoupling protein 1 (UCP1) plays acentral role in nonshivering thermogenesis inbrown fat; however, its role in beige fat remainsunclear. Here we report a robustUCP1-independent thermogenic mechanism inbeige fat that involves enhanced ATP-dependentCa2+ cycling by sarco/endoplasmic reticulumCa2+-ATPase 2b (SERCA2b) and ryanodinereceptor 2 (RyR2). Inhibition of SERCA2b impairsUCP1-independent beige fat thermogenesis inhumans and mice as well as in pigs, a speciesthat lacks a functional UCP1 protein. Conversely,enhanced Ca2+ cycling by activation of α1-and/or β3-adrenergic receptors or theSERCA2b-RyR2 pathway stimulatesUCP1-independent thermogenesis in beigeadipocytes. In the absence of UCP1, beige fatdynamically expends glucose through enhancedglycolysis, tricarboxylic acid metabolism and", "metadata": {}}
+{"_id": "19255949", "title": "", "text": "Poly(A)-specific ribonuclease (PARN) mediates3′-end maturation of the telomerase RNAcomponentMutations in the PARN gene (encodingpoly(A)-specific ribonuclease) cause telomerediseases including familial idiopathic pulmonaryfibrosis (IPF) and dyskeratosis congenita, buthow PARN deficiency impairs telomeremaintenance is unclear. Here, using somatic cellsand induced pluripotent stem cells (iPSCs) frompatients with dyskeratosis congenita with PARNmutations, we show that PARN is required for the3′-end maturation of the telomerase RNAcomponent (TERC). Patient-derived cells as wellas immortalized cells in which PARN is disruptedshow decreased levels of TERC. Deep sequencingof TERC RNA 3′ termini shows that PARN isrequired for removal of post-transcriptionallyacquired oligo(A) tails that target nuclear RNAsfor degradation. Diminished TERC levels and theincreased proportion of oligo(A) forms of TERCare normalized by restoring PARN, which islimiting for TERC maturation in cells. Our results", "metadata": {}}
+{"_id": "19278208", "title": "", "text": "Folic acid supplementation and dietary folateintake, and risk ofpreeclampsiaBackground/Objectives:Folic acidsupplementation has been suggested to reducethe risk of preeclampsia. However, results fromfew epidemiologic studies have beeninconclusive. We investigated the hypothesis thatfolic acid supplementation and dietary folateintake before conception and during pregnancyreduce the risk of preeclampsia.Subjects/Methods:A birth cohort study wasconducted in 2010–2012 at the Gansu ProvincialMaternity & Child Care Hospital in Lanzhou,China. A total of 10 041 pregnant women withoutchronic hypertension or gestational hypertensionwere enrolled. Results:Compared with nonusers,folic acid supplement users had a reduced risk ofpreeclampsia (OR=0.61, 95% CI: 0.43–0.87). Asignificant dose–response of duration of use wasobserved among women who used folic acidsupplemention during pregnancy only(P-trend=0.007). The reduced risk associated", "metadata": {}}
+{"_id": "19293654", "title": "", "text": "Model-based Analysis of ChIP-Seq (MACS)Wepresent Model-based Analysis of ChIP-Seq data,MACS, which analyzes data generated by shortread sequencers such as Solexa's GenomeAnalyzer. MACS empirically models the shift sizeof ChIP-Seq tags, and uses it to improve thespatial resolution of predicted binding sites.MACS also uses a dynamic Poisson distribution toeffectively capture local biases in the genome,allowing for more robust predictions. MACScompares favorably to existing ChIP-Seqpeak-finding algorithms, and is freely available.", "metadata": {}}
+{"_id": "19307912", "title": "", "text": "Familial obesity and leanness.Using the PrincetonSchool District Family Study cohort, our specificaim was to estimate the prevalence of suspectedfamilial ponderosity and leanness, to provideempirical risk estimates for the proportion ofprobands' first-degree relatives who weresimilarly affected, and to estimate thecontributions of diseases, drugs and caloricintake to relative obesity and leanness. Westudied 379 probands, 125 whites and 52 blacksfrom a random recall group, 147 whites and 55blacks from a hyperlipidemic recall group.Suspected familial obesity and leanness werearbitrarily identified in those kindreds with atleast two first-degree relatives in the sameQuetelet index decile as the proband, top orbottom respectively. Suspected familial obesitywas observed in 2.4 percent and 6 percentrespectively of random and hyperlipidemic recallgroup whites. Suspected familial leanness wasidentified in 2.4 percent and 1.4 percent ofrandom and hyperlipidemic recall whites and in", "metadata": {}}
+{"_id": "19308127", "title": "", "text": "In-hospital switching of oral P2Y12 inhibitortreatment in patients with acute coronarysyndrome undergoing percutaneous coronaryintervention: prevalence, predictors andshort-term outcome.BACKGROUND P2Y12inhibitor switching has appeared in clinicalpractice as a consequence of prasugrel andticagrelor availability, apart from clopidogrel, foruse in patients with acute coronary syndrome(ACS) undergoing percutaneous coronaryintervention (PCI). METHODS In the context ofthe GReek AntiPlatelet REgistry (GRAPE) weassessed the prevalence, predictive factors andshort-term outcome of in-hospital P2Y12inhibitor switching in 1794 ACS patientsundergoing PCI. RESULTS Switching occurred in636 (35.5%) patients of which in the form ofclopidogrel to a novel agent, novel agent toclopidogrel and between prasugrel and ticagrelorin 574 (90.4%), 34 (5.3%) and 27 (4.3%)patients, respectively. Presentation to nonPCI-capable hospital, bivalirudin use, age ≥75", "metadata": {}}
+{"_id": "19313533", "title": "", "text": "Structural basis of allosteric and synergisticactivation of AMPK by furan-2-phosphonicderivative C2 binding.The metabolicstress-sensing enzyme AMP-activated proteinkinase (AMPK) is responsible for regulatingmetabolism in response to energy supply anddemand. Drugs that activate AMPK may beuseful in the treatment of metabolic diseasesincluding type 2 diabetes. We have determinedthe crystal structure of AMPK in complex with itsactivator5-(5-hydroxyl-isoxazol-3-yl)-furan-2-phosphonicacid (C2), revealing two C2-binding sites in theγ-subunit distinct from nucleotide sites. C2 actssynergistically with the drug A769662 to activateAMPK α1-containing complexes independent ofupstream kinases. Our results show that dualdrug therapies could be effective AMPK-targetingstrategies to treat metabolic diseases.", "metadata": {}}
+{"_id": "19315511", "title": "", "text": "Validity of age at menarche self-reported inadulthood.OBJECTIVE To test the validity of ageat menarche self-reported in adulthood andexamine whether socioeconomic position,education, experience of gynaecological eventsand psychological symptoms influence theaccuracy of recall. DESIGN Prospective birthcohort study. SETTING England, Scotland andWales. PARTICIPANTS 1050 women from theMedical Research Council National Survey ofHealth and Development, with two measures ofage at menarche, one recorded in adolescenceand the other self-reported at age 48 years.RESULTS By calculating the limits of agreement,kappa statistic and Pearson's correlationcoefficients (r), we found that the validity of ageat menarche self-reported in middle agecompared with that recorded in adolescence wasmoderate (kappa = 0.35, r = 0.66, n = 1050).Validity was improved by categorising age atmenarche into three groups: early, normal andlate (kappa = 0.43). Agreement was influenced", "metadata": {}}
+{"_id": "19327364", "title": "", "text": "Seroepidemiologic survey of captive Old-Worldprimates for antibodies to human and simianretroviruses, and isolation of a lentivirus fromsooty mangabeys (Cercocebus atys).Sera from526 Old-World monkeys and apes, representing50 species and 20 genera and living in US zoosand vivaria, were screened for antibodies toHTLV-I, HTLV-III/LAV, and simian-AIDSretrovirus, type I (SRV-I). Sera were screenedinitially by ELISA, and ELISA-positive sera, aswell as ELISA-negative sera from cage contacts,were further tested by Western blotting. A largenumber of false-positive and a small number offalse-negative ELISA sera were identified.Although most true positive reactions weredirected to a single retrovirus, a number ofindividuals from 4 species were positive for morethan one retrovirus. Specific seroreactivity toHTLV-I was found in 39/526 (7%) animals of 15species. True positive reactions to SRV-I werefound in 21/516 (4%) animals, includingtalapoins and 2 species of macaques. Specific", "metadata": {}}
+{"_id": "19332616", "title": "", "text": "Coronary plaque disruption.Coronaryatherosclerosis is by far the most frequent causeof ischemic heart disease, and plaque disruptionwith superimposed thrombosis is the main causeof the acute coronary syndromes of unstableangina, myocardial infarction, and suddendeath.1 2 3 4 5 Therefore, for event-freesurvival, the vital question is not whyatherosclerosis develops but rather why, afteryears of indolent growth, it suddenly becomescomplicated by life-threatening thrombosis. Thecomposition and vulnerability of plaque ratherthan its volume or the consequent severity ofstenosis produced have emerged as being themost important determinants for thedevelopment of the thrombus-mediated acutecoronary syndromes; lipid-rich and soft plaquesare more dangerous than collagen-rich and hardplaques because they are more unstable andrupture-prone and highly thrombogenic afterdisruption.6 This review will explore potentialmechanisms responsible for the sudden", "metadata": {}}
+{"_id": "19343151", "title": "", "text": "p16INK4A is a robust in vivo biomarker ofcellular aging in human skin.The cell-cycleregulating gene, p16INK4A, encoding an inhibitorof cyclin-dependent kinases 4 and 6, isconsidered to play an important role in cellularaging and in premature senescence. Althoughthere is an age-dependent increase of p16INK4Aexpression in human fibroblast senescence invitro, no data are available regarding the agedependency of p16INK4A in vivo. To determinewhether p16INK4A expression in human skincorrelates with donor age, p16INK4A expressionwas analyzed by immunohistochemistry as wellas the expression of the p16INK4A repressorBMI1. Samples from the age groups 0-20, 21-70,and 71-95 years were selected from a bank ofhealthy human skin. We show that the numberof p16INK4A positive cells is significantly higherin elderly individuals compared to the youngerage groups. The number of p16INK4A positivecells was found to be increased in both epidermisand dermis, compartments with strictly different", "metadata": {}}
+{"_id": "19356271", "title": "", "text": "hPrimpol1/CCDC111 is a human DNAprimase-polymerase required for themaintenance of genome integrity.Prim-pol is arecently identified DNA primase-polymerasebelonging to the archaeao-eukaryotic primase(AEP) superfamily. Here, we characterize apreviously unrecognized prim-pol in human cells,which we designate hPrimpol1 (humanprimase-polymerase 1). hPrimpol1 possessesprimase and DNA polymerase activities in vitro,interacts directly with RPA1 and is recruited tosites of DNA damage and stalled replication forksin an RPA1-dependent manner. Cells depleted ofhPrimpol1 display increased spontaneous DNAdamage and defects in the restart of stalledreplication forks. Both RPA1 binding and theprimase activity of hPrimpol1 are required for itscellular function during DNA replication. Ourresults indicate that hPrimpol1 is a novel factorinvolved in the response to DNA replicationstress.", "metadata": {}}
+{"_id": "19358586", "title": "", "text": "Functional proteomics identifies miRNAs to targeta p27/Myc/phospho-Rb signature in breast andovarian cancerThe myc oncogene isoverexpressed in almost half of all breast andovarian cancers, but attempts at therapeuticinterventions against myc have proven to bechallenging. Myc regulates multiple biologicalprocesses, including the cell cycle, and as such isassociated with cell proliferation and tumorprogression. We identified a protein signature ofhigh myc, low p27 and high phospho-Rbsignificantly correlated with poor patient survivalin breast and ovarian cancers. Screening of amiRNA library by functional proteomics inmultiple cell lines and integration of data frompatient tumors revealed a panel of fivemicroRNAs (miRNAs) (miR-124, miR-365,miR-34b*, miR-18a and miR-506) as potentialtumor suppressors capable of reversing thep27/myc/phospho-Rb protein signature.Mechanistic studies revealed an RNA-activationfunction of miR-124 resulting in direct induction", "metadata": {}}
+{"_id": "19368793", "title": "", "text": "The potential role of miRNAs 21 and 199-a inearly diagnosis of hepatocellularcarcinoma.BACKGROUND Hepatocellularcarcinoma (HCC) is regarded as one of the mostcommon malignancies and among the leadingcauses of cancer death among the whole world.The most urgent needs are to find sensitivemarkers for early diagnosis for HCC. MicroRNAs(miRNAs) are reported as a group of smallnon-coding RNAs that can function asendogenous RNA interference to regulateexpression of the targeted genes. This study wasconducted to detect the serum and tissueexpression of miR 21 and miR 199-a to beapplied as early detectors for HCC. METHODS Atotal of 40 serum and tissue samples (17samples from chronic hepatitis and 23 samplesfrom HCC patients) were collected. The levels ofthe two mature miRNAs (miR-21 and miR-199-a)were detected by real time quantitativereverse-transcriptase PCR (RT-qPCR) in sera andtissues of chronic hepatitis and HCC patients.", "metadata": {}}
+{"_id": "19384430", "title": "", "text": "Tex10 Coordinates Epigenetic Control ofSuper-Enhancer Activity in Pluripotency andReprogramming.Super-enhancers (SEs) arelarge clusters of transcriptional enhancers thatare co-occupied by multiple lineage-specifictranscription factors driving expression of genesthat define cell identity. In embryonic stem cells(ESCs), SEs are highly enriched for the corepluripotency factors Oct4, Sox2, and Nanog. Inthis study, we sought to dissect the molecularcontrol mechanism of SE activity in pluripotencyand reprogramming. Starting from a proteininteraction network surrounding Sox2, weidentified Tex10 as a key pluripotency factor thatplays a functionally significant role in ESCself-renewal, early embryo development, andreprogramming. Tex10 is enriched at SEs in aSox2-dependent manner and coordinates histoneacetylation and DNA demethylation at SEs.Tex10 activity is also important for pluripotencyand reprogramming in human cells. Our studytherefore highlights Tex10 as a core component", "metadata": {}}
+{"_id": "19408393", "title": "", "text": "Value of whole brain re-irradiation for brainmetastases--single centre experience.AIMSThere is controversy in published studiesregarding the role of repeat whole brain radiation(WBRT) for previously irradiated brainmetastases. The aim of our retrospective studywas to document the practice at PrincessMargaret Hospital with respect to there-irradiation of patients with progressive orrecurrent brain metastatic disease after initialWBRT. MATERIALS AND METHODS Acomprehensive computerised database was usedto identify patients treated for brain metastaseswith more than one course of WBRT between1997 and 2003. Seventy-two patients weretreated with WBRT for brain metastases andretreated with WBRT at a later date. The recordsof these patients were reviewed. RESULTS Themedian age was 56.5 years. The most commonprimary sites were lung (51 patients) and breast(17 patients). The most frequent dose used forthe initial radiotherapy was 20 Gy/5 fractions (62", "metadata": {}}
+{"_id": "19419439", "title": "", "text": "Bisphosphonates in oncology: rising stars orfallen heroes.The introduction ofbisphosphonates in oncology has dramaticallychanged the management of patients withmetastatic bone disease. In this manuscript, wethoroughly scrutinize the available body ofclinical trials supporting the use ofbisphosphonates in this setting and review newand ongoing research. Additionally, wesummarize the data showing the benefits ofbisphosphonate use in the prevention oftreatment-induced bone loss and the intriguingemerging evidence on the antitumor potential ofsome of these agents when used in the adjuvantsetting. Finally, we address the need for a carefulconsideration of potential benefits ofbisphosphonate therapy and the risk forosteonecrosis of the jaw, a recently recognizedlate-toxicity of their use.", "metadata": {}}
+{"_id": "19427410", "title": "", "text": "IL-33, a recently identified interleukin-1 genefamily member, is expressed in humanadipocytes.Inflammation occurs in adipose tissuein obesity. We have examined whether IL-33, arecently identified IL-1 gene family member, andits associated receptors are expressed in humanadipocytes. IL-33, IL-1RL1 and IL-1RAP geneexpression was observed in human visceral whitefat, in preadipocytes and in adipocytes (SGBScells). Treatment with TNFalpha for 24h induceda 6-fold increase in IL-33 mRNA level inpreadipocytes and adipocytes. Time-coursestudies with adipocytes showed that the increasein IL-33 mRNA with TNFalpha was maximal(>55-fold) at 12h. This response was markedlydifferent to IL-1beta (peak mRNA increase at 2h;5.4-fold) and 1L-18 (peak mRNA increase at 6h;>1500-fold). Exposure of adipocytes to hypoxia(1% O(2), 24h) did not alter IL-33 mRNA level;in preadipocytes, however, there was a 3-foldincrease. Human adipocytes and preadipocytesexpress IL-33, but the various IL-1 family", "metadata": {}}
+{"_id": "19450341", "title": "", "text": "Imaging techniques for assaying lymphocyteactivation in actionImaging techniques havegreatly improved our understanding oflymphocyte activation. Technical advances inspatial and temporal resolution and new labellingtools have enabled researchers to directlyobserve the activation process. Consequently,research using imaging approaches to studylymphocyte activation has expanded, providingan unprecedented level of cellular and moleculardetail in the field. As a result, certain models oflymphocyte activation have been verified, othershave been revised and yet others have beenreplaced with new concepts. In this article, wereview the current imaging techniques that areused to assess lymphocyte activation in differentcontexts, from whole animals to singlemolecules, and discuss the advantages andpotential limitations of these methods.", "metadata": {}}
+{"_id": "19460822", "title": "", "text": "Extending healthy life span--from yeast tohumans.When the food intake of organisms suchas yeast and rodents is reduced (dietaryrestriction), they live longer than organisms feda normal diet. A similar effect is seen when theactivity of nutrient-sensing pathways is reducedby mutations or chemical inhibitors. In rodents,both dietary restriction and decreasednutrient-sensing pathway activity can lower theincidence of age-related loss of function anddisease, including tumors andneurodegeneration. Dietary restriction alsoincreases life span and protects against diabetes,cancer, and cardiovascular disease in rhesusmonkeys, and in humans it causes changes thatprotect against these age-related pathologies.Tumors and diabetes are also uncommon inhumans with mutations in the growth hormonereceptor, and natural genetic variants innutrient-sensing pathways are associated withincreased human life span. Dietary restrictionand reduced activity of nutrient-sensing", "metadata": {}}
+{"_id": "19464037", "title": "", "text": "Hospital and 1-year survival of patients admittedto intensive care units with acute exacerbation ofchronic obstructive pulmonarydisease.OBJECTIVE To describe outcomes andidentify variables associated with hospital and1-year survival for patients admitted to anintensive care unit (ICU) with an acuteexacerbation of chronic obstructive pulmonarydisease (COPD). DESIGN Prospective,multicenter, inception cohort study. SETTINGForty-two ICUs at 40 US hospitals. PATIENTS Atotal of 362 admissions for COPD exacerbationselected from the Acute Physiology and ChronicHealth Evaluation (APACHE) III database of17,440 ICU admissions. MEASUREMENTS ANDRESULTS Hospital mortality for the 362admissions was 24%. For the 167 patients aged65 years or older, mortality was 30% at hospitaldischarge, 41% at 90 days, 47% at 180 days,and 59% at 1 year. Median survival for allpatients was 224 days, and median survival forthe patients who died within 1 year was 30.5", "metadata": {}}
+{"_id": "19482914", "title": "", "text": "Kindlin-3 is essential for integrin activation andplatelet aggregationIntegrin-mediated plateletadhesion and aggregation are essential forsealing injured blood vessels and preventingblood loss, and excessive platelet aggregationcan initiate arterial thrombosis, causing heartattacks and stroke. To ensure that plateletsaggregate only at injury sites, integrins oncirculating platelets exist in a low-affinity stateand shift to a high-affinity state (in a processknown as integrin activation or priming) aftercontacting a wounded vessel. The shift ismediated through binding of the cytoskeletalprotein Talin to the β subunit cytoplasmic tail.Here we show that platelets lacking the adhesionplaque protein Kindlin-3 cannot activate integrinsdespite normal Talin expression. As a directconsequence, Kindlin-3 deficiency results insevere bleeding and resistance to arterialthrombosis. Mechanistically, Kindlin-3 candirectly bind to regions of β-integrin tails distinctfrom those of Talin and trigger integrin", "metadata": {}}
+{"_id": "19485243", "title": "", "text": "Opening of compacted chromatin by earlydevelopmental transcription factors HNF3 (FoxA)and GATA-4.The transcription factors HNF3(FoxA) and GATA-4 are the earliest known tobind the albumin gene enhancer in liverprecursor cells in embryos. To understand howthey access sites in silent chromatin, weassembled nucleosome arrays containingalbumin enhancer sequences and compactedthem with linker histone. HNF3 and GATA-4, butnot NF-1, C/EBP, and GAL4-AH, bound their sitesin compacted chromatin and opened the localnucleosomal domain in the absence ofATP-dependent enzymes. The ability of HNF3 toopen chromatin is mediated by a high affinityDNA binding site and by the C-terminal domainof the protein, which binds histones H3 and H4.Thus, factors that potentiate transcription indevelopment are inherently capable of initiatingchromatin opening events.", "metadata": {}}
+{"_id": "19485649", "title": "", "text": "N- and E-cadherins in Xenopus are specificallyrequired in the neural and non-neural ectoderm,respectively, for F-actin assembly andmorphogenetic movements.Transmembranecadherins are calcium-dependent intercellularadhesion molecules. Recently, they have alsobeen shown to be sites of actin assembly duringadhesive contact formation. However, the rolesof actin assembly on transmembrane cadherinsduring development are not fully understood. Weshow here, using the developing ectoderm of theXenopus embryo as a model, that F-actinassembly is a primary function of bothN-cadherin in the neural ectoderm andE-cadherin in the non-neural (epidermal)ectoderm, and that each cadherin is essential forthe characteristic morphogenetic movements ofthese two tissues. However, depletion ofN-cadherin and E-cadherin did not causedissociation in these tissues at the neurula stage,probably owing to the expression of C-cadherinin each tissue. Depletion of each of these", "metadata": {}}
+{"_id": "19487477", "title": "", "text": "Mutation of the fumarase gene in two siblingswith progressive encephalopathy and fumarasedeficiency.We report an inborn error of thetricarboxylic acid cycle, fumarase deficiency, intwo siblings born to first cousin parents. Theypresented with progressive encephalopathy,dystonia, leucopenia, and neutropenia. Elevationof lactate in the cerebrospinal fluid and highfumarate excretion in the urine led us toinvestigate the activities of the respiratory chainand of the Krebs cycle, and to finally identifyfumarase deficiency in these two children. Thedeficiency was profound and present in alltissues investigated, affecting the cytosolic andthe mitochondrial fumarase isoenzymes to thesame degree. Analysis of fumarase cDNAdemonstrated that both patients werehomozygous for a missense mutation, aG-955-->C transversion, predicting aGlu-319-->Gln substitution. This substitutionoccurred in a highly conserved region of thefumarase cDNA. Both parents exhibited half the", "metadata": {}}
+{"_id": "19489351", "title": "", "text": "Adult Neurogenesis Is Sustained by SymmetricSelf-Renewal and Differentiation.Somatic stemcells have been identified in multiple adulttissues. Whether self-renewal occurssymmetrically or asymmetrically is key tounderstanding long-term stem cell maintenanceand generation of progeny for cell replacement.In the adult mouse brain, neural stem cells(NSCs) (B1 cells) are retained in the walls of thelateral ventricles (ventricular-subventricular zone[V-SVZ]). The mechanism of B1 cell retentioninto adulthood for lifelong neurogenesis isunknown. Using multiple clonal labelingtechniques, we show that the vast majority of B1cells divide symmetrically. Whereas 20%-30%symmetrically self-renew and can remain in theniche for several months before generatingneurons, 70%-80% undergo consuming divisionsgenerating progeny, resulting in the depletion ofB1 cells over time. This cellular mechanismdecouples self-renewal from the generation ofprogeny. Limited rounds of symmetric", "metadata": {}}
+{"_id": "19497526", "title": "", "text": "A common missense variant in NUDT15 conferssusceptibility to thiopurine-inducedleukopeniaThiopurine therapy, commonly used inautoimmune conditions, can be complicated bylife-threatening leukopenia. This leukopenia isassociated with genetic variation in TPMT(encoding thiopurine S-methyltransferase).Despite a lower frequency of TPMT mutations inAsians, the incidence of thiopurine-inducedleukopenia is higher in Asians than in individualsof European descent. Here we performed anImmunochip-based 2-stage association study in978 Korean subjects with Crohn's disease treatedwith thiopurines. We identified a nonsynonymousSNP in NUDT15 (encoding p. Arg139Cys) thatwas strongly associated with thiopurine-inducedearly leukopenia (odds ratio (OR) = 35.6;Pcombined = 4.88 × 10−94). In Koreans, thisvariant demonstrated sensitivity and specificityof 89.4% and 93.2%, respectively, forthiopurine-induced early leukopenia (incomparison to 12.1% and 97.6% for TPMT", "metadata": {}}
+{"_id": "19510470", "title": "", "text": "Induction of cell cycle entry eliminates humanleukemia stem cells in a mouse model ofAMLCancer stem cells have been proposed to beimportant for initiation, maintenance andrecurrence of various malignancies, includingacute myeloid leukemia (AML). We havepreviously reported that CD34+CD38− humanprimary AML stem cells residing in the endostealregion of the bone marrow are relativelychemotherapy resistant. Using aNOD/SCID/IL2rγnull mouse model of humanAML, we now show that the AML stem cells in theendosteal region are cell cycle quiescent and thatthese stem cells can be induced to enter the cellcycle by treatment with granulocytecolony-stimulating factor (G-CSF). Incombination with cell cycle-dependentchemotherapy, G-CSF treatment significantlyenhances induction of apoptosis and eliminationof human primary AML stem cells in vivo. Thecombination therapy leads to significantlyincreased survival of secondary recipients after", "metadata": {}}
+{"_id": "19511011", "title": "", "text": "Reconstitution of the immune system afterhematopoietic stem cell transplantation inhumansHematopoietic stem cell transplantationis associated with a severe immune deficiency.As a result, the patient is at high risk ofinfections. Innate immunity, including epithelialbarriers, monocytes, granulocytes, and NK cellsrecovers within weeks after transplantation. Bycontrast, adaptive immunity recovers muchslower. B- and T-cell counts normalize during thefirst months after transplantation, but inparticular, T-cell immunity may remain impairedfor years. During the last decade, much of theunderlying mechanisms have been identified.These insights may provide new therapies toaccelerate recovery.", "metadata": {}}
+{"_id": "19521501", "title": "", "text": "Vision tests in the mouse: Functionalphenotyping withelectroretinography.Electroretinography (ERG) isan established diagnostic technique in clinicalophthalmology and provides objectiveinformation about retinal function. This techniqueis also applied in basic research, where animalmodels of hereditary retinopathies havesignificantly contributed to our understanding ofthe composition of ERG responses in general andhow retinal degenerative pathologies alter retinalfunction specifically. Indeed, electrophysiologicassessment of transgenic mice, which aregenetically engineered to mimic humanmutations that lead to retinal diseases, can bewell compared with clinical data. Furthermore,limitations on examinations (e.g. length ofmeasurement, range of light intensity) are muchless of a concern when assessing mice comparedto human patients. In order to measure andanalyze retinal responses properly, severalimportant aspects have to be considered. This", "metadata": {}}
+{"_id": "19522248", "title": "", "text": "Cyclin-dependent kinase 2 is essential formeiosis but not for mitotic cell division in miceWetargeted the locus encoding the cyclin-dependentkinase 2 (CDK2) by homologous recombinationin mouse embryonic stem (ES) cells. Embryonicfibroblasts lacking CDK2 proliferate normally andbecome immortal after continuous passage inculture. Elimination of a conditional Cdk2 allele inimmortal cells does not have a significant effecton proliferation. Cdk2−/− mice are viable andsurvive for up to two years, indicating that CDK2is also dispensable for proliferation and survivalof most cell types. But CDK2 is essential forcompletion of prophase I during meiotic celldivision in male and female germ cells, anunforeseen role for this cell cycle kinase.", "metadata": {}}
+{"_id": "19529370", "title": "", "text": "Capsaicin-sensitive sensory nerve fiberscontribute to the generation and maintenance ofskeletal fracture pain.Although skeletal pain canhave a marked impact on a patient's functionalstatus and quality of life, relatively little is knownabout the specific populations of peripheral nervefibers that drive non-malignant bone pain. In thepresent report, neonatal male Sprague-Dawleyrats were treated with capsaicin or vehicle andfemoral fracture was produced when the animalswere young adults (15-16 weeks old). Capsaicintreatment, but not vehicle, resulted in asignificant (>70%) depletion in the density ofcalcitonin-gene related peptide positive(CGRP(+)) sensory nerve fibers, but not 200 kDaneurofilament H positive (NF200(+)) sensorynerve fibers in the periosteum. The periosteum isa thin, cellular and fibrous tissue that tightlyadheres to the outer surface of all but thearticulated surface of bone and appears to play apivotal role in driving fracture pain. In animalstreated with capsaicin, but not vehicle, there was", "metadata": {}}
+{"_id": "19532163", "title": "", "text": "Surgical therapy for dystonia.Surgical treatmentsfor dystonia have been available since the early20th century, but have improved in their efficacyto adversity ratio through a combination oftechnologic advances and better understandingof the role of the basal ganglia in dystonia. Theword \"dystonia\" describes a phenotype ofinvoluntary movement that may manifest from avariety of conditions. Dystonia may affect onlycertain regions of the body or may begeneralized. It appears to be critical todetermine whether the etiology underlying thedystonia is \"primary\" (ie, occurring from agenetic or idiopathic origin) or \"secondary\" (ie,occurring as a result of structural, metabolic, orneurodegenerative disorders). Secondarydystonias are far more common than primarydystonias. Primary dystonias respond well topallidotomy or deep brain stimulation of theinternal segment of the globus pallidum, whereassecondary dystonias appear to respond partiallyat best. Limited historic and current data suggest", "metadata": {}}
+{"_id": "19541444", "title": "", "text": "MEG3 imprinted gene contribution intumorigenesis.Maternally expressed gene 3(MEG3) is a maternally expressed imprintedgene representing a large noncoding RNA inwhich microRNAs (miRNAs) and small nucleolarRNAs are also hosted. It is capable of interactingwith cyclic AMP, p53, murine double minute 2(MDM2) and growth differentiation factor 15(GDF15) playing a role in cell proliferationcontrol. MEG3 expression is under epigeneticcontrol, and aberrant CpG methylation has beenobserved in several types of cancer. Moreover,gene copy number loss has been reported asadditional mechanism associated withtumorigenesis. MEG3 deletion seems toupregulate the paternally expressed genes andon the other hand downregulate the expressionof downstream maternally expressed genes andtumor suppressor miRNAs, although there areconflicting data on the topic. MEG3 couldrepresent a tumor suppressor gene located inchromosome 14q32 and its association with", "metadata": {}}
+{"_id": "19546104", "title": "", "text": "Uptake of rosuvastatin by isolated rathepatocytes: comparison with pravastatin.1. Theliver is the target organ for the lipid-regulatingeffect of rosuvastatin, a new3-hydroxy-3-methylglutaryl coenzyme Areductase inhibitor, and liver-selective uptake ofthis drug is therefore a desirable property. Theuptake kinetics of rosuvastatin were investigatedand compared with those of pravastatin usingisolated rat hepatocytes. 2. Uptake for bothdrugs involved both active transport and passivediffusion processes. The Michaelis constant(K(m)) of uptake rate for rosuvastatin (9.17micro M) was approximately half that forpravastatin (16.5 micro M). However, themaximum uptake rate (V(max)) andcarrier-mediated uptake clearance(V(max)/K(m)) of rosuvastatin were significantly(p < 0.01) greater than those of pravastatin, anda larger contribution of carrier-mediated uptakeclearance to total uptake clearance was shownfor rosuvastatin (contribution ratio 0.903 versus", "metadata": {}}
+{"_id": "19561411", "title": "", "text": "Junctophilin-4, a component of the endoplasmicreticulum-plasma membrane junctions, regulatesCa2+ dynamics in T cells.Orai1 and stromalinteraction molecule 1 (STIM1) mediatestore-operated Ca(2+) entry (SOCE) in immunecells. STIM1, an endoplasmic reticulum (ER)Ca(2+) sensor, detects store depletion andinteracts with plasma membrane (PM)-residentOrai1 channels at the ER-PM junctions. However,the molecular composition of these junctions in Tcells remains poorly understood. Here, we showthat junctophilin-4 (JP4), a member of junctionalproteins in excitable cells, is expressed in T cellsand localized at the ER-PM junctions to regulateCa(2+) signaling. Silencing or geneticmanipulation of JP4 decreased ER Ca(2+)content and SOCE in T cells, impaired activationof the nuclear factor of activated T cells (NFAT)and extracellular signaling-related kinase (ERK)signaling pathways, and diminished expressionof activation markers and cytokines.Mechanistically, JP4 directly interacted with", "metadata": {}}
+{"_id": "19565018", "title": "", "text": "The PI3K inhibitor arsenal: choose yourweapon!Owing to its widespread activation ininflammation and cancer, a growing appreciationof the therapeutic potential of inhibitors of thephosphoinositide 3-kinase (PI3K) pathway hasstimulated intense interest in compounds withsuitable pharmacological profiles. These areprimarily directed toward PI3K itself. However,as class I PI3Ks are also essential for a range ofnormal physiological processes, broad spectrumPI3K inhibition could be poorly tolerated. Inrecent years, patents describing a newgeneration of PI3K inhibitors have started toappear, with a particular focus on thedevelopment of compounds with enhancedisoform selectivity for use as anti-cancer andanti-inflammatory therapies. However,challenges remain for the efforts topharmacologically target this enzyme family in asuccessful manner.", "metadata": {}}
+{"_id": "19571273", "title": "", "text": "Infralimbic BDNF/TrkB enhancement of GluN2Bcurrents facilitates extinction of acocaine-conditioned placepreference.Brain-derived neurotrophic factor(BDNF) regulates synaptic activity andbehavioral flexibility, and reduction of BDNFstrongly predicts psychiatric disorders andcognitive dysfunction. Restoration ofBDNF-dependent activity could alleviate theseimpairments, but BDNF has limited clinical utilitydue to its pharmacokinetics. Here wedemonstrate that activation of a primary BDNFtarget, the tropomyosin-related kinase B (TrkB)receptor, enhances the amplitude and prolongsthe decay kinetics of N-methyl-d-aspartatereceptor (NMDAR) currents in male ratinfralimbic prefrontal pyramidal neurons.Moreover, these effects were prevented andreversed by blockade of NMDARs containing theGluN2B subunit. Our results show that thissignaling cascade bidirectionally regulatesextinction of a cocaine-induced conditioned place", "metadata": {}}
+{"_id": "19572798", "title": "", "text": "Compaction of chromatin by diverse Polycombgroup proteins requires localized regions of highcharge.Polycomb group (PcG) proteins arerequired for the epigenetic maintenance ofdevelopmental genes in a silent state. Proteins inthe Polycomb-repressive complex 1 (PRC1) classof the PcG are conserved from flies to humansand inhibit transcription. One hypothesis forPRC1 mechanism is that it compacts chromatin,based in part on electron microscopyexperiments demonstrating that Drosophila PRC1compacts nucleosomal arrays. We show that thisfunction is conserved between Drosophila andmouse PRC1 complexes and requires a regionwith an overrepresentation of basic amino acids.While the active region is found in the PosteriorSex Combs (PSC) subunit in Drosophila, it isunexpectedly found in a different PRC1 subunit,a Polycomb homolog called M33, in mice. Weprovide experimental support for the generalimportance of a charged region by predicting thecompacting capability of PcG proteins from", "metadata": {}}
+{"_id": "19583924", "title": "", "text": "Angiopoietin-like proteins stimulate ex vivoexpansion of hematopoietic stem cellsSuccessfulex vivo expansion of hematopoietic stem cells(HSCs) would greatly benefit the treatment ofdisease and the understanding of crucialquestions of stem cell biology. Here we show,using microarray studies, that theHSC-supportive mouse fetal liver CD3+ cellsspecifically express the proteins angiopoietin-like2 (Angptl2) and angiopoietin-like 3 (Angptl3).We observed a 24- or 30-fold net expansion oflong-term HSCs by reconstitution analysis whenwe cultured highly enriched HSCs for 10 days inthe presence of Angptl2 or Angptl3 together withsaturating levels of other growth factors. Thecoiled-coil domain of Angptl2 was capable ofstimulating expansion of HSCs. Furthermore,angiopoietin-like 5, angiopoietin-like 7 andmicrofibril-associated glycoprotein 4 alsosupported expansion of HSCs in culture.", "metadata": {}}
+{"_id": "19603353", "title": "", "text": "Balancing co-stimulation and inhibition with BTLAand HVEMThe interaction between B- andT-lymphocyte attenuator (BTLA), an inhibitoryreceptor whose extracellular domain belongs tothe immunoglobulin superfamily, andherpesvirus-entry mediator (HVEM), aco-stimulatory tumour-necrosis factor receptor,is unique in that it is the only receptor–ligandinteraction that directly bridges these twofamilies of receptors. This interaction has raisedmany questions about how receptors from twodifferent families could interact and whatdownstream signalling events might occur as aresult of receptor ligation. As we discuss, recentstudies show that engagement of HVEM with itsendogenous ligand (LIGHT) from thetumour-necrosis factor family induces a powerfulimmune response, whereas HVEM interactionswith BTLA negatively regulate T-cell responses.", "metadata": {}}
+{"_id": "19644821", "title": "", "text": "Lin28b is sufficient to drive liver cancer andnecessary for its maintenance in murinemodels.Lin28a/b are RNA-binding proteins thatinfluence stem cell maintenance, metabolism,and oncogenesis. Poorly differentiated,aggressive cancers often overexpress Lin28, butits role in tumor initiation or maintenance hasnot been definitively addressed. We report thatLIN28B overexpression is sufficient to initiatehepatoblastoma and hepatocellular carcinoma inmurine models. We also detected Lin28boverexpression in MYC-driven hepatoblastomas,and liver-specific deletion of Lin28a/b reducedtumor burden, extended latency, and prolongedsurvival. Both intravenous siRNA against Lin28band conditional Lin28b deletion reduced tumorburden and prolonged survival. Igf2bp proteinsare upregulated, and Igf2bp3 is required in thecontext of LIN28B overexpression to promotegrowth. Therefore, multiple murine modelsdemonstrate that Lin28b is both sufficient toinitiate liver cancer and necessary for its", "metadata": {}}
+{"_id": "19651306", "title": "", "text": "Nanoenzymology of the 20S proteasome:proteasomal actions are controlled by theallosteric transition.The proteasome is a majorcytosolic proteolytic assembly, essential for thephysiology of eukaryotic cells. Both thearchitecture and enzymatic properties of the 20Sproteasome are relatively well understood.However, despite longstanding interest, theintegration of structural and functional propertiesof the proteasome into a coherent modelexplaining the mechanism of its enzymaticactions has been difficult. Recently, we usedtapping mode atomic force microscopy (AFM) inliquid to demonstrate that the alpha-rings of theproteasome imaged in a top-view positionrepeatedly switched between their open andclosed conformations, apparently to controlaccess to the central channel. Here, we showwith AFM that the molecules in a side-viewposition acquired two stable conformations. Theoverall shapes of the 20S particles wereclassified as either barrel-like or cylinder-like.", "metadata": {}}
+{"_id": "19658917", "title": "", "text": "Changes in plasma copeptin, the c-terminalportion of arginine vasopressin during waterdeprivation and excess in healthysubjects.CONTEXT The measurement of argininevasopressin (AVP) is often cumbersome becauseit is unstable with a short half-life time. AVP isderived from a larger precursor peptide alongwith the more stable peptide copeptin. Copeptinis the C-terminal part of provasopressin and hasbeen shown to be a useful tool to indicate AVPconcentration in critically ill patients. OBJECTIVEThe objective of the study was to evaluate theclinical usefulness of copeptin as a new marker indisordered states of blood volume and plasmaosmolality. DESIGN AND SETTING This was aprospective observational study in a universityhospital. PARTICIPANTS AND MAIN OUTCOMEMEASURES Three techniques with respectivecontrol studies were used in 24 healthy adults toproduce changes in plasma osmolality and/orvolume: 1) a 28-h water deprivation, 2) a 17-hhypertonic saline infusion combined with", "metadata": {}}
+{"_id": "19661996", "title": "", "text": "Propagation and recovery of intact, infectiousEpstein-Barr virus from prokaryotic to humancells.With current techniques, genetic alterationsof herpesviruses are difficult to perform, mostlybecause of the large size of their genomes. Tosolve this problem, we have designed a systemthat allows the cloning of anygamma-herpesvirus in Escherichia coli onto an Ffactor-derived plasmid. Immortalized B cell lineswere readily established with recombinantEpstein-Barr virus (EBV), demonstrating that theF factor-cloned EBV genome has all thecharacteristics of wild-type EBV. Because anygenetic modification is possible in E. coli, thisexperimental approach opens the way to thegenetic analysis of all EBV functions. Moreover, itis now feasible to generate attenuated EBVstrains in vitro such that vaccine strains can bedesigned. Because we incorporated the genes forhygromycin resistance and green fluorescentprotein onto the E. coli cloned EBV genome, thestill open question of the EBV target cells other", "metadata": {}}
+{"_id": "19673227", "title": "", "text": "Chemosensitivity profile assay of circulatingcancer cells: prognostic and predictive value inepithelial tumors.The prognostic value associatedwith the detection of circulating tumor cells(CTCs) in metastatic breast cancer by theCellSearch technology raise additional issuesregarding the biological value of this information.We postulated that a drug-resistance profile ofCTCs may predict response to chemotherapy incancer patients and therefore could be used forpatient selection. One hundred 5 patients withdiagnosis of carcinoma were enrolled in aprospective trial. CTCs were isolated fromperipheral blood, and positive samples wereevaluated for the expression of a panel of genesinvolved in anticancer drugs resistance. Thedrug-resistance profile was correlated withdisease-free survival (DFS; patients in adjuvantsetting) and time to progression (TTP; metastaticpatients) in a 24-months follow-up. Objectiveresponse correlation was a secondary end point.Fifty-one percent of patients were found positive", "metadata": {}}
+{"_id": "19675911", "title": "", "text": "Trends in heart failure incidence and survival in acommunity-based population.CONTEXT Theepidemic of heart failure has yet to be fullyinvestigated, and data on incidence, survival,and sex-specific temporal trends incommunity-based populations are limited.OBJECTIVE To test the hypothesis that theincidence of heart failure has declined andsurvival after heart failure diagnosis hasimproved over time but that secular trends havediverged by sex. DESIGN, SETTING, ANDPARTICIPANTS Population-based cohort studyusing the resources of the RochesterEpidemiology Project conducted in OlmstedCounty, Minnesota. Patients were 4537 OlmstedCounty residents (57% women; mean [SD] age,74 [14] years) with a diagnosis of heart failurebetween 1979 and 2000. Framingham criteriaand clinical criteria were used to validate thediagnosis   MAIN OUTCOME MEASURESIncidence of heart failure and survival after heartfailure diagnosis. RESULTS The incidence of", "metadata": {}}
+{"_id": "19683625", "title": "", "text": "Doxycycline induces apoptosis in PANC-1pancreatic cancer cells.BACKGROUNDTetracyclines such as doxycycline are reported topossess cytotoxic activity against mammaliantumor cells, but the mechanism of their effectson cell proliferation remains unclear. MATERIALSAND METHODS The antitumor effect ofdoxycycline was investigated in humanpancreatic cancer cell line, PANC-1. We alsoinvestigated the effect of doxycycline onexpression of a potent proangiogenic factor,interleukin (IL)-8. RESULTS In excess of 20microg/ml, cytotoxic effects of doxycycline wereaccompanied by G(1)-S cell cycle arrest and DNAfragmentation in PANC-1 cells. Doxycyclineconsistently activated transcription of p53, p21and Fas/FasL-cascade-related genes, whilereducing the expression of Bcl-xL and Mcl-1.Doxycycline (5 microg/ml) below the cytotoxiclevel suppressed endogenous andpaclitaxel-induced IL-8 expression. In the mousexenograft model, doxycycline treatment was", "metadata": {}}
+{"_id": "19685306", "title": "", "text": "Orientationally invariant indices of axon diameterand density from diffusion MRI.This paperproposes and tests a technique for imagingorientationally invariant indices of axon diameterand density in white matter using diffusionmagnetic resonance imaging. Such indicespotentially provide more specific markers ofwhite matter microstructure than standardindices from diffusion tensor imaging.Orientational invariance allows for combinationwith tractography and presents newopportunities for mapping brain connectivity andquantifying disease processes. The techniqueuses a four-compartment tissue model combinedwith an optimized multishellhigh-angular-resolutionpulsed-gradient-spin-echo acquisition. We testthe method in simulation, on fixed monkeybrains using a preclinical scanner and on livehuman brains using a clinical 3T scanner. Thehuman data take about one hour to acquire. Thesimulation experiments show that both monkey", "metadata": {}}
+{"_id": "19688024", "title": "", "text": "IFI16 and cGAS cooperate in the activation ofSTING during DNA sensing in humankeratinocytesMany human cells can sense thepresence of exogenous DNA during infectionthough the cytosolic DNA receptor cyclicGMP-AMP synthase (cGAS), which produces thesecond messenger cyclic GMP-AMP (cGAMP).Other putative DNA receptors have beendescribed, but whether their functions areredundant, tissue-specific or integrated in thecGAS-cGAMP pathway is unclear. Here we showthat interferon-γ inducible protein 16 (IFI16)cooperates with cGAS during DNA sensing inhuman keratinocytes, as both cGAS and IFI16are required for the full activation of an innateimmune response to exogenous DNA and DNAviruses. IFI16 is also required for thecGAMP-induced activation of STING, andinteracts with STING to promote STINGphosphorylation and translocation. We proposethat the two DNA sensors IFI16 and cGAScooperate to prevent the spurious activation of", "metadata": {}}
+{"_id": "19701340", "title": "", "text": "Oncostatic effects of the indole melatonin andexpression of its cytosolic and nuclear receptorsin cultured human melanoma cell lines.Melatoninhas been shown to have oncostatic effects onmalignant melanoma in vitro and in vivo. Westudied the growth suppressive effects ofmelatonin over a wide range of concentrations infour melanoma cell lines (SBCE2, WM-98,WM-164 and SKMEL-188) representative fordifferent growth stages and phenotype.Melanoma cells were incubated with melatonin10(-12)-10(-3) M, and proliferation andclonogenicity was assessed at 12 h and 14 days,respectively. We also determined the expressionof cytosolic quinone oxidoreductases NQO1,NQO2 (known as MT3 receptor) and nuclearreceptor RORalpha by RT-PCR. Melatonin atpharmacological concentrations (10(-3)-10(-7)M) suppressed proliferation in all melanoma celllines. In SKMEL-188 cells cultured in serum-freemedia, melatonin at low concentrations(10(-12)-10(-10) M) also slightly attenuated the", "metadata": {}}
+{"_id": "19708993", "title": "", "text": "Lysosomal localization of TRPML3 depends onTRPML2 and the mucolipidosis-associated proteinTRPML1.Mucolipidosis type IV is an autosomalrecessive lysosomal storage disordercharacterized by severe neurodegeneration,achlorhydria, and visual impairments such ascorneal opacity and strabismus. The diseasearises due to mutations in a group 2 transientreceptor potential (TRP)-related cation channel,TRPML1. Mammals encode two additional TRPMLproteins named TRPML2 and TRPML3.Information regarding the propensity of theseproteins to multimerize, their subcellulardistribution and mechanisms that regulate theirtrafficking are limited. Here we demonstrate thatTRPMLs interact to form homo- andheteromultimers. Moreover, the presence ofeither TRPML1 or TRPML2 specifically influencesthe spatial distribution of TRPML3. TRPML1 andTRPML2 homomultimers are lysosomal proteins,whereas TRPML3 homomultimers are in theendoplasmic reticulum. However, TRPML3", "metadata": {}}
+{"_id": "19736671", "title": "", "text": "Evolution of metastasis revealed by mutationallandscapes of chemically induced skincancersHuman tumors show a high level ofgenetic heterogeneity, but the processes thatinfluence the timing and route of metastaticdissemination of the subclones are unknown.Here we have used whole-exome sequencing of103 matched benign, malignant and metastaticskin tumors from genetically heterogeneous miceto demonstrate that most metastasesdisseminate synchronously from the primarytumor, supporting parallel rather than linearevolution as the predominant model ofmetastasis. Shared mutations between primarycarcinomas and their matched metastases havethe distinct A-to-T signature of the initiatingcarcinogen dimethylbenzanthracene, butnon-shared mutations are primarily G-to-T, asignature associated with oxidative stress. Theexistence of carcinomas that either did or did notmetastasize in the same host animal suggeststhat there are tumor-intrinsic factors that", "metadata": {}}
+{"_id": "19752008", "title": "", "text": "A specific inhibitor of phosphatidylinositol3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002).Phosphatidylinositol(PtdIns) 3-kinase is an enzyme implicated ingrowth factor signal transduction by associatingwith receptor and nonreceptor tyrosine kinases,including the platelet-derived growth factorreceptor. Inhibitors of PtdIns 3-kinase couldpotentially give a better understanding of thefunction and regulatory mechanisms of theenzyme. Quercetin, a naturally occurringbioflavinoid, was previously shown to inhibitPtdIns 3-kinase with an IC50 of 1.3microgram/ml (3.8 microM); inhibition appearedto be directed at the ATP-binding site of thekinase. Analogs of quercetin were investigated asPtdIns 3-kinase inhibitors, with the most potentones exhibiting IC50 values in the range of1.7-8.4 micrograms/ml. In contrast, genistein, apotent tyrosine kinase inhibitor of the isoflavoneclass, did not inhibit PtdIns 3-kinase significantly(IC50 > 30 micrograms/ml). Since quercetin has", "metadata": {}}
+{"_id": "19756935", "title": "", "text": "A simple two-step protocol for the purification ofhuman pancreatic beta cellsIsolated pure humanbeta cells would be helpful for a number ofresearch purposes. However, lack of betacell-specific surface antigens has been a majorproblem. We aimed to develop a simple methodfor human beta cell isolation based on the initialelimination of ductal cells by their expression ofcarbohydrate antigen 19-9 (CA19-9), followed bypositive selection of beta cells by theirexpression of polysialic acid–neural cell adhesionmolecule (PSA-NCAM). Cell type-specificexpression of CA19-9, NCAM and PSA-NCAM wasstudied in sections of adult human pancreas andin cultured primary endocrine and exocrine cells.Dispersed human islet cells were purified in twosteps, after 4 days of suspension culture, bybinding to magnetic microbeads coupled toantibodies against CA19-9 and PSA-NCAM. NCAMexpression was detected in ducts and islets inthe human pancreas. In contrast, PSA-NCAMimmunoreactivity was detected only in islets.", "metadata": {}}
+{"_id": "19770974", "title": "", "text": "Prev | Table of Contents Reports EmbryonicStem Cell Lines Derived from HumanHumanblastocyst-derived, pluripotent cell lines aredescribed that have normal karyotypes, expresshigh levels of telomerase activity, and expresscell surface markers that characterize primateembryonic stem cells but do not characterizeother early lineages. After undifferentiatedproliferation in vitro for 4 to 5 months, thesecells still maintained the developmental potentialto form trophoblast and derivatives of all threeembryonic germ layers, including gut epithelium(endoderm); cartilage, bone, smooth muscle,and striated muscle (mesoderm); and neuralepithelium, embryonic ganglia, and stratifiedsquamous epithelium (ectoderm). These celllines should be useful in human developmentalbiology, drug discovery, and transplantationmedicine.", "metadata": {}}
+{"_id": "19799455", "title": "", "text": "Ascorbic-acid transporter Slc23a1 is essential forvitamin C transport into the brain and forperinatal survivalThe only proven requirementfor ascorbic acid (vitamin C) is in preventingscurvy, presumably because it is a cofactor forhydroxylases required for post-translationalmodifications that stabilize collagen. We havecreated mice deficient in the mouse ortholog(solute carrier family 23 member 1 or Slc23a1)of a rat ascorbic-acid transporter, Svct2 (ref. 4).Cultured embryonic fibroblasts from homozygousSlc23a1−/− mice had less than 5% of normalascorbic-acid uptake. Ascorbic-acid levels wereundetectable or markedly reduced in the bloodand tissues of Slc23a1−/− mice. Prenatalsupplementation of pregnant females did notelevate blood ascorbic acid in Slc23a1−/−fetuses, suggesting Slc23a1 is important inplacental ascorbic-acid transport. Slc23a1−/−mice died within a few minutes of birth withrespiratory failure and intraparenchymal brainhemorrhage. Lungs showed no postnatal", "metadata": {}}
+{"_id": "19800147", "title": "", "text": "MVP-mediated exosomal sorting of miR-193apromotes colon cancer progressionExosomes areemerging mediators of intercellularcommunication; whether the release ofexosomes has an effect on the exosome donorcells in addition to the recipient cells has notbeen investigated to any extent. Here, weexamine different exosomal miRNA expressionprofiles in primary mouse colon tumour, livermetastasis of colon cancer and naive colontissues. In more advanced disease, higher levelsof tumour suppressor miRNAs are encapsulatedin the exosomes. miR-193a interacts with majorvault protein (MVP). Knockout of MVP leads tomiR-193a accumulation in the exosomal donorcells instead of exosomes, inhibiting tumourprogression. Furthermore, miR-193a causes cellcycle G1 arrest and cell proliferation repressionthrough targeting of Caprin1, which upregulatesCcnd2 and c-Myc. Human colon cancer patientswith more advanced disease show higher levelsof circulating exosomal miR-193a. In summary,", "metadata": {}}
+{"_id": "19804204", "title": "", "text": "Casual blood pressure and neurocognitivefunction in children with chronic kidney disease:a report of the children with chronic kidneydisease cohort study.BACKGROUND ANDOBJECTIVES Children with chronic kidneydisease (CKD) are at risk for cognitivedysfunction, and over half have hypertension.Data on the potential contribution ofhypertension to CKD-associated neurocognitivedeficits in children are limited. Our objective wasto determine whether children with CKD andelevated BP (EBP) had decreased performanceon neurocognitive testing compared with childrenwith CKD and normal BP. DESIGN, SETTING,PARTICIPANTS, & MEASUREMENTS This was across-sectional analysis of the relation betweenauscultatory BP and neurocognitive testperformance in children 6 to 17 years enrolled inthe Chronic Kidney Disease in Children (CKiD)project. RESULTS Of 383 subjects, 132 (34%)had EBP (systolic BP and/or diastolic BP ≥90(th)percentile). Subjects with EBP had lower mean", "metadata": {}}
+{"_id": "19822046", "title": "", "text": "Bone marrow failure and developmental delaycaused by mutations in poly(A)-specificribonuclease (PARN).BACKGROUNDDeadenylation regulates RNA function and fate.Poly(A)-specific ribonuclease (PARN) is adeadenylase that processes mRNAs andnon-coding RNA. Little is known about thebiological significance of germline mutations inPARN. METHODS We identified mutations inPARN in patients with haematological andneurological manifestations. Genomic,biochemical and knockdown experiments inhuman marrow cells and in zebrafish have beenperformed to clarify the role of PARN in thehuman disease. RESULTS We identified largemonoallelic deletions in PARN in four patientswith developmental delay or mental illness. Onepatient in particular had a severe neurologicalphenotype, central hypomyelination and bonemarrow failure. This patient had an additionalmissense mutation on the non-deleted allele andseverely reduced PARN protein and", "metadata": {}}
+{"_id": "19824183", "title": "", "text": "The changing epidemiology of malaria in IfakaraTown, southern Tanzania.Between 1995 and2000 there were marked changes in theepidemiology of malaria in Ifakara, southernTanzania. We documented these changes usingparasitological and clinical data from a series ofcommunity- and hospital-based studies involvingchildren up to the age of 5 years. There was aright shift and lowering in the age-specificparasite prevalence in the community-basedcohort studies. The incidence of clinical malariain placebo-receiving infants in additional studycohorts dropped from 0.8 in 1995 to 0.43episodes per infant per year in 2000, anincidence rate ratio of 0.53 (95% confidenceinterval: 0.404, 0.70, P<0.0001). At the sametime, there was an increase in the total numberof malaria admissions and a marked right shift inthe age pattern of these admissions (median agein 1995 1.55 years vs. 2.33 in 2000, P<0.0001).However, the burden of malaria deaths remainedin infants. We discuss how these dramatic", "metadata": {}}
+{"_id": "19828689", "title": "", "text": "MicroRNA-192 in diabetic kidney glomeruli andits function in TGF-beta-induced collagenexpression via inhibition of E-box repressors.Keyfeatures of diabetic nephropathy (DN) includethe accumulation of extracellular matrix proteinssuch as collagen 1-alpha 1 and -2 (Col1a1 and-2). Transforming growth factor beta1(TGF-beta), a key regulator of these extracellularmatrix genes, is increased in mesangial cells(MC) in DN. By microarray profiling, we notedthat TGF-beta increased Col1a2 mRNA in mouseMC (MMC) but also decreased mRNA levels of anE-box repressor, deltaEF1. TGF-beta treatmentor short hairpin RNAs targeting deltaEF1increased enhancer activity of upstream E-boxelements in the Col1a2 gene. TGF-beta alsodecreased the expression of Smad-interactingprotein 1 (SIP1), another E-box repressor similarto deltaEF1. Interestingly, we noted that SIP1 isa target of microRNA-192 (miR-192), a key miRhighly expressed in the kidney. miR-192 levelsalso were increased by TGF-beta in MMC.", "metadata": {}}
+{"_id": "19843244", "title": "", "text": "Activation of PAR(2) receptors sensitizes primaryafferents and causes leukocyte rolling andadherence in the rat knee joint.BACKGROUNDAND PURPOSE The PAR(2) receptors are involvedin chronic arthritis by mechanisms that are asyet unclear. Here, we examined PAR(2)activation in the rat knee joint. EXPERIMENTALAPPROACH PAR(2) in rat knee joint dorsal rootganglia (DRG) cells at L3-L5, retrogradelylabelled with Fluoro-gold (FG) weredemonstrated immunohistochemically.Electrophysiological recordings from knee jointnerve fibres in urethane anaesthetized Wistarrats assessed the effects of stimulating jointPAR(2) with its activating peptide,2-furoyl-LIGRLO-NH(2) (1-100 nmol·100 μL(-1) ,via close intra-arterial injection). Fibre firing ratewas recorded during joint rotations before and15 min after administration of PAR(2) activatingpeptide or control peptide. Leukocyte kinetics inthe synovial vasculature upon PAR(2) activationwere followed by intravital microscopy for 60 min", "metadata": {}}
+{"_id": "19851614", "title": "", "text": "Polyphosphate kinase 1, a central node in thestress response network of Mycobacteriumtuberculosis, connects the two-componentsystems MprAB and SenX3-RegX3 and theextracytoplasmic function sigma factor, sigmaE.Polyphosphate (poly P) metabolism regulatesthe stress response in mycobacteria. Here wedescribe the regulatory architecture of a signaltransduction system involving thetwo-component system (TCS) SenX3-RegX3, theextracytoplasmic function sigma factor sigma E(SigE) and the poly P-synthesizing enzymepolyphosphate kinase 1 (PPK1). The ppk1promoter of Mycobacterium tuberculosis isactivated under phosphate starvation. This isattenuated upon deletion of an imperfectpalindrome likely representing a binding site forthe response regulator RegX3, a component ofthe two-component system SenX3-RegX3 thatresponds to phosphate starvation. Binding ofphosphorylated RegX3 to this site was confirmedby electrophoretic mobility shift assay. The", "metadata": {}}
+{"_id": "19854543", "title": "", "text": "Natural history of asymptomatic unrupturedcerebral aneurysms evaluated at CTangiography: growth and rupture incidence andcorrelation with epidemiologic riskfactors.PURPOSE To characterize the relationshipbetween aneurysm size and epidemiologic riskfactors with growth and rupture by usingcomputed tomographic (CT) angiography.MATERIALS AND METHODS In thisHIPAA-compliant, institutional review boardapproved study, patients with knownasymptomatic unruptured intracerebralaneurysms were followed up longitudinally withCT angiographic examinations. Growth wasdefined as an increase in one or moredimensions above the measurement error, andat least 5% volume by using the ABC/2 method.Associations of epidemiologic factors withaneurysm growth and rupture were analyzed byusing logistic regression analysis. Intra- andinterobserver agreement coefficients fordimension, volume, and growth were evaluated", "metadata": {}}
+{"_id": "19854744", "title": "", "text": "A search for the presence of the enteroviralcapsid protein VP1 in pancreases of patients withType 1 (insulin-dependent) diabetes andpancreases and hearts of infants who died ofcoxsackieviral myocarditisUsing an antiserumraised to a recombinant coxsackie virus B3capsid protein, VP1, an immunocytochemicaltechnique was developed which was capable ofdetecting the presence of all coxsackie B virusesin formalin fixed paraffin embedded infectedtissue culture cells. This technique was tested onautopsy heart and pancreas from 21 patientswho were thought to have died of acutecoxsackievirus B myocarditis. Cardiac myocyteswere positive for the VP1 protein in 12 of 20cases where the heart was available for study.Insulitis was present in the pancreas in seven ofthese cases and in all seven islet endocrine cellscontaining VP1 were found. VP1 was only rarelyfound in exocrine pancreas. In heart andpancreas, cells shown to contain VP1 usuallyshowed signs of necrosis. Autopsy pancreases", "metadata": {}}
+{"_id": "19855358", "title": "", "text": "Direct reprogramming of mouse fibroblasts tocardiomyocyte-like cells using Yamanaka factorson engineered poly(ethylene glycol) (PEG)hydrogels.Direct reprogramming strategiesenable rapid conversion of somatic cells tocardiomyocytes or cardiomyocyte-like cellswithout going through the pluripotent state. Arecently described protocol couples Yamanakafactor induction with pluripotency inhibitionfollowed by BMP4 treatment to achieve rapidreprogramming of mouse fibroblasts to beatingcardiomyocyte-like cells. The original study wasperformed using Matrigel-coated tissue culturepolystyrene (TCPS), a stiff material that alsonon-specifically adsorbs serum proteins. Proteinadsorption-resistant poly(ethylene glycol) (PEG)materials can be covalently modified to presentprecise concentrations of adhesion proteins orpeptides without the unintended effects ofnon-specifically adsorbed proteins. Here, wedescribe an improved protocol that incorporatescustom-engineered materials. We first", "metadata": {}}
+{"_id": "19878070", "title": "", "text": "Effects of risedronate treatment on vertebral andnonvertebral fractures in women withpostmenopausal osteoporosis: a randomizedcontrolled trial. Vertebral Efficacy WithRisedronate Therapy (VERT) StudyGroup.CONTEXT Risedronate, a potentbisphosphonate, has been shown to be effectivein the treatment of Paget disease of bone andother metabolic bone diseases but, to ourknowledge, it has not been evaluated in thetreatment of established postmenopausalosteoporosis. OBJECTIVE To test the efficacy andsafety of daily treatment with risedronate toreduce the risk of vertebral and other fractures inpostmenopausal women with establishedosteoporosis. DESIGN, SETTING, ANDPARTICIPANTS Randomized, double-blind,placebo-controlled trial of 2458 ambulatorypostmenopausal women younger than 85 yearswith at least 1 vertebral fracture at baseline whowere enrolled at 1 of 110 centers in NorthAmerica conducted between December 1993 and", "metadata": {}}
+{"_id": "19882228", "title": "", "text": "Hypoxia — a key regulatory factor in tumourgrowthCells undergo a variety of biologicalresponses when placed in hypoxic conditions,including activation of signalling pathways thatregulate proliferation, angiogenesis and death.Cancer cells have adapted these pathways,allowing tumours to survive and even growunder hypoxic conditions, and tumour hypoxia isassociated with poor prognosis and resistance toradiation therapy. Many elements of thehypoxia-response pathway are therefore goodcandidates for therapeutic targeting.", "metadata": {}}
+{"_id": "19912367", "title": "", "text": "Loss of fibronectin from the aged stem cell nicheaffects the regenerative capacity of skeletalmuscle in miceAge-related changes in the nichehave long been postulated to impair the functionof somatic stem cells. Here we demonstrate thatthe aged stem cell niche in skeletal musclecontains substantially reduced levels offibronectin (FN), leading to detrimentalconsequences for the function and maintenanceof muscle stem cells (MuSCs). Deletion of thegene encoding FN from young regeneratingmuscles replicates the aging phenotype andleads to a loss of MuSC numbers. By using anextracellular matrix (ECM) library screen andpathway profiling, we characterize FN as apreferred adhesion substrate for MuSCs anddemonstrate that integrin-mediated signalingthrough focal adhesion kinase and the p38mitogen-activated protein kinase pathway isstrongly de-regulated in MuSCs from aged micebecause of insufficient attachment to the niche.Reconstitution of FN levels in the aged niche", "metadata": {}}
+{"_id": "19922508", "title": "", "text": "Monitoring starvation-induced reactive oxygenspecies formation.Reactive oxygen species (ROS)are potentially harmful to cells because of theirability to oxidize cell constituents such as DNA,proteins, and lipids. However, at low levels, andunder tight control, this feature makes themexcellent modifiers in a variety of signaltransduction pathways, including autophagy.Autophagy was traditionally associated withoxidative stress, acting in the degradation ofoxidized proteins and organelles. Recently, asignaling role was suggested for ROS in theregulation of autophagy, leading, under differentcircumstances, either to survival or to death. Tostudy the effects of ROS on this pathway, onemust determine the localization, intensity,kinetics, and essentiality of the oxidative signalin autophagy. Moreover, once characterized,detection and manipulation of ROS formationcould be used to monitor and control autophagicactivity. In this chapter we discuss methods toexamine ROS in the context of autophagy.", "metadata": {}}
+{"_id": "19945096", "title": "", "text": "Why do patients with multimorbidity in Englandreport worse experiences in primary care?Evidence from the General Practice PatientSurveyOBJECTIVES To describe and explain theprimary care experiences of people with multiplelong-term conditions in England. DESIGN ANDMETHODS Using questionnaire data from906,578 responders to the English 2012 GeneralPractice Patient Survey, we describe the primarycare experiences of patients with long-termconditions, including 583,143 patients whoreported one or more long-term conditions. Weemployed mixed effect logistic regressions toanalyse data on six items covering three caredomains (access, continuity and communication)and a single item on overall primary careexperience. We controlled for sociodemographiccharacteristics, and for general practice using arandom effect, and further, controlled for, andexplored the importance of, health-relatedquality of life measured using the EuroQoL(EQ-5D) scale. RESULTS Most patients with", "metadata": {}}
+{"_id": "19950357", "title": "", "text": "The rice FISH BONE gene encodes a tryptophanaminotransferase, which affects pleiotropicauxin-related processes.Auxin is a fundamentalplant hormone and its localization within organsplays pivotal roles in plant growth anddevelopment. Analysis of many Arabidopsismutants that were defective in auxinbiosynthesis revealed that the indole-3-pyruvicacid (IPA) pathway, catalyzed by theTRYPTOPHAN AMINOTRANSFERASE OFARABIDOPSIS (TAA) and YUCCA (YUC) families,is the major biosynthetic pathway ofindole-3-acetic acid (IAA). In contrast, littleinformation is known about the molecularmechanisms of auxin biosynthesis in rice. In thisstudy, we identified a auxin-related rice mutant,fish bone (fib). FIB encodes an orthologue of TAAgenes and loss of FIB function resulted inpleiotropic abnormal phenotypes, such as smallleaves with large lamina joint angles, abnormalvascular development, small panicles, abnormalorgan identity and defects in root development,", "metadata": {}}
+{"_id": "19951373", "title": "", "text": "Successful mouse cloning of an outbred strain bytrichostatin A treatment after somatic nucleartransfer.Although the somatic cloning techniquehas been used for numerous applications andbasic research of reprogramming in variousspecies, extremely low success rates haveplagued this technique for a decade. Further inmice, the \"clonable\" strains have been limited tomainly hybrid F1 strains such as B6D2F1.Recently, we established a new efficient cloningtechnique using trichostatin A (TSA) which leadsto a 2-5 fold increase in success rates for mousecloning of B6D2F1 cumulus cells. To further testthe validity of this TSA cloning technique, wetried to clone the adult ICR mouse, an outbredstrain, which has never been directly clonedbefore. Only when TSA was used did we obtainboth male and female cloned mice from cumulusand fibroblast cells of adult ICR mice with 4-5%success rates, which is comparable to 5-7% ofB6D2F1. Thus, the TSA treatment is the firstcloning technique to allow us to successfully", "metadata": {}}
+{"_id": "19957813", "title": "", "text": "A Genome-wide CRISPR Death Screen IdentifiesGenes Essential for OxidativePhosphorylation.Oxidative phosphorylation(OXPHOS) is the major pathway for ATPproduction in humans. Deficiencies in OXPHOScan arise from mutations in either mitochondrialor nuclear genomes and comprise the largestcollection of inborn errors of metabolism. Atpresent we lack a complete catalog of humangenes and pathways essential for OXPHOS. Herewe introduce a genome-wide CRISPR \"deathscreen\" that actively selects dying cells to revealhuman genes required for OXPHOS, inspired bythe classic observation that human cells deficientin OXPHOS survive in glucose but die ingalactose. We report 191 high-confidence hitsessential for OXPHOS, including 72 underlyingknown OXPHOS diseases. Our screen reveals afunctional module consisting of NGRN,WBSCR16, RPUSD3, RPUSD4, TRUB2, andFASTKD2 that regulates the mitochondrial 16SrRNA and intra-mitochondrial translation. Our", "metadata": {}}
+{"_id": "19958277", "title": "", "text": "RecQ helicases: caretakers of the genomeRecQhelicases are highly conserved from bacteria toman. Germline mutations in three of the fiveknown family members in humans give rise todebilitating disorders that are characterized by,amongst other things, a predisposition to thedevelopment of cancer. One of these disorders —Bloom's syndrome — is uniquely associated witha predisposition to cancers of all types. So howdo RecQ helicases protect against cancer? Theyseem to maintain genomic stability byfunctioning at the interface between DNAreplication and DNA repair.", "metadata": {}}
+{"_id": "19961177", "title": "", "text": "Mortality from causes amenable andnon-amenable to medical care: the experience ofeastern Europe.OBJECTIVE To investigatecomparative national trends in mortality fromconditions amenable to timely, appropriatemedical care and from those considered not tobe amenable to such care. DESIGN Analysis oftrends in direct age standardised mortality fromthe 1950s to 1987. SETTING Four easternEuropean nations (Hungary, Czechoslovakia,Poland, the German Democratic Republic) andtwo western European (the Federal Republic ofGermany and England and Wales) and two NorthAmerican nations (United States and Canada).SUBJECTS The total populations of the relevantcountries during the period examined. MAINOUTCOME MEASURES Proportional changes overtime in age standardised mortality. Mortalityfrom amenable and non-amenable causes wasrestricted to the age group 0-64. RESULTS Adivergence in the trends for all cause mortalitybetween eastern Europe and the western nations", "metadata": {}}
+{"_id": "19966976", "title": "", "text": "Dynamic regulation of heterochromatin functionvia phosphorylation of HP1-familyproteins.Heterochromatin is characterized bymethylation of histone H3 at lysine 9, which isrecognized by well-conserved HP1-familyproteins. Heterochromatin participates in variouschromosome functions, which includetranscriptional gene silencing andsister-chromatid cohesion. Theseheterochromatic functions are carried out byvarious effector proteins that associate withHP1-family proteins; however, the regulation ofthis association with the effectors is not wellunderstood. Recently, we showed thatphosphorylation of the fission-yeast HP1homolog Swi6 regulates the association of thetranscriptional regulators differentially andchanges the transcriptional activity ofheterochromatin, without affectingsister-chromatid cohesion. This study, togetherwith another study performed using othersystems, indicates that phosphorylation of", "metadata": {}}
+{"_id": "19970015", "title": "", "text": "Modeling neurogenesis impairment in Downsyndrome with induced pluripotent stem cellsfrom Trisomy 21 amniotic fluid cells.Downsyndrome (DS), or Trisomy 21 (T21) syndrome,one of the most common chromosomalabnormalities, is caused by an extra duplicationof chromosome 21. In studies of neurondevelopment, experimental models based onhuman cells are considered to be the mostdesired and accurate for basic research. Thegeneration of diseased induced pluripotetn stem(iPS) cell is a critical step in understanding thedevelopmental stages of complex neuronaldiseases. Here, we generated human DS iPS celllines from second trimester amniotic fluid (AF)cells with T21 by co-expressing Yamanakafactors through lentiviral delivery andsubsequently differentiated them into neuronalprogenitor cells (NPCs) for further analyses. T21AF-iPS cells were characterized for theexpression of pluripotent markers and for theirability to differentiate into all three germ layers", "metadata": {}}
+{"_id": "19974105", "title": "", "text": "Control over DNA replication in time andspace.DNA replication is precisely regulated intime and space, thereby safeguarding genomicintegrity. In eukaryotes, replication initiates frommultiple sites along the genome, termed originsof replication, and propagates bidirectionally.Dynamic origin bound complexes dictate whereand when replication should initiate. During latemitosis and G1 phase, putative origins arerecognized and become \"licensed\" through theassembly of pre-replicative complexes (pre-RCs)that include the MCM2-7 helicases.Subsequently, at the G1/S phase transition, afraction of pre-RCs are activated giving rise tothe establishment of replication forks. Originlocation is influenced by chromatin and nuclearorganization and origin selection exhibitsstochastic features. The regulatory mechanismsthat govern these cell cycle events rely on theperiodic fluctuation of cyclin dependent kinase(CDK) activity through the cell cycle.", "metadata": {}}
+{"_id": "19979816", "title": "", "text": "MYC/MIZ1-dependent gene repression inverselycoordinates the circadian clock with cell cycleand proliferationThe circadian clock and the cellcycle are major cellular systems that organizeglobal physiology in temporal fashion. It seemsconceivable that the potentially conflictingprograms are coordinated. We show here thatoverexpression of MYC in U2OS cells attenuatesthe clock and conversely promotes cellproliferation while downregulation of MYCstrengthens the clock and reduces proliferation.Inhibition of the circadian clock is cruciallydependent on the formation of repressivecomplexes of MYC with MIZ1 and subsequentdownregulation of the core clock genes BMAL1(ARNTL), CLOCK and NPAS2. We showfurthermore that BMAL1 expression levelscorrelate inversely with MYC levels in 102 humanlymphomas. Our data suggest that MYC acts as amaster coordinator that inversely modulates theimpact of cell cycle and circadian clock on geneexpression.", "metadata": {}}
+{"_id": "19994006", "title": "", "text": "Relevance of asystole during head-up tilttesting.The prognosis of patients manifestingprolonged asystole during head-up tilt testing isunclear. In 209 consecutive patients with ahistory of syncope and positive head-up tilt tests,19 had asystole lasting > 5 seconds (meanduration 15 +/- 10) (group 1a). When comparedwith patients without asystole (group 1b), group1a patients were younger (32 +/- 12 vs 47 +/-21 years, p < 0.005), but clinical manifestationswere not any more dramatic (the number ofepisodes of syncope [7 +/- 5 vs 8 +/- 6episodes, p = NS] and injury during syncope [2vs 13 patients, p = NS] were similar). Duringfollow-up (mean 2 +/- 1 year), with the patienttaking pharmacologic therapy such as betablockers, ephedrine, theophylline, ordisopyramide, the recurrence rate was 11% and8% in groups 1a and 1b (p = NS). No patient inthe asystole group underwent pacemakerimplantation. Additionally, of 75 normalvolunteers (group 2) with no history of syncope", "metadata": {}}
+{"_id": "20008796", "title": "", "text": "Increasing informed uptake and non-uptake ofscreening: evidence from a systematicreview.OBJECTIVE To report data relating to theinformed uptake of screening tests. SEARCHSTRATEGY Electronic databases, bibliographiesand experts were used to identify relevantpublished and unpublished studies up untilAugust 2000. INCLUSION CRITERIA RCTs,quasi-RCTs and controlled trials of interventionsaimed at increasing the informed uptake ofscreening. All participants were eligible asdefined by the entry criteria of individualprogrammes. Studies had to report actual uptakeand meet three out of four criteria used to defineinformed uptake. DATA EXTRACTION ANDSYNTHESIS Relevant studies were identified,data extracted and their validity assessed by tworeviewers independently. Outcome data includedscreening uptake, knowledge, informeddecision-making and attitudes to screening. Arandom-effects model was used to calculateindividual relative risks and 95% confidence", "metadata": {}}
+{"_id": "20018321", "title": "", "text": "Mitochondrial RNA Granules Are Centers forPosttranscriptional RNA Processing and RibosomeBiogenesis.Cytoplasmic RNA granules play acentral role in mRNA metabolism, but theimportance of mitochondrial RNA granulesremains relatively unexplored. We characterizedtheir proteome and found that they contain alarge toolbox of proteins dedicated to RNAmetabolism. Investigation of fouruncharacterized putative RNA-bindingproteins-two RNA helicases, DHX30 and DDX28,and two proteins of the Fas-activatedserine-threonine kinase (FASTKD) family,FASTKD2 and FASTKD5-demonstrated that bothhelicases and FASTKD2 are required formitochondrial ribosome biogenesis.RNA-sequencing (RNA-seq) analysis showed thatDDX28 and FASTKD2 bound the 16S rRNA.FASTKD5 is required for maturing precursormRNAs that are not flanked by tRNAs and thattherefore cannot be processed by the canonicalmRNA maturation pathway. Silencing FASTKD5", "metadata": {}}
+{"_id": "20028729", "title": "", "text": "Controlling nuclear receptors: the circular logic ofcofactor cyclesNuclear receptors regulate manybiologically important processes in developmentand homeostasis by their bimodal function asrepressors and activators of gene transcription. Afinely tuned modulation of the transcriptionalactivities of nuclear receptors is crucial fordetermining highly specific and diversifiedprogrammes of gene expression. Recent studieshave provided insights into the molecularmechanisms that are required to switch betweenrepression and activation functions, thecombinatorial roles of the multiple cofactorcomplexes that are required for mediatingtranscriptional regulation, and the centralquestion of how several different signallingpathways can be integrated at the nuclear levelto achieve specific profiles of gene expression.", "metadata": {}}
+{"_id": "20033112", "title": "", "text": "Reprogramming fibroblasts into bipotentialhepatic stem cells by defined factors.Recentstudies have demonstrated directreprogramming of fibroblasts into a range ofsomatic cell types, but to date stem orprogenitor cells have only been reprogrammedfor the blood and neuronal lineages. Wepreviously reported generation of inducedhepatocyte-like (iHep) cells by transduction ofGata4, Hnf1α, and Foxa3 in p19 Arf null mouseembryonic fibroblasts (MEFs). Here, we showthat Hnf1β and Foxa3, liver organogenesistranscription factors, are sufficient to reprogramMEFs into induced hepatic stem cells (iHepSCs).iHepSCs can be stably expanded in vitro andpossess the potential of bidirectionaldifferentiation into both hepatocytic andcholangiocytic lineages. In the injured liver offumarylacetoacetate hydrolase (Fah)-deficientmice, repopulating iHepSCs becomehepatocyte-like cells. They also engraft ascholangiocytes into bile ducts of mice with", "metadata": {}}
+{"_id": "20045514", "title": "", "text": "Spatial genome organization: contrasting viewsfrom chromosome conformation capture andfluorescence in situ hybridization.Althoughimportant for gene regulation, most studies ofgenome organization use either fluorescence insitu hybridization (FISH) or chromosomeconformation capture (3C) methods. FISHdirectly visualizes the spatial relationship ofsequences but is usually applied to a few loci at atime. The frequency at which sequences areligated together by formaldehyde cross-linkingcan be measured genome-wide by 3C methods,with higher frequencies thought to reflect shorterdistances. FISH and 3C should therefore give thesame views of genome organization, but this hasnot been tested extensively. We investigated themurine HoxD locus with 3C carbon copy (5C) andFISH in different developmental and activitystates and in the presence or absence ofepigenetic regulators. We identified situations inwhich the two data sets are concordant butfound other conditions under which chromatin", "metadata": {}}
+{"_id": "20048431", "title": "", "text": "Development and evaluation of aself-administered computerized 24-h dietaryrecall method for adolescents inEuropeObjective:To describe the development ofa European computerized 24-h dietary recallmethod for adolescents, and to investigate thefeasibility of self-administration (self report) bycomparison with administration by a dietician(interview).Methods:Two hundred and thirty-sixadolescents (mean age 14.6 years (s.d.=1.7)) ofeight European cities completed the 24-h recall(Young Adolescents Nutrition Assessment onComputer (YANA-C)) twice (once by self-reportand once by interview).Results:A small butsignificant underestimate in energy (61(s.e.=31) kcal) and fat (4.2 (s.e.=1.7) g) intakewas found in the self-reports in comparison withthe interviews; no significant differences werefound for the intake of carbohydrates, proteins,fibre, calcium, iron and ascorbic acid.Spearman's correlations were highly significantfor all nutrients and energy ranging between", "metadata": {}}
+{"_id": "20052986", "title": "", "text": "JTK_CYCLE: an efficient nonparametric algorithmfor detecting rhythmic components ingenome-scale data sets.Circadian rhythms areoscillations of physiology, behavior, andmetabolism that have period lengths near 24hours. In several model organisms and humans,circadian clock genes have been characterizedand found to be transcription factors. Because ofthis, researchers have used microarrays tocharacterize global regulation of gene expressionand algorithmic approaches to detect cycling.This article presents a new algorithm,JTK_CYCLE, designed to efficiently identify andcharacterize cycling variables in large data sets.Compared with COSOPT and the Fisher's G test,two commonly used methods for detectingcycling transcripts, JTK_CYCLE distinguishesbetween rhythmic and nonrhythmic transcriptsmore reliably and efficiently. JTK_CYCLE'sincreased resistance to outliers results inconsiderably greater sensitivity and specificity.Moreover, JTK_CYCLE accurately measures the", "metadata": {}}
+{"_id": "20054396", "title": "", "text": "Polo-like kinase 1 regulates Nlp, a centrosomeprotein involved in microtubule nucleation.Inanimal cells, most microtubules are nucleated atcentrosomes. At the onset of mitosis,centrosomes undergo a structural reorganization,termed maturation, which leads to increasedmicrotubule nucleation activity. Centrosomematuration is regulated by several kinases,including Polo-like kinase 1 (Plk1). Here, weidentify a centrosomal Plk1 substrate, termedNlp (ninein-like protein), whose propertiessuggest an important role in microtubuleorganization. Nlp interacts with two componentsof the gamma-tubulin ring complex andstimulates microtubule nucleation. Plk1phosphorylates Nlp and disrupts both itscentrosome association and its gamma-tubulininteraction. Overexpression of an Nlp mutantlacking Plk1 phosphorylation sites severelydisturbs mitotic spindle formation. We proposethat Nlp plays an important role in microtubuleorganization during interphase, and that the", "metadata": {}}
+{"_id": "20083834", "title": "", "text": "Consumption of isoflavone-rich soy protein doesnot alter homocysteine or markers ofinflammation in postmenopausalwomenBackground/Objective:To investigate theeffect of soy protein containing isoflavones onhomocysteine (Hcy), C-reactive protein (CRP),soluble E-selectin (sE-selectin), soluble vascularadhesion molecule-1 (sVCAM-1) and solubleintercellular adhesion molecule-1(sICAM-1).Subject/Methods:In a randomizedcrossover design, 34 postmenopausal womenconsumed soy protein isolate (26±5 g proteincontaining 44±8 mg isoflavones per day) or milkprotein isolate (26±5 g protein per day) for 6weeks each. Fasting blood samples werecollected at the end of each diet period and endpoints analyzed by enzyme-linkedimmunosorbent assay. Results:Concentrations ofHcy, CRP, sE-selectin, sVCAM-1 and sICAM-1were not different between soy and milk diettreatments. Results did not differ by equolproduction status or by baseline lipid", "metadata": {}}
+{"_id": "20101846", "title": "", "text": "Homogeneously dispersed multimetaloxygen-evolving catalystsEarth-abundantfirst-row (3d) transition metal–based catalystshave been developed for the oxygen-evolutionreaction (OER); however, they operate atoverpotentials substantially abovethermodynamic requirements. Density functionaltheory suggested that non-3d high-valencymetals such as tungsten can modulate 3d metaloxides, providing near-optimal adsorptionenergies for OER intermediates. We developed aroom-temperature synthesis to produce gelledoxyhydroxides materials with an atomicallyhomogeneous metal distribution. These gelledFeCoW oxyhydroxides exhibit the lowestoverpotential (191 millivolts) reported at 10milliamperes per square centimeter in alkalineelectrolyte. The catalyst shows no evidence ofdegradation after more than 500 hours ofoperation. X-ray absorption and computationalstudies reveal a synergistic interplay betweentungsten, iron, and cobalt in producing a", "metadata": {}}
+{"_id": "20109325", "title": "", "text": "Global strategy for the diagnosis, management,and prevention of chronic obstructive pulmonarydisease: GOLD executive summary.Chronicobstructive pulmonary disease (COPD) is a globalhealth problem, and since 2001, the GlobalInitiative for Chronic Obstructive Lung Disease(GOLD) has published its strategy document forthe diagnosis and management of COPD. Thisexecutive summary presents the main contentsof the second 5-year revision of the GOLDdocument that has implemented some of thevast knowledge about COPD accumulated overthe last years. Today, GOLD recommends thatspirometry is required for the clinical diagnosis ofCOPD to avoid misdiagnosis and to ensureproper evaluation of severity of airflow limitation.The document highlights that the assessment ofthe patient with COPD should always includeassessment of (1) symptoms, (2) severity ofairflow limitation, (3) history of exacerbations,and (4) comorbidities. The first three points canbe used to evaluate level of symptoms and risk", "metadata": {}}
+{"_id": "20127522", "title": "", "text": "Circulating tumor cells: a useful predictor oftreatment efficacy in metastatic breastcancer.PURPOSE Five or more circulating tumorcells (CTCs) per 7.5 mL of blood predicts forpoorer progression-free survival (PFS) in patientswith metastatic breast cancer (MBC). Weconducted a prospective study to demonstratethat CTC results correlate strongly withradiographic disease progression at the time ofand in advance of imaging. PATIENTS ANDMETHODS Serial CTC levels were obtained inpatients starting a new treatment regimen forprogressive, radiographically measurable MBC.Peripheral blood was collected for CTCenumeration at baseline and at 3- to 4-weekintervals. Clinical outcomes were based onradiographic studies performed in 9- to 12-weekintervals. RESULTS Sixty-eight patients wereevaluable for the CTC-imaging correlations, and74 patients were evaluable for the PFS analysis.Median follow-up was 13.3 months. A statisticallysignificant correlation was demonstrated", "metadata": {}}
+{"_id": "20128547", "title": "", "text": "Recovery of supraspinal control of stepping viaindirect propriospinal relay connections afterspinal cord injurySpinal cord injuries (SCIs) inhumans and experimental animals are oftenassociated with varying degrees of spontaneousfunctional recovery during the first months afterinjury. Such recovery is widely attributed toaxons spared from injury that descend from thebrain and bypass incomplete lesions, but itsmechanisms are uncertain. To investigate theneural basis of spontaneous recovery, we usedkinematic, physiological and anatomical analysesto evaluate mice with various combinations ofspatially and temporally separated lateralhemisections with or without the excitotoxicablation of intrinsic spinal cord neurons. Weshow that propriospinal relay connections thatbypass one or more injury sites are able tomediate spontaneous functional recovery andsupraspinal control of stepping, even when therehas been essentially total and irreversibleinterruption of long descending supraspinal", "metadata": {}}
+{"_id": "20130904", "title": "", "text": "\"Grazing\": a high-risk behavior.BACKGROUNDGastric bypass patients with a range of disturbedeating patterns before surgery may be at risk ofreturning to old patterns postoperatively. Recentresearch has shown that binge eating is commonamong the obese before surgery as well as in thepostoperative maintenance phase and appears tobe linked to poorer outcome. Although \"grazing\"behavior has not been specifically studied, it isalso a high-risk pattern. This paper is adescriptive investigation summarizingpostoperative eating patterns in a group ofpatients. METHODS Patients completedself-report questionnaires before surgery andwere seen for a preoperative mental healthevaluation with particular focus on assessingeating patterns. Patients with high-risk eatingpatterns, both binge eating and \"grazing\", wereidentified, invited to attend a post-surgerytherapy group, and were given additionalfollow-up questionnaires regarding postoperativeeating patterns. RESULTS Consistent with recent", "metadata": {}}
+{"_id": "20132778", "title": "", "text": "Molecular strategies in biological evolution ofantimicrobial peptides.Gene-encodedantimicrobial peptides that protect the skin ofhylid and ranin frogs against noxiousmicroorganisms are processed from a uniquefamily of precursor polypeptides with a uniquepattern of conserved and variable regionsopposite to that of conventional secretedpeptides. Precursors belonging to this family,designated the preprodermaseptin, have acommon N-terminal preproregion that isremarkably well conserved both within andbetween species, but a hypervariable C-terminaldomain corresponding to antimicrobial peptideswith very different lengths, sequences, chargesand antimicrobial spectra. Each frog species hasits own distinct panoply of 10-20 antimicrobialpeptides so that the 5000 species of ranids andhylids may produce approximately 100,000different peptide antibiotics. The strategy thatthese frogs have evolved to generate thisenormous array of peptides includes repeated", "metadata": {}}
+{"_id": "20148808", "title": "", "text": "Microbiome-driven allergic lung inflammation isameliorated by short-chain fatty acidsThemammalian gastrointestinal tract harbors amicrobial community with metabolic activitycritical for host health, including metabolites thatcan modulate effector functions of immune cells.Mice treated with vancomycin have an alteredmicrobiome and metabolite profile, exhibitexacerbated T helper type 2 cell (Th2)responses, and are more susceptible to allergiclung inflammation. Here we show that dietarysupplementation with short-chain fatty acids(SCFAs) ameliorates this enhanced asthmasusceptibility by modulating the activity of T cellsand dendritic cells (DCs). Dysbiotic mice treatedwith SCFAs have fewer interleukin-4(IL4)-producing CD4+ T cells and decreasedlevels of circulating immunoglobulin E (IgE). Inaddition, DCs exposed to SCFAs activate T cellsless robustly, are less motile in response toCCL19 in vitro, and exhibit a dampened ability totransport inhaled allergens to lung draining", "metadata": {}}
+{"_id": "20155713", "title": "", "text": "Promiscuous gene expression in medullarythymic epithelial cells mirrors the peripheralselfExpression of peripheral antigens in thethymus has been implicated in T cell toleranceand autoimmunity. Here we identified medullarythymic epithelial cells as being a unique cell typethat expresses a diverse range of tissue-specificantigens. We found that this promiscuous geneexpression was a cell-autonomous property ofmedullary epithelial cells and was maintainedduring the entire period of thymic T cell output.It may facilitate tolerance induction toself-antigens that would otherwise be temporallyor spatially secluded from the immune system.However, the array of promiscuously expressedself-antigens appeared random rather thanselected and was not confined to secludedself-antigens.", "metadata": {}}
+{"_id": "20179918", "title": "", "text": "Signal transducer and activator of transcription 3is a transcriptional factor regulating the geneexpression of SALL4.Both signal transducer andactivator of transcription 3 (STAT3) and SALL4are important in maintaining the pluripotent andself-renewal state of embryonic stem cells. Wehypothesized that STAT3, a latent transcriptionalfactor, may regulate the gene expression ofSALL4. In support of this hypothesis, DNAsequence analysis of the SALL4 gene promoterrevealed four putative STAT3-binding sites.Using a SALL4-luciferase reporter gene assay,we found that modulation of the STAT3 activitysignificantly up-regulated the luciferase activity.By chromatin immunoprecipitation, the segmentof the SALL4 promoter showing the highestaffinity to STAT3 was localized to -366 to -163,in which there was only one putative STAT3binding site starting at -199. Site-directedmutagenesis of all four putative STAT3-bindingsites in the SALL4 promoter significantly reducedits responsiveness to STAT3, although the most", "metadata": {}}
+{"_id": "20183360", "title": "", "text": "GATA3 transcription factor abrogates Smad4transcription factor-mediated fascinoverexpression, invadopodium formation, andbreast cancer cell invasion.Transforming growthfactor β (TGFβ) is a potent andcontext-dependent regulator of tumorprogression. TGFβ promotes the lung metastasisof basal-like (but not the luminal-like) breastcancer. Here, we demonstrated that fascin, apro-metastasis actin bundling protein, was adirect target of the canonical TGFβ-Smad4signaling pathway in basal-like breast cancercells. TGFβ and Smad4 induced fascinoverexpression by directly binding to a Smadbinding element on the fascin promoter. Weidentified GATA3, a transcription factor crucial formammary gland morphogenesis and luminaldifferentiation, as a negative regulator of TGFβ-and Smad4-induced fascin overexpression. Whenectopically expressed in basal-like breast cancercells, GATA-3 abrogated TGFβ- andSmad4-mediated overexpression of fascin and", "metadata": {}}
+{"_id": "20186513", "title": "", "text": "The American Rheumatism Association 1987revised criteria for the classification ofrheumatoid arthritis.The revised criteria for theclassification of rheumatoid arthritis (RA) wereformulated from a computerized analysis of 262contemporary, consecutively studied patientswith RA and 262 control subjects with rheumaticdiseases other than RA (non-RA). The newcriteria are as follows: 1) morning stiffness inand around joints lasting at least 1 hour beforemaximal improvement; 2) soft tissue swelling(arthritis) of 3 or more joint areas observed by aphysician; 3) swelling (arthritis) of the proximalinterphalangeal, metacarpophalangeal, or wristjoints; 4) symmetric swelling (arthritis); 5)rheumatoid nodules; 6) the presence ofrheumatoid factor; and 7) radiographic erosionsand/or periarticular osteopenia in hand and/orwrist joints. Criteria 1 through 4 must have beenpresent for at least 6 weeks. Rheumatoidarthritis is defined by the presence of 4 or morecriteria, and no further qualifications (classic,", "metadata": {}}
+{"_id": "20186814", "title": "", "text": "A new look at the origin, function, and\"stem-cell\" status of muscle satellite cells.Musclesatellite cells have long been considered adistinct myogenic lineage responsible forpostnatal growth, repair, and maintenance ofskeletal muscle. Recent studies in mice,however, have revealed the potential for highlypurified hematopoietic stem cells from bonemarrow to participate in muscle regeneration.Perhaps more significantly, a population ofputative stem cells isolated directly from skeletalmuscle efficiently reconstitutes thehematopoietic compartment and participates inmuscle regeneration following intravenousinjection in mice. The plasticity of muscle stemcells has raised important questions regardingthe relationship between the muscle-derivedstem cells and the skeletal muscle satellite cells.Furthermore, the ability of hematopoietic cells toundergo myogenesis has prompted newinvestigations into the embryonic origin ofsatellite cells. Recent developmental studies", "metadata": {}}
+{"_id": "20187433", "title": "", "text": "Involving family members in cancer care: focusgroup considerations of patients and oncologicalproviders.Family members are an integral part ofa patient's cancer care from the moment thediagnosis is delivered to the conclusion oftreatment. Family members bring with them arange of emotional reactions, interpersonaldynamics and expectations for the care thepatient receives. This study is part of amulti-institutional project to continue to improvethe process of cancer care. In this study, 19focus groups (11 patient and 8 provider) wereconducted concerning issues related todoctor-patient communication in eight cancercenters in the United States. The content of theconversations was analyzed and thematiccategories emerged that highlight the variousstrengths and difficulties associated with familyinvolvement. The focus groups' commentssupport the need for explicit conversationsbetween professional caregivers, patients andtheir loved ones, in order to negotiate the", "metadata": {}}
+{"_id": "20188586", "title": "", "text": "Improving Adherence to Antiretroviral TherapyWith Triggered Real-time Text MessageReminders: The China Adherence ThroughTechnology Study.BACKGROUND Real-timeadherence monitoring is now possible throughmedication storage devices equipped withcellular technology. We assessed the effect oftriggered cell phone reminders and counselingusing objective adherence data on antiretroviraltherapy (ART) adherence among ChineseHIV-infected patients. METHODS We providedART patients in Nanning, China, with amedication device (Wisepill) to monitor their ARTadherence electronically. After 3 months, werandomized subjects within optimal (≥95%) andsuboptimal (<95%) adherence strata tointervention vs. control arms. In months 4-9,intervention subjects received individualizedreminders triggered by late dose taking (nodevice opening by 30 minutes past dose time)and counseling using device-generated data.Controls received no reminders or data-informed", "metadata": {}}
+{"_id": "20220731", "title": "", "text": "Origin and T cell receptor diversity ofFoxp3+CD4+CD25+ Tcells.Foxp3(+)CD4(+)CD25(+) regulatory T cellscan differentiate from Foxp3(-)CD4(+) medullarythymocytes and Foxp3(-)CD4(+) naive T cells.However, the impact of these two processes onsize and composition of the peripheral repertoireof regulatory T cells is unclear. Here we followedthe fate of individual Foxp3(+)CD4(+)CD25(+)thymocytes and T cells in vivo in T cell receptor(TCR) transgenic mice that express a restrictedbut polyclonal repertoire of TCRs. By utilizinghigh-throughput single-cell analysis, we showedthat Foxp3(+)CD4(+) peripheral T cells werederived from thymic precursors that expressed adifferent TCRs than Foxp3(-)CD4(+) medullarythymocytes and Foxp3(-)CD4(+) T cells.Furthermore, the diversity of TCRs onFoxp3(+)CD4(+) regulatory T cells exceeded thediversity of TCRs on Foxp3(-)CD4(+) naive Tcells, even in mice that lack expression oftissue-specific antigens. Our results imply that", "metadata": {}}
+{"_id": "20221907", "title": "", "text": "Reproducibility of the diagnosis of atypicalendometrial hyperplasia: a Gynecologic OncologyGroup study.BACKGROUND Most gynecologistsdetermine therapy based on currentInternational Society of Gynecologic Pathologists(ISGP)/World Health Organization classificationof endometrial hyperplasia, the reproducibility ofwhich has been questioned. The GynecologicOncology Group (GOG) initiated a protocol toassess the efficacy of hormonal therapy ofatypical endometrial hyperplasia (AEH). Primarygoals of the first phase (Part A) were toprospectively determine reproducibility ofreferring institution's pathologist's diagnosis ofAEH by a panel of 3 gynecologic pathologists andto determine reproducibility of diagnoses bypanel members. METHODS Three hundred sixwomen were entered on this protocol with areferring institution's pathologist diagnosis ofAEH based on biopsy or curettage. Availableslides were assessed independently andinterpreted by each of a panel of 3 gynecologic", "metadata": {}}
+{"_id": "20231138", "title": "", "text": "Replication Fork Slowing and Reversal upon DNADamage Require PCNA Polyubiquitination andZRANB3 DNA Translocase ActivityDNA damagetolerance during eukaryotic replication isorchestrated by PCNA ubiquitination. Whilemonoubiquitination activates mutagenictranslesion synthesis, polyubiquitinationactivates an error-free pathway, elusive inmammals, enabling damage bypass by templateswitching. Fork reversal is driven in vitro bymultiple enzymes, including the DNA translocaseZRANB3, shown to bind polyubiquitinated PCNA.However, whether this interaction promotes forkremodeling and template switching in vivo wasunknown. Here we show that damage-inducedfork reversal in mammalian cells requires PCNAubiquitination, UBC13, and K63-linkedpolyubiquitin chains, previously involved inerror-free damage tolerance. Fork reversal invivo also requires ZRANB3 translocase activityand its interaction with polyubiquitinated PCNA,pinpointing ZRANB3 as a key effector of", "metadata": {}}
+{"_id": "20240998", "title": "", "text": "Bed sharing when parents do not smoke: is therea risk of SIDS? An individual level analysis of fivemajor case–control studiesOBJECTIVE To resolveuncertainty as to the risk of Sudden Infant DeathSyndrome (SIDS) associated with sleeping in bedwith your baby if neither parent smokes and thebaby is breastfed. DESIGN Bed sharing wasdefined as sleeping with a baby in the parents'bed; room sharing as baby sleeping in theparents' room. Frequency of bed sharing duringlast sleep was compared between babies whodied of SIDS and living control infants. Five largeSIDS case-control datasets were combined.Missing data were imputed. Random effectslogistic regression controlled for confoundingfactors. SETTING Home sleeping arrangementsof infants in 19 studies across the UK, Europeand Australasia. PARTICIPANTS 1472 SIDScases, and 4679 controls. Each study effectivelyincluded all cases, by standard criteria. Controlswere randomly selected normal infants of similarage, time and place. RESULTS In the combined", "metadata": {}}
+{"_id": "20261352", "title": "", "text": "Decoupling activation and exhaustion of B cells inspontaneous controllers of HIVinfection.OBJECTIVE To define the impact ofchronic viremia and associated immuneactivation on B-cell exhaustion in HIV infection.DESIGN Progressive HIV infection is marked byB-cell anergy and exhaustion coupled withdramatic hypergammaglobulinemia. Althoughboth upregulation of CD95 and loss of CD21 havebeen used as markers of infection-associatedB-cell dysfunction, little is known regarding thespecific profiles of dysfunctional B cells andwhether persistent viral replication and itsassociated immune activation play a central rolein driving B-cell dysfunction. METHODSMultiparameter flow cytometry was used todefine the profile of dysfunctional B cells. Thechanges in the expression of CD21 and CD95were tracked on B-cell subpopulations in patientswith differential control of viral replication.RESULTS : Although the emergence ofexhausted, CD21 tissue-like memory B cells", "metadata": {}}
+{"_id": "20279166", "title": "", "text": "Label-free DNA imaging in vivo with stimulatedRaman scattering microscopy.Label-free DNAimaging is highly desirable in biology andmedicine to perform live imaging withoutaffecting cell function and to obtain instanthistological tissue examination during surgicalprocedures. Here we show a label-free DNAimaging method with stimulated Ramanscattering (SRS) microscopy for visualization ofthe cell nuclei in live animals and intact freshhuman tissues with subcellular resolution.Relying on the distinct Raman spectral featuresof the carbon-hydrogen bonds in DNA, thedistribution of DNA is retrieved from the strongbackground of proteins and lipids by lineardecomposition of SRS images at three optimallyselected Raman shifts. Based on changes on DNAcondensation in the nucleus, we were able tocapture chromosome dynamics during celldivision both in vitro and in vivo. We trackedmouse skin cell proliferation, induced by drugtreatment, through in vivo counting of the", "metadata": {}}
+{"_id": "20280410", "title": "", "text": "A common variant in BRCA2 is associated withboth breast cancer risk and prenatalviabilityInherited mutations in the gene BRCA2predispose carriers to early onset breast cancer,but such mutations account for fewer than 2% ofall cases in East Anglia. It is likely that lowpenetrance alleles explain the greater part ofinherited susceptibility to breast cancer;polymorphic variants in strongly predisposinggenes, such as BRCA2, are candidates for thisrole. BRCA2 is thought to be involved in DNAdouble strand break-repair. Few mice in whichBrca2 is truncated survive to birth; of those thatdo, most are male, smaller than their normallittermates and have high cancer incidence. Herewe show that a common human polymorphism(N372H) in exon 10 of BRCA2 confers anincreased risk of breast cancer: the HHhomozygotes have a 1.31-fold (95% CI,1.07–1.61) greater risk than the NN group.Moreover, in normal female controls of all agesthere is a significant deficiency of homozygotes", "metadata": {}}
+{"_id": "20287253", "title": "", "text": "Pathophysiology of obstructive nephropathy inthe newborn.Congenital obstructive nephropathyis a consequence abnormal urinary tractdevelopment resulting in renal growth failure andinjury manifested by progressive tubular atrophyand interstitial fibrosis. We have studied therenal cellular and physiological response tounilateral ureteral obstruction (UUO) in theneonatal rodent (guinea pig, rat, and mouse).Whereas in the adult, UUO stimulates renalcellular proliferation, UUO in the neonate reducesnephrogenesis, glomerular maturation, andtubular cellular proliferation. This is accompaniedby a proportionately greater compensatorygrowth of the intact opposite kidney in theneonate. Impaired renal growth and tubularatrophy are likely owing at least in part tostimulation of renal tubular apoptosis. This, inturn, may result from a combination of factors,including loss of epithelial cell polarity, areduction in the oncoprotein bcl-2 and epidermalgrowth factor (EGF), and increased expression of", "metadata": {}}
+{"_id": "20288322", "title": "", "text": "Lipid homeostasis, lipotoxicity and the metabolicsyndrome.In the 20th century industrializednations have become afflicted with anunprecedented pandemic of increased adiposity.In the United States, the epicenter of theepidemic, over 2/3 of the population, isoverweight and 1 of every 6 Americans carriesthe diagnosis of metabolic syndrome. Althoughgenes determine susceptibility to environmentalfactors, the epidemic is clearly due to increasedconsumption of calorie-dense, highly lipogenicfoods, coupled with a marked decrease inphysical exertion resulting from moderntechnologies. If this lifestyle continues, morbidconsequences are virtually inevitable. Theyinclude type II diabetes and a cluster ofdisorders known as \"the metabolic syndrome\"usually appearing in middle age. The morbidconsequences of the chronic caloric surplus arebuffered before middle age by the partitioning ofthese calories as fat in the adipocytecompartment which is specifically designed to", "metadata": {}}
+{"_id": "20302714", "title": "", "text": "A twin-study of genetic contributions tomorningness-eveningness anddepression.Circadian rhythms are associatedwith the preference for sleep-wake timing, alsoknown as morningness-eveningness (ME). Bothcircadian rhythms and ME are influenced bygenetic factors. Studies show an associationbetween eveningness and depression. This studyinvestigates the heritability of ME and whetherME and depression share common geneticinfluences. Study participants (n = 1237) werefrom the Vietnam Era Twin Study of Aging, alongitudinal study of aging with a baseline inmidlife. Participants received theMorningness-Eveningness Questionnaire (MEQ)and the Center for Epidemiologic StudiesDepression (CES-D) Scale as part of an extensiveneurocognitive and psychosocial assessment.MEQ correlations between members of twin pairswere 0.41 (95% CI 0.31-0.49) for monozygotic(MZ) twins and 0.28 for dizygotic (DZ) twins(95% CI 0.19-0.41). CES-D correlations were", "metadata": {}}
+{"_id": "20310709", "title": "", "text": "The Transcription Factor T-bet RegulatesIntestinal Inflammation Mediated byInterleukin-7 Receptor+ Innate LymphoidCellsMice lacking the transcription factor T-bet inthe innate immune system developmicrobiota-dependent colitis. Here, we show thatinterleukin-17A (IL-17A)-producing IL-7Rα(+)innate lymphoid cells (ILCs) were potentpromoters of disease in Tbx21(-/-)Rag2(-/-)ulcerative colitis (TRUC) mice. TNF-α producedby CD103(-)CD11b(+) dendritic cells synergizedwith IL-23 to drive IL-17A production by ILCs,demonstrating a previously unrecognized layer ofcellular crosstalk between dendritic cells andILCs. We have identified Helicobacter typhloniusas a key disease trigger driving excess TNF-αproduction and promoting colitis in TRUC mice.Crucially, T-bet also suppressed the expressionof IL-7R, a key molecule involved in controllingintestinal ILC homeostasis. The importance ofIL-7R signaling in TRUC disease was highlightedby the dramatic reduction in intestinal ILCs and", "metadata": {}}
+{"_id": "20311968", "title": "", "text": "Chimeric Antigen Receptor-RedirectedRegulatory T Cells Suppress ExperimentalAllergic Airway Inflammation, a Model ofAsthmaCellular therapy with chimeric antigenreceptor (CAR)-redirected cytotoxic T cells hasshown impressive efficacy in the treatment ofhematologic malignancies. We explored aregulatory T cell (Treg)-based therapy in thetreatment of allergic airway inflammation, amodel for asthma, which is characterized by anairway hyper-reactivity (AHR) and a chronic, Thelper-2 (Th2) cell-dominated immune responseto allergen. To restore the immune balance inthe lung, we redirected Tregs by a CAR towardlung epithelia in mice upon experimentallyinduced allergic asthma, closely mimicking theclinical situation. Adoptively transferred CARTregs accumulated in the lung and intracheobronchial lymph nodes, reduced AHR anddiminished eosinophilic airway inflammation,indicated by lower cell numbers in thebronchoalveolar lavage fluid and decreased cell", "metadata": {}}
+{"_id": "20313748", "title": "", "text": "α-Catenin as a tension transducer that inducesadherens junction developmentAdherensjunctions (AJs), which are organized by adhesionproteins and the underlying actin cytoskeleton,probably sense pulling forces from adjacent cellsand modulate opposing forces to maintain tissueintegrity, but the regulatory mechanism remainsunknown at the molecular level. Although thepossibility that α-catenin acts as a direct linkerbetween the membrane and the actincytoskeleton for AJ formation and function hasbeen minimized, here we show that α-cateninrecruits vinculin, another main actin-bindingprotein of AJs, through force-dependent changesin α-catenin conformation. We identified regionsin the α-catenin molecule that are required for itsforce-dependent binding of vinculin byintroducing mutant α-catenin into cells and usingin vitro binding assays. Fluorescence recoveryafter photobleaching analysis for α-cateninmobility and the existence of an antibodyrecognizing α-catenin in a force-dependent", "metadata": {}}
+{"_id": "20321154", "title": "", "text": "A population-based cohort study to elucidatetemporal relationship between schizophrenia andmetabolic syndrome (KCIS no.PSY3).BACKGROUND The bidirectionalrelationships between metabolic syndrome(MetS) and schizophrenia (SCZ) play a crucialrole in clinical treatment of both diseases butsuch bidirectional causal effects have not beencomprehensively elucidated. AIMS To investigatethe influence of MetS on incident SCZ and theopposite direction as well as their predictors foreach direction with a population-based cohortsample. METHOD We enrolled 76,545 subjectswho had participated in a community-basedhealth screening program during 1999-2004.After excluding those with the existing MetS orSCZ at baseline, the two normal prospectivecohorts corresponding to each independentvariable of MetS or SCZ, respectively, werefollowed over time to ascertain incident outcomeof SCZ and MetS. The crude and adjusted hazardratios for the effect of the predictor on each", "metadata": {}}
+{"_id": "20326526", "title": "", "text": "DEVELOPMENT AND VALIDATION OF A MEASUREOF EMOTIONAL INTELLIGENCEThis series ofstudies describes the development of a measureof emotional intelligence based on the model ofemotional intelligence developed by Salovey andMayer [Salovey, P. & Mayer, J. D. (1990).Emotional intelligence. Imagination, Cognitionand Personality, 9, 185–211.]. A pool of 62 itemsrepresented the different dimensions of themodel. A factor analysis of the responses of 346participants suggested the creation of a 33-itemscale. Additional studies showed the 33-itemmeasure to have good internal consistency andtestretest reliability. Validation studies showedthat scores on the 33-item measure  1. (a)correlated with eight of nine theoretically relatedconstructs, including alexithymia, attention tofeelings, clarity of feelings, mood repair,optimism and impulse control;    2.  (b)predicted first-year college grades;    3. (c) weresignificantly higher for therapists than fortherapy clients or for prisoners;    4.  (d) were", "metadata": {}}
+{"_id": "20330519", "title": "", "text": "Cholesterol glucosylation promotes immuneevasion by Helicobacter pyloriHelicobacter pyloriinfection causes gastric pathology such as ulcerand carcinoma. Because H. pylori is auxotrophicfor cholesterol, we have explored theassimilation of cholesterol by H. pylori ininfection. Here we show that H. pylori follows acholesterol gradient and extracts the lipid fromplasma membranes of epithelial cells forsubsequent glucosylation. Excessive cholesterolpromotes phagocytosis of H. pylori byantigen-presenting cells, such as macrophagesand dendritic cells, and enhancesantigen-specific T cell responses. Acholesterol-rich diet during bacterial challengeleads to T cell–dependent reduction of the H.pylori burden in the stomach. Intrinsicα-glucosylation of cholesterol abrogatesphagocytosis of H. pylori and subsequent T cellactivation. We identify the gene hp0421 asencoding the enzymecholesterol-α-glucosyltransferase responsible for", "metadata": {}}
+{"_id": "20333864", "title": "", "text": "Regulation of in situ to invasive breast carcinomatransition.The transition of ductal carcinoma insitu (DCIS) to invasive carcinoma is a poorlyunderstood key event in breast tumorprogression. Here, we analyzed the role ofmyoepithelial cells and fibroblasts in theprogression of in situ carcinomas using a modelof human DCIS and primary breast tumors.Progression to invasion was promoted byfibroblasts and inhibited by normal myoepithelialcells. Molecular profiles of isolated luminalepithelial and myoepithelial cells identified anintricate interaction network involving TGFbeta,Hedgehog, cell adhesion, and p63 required formyoepithelial cell differentiation, the eliminationof which resulted in loss of myoepithelial cellsand progression to invasion.", "metadata": {}}
+{"_id": "20334484", "title": "", "text": "Health and access to care: perspectives ofhomeless youth in Baltimore City,U.S.A.Homeless youth suffer from high rates ofhealth problems, yet little is known about theirperceptions of or context for their own healthissues. In this study, a combination of qualitativetechniques from participatory rural appraisal andrapid assessment procedures was used toinvestigate the perceptions of health needs ofshelter-based youth in Baltimore, MD in theU.S.A. The most common youth-identified healthproblems included STDs, HIV/AIDS, pregnancy,depression, drug use and injuries. Thesecorrelate well with more objective health statusdata for the same youth. The youth spoke ofenvironmental safety threats of violence andvictimization by adults, as well as racism andsexism in their lives. Youth reported that trustedadult figures such as grandmothers areimportant sources of health advice. Manyhomeless youth from less than ideal familysituations remain in contact with and continue to", "metadata": {}}
+{"_id": "20344442", "title": "", "text": "Differential requirement for CARMA1 inagonist-selected T-cell development.Caspaserecruitment domain-containingmembrane-associated guanylate kinaseprotein-1 (CARMA1) is a critical component ofthe NF-kappaB signaling cascade mediated byTCR engagement. In addition to activation ofnaïve T cells, TCR signaling is important for thedevelopment of agonist-selected T-cell subsetssuch as Treg, NKT cells, and CD8-alpha alpha Tcells. However, little is known about the role ofCARMA1 in the development of these lineages.Here we show that CARMA1-deficient mice(CARMA1(-/-)) have altered populations ofspecific subsets of agonist-selected T cells.Specifically, CARMA1(-/-) mice have impairednatural and adaptive Treg development, whereasNKT cell numbers are normal compared withwild-type mice. Interestingly, CD8-alpha alpha Tcells, which may also be able to develop throughan extrathymic selection pathway, are enrichedin the gut of CARMA1(-/-) mice, whereas", "metadata": {}}
+{"_id": "20357868", "title": "", "text": "Simian immunodeficiency viruses of diverseorigin can use CXCR4 as a coreceptor for entryinto human cells.Primary simianimmunodeficiency virus (SIV) isolated from sootymangabey (SIVsm [n = 6]), stumptail (SIVstm[n = 1]), mandrill (SIVmnd [n = 1]), and Africangreen (SIVagm [n = 1]) primates were examinedfor their ability to infect human cells and for theircoreceptor requirements. All isolates infectedhuman peripheral blood mononuclear cells(PBMCs) from a CCR5(+/+) donor, and seven ofeight isolates tested also infected CCR5(-/-)PBMCs. Analysis of coreceptor utilization usingGHOST and U87 cell lines revealed that all of theisolates tested used CCR5 and the orphanreceptors STRL33 and GPR15. Coreceptors suchas CCR2b, CCR3, CCR8, and CX3CR1 were alsoutilized by some primary SIV isolates. Moreimportantly, we found that CXCR4 was used as acoreceptor by the SIVstm, the SIVagm, and fourof the SIVsm isolates in GHOST and U87 cells.These data suggest that primary SIV isolates", "metadata": {}}
+{"_id": "20363389", "title": "", "text": "Cloning of rat uncoupling protein-3 anduncoupling protein-2 cDNAs: their geneexpression in rats fed high-fat diet.In order toelucidate energy balance in the skeletal muscle,we cloned cDNA of a homologue of uncouplingprotein (UCP) from rat skeletal muscle. We alsocloned rat UCP-2 cDNA from rat brown adiposetissue (BAT). The UCP cloned from rat skeletalmuscle showed 57% and 72% identity with ratUCP-1 and UCP-2. The mRNA was expressedabundantly in the skeletal muscle, moderately inthe BAT, and slightly in the white adipose tissue(WAT) with a major band at 2.5 kb and a minorband at 2.8 kb, while the UCP-2 gene expressionwas widely detected in the whole body withsubstantial levels in the WAT and with slightlevels in the skeletal muscle and BAT. The ratUCP cloned in the present study showed 86%identity with the recently cloned human UCP-3,which was also expressed abundantly in theskeletal muscle with a signal of 2.4 kb.Therefore, the rat UCP was considered to be rat", "metadata": {}}
+{"_id": "20368353", "title": "", "text": "A two-step mechanism for epigeneticspecification of centromere identity andfunctionThe basic determinant of chromosomeinheritance, the centromere, is specified in manyeukaryotes by an epigenetic mark. Using genetargeting in human cells and fission yeast,chromatin containing the centromere-specifichistone H3 variant CENP-A is demonstrated to bethe epigenetic mark that acts through a two-stepmechanism to identify, maintain and propagatecentromere function indefinitely. Initially,centromere position is replicated and maintainedby chromatin assembled with thecentromere-targeting domain (CATD) of CENP-Asubstituted into H3. Subsequently, nucleation ofkinetochore assembly onto CATD-containingchromatin is shown to require either the amino-or carboxy-terminal tail of CENP-A forrecruitment of inner kinetochore proteins,including stabilizing CENP-B binding to humancentromeres or direct recruitment of CENP-C,respectively.", "metadata": {}}
+{"_id": "20372201", "title": "", "text": "Cancer stem cell theory in gastrointestinalmalignancies: recent progress and upcomingchallengesA growing body of evidence supportsthe notion that malignant tumors areheterogeneous and contain diversesubpopulations of cells with uniquecharacteristics including the ability to initiate atumor and metastasize. This phenomenon mightbe explained by the so-called cancer stem cell(CSC) theory. Recent technologicaldevelopments have allowed a deeperunderstanding and characterization of CSCs.Even though the application of this theory tohematopoietic malignancies and solid tumorsholds promise for new ways to treat cancer, italso brings some skepticism. Efficacioustherapeutic approaches targeting the CSCpopulation should be explored to overcometherapeutic failure and improve patientoutcomes. This review will focus on the intrinsicand extrinsic regulation of CSCs, as well as thedevelopment of therapeutic approaches against", "metadata": {}}
+{"_id": "20374609", "title": "", "text": "In vitro splicing pathways of pre-mRNAscontaining multiple intervening sequences?Weanalyzed the in vitro splicing pathways of threemulti-intervening-sequence (IVS) pre-mRNAs:human beta-globin, which contains two IVSs (K.M. Lang, V. L. van Santen, and R. A. Spritz,EMBO J. 4:1991-1996, 1985); ratalpha-lactalbumin, which contains three IVSs;and murine interleukin-3, which contains fourIVSs. We found that there are highly preferredpathways of IVS removal from these multi-IVSpre-mRNAs in vitro. The three IVSs of ratalpha-lactalbumin pre-mRNA were excisedsequentially from 5' to 3'; in most molecules,IVS1 was removed first, followed by IVS2 andfinally by IVS3. The splicing pathway ofinterleukin-3 pre-mRNA in vitro was morecomplex. The four IVSs were excised in a highlypreferred temporal order, but the order was notstrictly sequential or directional. In mostmolecules, IVS1 and IVS4 were removed first,either simultaneously or in rapid succession.", "metadata": {}}
+{"_id": "20375264", "title": "", "text": "Automated genome sequence analysis andannotation.MOTIVATION Large-scale genomeprojects generate a rapidly increasing number ofsequences, most of them biochemicallyuncharacterized. Research in bioinformaticscontributes to the development of methods forthe computational characterization of thesesequences. However, the installation andapplication of these methods require experienceand are time consuming. RESULTS We presenthere an automatic system for preliminaryfunctional annotation of protein sequences thathas been applied to the analysis of sets ofsequences from complete genomes, both torefine overall performance and to make newdiscoveries comparable to those made by humanexperts. The GeneQuiz system includes aWeb-based browser that allows examination ofthe evidence leading to an automatic annotationand offers additional information, views of theresults, and links to biological databases thatcomplement the automatic analysis. System", "metadata": {}}
+{"_id": "20381484", "title": "", "text": "GAPDH Mediates Nitrosylation of NuclearProteinsS-nitrosylation of proteins by nitric oxideis a major mode of signalling in cells.S-nitrosylation can mediate the regulation of arange of proteins, including prominent nuclearproteins, such as HDAC2 (ref. 2) and PARP1 (ref.3). The high reactivity of the nitric oxide groupwith protein thiols, but the selective nature ofnitrosylation within the cell, implies the existenceof targeting mechanisms. Specificity of nitricoxide signalling is often achieved by the bindingof nitric oxide synthase (NOS) to target proteins,either directly or through scaffolding proteinssuch as PSD-95 (ref. 5) and CAPON. As the threeprincipal isoforms of NOS--neuronal NOS(nNOS), endothelial NOS (eNOS) and inducibleNOS (iNOS)--are primarily non-nuclear, themechanisms by which nuclear proteins areselectively nitrosylated have been elusive.Glyceraldehyde-3-phosphate dehydrogenase(GAPDH) is physiologically nitrosylated at its Cys150 residue. Nitrosylated GAPDH (SNO-GAPDH)", "metadata": {}}
+{"_id": "20388894", "title": "", "text": "The transcription factor c-Maf controls theproduction of interleukin-4 but not other Th2cytokines.IL-4 promotes the differentiation ofnaive CD4+ T cells into IL-4-producing T helper 2(Th2) cells. Previous work provided suggestivebut not conclusive evidence that the transcriptionfactor c-Maf directed the tissue-specificexpression of IL-4. It was not known whetherc-Maf controlled the transcription of other Th2cytokine genes. To elucidate the role of c-Maf invivo, we examined cytokine production in micelacking c-Maf (c-maf(-/-)). CD4+ T cells and NKT cells from c-maf(-/-) mice were markedlydeficient in IL-4 production. However, the miceproduced normal levels of IL-13 and IgE, and,when differentiated in the presence of exogenousIL-4, c-maf(-/-) T cells produced approximatelynormal levels of other Th2 cytokines. Weconclude that c-Maf has a critical and selectivefunction in IL-4 gene transcription in vivo.", "metadata": {}}
+{"_id": "20399078", "title": "", "text": "Genome-wide association of IL28B with responseto pegylated interferon-α and ribavirin therapyfor chronic hepatitis CThe recommendedtreatment for patients with chronic hepatitis C,pegylated interferon-α (PEG-IFN-α) plus ribavirin(RBV), does not provide sustained virologicresponse (SVR) in all patients. We report agenome-wide association study (GWAS) to nullvirological response (NVR) in the treatment ofpatients with hepatitis C virus (HCV) genotype 1within a Japanese population. We found twoSNPs near the gene IL28B on chromosome 19 tobe strongly associated with NVR (rs12980275, P= 1.93 × 10−13, and rs8099917, 3.11 ×10−15). We replicated these associations in anindependent cohort (combined P values, 2.84 ×10−27 (OR = 17.7; 95% CI = 10.0–31.3) and2.68 × 10−32 (OR = 27.1; 95% CI =14.6–50.3), respectively). Compared to NVR,these SNPs were also associated with SVR(rs12980275, P = 3.99 × 10−24, andrs8099917, P = 1.11 × 10−27). In further fine", "metadata": {}}
+{"_id": "20402596", "title": "", "text": "The WUSCHEL-related homeobox gene WOX11 isrequired to activate shoot-borne crown rootdevelopment in rice.In rice (Oryza sativa), theshoot-borne crown roots are the major root typeand are initiated at lower stem nodes as part ofnormal plant development. However, theregulatory mechanism of crown rootdevelopment is poorly understood. In this work,we show that a WUSCHEL-related Homeobox(WOX) gene, WOX11, is involved in theactivation of crown root emergence and growth.WOX11 was found to be expressed in emergingcrown roots and later in cell division regions ofthe root meristem. The expression could beinduced by exogenous auxin or cytokinin.Loss-of-function mutation or downregulation ofthe gene reduced the number and the growthrate of crown roots, whereas overexpression ofthe gene induced precocious crown root growthand dramatically increased the root biomass byproducing crown roots at the upper stem nodesand the base of florets. The expressions of auxin-", "metadata": {}}
+{"_id": "20418809", "title": "", "text": "Inducible depletion of satellite cells in adult,sedentary mice impairs muscle regenerativecapacity without affecting sarcopeniaA keydeterminant of geriatric frailty is sarcopenia, theage-associated loss of skeletal muscle mass andstrength. Although the etiology of sarcopenia isunknown, the correlation during aging betweenthe loss of activity of satellite cells, which areendogenous muscle stem cells, and impairedmuscle regenerative capacity has led to thehypothesis that the loss of satellite cell activity isalso a cause of sarcopenia. We tested thishypothesis in male sedentary mice byexperimentally depleting satellite cells in youngadult animals to a degree sufficient to impairregeneration throughout the rest of their lives. Adetailed analysis of multiple muscles harvestedat various time points during aging in differentcohorts of these mice showed that the muscleswere of normal size, despite low regenerativecapacity, but did have increased fibrosis. Theseresults suggest that lifelong reduction of satellite", "metadata": {}}
+{"_id": "20419913", "title": "", "text": "Reproductive clonality in protozoanpathogens--truth or artefact?The debate aroundthe frequency and importance of geneticexchange in parasitic protozoa is now severaldecades old. Recently, fresh assertions havebeen made that predominant clonal evolutionexplains the population structures of several keyprotozoan pathogens. Here, we present analternative perspective. On the assumption thatmuch apparent clonality may be an artefact ofinadequate sampling and study design, wereview current research to define why sex mightbe so difficult to detect in protozoan parasitepopulations. In doing so, we contrast laboratorymodels of genetic exchange in parasitic protozoawith natural patterns of genetic diversity andconsider the fitness advantage of sex at differentevolutionary scales. We discuss approaches toimprove the accuracy of efforts to characterizegenetic exchange in the field. We also examinethe implications of the first population genomicstudies for the debate around sex and clonality in", "metadata": {}}
+{"_id": "20420780", "title": "", "text": "The ACF1 complex is required for DNAdouble-strand break repair in human cells.DNAdouble-strand breaks (DSBs) are repaired vianonhomologous end-joining (NHEJ) orhomologous recombination (HR), but cellularrepair processes remain elusive. We show herethat the ATP-dependent chromatin-remodelingfactors, ACF1 and SNF2H, accumulate rapidly atDSBs and are required for DSB repair in humancells. If the expression of ACF1 or SNF2H issuppressed, cells become extremely sensitive toX-rays and chemical treatments producing DSBs,and DSBs remain unrepaired. ACF1 interactsdirectly with KU70 and is required for theaccumulation of KU proteins at DSBs. TheKU70/80 complex becomes physically moreassociated with the chromatin-remodelingfactors of the CHRAC complex, which includesACF1, SNF2H, CHRAC15, and CHRAC17, aftertreatments producing DSBs. Furthermore, thefrequency of NHEJ as well as HR induced byDSBs in chromosomal DNA is significantly", "metadata": {}}
+{"_id": "20422174", "title": "", "text": "Findings to date from the ASCUS-LSIL TriageStudy (ALTS).Controversy exists in the UnitedStates regarding the proper evaluation andmanagement of low-grade squamousintraepithelial lesion (LSIL) and equivocal(atypical squamous cells of undeterminedsignificance [ASCUS, now ASC-US]) cervicalcytologic interpretations. To address this issue,the National Cancer Institute initiated theASCUS-LSIL Triage Study (ALTS). ALTS is amulticenter, randomized clinical trial designed toevaluate 3 alternative methods of management,namely, immediate colposcopy, cytologicfollow-up, and triage by human papillomavirus(HPV) DNA testing. This article summarizes themajor findings of ALTS that have been publishedto date. Patients with ASCUS (n = 3488) or LSIL(n = 1572) were randomly assigned to researcharms between November 1996 and December1998, and were monitored for 2 years. Thedisease outcome was histologic cervicalintraepithelial neoplasia (CIN) 3/cancer. The", "metadata": {}}
+{"_id": "20428155", "title": "", "text": "Marine organisms as a source of new anticanceragents.Various active anticancer agents arederived from plants and terrestrialmicroorganisms. The isolation of C-nucleosidesfrom the Caribbean sponge, Cryptotheca crypta,four decades ago, provided the basis for thesynthesis of cytarabine, the first marine-derivedanticancer agent to be developed for clinical use.Cytarabine is currently used in the routinetreatment of patients with leukaemia andlymphoma. Gemcitabine, one of its fluorinatedderivatives, has also been approved for use inpatients with pancreatic, breast, bladder, andnon-small-cell lung cancer. Over the pastdecade, several new experimental anticanceragents derived from marine sources haveentered preclinical and clinical trials. This fieldhas expanded significantly as a result ofimprovements in the technology of deep-seacollection, extraction, and large-scale productionthrough aquaculture and synthesis. In thispaper, examples of marine-derived experimental", "metadata": {}}
+{"_id": "20454006", "title": "", "text": "A randomized, placebo-controlled trial ofdiindolylmethane for breast cancer biomarkermodulation in patients takingtamoxifenDiindolylmethane (DIM), a bioactivemetabolite of indole-3-carbinol found incruciferous vegetables, has proposed cancerchemoprevention activity in the breast. There islimited evidence of clinically relevant activity ofDIM or long-term safety data of its regular use. Arandomized, double-blind, placebo-controlledtrial was conducted to determine the activity andsafety of combined use of BioResponse DIM®(BR-DIM) with tamoxifen. Women prescribedtamoxifen (n = 130) were randomly assignedoral BR-DIM at 150 mg twice daily or placebo, for12 months. The primary study endpoint waschange in urinary 2/16α-hydroxyestrone(2/16α-OHE1) ratio. Changes in4-hydroxyestrone (4-OHE1), serum estrogens,sex hormone-binding globulin (SHBG), breastdensity, and tamoxifen metabolites wereassessed. Ninety-eight women (51 placebo, 47", "metadata": {}}
+{"_id": "20456030", "title": "", "text": "Intracellular coenzymes as natural biomarkersfor metabolic activities and mitochondrialanomalies.Mitochondria play a pivotal role inenergy metabolism, programmed cell death andoxidative stress. Mutated mitochondrial DNA indiseased cells compromises the structure of keyenzyme complexes and, therefore, mitochondrialfunction, which leads to a myriad ofhealth-related conditions such as cancer,neurodegenerative diseases, diabetes and aging.Early detection of mitochondrial and metabolicanomalies is an essential step towards effectivediagnoses and therapeutic intervention. Reducednicotinamide adenine dinucleotide (NADH) andflavin adenine dinucleotide (FAD) play importantroles in a wide range of cellularoxidation-reduction reactions. Importantly,NADH and FAD are naturally fluorescent, whichallows noninvasive imaging of metabolicactivities of living cells and tissues. Furthermore,NADH and FAD autofluorescence, which can beexcited using distinct wavelengths for", "metadata": {}}
+{"_id": "20457190", "title": "", "text": "Biochemical differences in the alphabeta T cellreceptor.CD3 surface complex between CD8+and CD4+ human mature T lymphocytes.Wehave reported the existence of biochemical andconformational differences in the alphabeta T cellreceptor (TCR) complex between CD4(+) andCD8(+) CD3gamma-deficient (gamma(-))mature T cells. In the present study, we havefurthered our understanding and extended theobservations to primary T lymphocytes fromnormal (gamma(+)) individuals. SurfaceTCR.CD3 components from CD4(+) gamma(-) Tcells, other than CD3gamma, were detectableand similar in size to CD4(+) gamma(+)controls. Their native TCR.CD3 complex was alsosimilar to CD4(+) gamma(+) controls, except foran alphabeta(deltaepsilon)(2)zeta(2) instead ofan alphabetagammaepsilondeltaepsilonzeta(2)stoichiometry. In contrast, the surface TCRalpha,TCRbeta, and CD3delta chains of CD8(+)gamma(-) T cells did not possess their usualsizes. Using confocal immunofluorescence,", "metadata": {}}
+{"_id": "20459964", "title": "", "text": "Circulating mitochondrial DNA in serum ofpatients with granulomatosis withpolyangiitis.Neutrophil is a key cell inpathophysiology of granulomatosis withpolyangiitis. Recently, neutrophil extracellulartraps were described in this disease.Mitochondrial DNA is also released during trapsformation. We measured circulating cell-freemitochondrial and genomic DNA in serum ofpatients with granulomatosis with polyangiitis.Subjects with the disease (14 active and 11 inremission stage) and 10 healthy controls wereenrolled. Quantitative real-time polymerasechain reaction (PCR) was used to measure 79base pairs (bp) and 230 bp mtDNA fragments.Alu repeats were quantified to evaluateabundance of nuclear DNA in serum at thepresence of plasmid control. Both fragments ofmtDNA (79 bp and 230 bp) and genomic DNAwere elevated significantly in granulomatosiswith polyangiitis compared to controls. Only theshorter 79 bp mtDNA correlated with active", "metadata": {}}
+{"_id": "20460020", "title": "", "text": "Estrogen receptor-alpha promotes alternativemacrophage activation during cutaneousrepair.Efficient local monocyte/macrophagerecruitment is critical for tissue repair. Recruitedmacrophages are polarized toward classical(proinflammatory) or alternative (prohealing)activation in response to cytokines, with tighttemporal regulation crucial for efficient woundrepair. Estrogen acts as a potentanti-inflammatory regulator of cutaneoushealing. However, an understanding ofestrogen/estrogen receptor (ER) contribution tomacrophage polarization and subsequent localeffects on wound healing is lacking. Here weidentify, to our knowledge previously unreported,a role whereby estrogen receptor α (ERα)signaling preferentially polarizes macrophagesfrom a range of sources to an alternativephenotype. Cell-specific ER ablation studiesconfirm an in vivo role for inflammatory cell ERα,but not ERβ, in poor healing associated with analtered cytokine profile and fewer alternatively", "metadata": {}}
+{"_id": "20471181", "title": "", "text": "Disturbance in cerebral spinal fluid sphingolipidcontent is associated with memory impairment insubjects infected with the humanimmunodeficiency virusDespite widespread useof antiretroviral therapies to control replication ofthe human immunodeficiency virus (HIV),dysfunctions of cognition that are collectivelytermed HIV-associated neurocognitive disorders(HAND) still occur in approximately 50% of thoseinfected by the virus. Currently there is not abiomarker that can identify HIV-infected peoplewho are at risk for the development of HAND.Previous studies have identified particularsphingolipid species that are dysregulated inHAND, but the neurocognitive correlates of thesebiochemical findings are not currentlyunderstood. To address this question, wecompared cerebrospinal fluid (CSF) levels ofsphingomyelin, ceramide, and sterol species withperformance on standard neurological testsdesigned to assess the function of multiplecognitive and motor domains in HIV-infected", "metadata": {}}
+{"_id": "20473074", "title": "", "text": "An observational study fluid balance and patientoutcomes in the Randomized Evaluation ofNormal vs. Augmented Level of ReplacementTherapy trial.OBJECTIVE To examineassociations between mean daily fluid balanceduring intensive care unit study enrollment andclinical outcomes in patients enrolled in theRandomized Evaluation of Normal vs. AugmentedLevel (RENAL) replacement therapy study.DESIGN Statistical analysis of data frommulticenter, randomized, controlled trials.SETTING Thirty-five intensive care units inAustralia and New Zealand. PATIENTS Cohort of1453 patients enrolled in the RENAL study.INTERVENTIONS We analyzed the associationbetween daily fluid balance on clinical outcomesusing multivariable logistic regression, Coxproportional hazards, time-dependent analysis,and repeated measure analysis models.MEASUREMENTS AND MAIN RESULTS Duringintensive care unit stay, mean daily fluid balanceamong survivors was -234 mL/day compared", "metadata": {}}
+{"_id": "20491205", "title": "", "text": "Prison health care: a review of the literature.Theprison population is increasing and the healthproblems of prisoners are considerable. Prison isdesigned with punishment, correction andrehabilitation to the community in mind andthese goals may conflict with the aims of healthcare. A literature review showed that the mainissues in prison health care are mental health,substance abuse and communicable diseases.Women prisoners and older prisoners have needswhich are distinct from other prisoners. Healthpromotion and the health of the communityoutside prisons are desirable aims of prisonhealth care. The delivery of effective health careto prisoners is dependent upon partnershipbetween health and prison services andtelemedicine is one possible mode of delivery.", "metadata": {}}
+{"_id": "20492020", "title": "", "text": "A Brief History of Long-Term PotentiationSincethe discovery of long-term potentiation (LTP) in1973, thousands of papers have been publishedon this intriguing phenomenon, which provides acompelling cellular model for learning andmemory. Although LTP has suffered considerablegrowing pains over the years, LTP has finallycome of age. Here the rich history of LTP isreviewed. These are exciting times and the paceof discovery is remarkable.", "metadata": {}}
+{"_id": "20501163", "title": "", "text": "Tumor-Induced IL-6 Reprograms HostMetabolism to Suppress Anti-tumor ImmunityInpatients with cancer, the wasting syndrome,cachexia, is associated with caloric deficiency.Here, we describe tumor-induced alterations ofthe host metabolic response to caloric deficiencythat cause intratumoral immune suppression. Inpre-cachectic mice with transplanted colorectalcancer or autochthonous pancreatic ductaladenocarcinoma (PDA), we find that IL-6 reducesthe hepatic ketogenic potential throughsuppression of PPARalpha, the transcriptionalmaster regulator of ketogenesis. When thesemice are challenged with caloric deficiency, theresulting relative hypoketonemia triggers amarked rise in glucocorticoid levels. Multipleintratumoral immune pathways are suppressedby this hormonal stress response. Moreover,administering corticosterone to elevate plasmacorticosterone to a level that is lower than thatoccurring in cachectic mice abolishes theresponse of mouse PDA to an immunotherapy", "metadata": {}}
+{"_id": "20524091", "title": "", "text": "Chaperoning stem cells: a role for heat shockproteins in the modulation of stem cellself-renewal and differentiation?Self-renewal anddifferentiation of stem cells are tightly regulatedprocesses subject to intrinsic and extrinsicsignals. Molecular chaperones andco-chaperones, especially heat shock proteins(Hsp), are ubiquitous molecules involved in themodulation of protein conformational andcomplexation states. The function of Hsp, whichare typically associated with stress response andtolerance, is well characterized in differentiatedcells, while their role in stem cells remainsunclear. It appears that embryonic stem cellsexhibit increased stress tolerance andconcomitant high levels of chaperone expression.This review critically evaluates stem cell researchfrom a molecular chaperone perspective.Furthermore, we propose a model ofchaperone-modulated self-renewal in mouseembryonic stem cells.", "metadata": {}}
+{"_id": "20526907", "title": "", "text": "How much alcohol and how often? Populationbased case-control study of alcohol consumptionand risk of a major coronary event.OBJECTIVETo quantify the effects of quantity and frequencyof alcohol consumption on risk of acutemyocardial infarction and coronary death.DESIGN Case-control study. SETTING LowerHunter region of New South Wales, Australia,1983-94. SUBJECTS Men and women aged 35-69years. MAIN OUTCOME MEASURE Acutemyocardial infarction or coronary death.RESULTS Alcohol consumption patterns werecompared between 11,511 cases of acutemyocardial infarction or coronary death and6077 controls randomly selected from the samestudy population. After adjusting for the effectsof age, smoking, and medical history, men andwomen who consumed one or two drinks ofalcohol on five or six days a week had areduction in risk of a major coronary eventcompared with men and women who werenon-drinkers (odds ratios: men 0.31 (95%", "metadata": {}}
+{"_id": "20532591", "title": "", "text": "Tracking adipogenesis during white adiposetissue development, expansion andregenerationWhite adipose tissue displays highplasticity. We developed a system for theinducible, permanent labeling of matureadipocytes that we called the AdipoChasermouse. We monitored adipogenesis duringdevelopment, high-fat diet (HFD) feeding andcold exposure. During cold-induced 'browning' ofsubcutaneous fat, most 'beige' adipocytes stemfrom de novo–differentiated adipocytes. DuringHFD feeding, epididymal fat initiatesadipogenesis after 4 weeks, whereassubcutaneous fat undergoes hypertrophy for aperiod of up to 12 weeks. Gonadal fat developspostnatally, whereas subcutaneous fat developsbetween embryonic days 14 and 18. Our resultshighlight the extensive differences in adipogenicpotential in various fat depots.", "metadata": {}}
+{"_id": "20544428", "title": "", "text": "Blockade of adrenoreceptors inhibits the splenicresponse to stroke.Recent studies havehighlighted the involvement of the peripheralimmune system in delayed cellular degenerationafter stroke. In the permanent middle cerebralartery occlusion (MCAO) model of stroke, thespleen decreases in size. This reduction occursthrough the release of splenic immune cells.Systemic treatment with human umbilical cordblood cells (HUCBC) 24 h post-stroke blocks thereduction in spleen size while significantlyreducing infarct volume. Splenectomy 2 weeksprior to MCAO also reduces infarct volume,further demonstrating the detrimental role of thisorgan in stroke-induced neurodegeneration.Activation of the sympathetic nervous systemafter MCAO results in elevated catecholaminelevels both at the level of the spleen, throughdirect splenic innervation, and throughout thesystemic circulation upon release from theadrenal medulla. These catecholamines bind tosplenic alpha and beta adrenoreceptors. This", "metadata": {}}
+{"_id": "20554003", "title": "", "text": "Effects of Thiazolidinediones on Stroke Recovery:A Case-Matched ControlledStudyAnti-inflammatory therapy decreasesinfarct size and enhances stroke recovery.Thiazolidinedione peroxisomeproliferator-activated receptor (PPAR)gammaagonists have potent anti-inflammatory andinsulin-sensitizing anti-diabetic actions. Thirtystroke patients with type 2 diabetes admitted foracute inpatient stroke rehabilitation receivingpioglitazone or rosiglitazone were matched forage, sex, initial FIMTM score and intervalpost-stroke with 30 stroke patients with type 2diabetes not receiving thiazolidinediones.Relevant outcome variables were compared forboth groups. The thiazolidinedione treated groupshowed significantly greater mean improvementin FIMTM score compared to control group (25.6± 10.2 SD vs. 19.8 ± 10.5, respectively, P =0.015). There was no significant difference inlength of rehabilitation hospital stay (24.2 ± 7.6vs. 25.1 ± 7.4 days, P = 0.657) or final", "metadata": {}}
+{"_id": "20568364", "title": "", "text": "Crosstalk between tumor and endothelial cellspromotes tumor angiogenesis by MAPK activationof Notch signaling.While significant progress hasbeen made in understanding the induction oftumor vasculature by secreted angiogenicfactors, little is known regardingcontact-dependent signals that promote tumorangiogenesis. Here, we report that the Notchligand Jagged1 induced by growth factors viamitogen-activating protein kinase (MAPK) inhead and neck squamous cell carcinoma(HNSCC) cells triggered Notch activation inneighboring endothelial cells (ECs) and promotedcapillary-like sprout formation.Jagged1-expressing HNSCC cells significantlyenhanced neovascularization and tumor growthin vivo. Moreover, the level of Jagged1 wassignificantly correlated with tumor blood vesselcontent and associated with HNSCCdevelopment. Our results elucidate a novelmechanism by which the direct interplaybetween tumor cells and ECs promotes", "metadata": {}}
+{"_id": "20585600", "title": "", "text": "A Sequential splicing mechanism promotesselection of an optimal exon by repositioning adownstream 5' splice site in preprotachykininpre-mRNA.To explore the structural basis ofalternative splicing, we have analyzed thesplicing of pre-mRNAs containing an optionalexon, E4, from the preprotachykinin gene. Thisgene encodes substance P and related tachykininpeptides by alternative splicing of a commonpre-mRNA. We have shown that alternativesplicing of preprotachykinin pre-mRNA occurs bypreferential skipping of optional E4. Thecompeting mechanism that incorporates E4 intothe final spliced RNA is constrained by an initialblock to splicing of the immediate upstreamintervening sequence (IVS), IVS3. This block isrelieved by sequential splicing, in which theimmediate downstream IVS4 is removed first.The structural change resulting from the firstsplicing event is directly responsible foractivation of IVS3 splicing. This structuralrearrangement replaces IVS4 sequences with E5", "metadata": {}}
+{"_id": "20602517", "title": "", "text": "Melatonin and the circadian regulation of sleepinitiation, consolidation, structure, and the sleepEEG.The endogenous circadian rhythm ofmelatonin, driven by the suprachiasmaticnucleus, exhibits a close association with theendogenous circadian component of the sleeppropensity rhythm and the endogenous circadiancomponent of the variation inelectroencephalogram (EEG) oscillations such assleep spindles and slow waves. This associationis maintained even when the sleep-wake cycle isdesynchronized from the endogenous circadianrhythm of melatonin. Administration of melatoninduring the day increases daytime sleeppropensity as indexed by both the latency tosleep onset and sleep consolidation. The EEGduring daytime sleep after melatoninadministration exhibits characteristicsreminiscent of the nocturnal sleep EEG, that is,increased sleep spindle activity and reducedslow-wave sleep and slow-wave activity, asdetected by quantitative EEG analysis.", "metadata": {}}
+{"_id": "20606520", "title": "", "text": "Long-term survival, quality of life, andquality-adjusted life-years among critically illelderly patients.OBJECTIVES To assess mortality,quality of life (QOL), and quality-adjustedlife-years (QALYs) for critically ill elderlypatients. DESIGN Cross-sectional survey.SETTING A ten-bed medical-surgical intensivecare unit (ICU) in a tertiary care universityhospital. PATIENTS The study group included882 elderly patients (> or =65 yrs of age) and1,827 controls (<65 yrs of age) treated duringthe period of 1995 to 2000. INTERVENTIONNone. MEASUREMENTS AND MAIN RESULTSMortality was assessed during the ICU andhospital stays, and 12, 24, and 36 months afterICU discharge. The cumulative 3-yr mortalityrate among the elderly (57%) was higher (p <.05) than that among the controls (40%). Themajority (66%) of the elderly nonsurvivors diedwithin 1 month after intensive care discharge. Allelderly patients with day-1 Sequential OrganFailure (SOFA) scores >15 died during the ICU", "metadata": {}}
+{"_id": "20608982", "title": "", "text": "Recent developments and complexities inneutrophil transmigration.PURPOSE OF REVIEWAs the migration of neutrophils from blood toinflamed tissues is an essential component ofinnate immunity and a key contributing factor tothe pathogenesis of inflammatory disorders, thisaspect of leukocyte biology continues to be ahighly dynamic field of research. This reviewsummarizes recent findings in this area, focusingon the mechanisms that mediate neutrophiltransmigration, an area where significantprogress has been made. RECENT FINDINGS Thetopics to be covered will include responses thatare prerequisite to neutrophil migration throughvenular walls, such as leukocyte luminal crawlingand cellular and molecular changes in leukocytesand endothelial cells (e.g. formation ofprotrusions) that collectively support leukocytetransendothelial cell migration. Advances in bothparacellular and transcellular neutrophilmigration through endothelial cells will bediscussed, addressing the associated roles and", "metadata": {}}
+{"_id": "20610390", "title": "", "text": "Exploring the epidemiological characteristics ofcancers of unknown primary site in an Australianpopulation: implications for research and clinicalcare.OBJECTIVES To investigate incidence,mortality and case survival trends for cancer ofunknown primary site (CUP) and consider clinicalimplications. METHOD South Australian CancerRegistry data were used to calculateage-standardised incidence and mortality ratesfrom 1977 to 2004. Disease-specific survivals,socio-demographic, histological and secularpredictors of CUP, compared with cancers ofknown primary site, and of CUP histologicaltypes, using multivariable logistic regressionwere investigated. RESULTS Incidence andmortality rates increased approximately 60%between 1977--80 and 1981--84. Rates peakedin 1993--96. Male to female incidence andmortality rate ratios approximated 1.3:1.Incidence and mortality rates increased with age.The odds of unspecified histological type,compared with the more common", "metadata": {}}
+{"_id": "20610557", "title": "", "text": "Alkylating agent melphalan augments theefficacy of adoptive immunotherapy usingtumor-specific CD4+ T cells.In recent years, theimmune-potentiating effects of some widely usedchemotherapeutic agents have been increasinglyappreciated. This provides a rationale forcombining conventional chemotherapy withimmunotherapy strategies to achieve durabletherapeutic benefits. Previous studies haveimplicated the immunomodulatory effects ofmelphalan, an alkylating agent commonly usedto treat multiple myeloma, but the underlyingmechanisms remain obscure. In the presentstudy, we investigated the impact of melphalanon endogenous immune cells as well asadoptively transferred tumor-specific CD4(+) Tcells in tumor-bearing mice. We showed thatmelphalan treatment resulted in a rapid burst ofinflammatory cytokines and chemokines duringthe cellular recovery phase aftermelphalan-induced myelodepletion andleukodepletion. After melphalan treatment,", "metadata": {}}
+{"_id": "20611846", "title": "", "text": "Influence of cigarette smoking on inhaledcorticosteroid treatment in mildasthma.BACKGROUND Although inhaledcorticosteroids have an established role in thetreatment of asthma, studies have tended toconcentrate on non-smokers and little is knownabout the possible effect of cigarette smoking onthe efficacy of treatment with inhaled steroids inasthma. A study was undertaken to investigatethe effect of active cigarette smoking onresponses to treatment with inhaledcorticosteroids in patients with mild asthma.METHODS The effect of treatment with inhaledfluticasone propionate (1000 microg daily) orplacebo for 3 weeks was studied in a doubleblind, prospective, randomised, placebocontrolled study of 38 steroid naïve adultasthmatic patients (21 non-smokers). Efficacywas assessed using morning and evening peakexpiratory flow (PEF) readings, spirometricparameters, bronchial hyperreactivity, andsputum eosinophil counts. Comparison was made", "metadata": {}}
+{"_id": "20620012", "title": "", "text": "Hitting the target: emerging technologies in thesearch for kinase substrates.Throughphosphorylation, protein kinases can alter theactivity, localization, protein association, andstability of their targets. Despite the importanceto our understanding of all aspects of cellbiology, progress toward identifying bona fidesubstrates of specific protein kinases has beenslow. Traditionally used techniques to identifytrue kinase substrates, such as genetics, yeasttwo-hybrid screens, and biochemical purification,are often laborious and unreliable. However,several new approaches have recently beendeveloped and used successfully to identifygenuine in vivo substrates of certain proteinkinases. These methods include screening forphosphorylation of proteins from phageexpression libraries, peptide library screens todetermine optimal motifs favored by specifickinases, the use of phospho-motif antibodies,and an approach that uses structurally alteredkinases and allele-specific adenosine", "metadata": {}}
+{"_id": "20630805", "title": "", "text": "Histone phosphorylation: a chromatinmodification involved in diverse nuclearevents.Histone posttranslational modificationsare key components of diverse processes thatmodulate chromatin structure. These marksfunction as signals during variouschromatin-based events, and act as platforms forrecruitment, assembly or retention ofchromatin-associated factors. The best-knownfunction of histone phosphorylation takes placeduring cellular response to DNA damage, whenphosphorylated histone H2A(X) demarcates largechromatin domains around the site of DNAbreakage. However, multiple studies have alsoshown that histone phosphorylation plays crucialroles in chromatin remodeling linked to othernuclear processes. In this review, we summarizethe current knowledge of histonephosphorylation and describe the many kinasesand phosphatases that regulate it. We discussthe key roles played by this histone mark in DNArepair, transcription and chromatin compaction", "metadata": {}}
+{"_id": "20645335", "title": "", "text": "Neurodevelopmental Outcome After a SingleCourse of Antenatal Steroids in Children BornPreterm: A Systematic Review andMeta-analysis.OBJECTIVE To systematicallyreview and integrate data on theneurodevelopmental outcome of children afteradministration of a single course of antenatalcorticosteroids for threatened preterm labor.DATA SOURCES MEDLINE, Scopus, CENTRAL,and www.clinicaltrials.gov (inception to August2014) using combinations of the terms\"prenatal,\" \"antenatal,\" \"cortico*,\" \"*steroid*,\"\"betamethasone,\" \"dexamethasone,\"\"neurodevelopment*,\" \"*development*,\" and\"follow-up. \" We perused the references of theretrieved articles. METHODS OF STUDYSELECTION We included randomized andnonrandomized trials reporting on theneurodevelopmental outcomes of children whosemothers were administered a single course ofbetamethasone or dexamethasone antenatallyfor threatened preterm birth as opposed to", "metadata": {}}
+{"_id": "20645538", "title": "", "text": "Prognostic impact of minimal pleural effusion innon-small-cell lung cancer.PURPOSE Minimal (<10 mm thick) pleural effusion (PE) mayrepresent an early phase of malignant PE, but itsclinical relevance has rarely been studied.Therefore, we examined the proportion ofminimal PE in patients with non-small-cell lungcancer (NSCLC) and its impact on survival. Wealso considered possible accumulationmechanisms in our data set. PATIENTS ANDMETHODS On the basis of PE status from chestcomputed tomography scans at diagnosis, 2,061patients were classified into three groups: no PE,minimal PE, and malignant PE. Twenty-onevariables associated with four factors-patient,stage migration, tumor, and treatment-wereinvestigated for correlation with survival.RESULTS Minimal PE presented in 272 patients(13.2%). Of 2,061 patients, the proportion ofeach stage was the following: 5.2% stage I,10.9% stage II, 13.2% stage IIIA, 23.8% stageIIIB, and 13.9% stage IV. Minimal PE correlated", "metadata": {}}
+{"_id": "20646904", "title": "", "text": "Fusion proteins for versatile antigen targeting tocell surface receptors reveal differential capacityto prime immune responses.Targeting of proteinsto APCs is an attractive strategy for elicitingadaptive immune responses. However, therelationship between the choice of the targetedreceptor and the quality and quantity ofresponses remains poorly understood. Wedescribe a strategy for expression of Agsincluding hydrophobic proteins as soluble fusionproteins that are optimized forproteasome-dependent MHC class I-restrictedcross-presentation and form stable complexeswith a wide variety of targeting Abs. Upon s.c.immunization, these complexes were initiallytaken up by CD169+ lymph node subcapsularsinus macrophages. In the OVA model system,receptor-targeted antigenic complexes primedspecific T and B cell responses in vitro and invivo at least 100-fold more efficiently than Agalone. Comparison of 10 targeting receptorsallowed us to establish a ranking with respect to", "metadata": {}}
+{"_id": "20649327", "title": "", "text": "A sequential model for peptide binding andtransport by the transporters associated withantigen processing.The TAP proteins translocateantigenic peptides into the endoplasmicreticulum. Investigation of the specificity of thisprocess has been complicated byTAP-independent factors that influence theamount of peptide that accumulates in the ER intransport assays. We have developed anoverexpression system in which binding ofpeptides to the TAP substrate-binding site andpeptide transport by TAP can be quantifiedseparately. Efficiency of peptide accumulation inthe ER parallels affinity for the TAPsubstrate-binding site, but can be modified byinteraction with the glycosylation system withinthe ER and, probably, peptide efflux. Randompeptide mixtures of 9-16 aa display significantlyhigher affinity for the binding site than mixturesof shorter or longer peptides. Peptide binds toTAP heteromers in the absence of ATP and isreleased by the binding of ATP, suggesting a", "metadata": {}}
+{"_id": "20649735", "title": "", "text": "Outcome of repeated radiosurgery for recurrentmetastatic brain tumors.OBJECTIVE Weinvestigated the outcome of repeated gammaknife radiosurgery (GKS) for local or remoterecurrence after initial radiosurgery. MATERIALAND METHODS We retrospectively reviewed 204patients who were treated with GKS. Amongthem 43 patients (21%) underwent GKS morethan once. The second GKS was given forrecurrence at the previously treated sites in 16patients, new lesions at remote sites in 13, andboth local recurrence and new lesions in 14.RESULTS The median survival from the first GKSwas 36 (7-190) weeks in all patients and 68(16-156) weeks in 43 patients with repeatedGKS. The median time from the first GKS to thesecond was 37 weeks. The median survival fromthe second radiosurgical intervention was 32(7-132) weeks. Local control rate at 6 monthsafter salvage GKS was 90.7%. RPA class was thecommonly dominant prognostic factor in bothinitial and salvage GKS. CONCLUSION", "metadata": {}}
+{"_id": "20659283", "title": "", "text": "Human CYP3A4 and murine Cyp3A11 areregulated by equol and genistein via thepregnane X receptor in a species-specificmanner.Pregnane X receptor (PXR) is animportant component of the body's adaptivedefense system responsible for the elimination ofvarious toxic xenobiotics. PXR activation byendogenous and exogenous chemicals, includingsteroids, antibiotics, bile acids, and herbalcompounds, results in induction of drugmetabolism. We investigated the ability of theisoflavones genistein, daidzein, and the daidzeinmetabolite equol to activate human and mousePXR in vitro using cell-based transienttransfection studies and primary hepatocytesand in vivo in a mouse model. In transienttransfection assays, the isoflavones genisteinand daidzein activate full-length, wild-typemouse PXR, but not a mutant form, withgenistein being the most potent. In contrast,equol was a more potent activator of human PXRthan genistein or daidzein. In a mammalian", "metadata": {}}
+{"_id": "20672596", "title": "", "text": "Metabolism of glucose, glutamine, long-chainfatty acids and ketone bodies by murinemacrophages.Maximum activities of some keyenzymes of metabolism were studied in elicited(inflammatory) macrophages of the mouse andlymph-node lymphocytes of the rat. The activityof hexokinase in the macrophage is very high, ashigh as that in any other major tissue of thebody, and higher than that of phosphorylase or6-phosphofructokinase, suggesting that glucoseis a more important fuel than glycogen and thatthe pentose phosphate pathway is also importantin these cells. The latter suggestion is supportedby the high activities of bothglucose-6-phosphate dehydrogenase and6-phosphogluconate dehydrogenase. However,the rate of glucose utilization by 'resting'macrophages incubated in vitro is less than the10% of the activity of 6-phosphofructokinase:this suggests that the rate of glycolysis isincreased dramatically during phagocytosis orincreased secretory activity. The macrophages", "metadata": {}}
+{"_id": "20675284", "title": "", "text": "TGF-beta inhibition of endothelial cellproliferation: alteration of EGF binding andEGF-induced growth-regulatory (competence)gene expression.Transforming growthfactor-beta (TGF-beta) inhibits the growth ofendothelial cells derived from various sources,including human umbilical vein, bovine aorta,and rat heart. Long-term exposure of rat heartendothelial cells to TGF-beta also inducesdramatic changes in morphology that arecharacteristic of senescent cells. These changesare accompanied by a decrease in the number ofhigh-affinity receptors for epidermal growthfactor (EGF), with almost no change in totalreceptor number. Additionally, the EGF-inducedexpression of specific competence genes (c-myc,JE, KC) is decreased, whereas the induction ofc-fos gene expression by EGF is unaltered byTGF-beta treatment. These data suggest thatgrowth inhibitors such as TGF-beta may act byaltering the cell's response to growth-stimulatoryfactors.", "metadata": {}}
+{"_id": "20690388", "title": "", "text": "Human NK cells in acute myeloid leukaemiapatients: analysis of NK cell-activating receptorsand their ligandsNatural killer (NK) cell activationis strictly regulated to ensure that healthy cellsare preserved, but tumour-transformed orvirus-infected cells are recognized andeliminated. To carry out this selective killing, NKcells have an ample repertoire of receptors ontheir surface. Signalling by inhibitory andactivating receptors by interaction with theirligands will determine whether the NK cellbecomes activated and kills the target cell. Here,we show reduced expression of NKp46, NKp30,DNAM-1, CD244 and CD94/NKG2C activatingreceptors on NK cells from acute myeloidleukaemia patients. This reduction may beinduced by chronic exposure to their ligands onleukaemic blasts. The analysis of ligands for NKcell-activating receptors showed that leukaemicblasts from the majority of patients expressligands for NK cell-activating receptors. DNAM-1ligands are frequently expressed on blasts,", "metadata": {}}
+{"_id": "20696397", "title": "", "text": "Production of interleukin-6 in contracting humanskeletal muscles can account for theexercise-induced increase in plasmainterleukin-6.1. Plasma interleukin (IL)-6concentration is increased with exercise and ithas been demonstrated that contracting musclescan produce IL-The question addressed in thepresent study was whether the IL-6 productionby contracting skeletal muscle is of such amagnitude that it can account for the IL-6accumulating in the blood. 2. This was studied insix healthy males, who performed one-leggeddynamic knee extensor exercise for 5 h at 25 W,which represented 40% of peak power output(Wmax). Arterial-femoral venous (a-fv)differences over the exercising and the restingleg were obtained before and every hour duringthe exercise. Leg blood flow was measured inparallel by the ultrasound Doppler technique.IL-6 was measured by enzyme-linkedimmunosorbent assay (ELISA). 3. Arterialplasma concentrations for IL-6 increased 19-fold", "metadata": {}}
+{"_id": "20697217", "title": "", "text": "Symptoms of hypoglycemia in children withIDDM.OBJECTIVE To examine the symptoms ofhypoglycemia in children with insulin-dependentdiabetes, from the perspective both of the childand of the child's parents, and to compare thesymptom reporting of the diabetic children withthat of adult diabetic patients. RESEARCHDESIGN AND METHODS Interviews wereconducted with 100 parents and 43 of theirchildren. The frequency and intensity ofsymptoms of hypoglycemia were documentedusing a structured interview and classified intogroups using Principal Components Analysis(PCA). RESULTS Diabetic children and theirparents showed close agreement concerning therelative frequency and the intensity of symptomsreported. PCA of the symptom reports showedthat diabetic children and their parents identifiedthe same distinct subgroups ofhypoglycemia-related symptoms: behavioraldisturbance and autonomic-neuroglycopenicsubgroups. CONCLUSIONS Hypoglycemic", "metadata": {}}
+{"_id": "20707861", "title": "", "text": "Comparative Protein Structure Modeling UsingMODELLER.Comparative protein structuremodeling predicts the three-dimensionalstructure of a given protein sequence (target)based primarily on its alignment to one or moreproteins of known structure (templates). Theprediction process consists of fold assignment,target-template alignment, model building, andmodel evaluation. This unit describes how tocalculate comparative models using the programMODELLER and how to use the ModBasedatabase of such models, and discusses all foursteps of comparative modeling, frequentlyobserved errors, and some applications.Modeling lactate dehydrogenase fromTrichomonas vaginalis (TvLDH) is described asan example. The download and installation of theMODELLER software is also described. © 2016 byJohn Wiley & Sons, Inc.", "metadata": {}}
+{"_id": "20722510", "title": "", "text": "IL-6 as a keystone cytokine in health anddiseaseInterleukin 6 (IL-6) has a broad effect oncells of the immune system and those not of theimmune system and often displays hormone-likecharacteristics that affect homeostatic processes.IL-6 has context-dependent pro- andanti-inflammatory properties and is nowregarded as a prominent target for clinicalintervention. However, the signaling cassettethat controls the activity of IL-6 is complicated,and distinct intervention strategies can inhibitthis pathway. Clinical experience withantagonists of IL-6 has raised new questionsabout how and when to block this cytokine toimprove disease outcome and patient wellbeing.Here we discuss the effect of IL-6 on innate andadaptive immunity and the possible advantagesof various antagonists of IL-6 and consider howthe immunobiology of IL-6 may inform clinicaldecisions.", "metadata": {}}
+{"_id": "20725212", "title": "", "text": "Chaperoning 5S RNA assembly.In eukaryotes,three of the four ribosomal RNAs (rRNAs)—the5.8S, 18S, and 25S/28S rRNAs—are processedfrom a single pre-rRNA transcript and assembledinto ribosomes. The fourth rRNA, the 5S rRNA, istranscribed by RNA polymerase III and isassembled into the 5S ribonucleoprotein particle(RNP), containing ribosomal proteins Rpl5/uL18and Rpl11/uL5, prior to its incorporation intopreribosomes. In mammals, the 5S RNP is also acentral regulator of the homeostasis of the tumorsuppressor p53. The nucleolar localization of the5S RNP and its assembly into preribosomes areperformed by a specialized complex composed ofRpf2 and Rrs1 in yeast or Bxdc1 and hRrs1 inhumans. Here we report the structural andfunctional characterization of the Rpf2-Rrs1complex alone, in complex with the 5S RNA, andwithin pre-60S ribosomes. We show that theRpf2-Rrs1 complex contains a specialized 5S RNAE-loop-binding module, contacts the Rpl5protein, and also contacts the ribosome", "metadata": {}}
+{"_id": "20732789", "title": "", "text": "Chronic obstructive pulmonary disease andneutrophil infiltration: role of cigarette smokeand cyclooxygenase products.Cigarette smoke isthe main cause of chronic obstructive pulmonarydisease (COPD), where it can contribute to theobserved airway inflammation. PGE(2) isproduced within human airways, and both pro-and anti-inflammatory activities have beenreported. We quantitated PGE(2) concentrationsin induced sputum supernatants from differentgroups of subjects and correlated the obtainedvalues to neutrophil infiltration as well as to theexpression of cyclooxygenase-2 (COX-2).Cigarette smoke extract (CSE) was used toevaluate the effect of smoking on COX-2 andPGE(2) receptor expression as well as on PGE(2)release in neutrophils and alveolar macrophages(AM) obtained from normal donors. The effectsof PGE(2) and of PGE receptor agonists andantagonists were evaluated on the adhesion ofneutrophil to a human bronchial epithelial cellline (16HBE). PGE(2) levels, COX-2 expression,", "metadata": {}}
+{"_id": "20738970", "title": "", "text": "Non-receptor tyrosine kinase Etk is involved inthe apoptosis of small cell lung cancercells.Epithelial and endothelial tyrosine kinase(Etk), also known as Bmx (bone marrow Xkinase) plays an important role in apoptosis ofepithelial cells. The goal of this study was toinvestigate whether Etk is involved in apoptosisof small cell lung cancer (SCLC) cells andcorrelated with the expression levels ofapoptosis-associated proteins such as Bcl-2,Bcl-X(L) and p53. One hundred and seventy-onecases of lung cancer specimens includingseventy-one SCLCs and one hundred NSCLCswere immunostained for Etk, Bcl-2, Bcl-X(L) andp53. Parental SCLC H446 cell line, and its subline(H446-Etk) that overexpresses Etk, were used tostudy the role of Etk in apoptosis induced bydoxorubicin. It was found that high expression ofEtk occurs in 74.6% of SCLC cases, but only in40% of NSCLC cases, and there is markeddifference in the expression levels of Bcl-2,Bcl-X(L) and p53 between Etk-positive and", "metadata": {}}
+{"_id": "20743803", "title": "", "text": "No Pasaran! Role of the axon initial segment inthe regulation of protein transport and themaintenance of axonal identity.The transmissionof information in the brain depends on the highlypolarized architecture of neurons. A number ofcellular transport processes support thisorganization, including active targeting ofproteins and passive corralling betweencompartments. The axon initial segment (AIS),which separates the somatodendritic and axonalcompartments, has a key role in neuronalphysiology, as both the initiation site of actionpotentials and the gatekeeper of the axonalarborization. Over the years, the AIS maincomponents and their interactions have beenprogressively unraveled, as well as their role inthe AIS assembly and maintenance. Twomechanisms have been shown to contribute tothe regulation of protein transport at the AIS: asurface diffusion barrier and an intracellulartraffic filter. However, a molecular understandingof these processes is still lacking. In the view of", "metadata": {}}
+{"_id": "20746604", "title": "", "text": "The effectiveness of right heart catheterization inthe initial care of critically ill patients. SUPPORTInvestigators.OBJECTIVE To examine theassociation between the use of right heartcatheterization (RHC) during the first 24 hours ofcare in the intensive care unit (ICU) andsubsequent survival, length of stay, intensity ofcare, and cost of care. DESIGN Prospectivecohort study. SETTING Five US teachinghospitals between 1989 and 1994. SUBJECTS Atotal of 5735 critically ill adult patients receivingcare in an ICU for 1 of 9 prespecified diseasecategories. MAIN OUTCOME MEASURES Survivaltime, cost of care, intensity of care, and length ofstay in the ICU and hospital, determined fromthe clinical record and from the National DeathIndex. A propensity score for RHC wasconstructed using multivariable logisticregression. Case-matching and multivariableregression modeling techniques were used toestimate the association of RHC with specificoutcomes after adjusting for treatment selection", "metadata": {}}
+{"_id": "20754359", "title": "", "text": "Natural history of adult T-cellleukemia/lymphoma and approaches totherapyAfter cell-to-cell transmission, HTLV-Iincreases its viral genome by de novo infectionand proliferation of infected cells. Proliferation ofinfected cells is clonal and persistent in vivo.During the carrier state, infected cells areselected in vivo by the host's immune system,the genetic and epigenetic environment ofproviral integration sites, and other factors. Inleukemic cells, tax gene expression is frequentlyimpaired by genetic and epigenetic mechanisms.Such loss of Tax expression enables ATL cells toescape the host immune system. On the otherhand, ATL cells acquire the ability to proliferatewithout Tax by intracellular genetic andepigenetic changes. Despite advances in supportand the development of novel treatment agents,the prognosis for ATLL remains poor. A numberof therapies, however, do appear to improveprognosis compared to CHOP (VEPA). Theseinclude interferon-α plus zidovudine (probably", "metadata": {}}
+{"_id": "20758340", "title": "", "text": "Hierarchical organization of the plasmamembrane: investigations by single-moleculetracking vs. fluorescence correlationspectroscopy.Single-molecule tracking andfluorescence correlation spectroscopy (FCS)applied to the plasma membrane in living cellshave allowed a number of unprecedentedobservations, thus fostering a new basicunderstanding of molecular diffusion, interaction,and signal transduction in the plasmamembrane. It is becoming clear that the plasmamembrane is a heterogeneous entity, containingdiverse structures on nano-meso-scales (2-200nm) with a variety of lifetimes, where certainmembrane molecules stay together for limiteddurations. Molecular interactions occur in thetime-dependent inhomogeneoustwo-dimensional liquid of the plasma membrane,which might be a key for plasma membranefunctions.", "metadata": {}}
+{"_id": "20761364", "title": "", "text": "Stability of the antimalarial drugdihydroartemisinin under physiologically relevantconditions: implications for clinical treatment andpharmacokinetic and in vitro assays.Artemisininsare peroxidic antimalarial drugs known to bevery potent but highly chemically unstable; theydegrade in the presence of ferrous iron,Fe(II)-heme, or biological reductants. Lessdocumented is how this translates into chemicalstability and antimalarial activity across a rangeof conditions applying to in vitro testing andclinical situations. Dihydroartemisinin (DHA) isstudied here because it is an antimalarial drug onits own and the main metabolite of otherartemisinins. The behaviors of DHA inphosphate-buffered saline, plasma, orerythrocyte lysate at different temperatures andpH ranges were examined. The antimalarialactivity of the residual drug was evaluated usingthe chemosensitivity assay on Plasmodiumfalciparum, and the extent of decomposition ofDHA was established through use of", "metadata": {}}
+{"_id": "20764484", "title": "", "text": "Modulation of anxiety through blockade ofanandamide hydrolysisThe psychoactiveconstituent of cannabis,Δ9-tetrahydrocannabinol, produces in humanssubjective responses mediated by CB1cannabinoid receptors, indicating thatendogenous cannabinoids may contribute to thecontrol of emotion. But the variable effects ofΔ9-tetrahydrocannabinol obscure theinterpretation of these results and limit thetherapeutic potential of direct cannabinoidagonists. An alternative approach may be todevelop drugs that amplify the effects ofendogenous cannabinoids by preventing theirinactivation. Here we describe a class of potent,selective and systemically active inhibitors offatty acid amide hydrolase, the enzymeresponsible for the degradation of theendogenous cannabinoid anandamide. Likeclinically used anti-anxiety drugs, in rats theinhibitors exhibit benzodiazepine-like propertiesin the elevated zero-maze test and suppress", "metadata": {}}
+{"_id": "20767776", "title": "", "text": "Familial clustering of refluxsymptomsObjective:A number of case reportsdescribe multiple family members withgastroesophageal reflux disease and Barrett'sesophagus. The wider importance of familialfactors in gastroesophageal reflux disease hasnot been established. Therefore, we have studiedthe prevalence of reflux symptoms andmedication use among relatives of patients withdocumented gastroesophageal reflux disease.Methods:A postal questionnaire study of the firstdegree relatives of six groups of matchedpatients. The groups comprised patients with 1)no dyspeptic symptoms; 2) reflux symptoms anda normal pH study; 3) reflux symptoms, anabnormal pH study, and a lower esophagealsphincter (LOS) pressure more than 10 mm Hg;4) reflux symptoms, an abnormal pH study, anda LOS pressure less than 10 mm Hg; 5) Barrett'sesophagus; and 6) peptic stricture. Results:Fourhundred eighteen subjects replied (78%response). Infrequent reflux symptoms were", "metadata": {}}
+{"_id": "20781656", "title": "", "text": "Histone chaperones: 30 years from isolation toelucidation of the mechanisms of nucleosomeassembly and disassemblySome three decadeshave passed since the discovery of nucleosomesin 1974 and the first isolation of a histonechaperone in 1978. While various types ofhistone chaperones have been isolated andfunctionally analyzed, the elementary processesof nucleosome assembly and disassembly havebeen less well characterized. Recently, thetertiary structure of a hetero-trimeric complexcomposed of the histone chaperone CIA/ASF1and the histone H3-H4 dimer was determined,and this complex was proposed to be anintermediate in nucleosome assembly anddisassembly reactions. In addition, CIA alonewas biochemically shown to dissociate thehistone (H3-H4)2 tetramer into two histoneH3-H4 dimers. This activity suggested that CIAregulates the semi-conservative replication ofnucleosomes. Here, we provide an overview ofprominent histone chaperones with the goal of", "metadata": {}}
+{"_id": "20821402", "title": "", "text": "Specificity of the dRP/AP lyase of Ku promotesnonhomologous end joining (NHEJ) fidelity atdamaged ends.Nonhomologous end joining(NHEJ) is essential for efficient repair ofchromosome breaks. However, the NHEJ ligationstep is often obstructed by break-associatednucleotide damage, including base loss (abasicsite or 5'-dRP/AP sites). Ku, a 5'-dRP/AP lyase,can excise such damage at ends in preparationfor the ligation step. We show here that thisactivity is greatest if the abasic site is within ashort 5' overhang, when this activity is necessaryand sufficient to prepare such termini forligation. In contrast, Ku is less active near 3'strand termini, where excision would leave aligation-blocking α,β-unsaturated aldehyde. TheKu AP lyase activity is also strongly suppressedby as little as two paired bases 5' of the abasicsite. Importantly, in vitro end joiningexperiments show that abasic sites significantlyembedded in double-stranded DNA do not blockthe NHEJ ligation step. Suppression of the", "metadata": {}}
+{"_id": "20829129", "title": "", "text": "Gut-expressed gustducin and taste receptorsregulate secretion of glucagon-likepeptide-1.Glucagon-like peptide-1 (GLP-1),released from gut endocrine L cells in responseto glucose, regulates appetite, insulin secretion,and gut motility. How glucose given orally, butnot systemically, induces GLP-1 secretion isunknown. We show that human duodenal L cellsexpress sweet taste receptors, the taste Gprotein gustducin, and several other tastetransduction elements. Mouse intestinal L cellsalso express alpha-gustducin. Ingestion ofglucose by alpha-gustducin null mice revealeddeficiencies in secretion of GLP-1 and theregulation of plasma insulin and glucose.Isolated small bowel and intestinal villi fromalpha-gustducin null mice showed markedlydefective GLP-1 secretion in response to glucose.The human L cell line NCI-H716 expressesalpha-gustducin, taste receptors, and severalother taste signaling elements. GLP-1 releasefrom NCI-H716 cells was promoted by sugars", "metadata": {}}
+{"_id": "20839751", "title": "", "text": "Apoptosis in breast cancer: relationship withother pathological parameters.Apoptosis is afrequent phenomenon in breast cancer and it canbe detected by light microscopy in conventionalhistopathological sections or by special stainingtechniques. The number of apoptotic cells as apercentage of cells present, or the number ofapoptotic cells per square millimetre ofneoplastic tissue, is usually described as theapoptotic index (AI). In breast cancer, the AI isnot related to tumour size, axillary lymph nodemetastasis or distant metastasis at diagnosis. Itis greater in invasive ductal carcinomas than inother histological types. High AI is also related tohigh histological grade, high nuclear grade,comedo-type necrosis, lack of tubule formation,and dense infiltration of the tumour bylymphocytes. Sex steroid receptor-negativetumours have greater AIs than the sex steroidreceptor-positive ones. Aneuploid breast cancerswith high S-phase fractions (SPFs) also havehigh AI values compared with diploid tumours", "metadata": {}}
+{"_id": "20851402", "title": "", "text": "Dietary flavonoids: bioavailability, metaboliceffects, and safety.Flavonoids comprise the mostcommon group of plant polyphenols and providemuch of the flavor and color to fruits andvegetables. More than 5000 different flavonoidshave been described. The six major subclasses offlavonoids include the flavones (e.g., apigenin,luteolin), flavonols (e.g., quercetin, myricetin),flavanones (e.g., naringenin, hesperidin),catechins or flavanols (e.g., epicatechin,gallocatechin), anthocyanidins (e.g., cyanidin,pelargonidin), and isoflavones (e.g., genistein,daidzein). Most of the flavonoids present inplants are attached to sugars (glycosides),although occasionally they are found asaglycones. Interest in the possible healthbenefits of flavonoids has increased owing totheir potent antioxidant and free-radicalscavenging activities observed in vitro. There isgrowing evidence from human feeding studiesthat the absorption and bioavailability of specificflavonoids is much higher than originally", "metadata": {}}
+{"_id": "20864487", "title": "", "text": "Virus-specific cytotoxic T-lymphocyte responsesselect for amino-acid variation in simianimmunodeficiency virus Env and NefCytotoxicT-lymphocyte (CTL) responses to humanimmunodeficiency virus arise early afterinfection, but ultimately fail to preventprogression to AIDS. Human immunodeficiencyvirus may evade the CTL response byaccumulating amino-acid replacements withinCTL epitopes. We studied 10 CTL epitopes duringthe course of simian immunodeficiency virusdisease progression in three related macaques.All 10 of these CTL epitopes accumulatedamino-acid replacements and showed evidenceof positive selection by the time the macaquesdied. Many of the amino-acid replacements inthese epitopes reduced or eliminated majorhistocompatibility complex class I binding and/orCTL recognition. These findings strongly supportthe CTL 'escape' hypothesis.", "metadata": {}}
+{"_id": "20868160", "title": "", "text": "TRICHOME BIREFRINGENCE and its homologAT5G01360 encode plant-specific DUF231proteins required for cellulose biosynthesis inArabidopsis.The Arabidopsis (Arabidopsisthaliana) trichome birefringence (tbr) mutant hasseverely reduced crystalline cellulose intrichomes, but the molecular nature of TBR wasunknown. We determined TBR to belong to theplant-specific DUF231 domain gene familycomprising 46 members of unknown function inArabidopsis. The genes harbor anotherplant-specific domain, called the TBL domain,which contains a conserved GDSL motif knownfrom some esterases/lipases. TBR and TBR-like3(TBL3) are transcriptionally coordinated withprimary and secondary CELLULOSE SYNTHASE(CESA) genes, respectively. The tbr and tbl3mutants hold lower levels of crystalline celluloseand have altered pectin composition in trichomesand stems, respectively, tissues generallythought to contain mainly secondary wallcrystalline cellulose. In contrast, primary wall", "metadata": {}}
+{"_id": "20886584", "title": "", "text": "Genetic predictors of taxane-inducedneurotoxicity in a SWOG phase III intergroupadjuvant breast cancer treatment trial(S0221)Taxanes have resulted in improvedsurvival for breast cancer patients, but oftencause neurological toxicities. Identification ofbiomarkers related to toxicities could beimportant for dictating treatment regimen. Weevaluated single nucleotide polymorphisms(SNPs) in the Fanconi Anemia (FA)/BRCApathway in relation to grade 3/4 neurotoxicitiesin patients (n = 888) from SWOG0221, a phaseIII adjuvant trial for breast cancer of 4dose/schedules of cyclophosphamide (C),doxorubicin (A), and paclitaxel (T). In a separatecohort, we measured the correlation ofsignificant FANCD2 SNPs with correspondinggene expression. For FANCD2, permutationtesting revealed that 4 (out of 20) SNPs weresignificantly associated with an almost two-foldincreased risk of toxicity. Two FANCD2haplotypes were also associated with", "metadata": {}}
+{"_id": "20887554", "title": "", "text": "Preoperative C-reactive protein predictsmid-term outcome after cardiacsurgery.BACKGROUND C-reactive protein (CRP)is a known risk factor for cardiovascular eventsin the healthy population and in patients withcoronary artery disease. High CRP levels beforecardiac surgery are associated with worseshort-term outcome, but its role after dischargehome remains unknown. The study objective wasto evaluate the effect of CRP on short-term andmid-term outcome after cardiac surgery.METHODS From August 2000 to May 2004,values for preoperative CRP were available for597 unselected patients undergoing cardiacoperations. CRP was used to divide this cohort intwo groups: a low inflammatory status (LHS)group of 354 patients with CRP of less than 0.5mg/dL, and a high inflammatory status (HIS)group of 243 patients with a CRP of 0.5 mg/dL ormore. Follow-up lasted a maximum of 3 years(median, 1.8 +/- 1.5 years) and was 92.6%complete. RESULTS In-hospital mortality was", "metadata": {}}
+{"_id": "20888849", "title": "", "text": "Inhibition of Hedgehog signaling enhancesdelivery of chemotherapy in a mouse model ofpancreatic cancer.Pancreatic ductaladenocarcinoma (PDA) is among the most lethalhuman cancers in part because it is insensitive tomany chemotherapeutic drugs. Studying amouse model of PDA that is refractory to theclinically used drug gemcitabine, we found thatthe tumors in this model were poorly perfusedand poorly vascularized, properties that areshared with human PDA. We tested whether thedelivery and efficacy of gemcitabine in the micecould be improved by coadministration ofIPI-926, a drug that depletes tumor-associatedstromal tissue by inhibition of the Hedgehogcellular signaling pathway. The combinationtherapy produced a transient increase inintratumoral vascular density and intratumoralconcentration of gemcitabine, leading totransient stabilization of disease. Thus, inefficientdrug delivery may be an important contributor tochemoresistance in pancreatic cancer.", "metadata": {}}
+{"_id": "20904154", "title": "", "text": "Mutant SOD1 inhibits ER-Golgi transport inamyotrophic lateral sclerosis.Cu/Zn-superoxidedismutase is misfolded in familial and sporadicamyotrophic lateral sclerosis, but it is not clearhow this triggers endoplasmic reticulum (ER)stress or other pathogenic processes. Here, wedemonstrate that mutant SOD1 (mSOD1) ispredominantly found in the cytoplasm inneuronal cells. Furthermore, we show thatmSOD1 inhibits secretory protein transport fromthe ER to Golgi apparatus. ER-Golgi transport islinked to ER stress, Golgi fragmentation andaxonal transport and we also show that inhibitionof ER-Golgi trafficking preceded ER stress, Golgifragmentation, protein aggregation andapoptosis in cells expressing mSOD1.Restoration of ER-Golgi transport byover-expression of coatomer coat protein IIsubunit Sar1 protected against inclusionformation and apoptosis, thus linking dysfunctionin ER-Golgi transport to cellular pathology. Thesefindings thus link several cellular events in", "metadata": {}}
+{"_id": "20931483", "title": "", "text": "High spatial resolution mapping of malariatransmission risk in the Gambia, west Africa,using LANDSAT TM satelliteimagery.Understanding local variability inmalaria transmission risk is critically importantwhen designing intervention or vaccine trials.Using a combination of field data, satellite imageanalysis, and GIS modeling, we developed ahigh-resolution map of malaria entomologicalinoculation rates (EIR) in The Gambia, WestAfrica. The analyses are based on the variation inexposure to malaria parasites experienced in 48villages in 1996 and 21 villages in 1997. Theentomological inoculation rate (EIR) varied from0 to 166 infective bites per person per rainyseason. Detailed field surveys identified themajor Anopheles gambiae s.l. breeding habitats.These habitats were mapped by classification ofa LANDSAT TM satellite image with an overallaccuracy of 85%. Village EIRs decreased as apower function based on the breeding areas sizeand proximity. We use this relationship and the", "metadata": {}}
+{"_id": "20935673", "title": "", "text": "Functional analysis of repressor binding sites inthe iab-2 regulatory region of the abdominal-Ahomeotic gene.Spatial boundaries of homeoticgene expression are initiated and maintained bytwo sets of transcriptional repressors: the gapgene products and the Polycomb group proteins.Previously, the Hunchback (HB) protein has beenimplicated in setting the anterior expression limitof the UBX homeotic protein in parasegment 6.Here we investigate DNA elements andtrans-acting repressors that control spatialexpression of the Abdominal-A (ABD-A) homeoticprotein. Analysis of a 1.7-kb enhancer element[iab-2(1.7)] from the iab-2 regulatory regionshows that in contrast to Ubx enhancerelements, both HB and Krüppel (KR) are requiredto set the ABD-A anterior boundary inparasegment 7. DNase I footprinting andsite-directed mutagenesis show that HB and KRare direct regulators of this iab-2 enhancer. Thesingle KR site can be moved to a new location100 bp away and still maintain repressive", "metadata": {}}
+{"_id": "20937018", "title": "", "text": "Apolipoprotein E: high-avidity binding tobeta-amyloid and increased frequency of type 4allele in late-onset familial Alzheimerdisease.Apolipoprotein E is immunochemicallylocalized to the senile plaques, vascular amyloid,and neurofibrillary tangles of Alzheimer disease.In vitro, apolipoprotein E in cerebrospinal fluidbinds to synthetic beta A4 peptide (the primaryconstituent of the senile plaque) with highavidity. Amino acids 12-28 of the beta A4peptide are required. The gene for apolipoproteinE is located on chromosome 19q13.2, within theregion previously associated with linkage oflate-onset familial Alzheimer disease. Analysis ofapolipoprotein E alleles in Alzheimer disease andcontrols demonstrated that there was a highlysignificant association of apolipoprotein E type 4allele (APOE-epsilon 4) and late-onset familialAlzheimer disease. The allele frequency of theAPOE-epsilon 4 in 30 random affected patients,each from a different Alzheimer disease family,was 0.50 +/- 0.06; the allele frequency of", "metadata": {}}
+{"_id": "20942644", "title": "", "text": "Unmarked gene deletion and host–vector systemfor the hyperthermophilic crenarchaeonSulfolobus islandicusSulfolobus islandicus isbeing used as a model for studying archaealbiology, geo-biology and evolution. However, nogenetic system is available for this organism. Toproduce an S. islandicus mutant suitable forgenetic analyses, we screened for colonies with aspontaneous pyrEF mutation. One mutant wasobtained containing only 233 bp of the originalpyrE sequence in the mutant allele and it wasused as a host to delete the β-glycosidase (lacS)gene. Two unmarked gene deletion methodswere employed, namely plasmid integration andsegregation, and marker replacement andlooping out, and unmarked lacS mutants wereobtained by each method. A new alternativerecombination mechanism, i.e., markercircularization and integration, was shown tooperate in the latter method, which did not yieldthe designed deletion mutation. Subsequently,Sulfolobus–E. coli plasmid shuttle vectors were", "metadata": {}}
+{"_id": "20943272", "title": "", "text": "ADAM13 disintegrin and cysteine-rich domainsbind to the second heparin-binding domain offibronectin.ADAM13 is a member of thedisintegrin and metalloprotease protein familythat is expressed on cranial neural crest cellssurface and is essential for their migration.ADAM13 is an active protease that can cleavefibronectin in vitro and remodel a fibronectinsubstrate in vivo. Using a recombinant secretedprotein containing both disintegrin andcysteine-rich domains of ADAM13, we show thatthis \"adhesive\" region of the protein bindsdirectly to fibronectin. Fibronectin fusion proteinscorresponding to the various functional domainswere used to define the second heparin-bindingdomain as the ADAM13 binding site. Mutation ofthe syndecan-binding site (PPRR --> PPTM)within this domain abolishes binding of therecombinant disintegrin and cysteine-richdomains of ADAM13. We further show that theadhesive disintegrin and cysteine-rich domain ofADAM13 can promote cell adhesion via beta(1)", "metadata": {}}
+{"_id": "20945963", "title": "", "text": "Clinical epidemiology of heart failure.The aim ofthis paper is to review the clinical epidemiologyof heart failure. The last paper comprehensivelyaddressing the epidemiology of heart failure inHeart appeared in 2000. Despite an increase inmanuscripts describing epidemiological aspectsof heart failure since the 1990s, additionalinformation is still needed, as indicated byvarious editorials.", "metadata": {}}
+{"_id": "20960682", "title": "", "text": "Toll-like receptor 7 agonist GS-9620 inducesprolonged inhibition of HBV via a type Iinterferon-dependent mechanism.BACKGROUND& AIMS GS-9620, an oral agonist of toll-likereceptor 7 (TLR7), is in clinical development forthe treatment of chronic hepatitis B (CHB).GS-9620 was previously shown to induceprolonged suppression of serum viral DNA andantigens in the woodchuck and chimpanzeemodels of CHB. Herein, we investigated themolecular mechanisms that contribute to theantiviral response to GS-9620 using in vitromodels of hepatitis B virus (HBV) infection.METHODS Cryopreserved primary humanhepatocytes (PHH) and differentiated HepaRG(dHepaRG) cells were infected with HBV andtreated with GS-9620, conditioned media fromhuman peripheral blood mononuclear cellstreated with GS-9620 (GS-9620 conditionedmedia [GS-9620-CM]), or other innate immunestimuli. The antiviral and transcriptional responseto these agents was determined. RESULTS", "metadata": {}}
+{"_id": "20977638", "title": "", "text": "Depletion of glutathione induces4-hydroxynonenal protein adducts andhydroxyurea teratogenicity in the organogenesisstage mouse embryo.Glutathione (GSH)homeostasis is important during organogenesis.To elucidate the impact of GSH depletion inorganogenesis stage embryos on oxidative stressand drug teratogenicity,l-buthionine-S,R-sulfoximine (BSO) was given totimed pregnant CD-1 mice 4 h before exposureto a model teratogen, hydroxyurea (HU) [400mg/kg (HU-400) or 600 mg/kg (HU-600)].Treatment with BSO or HU alone or with BSOplus HU-400 did not alter the ratios ofglutathione disulfide/GSH in the embryo; incontrast, the combination of BSO plus HU-600did increase this ratio at both 0.5 and 3 hpost-HU, indicating the induction of oxidativestress in the embryos. Immunoreactivity to aproduct of lipid peroxidation, 4-hydroxynonenal(4-HNE) protein adducts, was detected insaline-treated embryos; the intensity and", "metadata": {}}
+{"_id": "20996244", "title": "", "text": "Nonproductive human immunodeficiency virustype 1 infection in nucleoside-treated G0lymphocytes.Productive infection by humanimmunodeficiency virus type 1 (HIV-1) requiresthe activation of target cells. Infection ofquiescent peripheral CD4 lymphocytes by HIV-1results in incomplete, labile, reverse transcripts.We have previously identified G1b as the cellcycle stage required for the optimal completionof the reverse transcription process in Tlymphocytes. However, the mechanism(s)involved in the blockage of reverse transcriptionremains undefined. In this study we investigatedwhether nucleotide levels influence viral reversetranscription in G0 cells. For this purpose the roleof the enzyme ribonucleotide reductase wasbypassed, by adding exogenousdeoxyribonucleosides to highly purified T cells inthe G0 or the G1a phase of the cell cycle. Ourdata showed a significant increase in theefficiency of the reverse transcription processfollowing the addition of the", "metadata": {}}
+{"_id": "20999249", "title": "", "text": "Imported malaria in children: a nationalsurveillance in the Netherlands and a review ofEuropean studies.BACKGROUND Falciparummalaria or malaria tropica is one of the leadingcauses of childhood mortality worldwide.Malaria-related deaths occur mainly insub-Saharan Africa, where an estimated 365million clinical cases of Plasmodium falciparummalaria occur each year. In Europe, importedmalaria cases occur due to returning travellers orimmigration mostly from African countries.Children are more at risk than adults. Theobjective of this study was to identify high riskgroups for imported childhood malaria in Europein order to guide development of strategies forprevention, early recognition and management.METHODS In the period May 2003-January 2005we reviewed all cases of paediatric malaria in theNetherlands notified by the Dutch PaediatricSurveillance System (Nederland SignaleringsCentrum Kindergeneeskunde, NSCK) and theliterature on imported malaria in children in", "metadata": {}}
+{"_id": "21003930", "title": "", "text": "Respiratory and cardiovascular responses towalking down a traffic-polluted road comparedwith walking in a traffic-free area in participantsaged 60 years and older with chronic lung orheart disease and age-matched healthy controls:a randomised, crossover studyBACKGROUNDLong-term exposure to pollution can lead to anincrease in the rate of decline of lung function,especially in older individuals and in those withchronic obstructive pulmonary disease (COPD),whereas shorter-term exposure at higherpollution levels has been implicated in causingexcess deaths from ischaemic heart disease andexacerbations of COPD. We aimed to assess theeffects on respiratory and cardiovascularresponses of walking down a busy street withhigh levels of pollution compared with walking ina traffic-free area with lower pollution levels inolder adults. METHODS In this randomised,crossover study, we recruited men and womenaged 60 years and older with angiographicallyproven stable ischaemic heart disease or stage 2", "metadata": {}}
+{"_id": "21009874", "title": "", "text": "Overall and cancer related mortality amongpatients with ocular inflammation treated withimmunosuppressive drugs: retrospective cohortstudy.CONTEXT Whether immunosuppressivetreatment adversely affects survival is unclear.OBJECTIVE To assess whetherimmunosuppressive drugs increase mortality.DESIGN Retrospective cohort study evaluatingoverall and cancer mortality in relation toimmunosuppressive drug exposure amongpatients with ocular inflammatory diseases.Demographic, clinical, and treatment dataderived from medical records, and mortalityresults from United States National Death Indexlinkage. The cohort's mortality risk wascompared with US vital statistics usingstandardised mortality ratios. Overall and cancermortality in relation to use or non-use ofimmunosuppressive drugs within the cohort wasstudied with survival analysis. SETTING Fivetertiary ocular inflammation clinics. Patients7957 US residents with non-infectious ocular", "metadata": {}}
+{"_id": "21012916", "title": "", "text": "Ephrin B1–mediated repulsion and signalingcontrol germinal center T cell territoriality andfunctionFollicular T helper (TFH) cells orchestratethe germinal center (GC) reaction locally. Localmechanisms regulating their dynamics andhelper functions are not well defined. Here wefound that GC-expressed ephrin B1 (EFNB1)repulsively inhibited T cell to B cell adhesion andGC TFH retention by signaling throughTFH-expressed EPHB6 receptor. At the sametime, EFNB1 promoted interleukin-21 productionfrom GC TFH cells by signaling predominantlythrough EPHB4. Consequently, EFNB1-null GCswere associated with defective production ofplasma cells despite harboring excessive TFHcells. In a competitive GC reaction,EFNB1-deficient B cells more efficientlyinteracted with TFH cells and produced morebone-marrow plasma cells, likely as a result ofgaining more contact-dependent help. Ourresults reveal a contact-dependent repulsiveguidance system that controls GC TFH dynamics", "metadata": {}}
+{"_id": "21033230", "title": "", "text": "Molecular profiling and predictive value ofcirculating tumor cells in patients with metastaticbreast cancer: an option for monitoring responseto breast cancer related therapiesPurpose Weanalyzed circulating tumor cells (CTC) in blood ofmetastatic breast cancer patients (n = 42) anddetermined the ability of this method to predicttherapy response. Methods CTC from blood wereanalyzed before and during therapy for EpCAM,MUC1 and HER2 transcripts with the AdnaTestBreastCancer. The estrogen (ER) andprogesterone (PR) receptor expression wasassessed by RT-PCR. Results The overalldetection rate for CTC was 52% (thereof 86%EpCAM; 86% MUC1; 32% HER2; 35% ER; 12%PR). CTC were ER, PR and HER2 negative in 45%(ER), 78% (PR) and 60% (HER-2) of patientswith steroid receptor-positive tumors. 29% ofpatients with HER2-negative tumors hadHER2-positive CTC. The test predicted therapyresponse in 78% of all cases. Persistence of CTCsignificantly correlated with shorter overall", "metadata": {}}
+{"_id": "21046889", "title": "", "text": "Alternate-day wheel access: effects on feeding,body weight, and running.For rats access to arunning wheel results in a pronounced buttemporary suppression of feeding. The reasonsfor the feeding suppression and its temporarynature are unclear. The effects of alternate-daywheel access were explored by comparingfeeding and running in 25 male Sprague-Dawleyrats given either no wheel access, continuouswheel access, or alternate-day wheel access.With alternate-day wheel access food intake wassuppressed on wheel days and elevated onnon-wheel days for the full 32 days of theexperiment. Body weight decreased on wheeldays and showed a large increase on non-wheeldays. Acquisition of running over days wassimilar in both wheel groups and plateaued atthe same level, but running was elevated,compared to continuous-access rats, for the firstfew hours when alternate-day rats were returnedto the wheel. These results suggest thatwheel-induced feeding suppression is not due to", "metadata": {}}
+{"_id": "21048969", "title": "", "text": "Evaluation of the association between the firstobservation and the longitudinal change inC-reactive protein, and all-causemortality.OBJECTIVE To evaluate the associationbetween vascular inflammation as measured bysubacute C-reactive protein (CRP; 1-10 mg/l)and all-cause mortality and the associationbetween change in CRP status (normal <or=3mg/l and elevated >3 mg/l) and all-causemortality. METHODS Probabilistic record linkagewas used to match hospital episode data,laboratory reports and mortality statistics in alarge urban population. Survival was evaluatedusing Cox proportional hazards regressionmodels. RESULTS 22 962 patients had their firstCRP measurement in the subacute range (1-10mg/l). Analysis grouped by each additional unitincrease in CRP across the subacute range wasassociated with a 7.3% (95% CI 5.4% to 9.2%)increase in the hazard ratio (HR) of death over 4years, after controlling for confounding factors(p<0.001). Repeated CRP observations around 1", "metadata": {}}
+{"_id": "21050357", "title": "", "text": "Research Priorities in Sudden Unexpected InfantDeath: An International Consensus.Despite thesuccess of safe sleep campaigns and theprogress in understanding risk factors, the rateof reduction in the cases of sudden infant deathsyndrome has now slowed and it remains aleading cause of postneonatal mortality in manydeveloped countries. Strategic action is neededto tackle this problem and it is now vital toidentify how the sudden infant death researchcommunity may best target its efforts. TheGlobal Action and Prioritization of Sudden InfantDeath Project was an international consensusprocess that aimed to define and direct futureresearch by investigating the priorities of expertand lay members of the sudden unexpectedinfant death (SUID) community across countries.The aim was to identify which areas of researchshould be prioritized to reduce the number ofSUID deaths globally. Scientific researchers,clinicians, counselors, educators, and SUIDparents from 25 countries took part across 2", "metadata": {}}
+{"_id": "21053753", "title": "", "text": "Modification of the Constant-Murley shoulderscore-introduction of the individual relativeConstant score Individual shoulderassessment.The Constant-Murley shoulderassessment score has proven to be a valuablediagnostic instrument. Thus, in the literature ithas been mentioned that the clinical accuracy ofthis score varies especially when comparingpatients in larger, inhomogeneous patientgroups. The \"relative Constant score\" (CS(rel))tries to minimize these problems by usingreference parameters out of healthy age andgender related control groups. The authors ofthis study tried to show that it is even moreaccurate to use the functional performance of theuninjured collateral shoulder of the sameindividual as reference, introducing the\"individual relative Constant score\" (CS(indiv)).The CS(indiv) and the CS(rel) were compared for125 consecutive patients with shoulderdisorders, and a group of 125 healthy volunteersas a control group. In a non-parametric", "metadata": {}}
+{"_id": "21060008", "title": "", "text": "Celiac disease screening byimmunochromatographic visual assays: resultsof a multicenter study.OBJECTIVE To assay theefficiency for celiac disease (CD) screening of 2immunochromatographic visual stick assaysbased on human recombinant tissuetransglutaminase (tTG). One was the antitissuetransglutaminase antibodies (AtTGA) stick forIgA/G antibodies to tTG detection, the other wasthe AtTGA/antigliadin antibodies (AGA) stick forIgA antibodies for tTG and/or gliadins. PATIENTSAND METHODS In a prospective multicenterstudy, 4 pediatric gastroenterology units fromSpain and 2 from Latin America enrolled 72control children with a normal small bowelmucosa and 113 untreated patients with CD withMarsh type 3 lesions. RESULTS Evaluation ofresults by the gastroenterologists and by 2independent observers at the coordination centershowed a remarkably low interobservervariability. For the AtTGA stick, sensitivity was96.5% and specificity was 98.6%. The", "metadata": {}}
+{"_id": "21063817", "title": "", "text": "Down-regulation of keratin 4 and keratin 13expression in oral squamous cell carcinoma andepithelial dysplasia: a clue forhistopathogenesis.AIMS This study aimed toidentify relevant keratin subtypes that mayassociate with the pathogenesis of oral epithelialneoplasms. METHODS AND RESULTS Expressionof all the keratin subtypes was examined bycDNA microarray analysis of 43 oral squamouscell carcinoma (OSCC) cases.Immunohistochemical expression of the majorkeratins was examined in 100 OSCC and oralepithelial dysplasia (OED) cases. Many changesin keratin expression were observed and,significantly, consistent down-regulation ofkeratin 4 (K4) and K13 expression was observed.Aberrant expression of K4 and K13 wasassociated with morphological changes in theaffected oral epithelium. Experiments with cellcultures transfected with various keratinsubtypes suggested that alterations in keratinsubtype expression can cause changes in cell", "metadata": {}}
+{"_id": "21093407", "title": "", "text": "Identification of short-lived long non-codingRNAs as surrogate indicators for chemical stressresponse.Abiotic and biotic stressors in humancells are often a result of sudden and/or frequentchanges in environmental factors. The molecularresponse to stress involves elaborate modulationof gene expression and is of homeostatic,ecological, and evolutionary importance.Although attention has primarily focused onsignaling pathways and protein networks, longnon-coding RNAs (ncRNAs) are increasinglyinvolved in the molecular mechanisms associatedwith responses to cellular stresses. We identifiedsix novel short-lived long ncRNAs (MIR22HG,GABPB-AS1, LINC00152, IDI2-AS1, SNHG15,and FLJ33630) that responded to chemicalstressors (cisplatin, cycloheximide, and mercury(II) oxide) in HeLa Tet-off cells. Our resultsindicate that short-lived long ncRNAs respond togeneral and specific chemical stressors. Theexpression levels of the short-lived long ncRNAswere elevated because of prolonged decay rates", "metadata": {}}
+{"_id": "21108759", "title": "", "text": "Isolation of a gene encoding a functional zincfinger protein homologous to erythroidKrüppel-like factor: identification of a newmultigene family.We have identified andcharacterized the gene for a novel zinc fingertranscription factor which we have termed lungKrüppel-like factor (LKLF). LKLF was isolatedthrough the use of the zinc finger domain oferythroid Krüppel-like factor (ELKF) as ahybridization probe and is closely related to thiserythroid cell-specific gene. LKLF is expressed ina limited number of tissues, with thepredominant expression seen in the lungs andspleen. The gene is developmentally controlled,with expression noted in the 7-day embryofollowed by a down-regulation at 11 days andsubsequent reactivation. A high degree ofsimilarity is noted in the zinc finger regions ofLKLF and EKLF. Beyond this domain, thesequences diverge significantly, although theputative transactivation domains for both LKLFand EKLF are proline-rich regions. In the", "metadata": {}}
+{"_id": "21114100", "title": "", "text": "A small molecule restores function to TRPML1mutant isoforms responsible for mucolipidosistype IV.Mucolipidosis type IV (MLIV) is anautosomal recessive lysosomal storage disorderoften characterized by severeneurodevelopmental abnormalities andneuro-retinal degeneration. Mutations in theTRPML1 gene are causative for MLIV. We usedlead optimization strategies to identify--andMLIV patient fibroblasts to test--small-moleculeactivators for their potential to restore TRPML1mutant channel function. Using thewhole-lysosome planar patch-clamp technique,we found that activation of MLIV mutant isoformsby the endogenous ligand PI(3,5)P2 is stronglyreduced, while activity can be increased usingsynthetic ligands. We also found that the F465Lmutation renders TRPML1 pH insensitive, whileF408Δ impacts synthetic ligand binding.Trafficking defects and accumulation of zinc inlysosomes of MLIV mutant fibroblasts can berescued by the small molecule treatment.", "metadata": {}}
+{"_id": "21141798", "title": "", "text": "Characterization of a murine monoclonalantibody to Cryptococcus neoformanspolysaccharide that is a candidate for humantherapeutic studies.The murine monoclonalantibody (MAb) 18B7 [immunoglobulinG1(kappa)] is in preclinical development fortreatment of Cryptococcus neoformansinfections. In anticipation of its use in humans,we defined the serological and biologicalproperties of MAb 18B7 in detail. Structuralcomparison to the related protective MAb 2H1revealed conservation of the antigen binding sitedespite several amino acid differences. MAb18B7 was shown by immunofluorescence andagglutination studies to bind to all four serotypesof C. neoformans, opsonize C. neoformansserotypes A and D, enhance human and mouseeffector cell antifungal activity, and activate thecomplement pathway leading to deposition ofcomplement component 3 (C3) on thecryptococcal capsule. Administration of MAb18B7 to mice led to rapid clearance of serum", "metadata": {}}
+{"_id": "21150010", "title": "", "text": "Treatment with cyclooxygenase-2 inhibitorsenables repeated administration of vaccinia virusfor control of ovarian cancer.Metastatic ovariancancer is the leading cause of death amongwomen with gynecologic malignancies in theUnited States. The lack of effective treatment forpatients with advanced ovarian cancer warrantsdevelopment of innovative therapies. Cancertherapy using oncolytic viruses represents apromising new approach for controlling tumors.Vaccinia virus has been shown to preferentiallyinfect tumor cells but not normal tissue.However, oncolytic therapy using recombinantviruses faces the limitation of viral clearance dueto generation of neutralizing antibodies. In thecurrent study, we found that cyclooxygenase-2(Cox-2) inhibitors circumvented this limitation,enabling repeated administration of vacciniavirus without losing infectivity. We quantified theantivaccinia antibody response usingenzyme-linked immunosorbent assay (ELISA)and neutralization assays to show that treatment", "metadata": {}}
+{"_id": "21164071", "title": "", "text": "Ser-752-->Pro mutation in the cytoplasmicdomain of integrin beta 3 subunit and defectiveactivation of platelet integrin alpha IIb beta 3(glycoprotein IIb-IIIa) in a variant of Glanzmannthrombasthenia.Integrins are membranereceptors which mediate cell-cell or cell-matrixadhesion. Integrin alpha IIb beta 3 (glycoproteinIIb-IIIa) acts as a fibrinogen receptor of plateletsand mediates platelet aggregation. Plateletactivation is required for alpha IIb beta 3 to shiftfrom noncompetent to competent for bindingsoluble fibrinogen. The steps involved in thistransition are poorly understood. We havestudied a variant of Glanzmann thrombasthenia,a congenital bleeding disorder characterized byabsence of platelet aggregation and fibrinogenbinding. The patient's platelets did not bindfibrinogen after platelet activation by ADP orthrombin, though his platelets contained alphaIIb beta 3. However, isolated alpha IIb beta 3was able to bind to an Arg-Gly-Asp-Ser affinitycolumn, and binding of soluble fibrinogen to the", "metadata": {}}
+{"_id": "21170174", "title": "", "text": "Crossover and noncrossover pathways in mousemeiosis.During meiosis, recombination betweenhomologous chromosomes generates crossover(CR) and noncrossover (NCR) products. CRsestablish connections between homologs,whereas intermediates leading to NCRs havebeen proposed to participate in homologouspairing. How these events are differentiated andregulated remains to be determined. We havedeveloped a strategy to detect, quantify, andmap NCRs in parallel to CRs, at the Psmb9meiotic recombination hot spot, in male andfemale mouse germ lines. Our results reportdirect molecular evidence for distinct CR andNCR pathways of DNA double-strand break(DSB) repair in mouse meiosis based on threeobservations: both CRs and NCRs require Spo11,NCR products have shorter conversion tractsthan CRs, and only CRs require the MutLhomolog Mlh1. We show that both products areformed from middle to late pachytene of meioticprophase and provide evidence for an", "metadata": {}}
+{"_id": "21179714", "title": "", "text": "IAP regulation ofmetastasis.Inhibitor-of-Apoptosis (IAP) proteinscontribute to tumor progression, but therequirements of this pathway are notunderstood. Here, we show that intermolecularcooperation between XIAP and survivinstimulates tumor cell invasion and promotesmetastasis. This pathway is independent of IAPinhibition of cell death. Instead, a survivin-XIAPcomplex activates NF-kappaB, which in turnleads to increased fibronectin gene expression,signaling by beta1 integrins, and activation ofcell motility kinases FAK and Src. Therefore, IAPsare direct metastasis genes, and theirantagonists could provide antimetastatictherapies in patients with cancer.", "metadata": {}}
+{"_id": "21181273", "title": "", "text": "15-Hydroxyprostaglandin dehydrogenase isdown-regulated in colorectalcancer.Prostaglandin E2 (PGE2) can stimulatetumor progression by modulating severalproneoplastic pathways, including proliferation,angiogenesis, cell migration, invasion, andapoptosis. Although steady-state tissue levels ofPGE2 stem from relative rates of biosynthesisand breakdown, most reports examining PGE2have focused solely on thecyclooxygenase-dependent formation of thisbioactive lipid. Enzymatic degradation of PGE2involves the NAD+-dependent15-hydroxyprostaglandin dehydrogenase(15-PGDH). The present study examined a rangeof normal tissues in the human and mouse andfound high levels of 15-PGDH in the largeintestine. By contrast, the expression of15-PGDH is decreased in several colorectalcarcinoma cell lines and in other humanmalignancies such as breast and lungcarcinomas. Consistent with these findings, we", "metadata": {}}
+{"_id": "21185923", "title": "", "text": "Stimulation of CD25+CD4+ regulatory T cellsthrough GITR breaks immunologicalself-toleranceCD25+CD4+ regulatory T cells innormal animals are engaged in the maintenanceof immunological self-tolerance. We show herethat glucocorticoid-induced tumor necrosis factorreceptor family–related gene (GITR, also knownas TNFRSF18)—a member of the tumor necrosisfactor–nerve growth factor (TNF-NGF) receptorgene superfamily—is predominantly expressedon CD25+CD4+ T cells and onCD25+CD4+CD8− thymocytes in normal naïvemice. We found that stimulation of GITRabrogated CD25+CD4+ T cell–mediatedsuppression. In addition, removal ofGITR-expressing T cells or administration of amonoclonal antibody to GITR producedorgan-specific autoimmune disease in otherwisenormal mice. Thus, GITR plays a key role indominant immunological self-tolerancemaintained by CD25+CD4+ regulatory T cellsand could be a suitable molecular target for", "metadata": {}}
+{"_id": "21186109", "title": "", "text": "The missing cases of tuberculosis in Malawi: thecontribution from cross-border registrations.Lowcase detection rates of new smear-positivepulmonary tuberculosis (PTB) patients globallyare a cause for concern. The aim of this studywas to determine for patients registered for TB inMalawi the number and percentage who lived ina neighbouring country and the registration,recording and reporting practices for these'foreign' patients. All 44 non-private hospitals,which register and treat all TB patients in thepublic health sector in Malawi, were visited. Ten(23%) hospitals in 2001 and 14 (32%) in 2002maintained a separate register for cross-borderTB cases. Patients recorded in these registerswere not formally reported to the MalawiNational TB Programme (NTP), the neighbouringcountry's NTP, nor to WHO. They thereforeconstitute missing cases. In Malawi, the numberof cross-border new smear-positive PTB caseswas 77 in 2001 and 91 in 2002, constitutingabout 3% of missing smear-positive cases in", "metadata": {}}
+{"_id": "21199527", "title": "", "text": "Parathyroid hormone induces E4bp4 messengerribonucleic acid expression primarily throughcyclic adenosine 3',5'-monophosphate signalingin osteoblasts.PTH binding to its receptoractivates protein kinase A (PKA), protein kinaseC (PKC), and calcium signaling to inducetranscription of primary response genes inosteoblasts. Adenovirus E4 promoter-bindingprotein/nuclear factor regulated by IL-3(E4BP4/NFIL3), a transcriptional repressor, is aPTH-induced primary response gene in primarymouse osteoblasts (MOBs). Here we investigatethe signaling pathway(s) that lead to PTHinduction of E4bp4 mRNA expression. Ten and100 nm PTH induced maximum E4bp4expression in MOBs. Forskolin (FSK), anadenylate cyclase inducer, 8-bromo-cAMP, acAMP analog, and phorbol myristate acetate, aPKC activator, increased E4bp4 mRNA levels,whereas ionomycin, a calcium ionophore, had noeffect. Pretreatment of cells with 30 microm H89,a PKA inhibitor, strongly inhibited PTH- and", "metadata": {}}
+{"_id": "21203899", "title": "", "text": "Managing finances of shipping living donorkidneys for donor exchanges.Kidney donorexchanges enable recipients withimmunologically incompatible donors to receivecompatible living donor grafts; however, thefinancial management of these exchanges,especially when an organ is shipped, is complexand thus has the potential to impede the broaderimplementation of donor exchange programs.Representatives from transplant centers thatutilize the National Kidney Registry database tofacilitate donor exchange transplants developeda financial model applicable to paired donorexchanges and donor chain transplants. The firsttenet of the model is to eliminate financialliability to the donor. Thereafter, it accounts forthe donor evaluation, donor nephrectomyhospital costs, donor nephrectomy physicianfees, organ transport, donor complications andrecipient inpatient services. Billing betweenhospitals is based on Medicare cost reportdefined costs rather than charges. We believe", "metadata": {}}
+{"_id": "21216726", "title": "", "text": "Human herpesvirus 8 infection and Kaposi'ssarcoma among human immunodeficiencyvirus-infected and -uninfected women.Little isknown about the epidemiology of humanherpesvirus 8 (HHV-8) infections among women.A cross-sectional study was conducted of HHV-8infection among human immunodeficiency virus(HIV)-infected and high-risk HIV-uninfectedwomen. Serological tests with noninduced(latent) and induced (lytic) HHV-8 antigens wereused to detect infection among 2483 participantsof a multisite cohort. Reactivity to latent antigenwas present in 4.1% and to induced antigens in12.0% of women. Seven of 8 women whoreported Kaposi's sarcoma had HHV-8antibodies. Among HIV-positive women, HHV-8infection was associated with use of crack,cocaine, or heroin (76% vs. 65%; P<.001), pastsyphilis (29% vs. 20%; P<.001), an injectiondrug-using male sex partner (61% vs. 53%;P=.014), black race (P=.010), and enrollmentsite (P=.015). In multivariate analysis, HIV", "metadata": {}}
+{"_id": "21219071", "title": "", "text": "Cloning of three novel neuronal Cdk5 activatorbinding proteins.Neuronal Cdc2-like kinase(Nclk) is involved in the regulation of neuronaldifferentiation and neuro-cytoskeleton dynamics.The active kinase consists of a catalytic subunit,Cdk5, and a 25 kDa activator protein (p25nck5a)derived from a 35 kDa neuronal-specific protein(p35nck5a). As an extension of our previousstudy (Qi, Z., Tang, D., Zhu, X., Fujita, D.J.,Wang, J.H., 1998. Association of neurofilamentproteins with neuronal Cdk5 activator. J. Biol.Chem. 270, 2329-2335), which showed thatneurofilament is one of the p35nck5a-associatedproteins, we now report the isolation of threeother novel p35nck5a-associated proteins usingthe yeast two-hybrid screen. The full-lengthforms of these three novel proteins, designatedC42, C48 and C53, have a molecular mass of 66,24, and 57 kDa, respectively. Northern analysisindicates that these novel proteins are widelyexpressed in human tissues, including the heart,brain, skeletal muscle, placenta, lung, liver,", "metadata": {}}
+{"_id": "21221346", "title": "", "text": "The Artemis:DNA-PKcs endonuclease cleavesDNA loops, flaps, and gaps.In eukaryotic cells,nonhomologous DNA end joining (NHEJ) is amajor pathway for repair of double-strand DNAbreaks (DSBs). Artemis and the 469kDaDNA-dependent protein kinase (DNA-PKcs)together form a key nuclease for NHEJ invertebrate organisms. The structure-specificendonucleolytic activity of Artemis is activated bybinding to and phosphorylation by DNA-PKcs. Wetested various DNA structures in order tounderstand the range of structural features thatare recognized by the Artemis:DNA-PKcscomplex. We find that all tested substrates thatcontain single-to-double-strand transitions canbe cleaved by the Artemis:DNA-PKcs complexnear the transition region. The cleavedsubstrates include heterologous loops,stem-loops, flaps, and gapped substrates. Suchversatile activity on single-/double-strandtransition regions is important in understandinghow reconstituted NHEJ systems that lack DNA", "metadata": {}}
+{"_id": "21230110", "title": "", "text": "A promoter derived from taro bacilliformbadnavirus drives strong expression intransgenic banana and tobacco plantsTarobacilliform virus (TaBV) is a pararetrovirus of thegenus Badnavirus which infects themonocotyledonous plant, taro (Colocasiaesculenta). A region of the TaBV genomespanning nucleotides 6,281 to 12 (T1200),including the 3′ end of open reading frame 3(ORF 3) and the intergenic region to the end ofthe tRNAmet-binding site, was tested forpromoter activity along with four different 5′deletion fragments (T600, T500, T250 andT100). In transient assays, only the T1200,T600, T500 fragments were shown to havepromoter activity in taro leaf, banana suspensioncells and tobacco callus. When these threepromoters were evaluated in stably transformed,in vitro-grown transgenic banana and tobaccoplants, all were found to drive near-constitutiveexpression of either the green fluorescent proteinor β-glucuronidase (GUS) reporter gene in the", "metadata": {}}
+{"_id": "21232018", "title": "", "text": "Age of ovary determines remaining lifeexpectancy in old ovariectomized mice.Weinvestigated the capacity of young ovaries,transplanted into old ovariectomized CBA mice,to improve remaining life expectancy of thehosts. Donor females were sexually mature2-month-olds; recipients were prepubertallyovariectomized at 3 weeks and receivedtransplants at 5, 8 or 11 months of age. Relativeto ovariectomized control females, lifeexpectancy at 11 months was increased by 60%in 11-month recipient females and by 40%relative to intact control females. Only 20% ofthe 11-month transplant females died in the300-day period following ovarian transplantation,whereas nearly 65% of the ovariectomizedcontrol females died during this same period.The 11-month-old recipient females resumedoestrus and continued to cycle up to severalmonths beyond the age of control femalereproductive senescence. Across the threerecipient age groups, transplantation of young", "metadata": {}}
+{"_id": "21239672", "title": "", "text": "Use of macrolides in mother and child and risk ofinfantile hypertrophic pyloric stenosis:nationwide cohort studyOBJECTIVE To assess theassociation between use of macrolide antibioticsin mothers and infants from pregnancy onsetuntil 120 days after birth and infantilehypertrophic pyloric stenosis (IHPS). DESIGNNationwide register based cohort study. SETTINGDenmark, 1996-2011. PARTICIPANTS 999,378liveborn singletons and linked individual levelinformation on macrolide prescriptions (maternaluse during pregnancy, n=30,091; maternal useafter birth, n=21,557; use in infants, n=6591),surgery for IHPS, and potential confounders.MAIN OUTCOME MEASURES Surgery for IHPS bythree categories of macrolide use: in mothersduring pregnancy, in mothers after birth, and ininfants after birth. RESULTS 880 infantsdeveloped IHPS (0.9 cases per 1000 births).Compared with infants with no use of macrolides,the adjusted rate ratio for IHPS in infants withuse of macrolides during days 0 to 13 after birth", "metadata": {}}
+{"_id": "21246752", "title": "", "text": "The psychiatric manifestations of mitochondrialdisorders: a case and review of theliterature.OBJECTIVE Mitochondrial disorders arecaused by gene mutations in mitochondrial ornuclear DNA and affect energy-dependent organssuch as the brain. Patients with psychiatricillness, particularly those with medicalcomorbidities, may have primary mitochondrialdisorders. To date, this issue has received littleattention in the literature, and mitochondrialdisorders are likely underdiagnosed in psychiatricpatients. DATA SOURCES This article describes apatient who presented with borderlinepersonality disorder and treatment-resistantdepression and was ultimately diagnosed withmitochondrial encephalomyopathy with lacticacidosis and stroke-like episodes (MELAS) 3271.We also searched the literature for all casereports of patients with mitochondrial disorderswho initially present with prominent psychiatricsymptoms by using MEDLINE (from1948-February 2011), Embase (from", "metadata": {}}
+{"_id": "21250322", "title": "", "text": "Polo kinase and Asp are needed to promote themitotic organizing activity ofcentrosomesInterfering with the activity ofpolo-like kinases can lead to the formation ofmonopolar spindles. Polo-like kinases alsoregulate mitotic entry, activation of theanaphase-promoting complex and the necessarypreconditions for cytokinesis. Similaritiesbetween the phenotypes of the Drosophilamutants asp and polo point towards a commonrole in spindle pole function. The abnormalspindles of asp mutants are bipolar but havedisorganized broad poles at which γ-tubulin hasan abnormal distribution. Moreover, thesynergism or of polo1 aspE3 double mutantsindicates a possible involvement of these genesin a common process. Asp is amicrotubule-associated protein of relativemolecular mass 220,000 (Mr 220K) found at theface of the centrosome that contacts spindlemicrotubules. In partially purified centrosomes, itis required with γ-tubulin to organize microtubule", "metadata": {}}
+{"_id": "21257564", "title": "", "text": "How long will long-term potentiation last?Theparamount feature of long-term potentiation(LTP) as a memory mechanism is itscharacteristic persistence over time. Althoughthe basic phenomenology of LTP persistence wasestablished 30 years ago, new insights haveemerged recently about the extent of LTPpersistence and its regulation by activity andexperience. Thus, it is now evident that LTP, atleast in the dentate gyrus, can either bedecremental, lasting from hours to weeks, orstable, lasting months or longer. Althoughmechanisms engaged during the induction of LTPregulate its subsequent persistence, themaintenance of LTP is also governed by activitypatterns post-induction, whether inducedexperimentally or generated by experience.These new findings establish dentate gyrus LTPas a useful model system for studying themechanisms governing the induction,maintenance and interference with long-termmemory, including very long-term memory", "metadata": {}}
+{"_id": "21258863", "title": "", "text": "An IL-13 inhibitor blocks the development ofhepatic fibrosis during a T-helper type2-dominated inflammatory response.Inschistosomiasis, chronic parasite egg-inducedgranuloma formation can lead to tissuedestruction and fibrosis, which causes much ofthe morbidity and mortality associated with thisdisease. Here we show the importance of IL-13in the pathogenesis of schistosomiasis, anddemonstrate, perhaps for the first time, thetherapeutic efficacy of an IL-13 inhibitor,sIL-13Ralpha2-Fc, in the control of hepaticfibrosis. T-helper type 2 (Th2) cytokinesdominate the immune response in mice infectedwith Schistosoma mansoni, yet the specificcontributions of IL-13 and IL-4 to thedevelopment of fibrosis were not previouslyinvestigated. Our studies demonstrate that bothcytokines play redundant roles in granulomaformation, which explains the ability ofIL-4-deficient mice to form granulomas aroundeggs. More importantly, however, these studies", "metadata": {}}
+{"_id": "21260231", "title": "", "text": "Validity and reliability of observational methodsfor studying medication administrationerrors.The validity and reliability of observationalmethods for studying medication administrationerrors (MAEs) were studied. Between Januaryand June 1998, two pharmacists observedconsecutive drug administration rounds bynurses on two wards in a U.K. hospital andrecorded all MAEs identified. The observersintervened in cases of potentially harmful errors.MAE records were audited to determine thepercentage of omitted doses for which acorresponding reason was documented for theobservation periods and for nonobservationperiods. Error rates for each drug administrationround were analyzed according to whether theywere for the nurse's first, second, third (and soon) observed round. Error rates were calculatedbefore and after the first intervention with nursesfor whom an intervention was made. Observerreliability was calculated by comparing the ratesof errors identified by the two observers. There", "metadata": {}}
+{"_id": "21271817", "title": "", "text": "Directly reprogrammed fibroblasts show globalepigenetic remodeling and widespread tissuecontribution.Ectopic expression of the fourtranscription factors Oct4, Sox2, c-Myc, and Klf4is sufficient to confer a pluripotent state upon thefibroblast genome, generating inducedpluripotent stem (iPS) cells. It remains unknownif nuclear reprogramming induced by these fourfactors globally resets epigenetic differencesbetween differentiated and pluripotent cells.Here, using novel selection approaches, we havegenerated iPS cells from fibroblasts tocharacterize their epigenetic state. Female iPScells showed reactivation of a somaticallysilenced X chromosome and underwent randomX inactivation upon differentiation. Genome-wideanalysis of two key histone modificationsindicated that iPS cells are highly similar to EScells. Consistent with these observations, iPScells gave rise to viable high-degree chimeraswith contribution to the germline. These datashow that transcription factor-induced", "metadata": {}}
+{"_id": "21272977", "title": "", "text": "Exocrine ontogenies: on the development ofpancreatic acinar, ductal and centroacinarcells.This review summarizes our currentunderstanding of exocrine pancreasdevelopment, including the formation of acinar,ductal and centroacinar cells. We discuss thetranscription factors associated with variousstages of exocrine differentiation, frommultipotent progenitor cells to fully differentiatedacinar and ductal cells. Within the branchingepithelial tree of the embryonic pancreas, thisinvolves the progressive restriction ofmultipotent pancreatic progenitor cells to eithera central \"trunk\" domain giving rise to the isletand ductal lineages, or a peripheral \"tip\" domaingiving rise to acinar cells. This review alsodiscusses the soluble morphogens and othersignaling pathways that influence these events.Finally, we examine centroacinar cells as anenigmatic pancreatic cell type whose lineageremains uncertain, and whose possibleprogenitor capacities continue to be explored.", "metadata": {}}
+{"_id": "21274496", "title": "", "text": "The history of SIVS and AIDS: epidemiology,phylogeny and biology of isolates from naturallySIV infected non-human primates (NHP) inAfrica.Simian immunodeficiency virus (SIV)naturally infects non-human primates in Africa.To date, 40 SIVs have been described both innatural hosts and in heterologous species. Theseviruses are highly diverse and the majoritycluster in 6 relatively equidistant phylogeneticlineages. At least 8 SIVs are currently consideredas recombinant viruses, based on differentclustering patterns in different genomic regions.Only three types of genomes are known, basedon the number of accessory genes:vpr-containing genomes, vpr-vpx containinggenomes and vpr-vpu-containing genomes. vpxresulted by a duplication of the vpr genefollowing non-homologous recombination and ischaracteristic of SIVs infecting the Papionini tribeof monkeys and HIV-2 in humans. vpu ischaracteristic of SIVcpz and HIV-1 and may haveoriginated from a recombination involving SIVs", "metadata": {}}
+{"_id": "21274919", "title": "", "text": "The association between common physicalimpairments and dementia in low and middleincome countries, and, among people withdementia, their association with cognitivefunction and disability. A 10/66 DementiaResearch Group population-basedstudy.OBJECTIVE Chronic physical comorbidity iscommon in dementia. However, there is anabsence of evidence to support good practiceguidelines for attention to these problems. Weaimed to study the extent of this comorbidity andits impact on cognitive function and disability inpopulation-based studies in low and middleincome countries, where chronic diseases andimpairments are likely to be both common andundertreated. METHODS A multicentrecross-sectional survey of all over 65 year oldresidents (n = 15 022) in 11 catchment areas inChina, India, Cuba, Dominican Republic,Venezuela, Mexico and Peru. We estimated theprevalence of pain, incontinence, hearing andvisual impairments, mobility impairment and", "metadata": {}}
+{"_id": "21287352", "title": "", "text": "Serum biomarkers as predictors of lung functiondecline in chronic obstructive pulmonarydisease.BACKGROUND Recent studies show thatCOPD patients exhibit low-grade systemicinflammation, and that plasma fibrinogen andhigh neutrophil counts are related to fasterdeclines in lung function. We examinedcorrelations between serum biomarkers and thedecline of lung function in COPD patients.METHOD Baseline levels of 9 serum biomarkers(TIMP-1, alpha1-antitrypsin, MMP-9, TNF-alpha,TGF-beta, IL-6, IL-8, neutrophil elastase andCRP), fibrinogen and white blood cell counts(WCC) were measured in 96 COPD patients.Lung function was measured at the time of bloodsampling and every 3-6 months during theobservation period (median 25.0 months).RESULTS Twenty patients were rapid decliners oflung function and 53 patients werenon-decliners. Neutrophil counts, serum CRP andMMP-9 were significantly higher in the rapiddecliners (p<0.05). The annual change of %", "metadata": {}}
+{"_id": "21295300", "title": "", "text": "Phosphorylation of ATM by Cdk5 mediates DNAdamage signaling and regulates neuronaldeathThe phosphatidylinositol-3-kinase-likekinase ATM (ataxia-telangiectasia mutated) hasa central role in coordinating DNA damageresponses, including cell-cycle checkpointcontrol, DNA repair and apoptosis. Mutations ofATM cause a spectrum of defects ranging fromneurodegeneration to cancer predisposition.However, the mechanism by which DNA damageactivates ATM is poorly understood. Here weshow that Cdk5 (cyclin-dependent kinase 5),activated by DNA damage, directlyphosphorylates ATM at Ser 794 in post-mitoticneurons. Phosphorylation at Ser 794 precedes,and is required for, ATM autophosphorylation atSer 1981, and activates ATM kinase activity. TheCdk5-ATM signal regulates phosphorylation andfunction of the ATM targets p53 and H2AX.Interruption of the Cdk5-ATM pathwayattenuates DNA-damage-induced neuronal cellcycle re-entry and expression of the p53 targets", "metadata": {}}
+{"_id": "21297708", "title": "", "text": "Nerve-induced release of nitric oxide in therabbit gastrointestinal tract as measured by invivo microdialysis.1. Nitric oxide (NO) has beensuggested as a gastrointestinal neurotransmitter,mediating the gastric receptive relaxation andthe relaxation in the peristaltic reflex. The aim ofthe present study was to measure nerve-inducedNO formation in vivo in the gastrointestinal tract.2. Formation of the nitric oxide oxidationproducts nitrite and nitrate during vagal nervestimulation were measured in the anaesthetizedrabbit. Microdialysis probes were inserted intothe wall of the stomach and proximal colon, andnitrite and nitrate in dialysate measured bycapillary electrophoresis. 3. During bilateralvagal nerve stimulation there was an increase innitrite and nitrate formation at the level of thestomach and in nitrite formation at the level ofthe colon. This increase was inhibited byintravenous administration of the NO synthaseinhibitor N omega-nitro-L-arginine methyl ester(L-NAME 30 mg kg-1). Furthermore, L-NAME", "metadata": {}}
+{"_id": "21301090", "title": "", "text": "Screening for concomitant diseases in peripheralvascular patients. Results of a systematicapproach.BACKGROUND Patients considered forarterial surgery, have been shown to have a highincidence of coexistent cardiac, vascular andother diseases, affecting operative risk andsurvival. We developed a systematic workupstrategy for detecting these coexistent diseasesin our vascular surgical patients, mainly basedon non-invasive diagnostic techniques.METHODS We evaluated 200 consecutivepatients, admitted to the department of vascularsurgery in an academic teaching hospital, inorder to establish the total incidence of relevantconcomitant disorders, the extent to which thisscreening yielded previously unknown diagnosticinformation, and the impact on short-term (oneyear) survival. RESULTS Coronary artery diseasewas present in 46% of the patients; 22% hadactive ischaemia, newly diagnosed in 5.5%.Impaired cardiac function was found in 37%:severely impaired in 12%, newly diagnosed in", "metadata": {}}
+{"_id": "21302115", "title": "", "text": "Archetypal trajectories of social, psychological,and spiritual wellbeing and distress in family caregivers of patients with lung cancer: secondaryanalysis of serial qualitativeinterviewsOBJECTIVE To assess if family caregivers of patients with lung cancer experiencethe patterns of social, psychological, and spiritualwellbeing and distress typical of the patient, fromdiagnosis to death. DESIGN Secondary analysisof serial qualitative interviews carried out everythree months for up to a year or tobereavement. SETTING South east Scotland.PARTICIPANTS 19 patients with lung cancer andtheir 19 family carers, totalling 88 interviews (42with patients and 46 with carers). RESULTSCarers followed clear patterns of social,psychological, and spiritual wellbeing anddistress that mirrored the experiences of thosefor whom they were caring, with some carersalso experiencing deterioration in physical healththat impacted on their ability to care.Psychological and spiritual distress were", "metadata": {}}
+{"_id": "21307488", "title": "", "text": "HER-2/neu induces p53 ubiquitination viaAkt-mediated MDM2 phosphorylationHER-2/neuamplification or overexpression can make cancercells resistant to apoptosis and promotes theirgrowth. p53 is crucial in regulating cell growthand apoptosis, and is often mutated or deleted inmany types of tumour. Moreover, many tumourswith a wild-type gene for p53 do not havenormal p53 function, suggesting that someoncogenic signals suppress the function of p53.In this study, we show that HER-2/neu-mediatedresistance to DNA-damaging agents requires theactivation of Akt, which enhancesMDM2-mediated ubiquitination and degradationof p53. Akt physically associates with MDM2 andphosphorylates it at Ser166 and Ser186.Phosphorylation of MDM2 enhances its nuclearlocalization and its interaction with p300, andinhibits its interaction with p19ARF, thusincreasing p53 degradation. Our study indicatesthat blocking the Akt pathway mediated byHER-2/neu would increase the cytotoxic effect of", "metadata": {}}
+{"_id": "21320417", "title": "", "text": "T cell memory.T cell memory induced by priorinfection or vaccination provides enhancedprotection against subsequent microbialinfections. The processes involved in generatingand maintaining T cell memory are becomingbetter understood due to recent technologicaladvances in identifying memory T cells andmonitoring their behavior and function in vivo.Memory T cells develop in response to aprogressive set of cues-starting with signals fromantigen-loaded, activated antigen-presentingcells (APCs) and inflammatory mediators inducedby the innate immune response, to the poorlydefined subsequent signals triggered as theimmune response wanes toward homeostasis.The persistence of the resting memory T cellsthat eventually develop is regulated bycytokines. This chapter discusses recent findingson how memory T cells develop to conferlong-term protective immunity.", "metadata": {}}
+{"_id": "21323587", "title": "", "text": "The impact of organisational change on outcomein an intensive care unit in the UnitedKingdomObjectives: To study the change inoutcome for patients admitted to an intensivecare unit following the establishment of a teamof resident medical staff and a change from an\"open\" to a \"closed\" organisational format.Design: Database review of prospectivelycollected data. Setting: Intensive care unit of apostgraduate teaching hospital. Subjects: 1134admissions to the intensive care unit over a3-year period, of whom 476 (42%) followedelective surgery. Main outcome measure:Hospital mortality corrected for illness severityby using the APACHE II scoring system. Results:Crude hospital mortality fell from 28% before thechanges to 20% afterwards (P=0.01). Withcorrection for case-mix factors, the probability ofdeath after the changes was reduced by almosthalf (OR 0.51; CI 0.32, 0.82, P=0.005).Conclusion: A \"closed\" format of organisation ofthe delivery of care may result in improved", "metadata": {}}
+{"_id": "21323758", "title": "", "text": "Monitoring effectiveness and safety of Tafamidisin transthyretin amyloidosis in Italy: alongitudinal multicenter study in a non-endemicareaTafamidis is a transthyretin (TTR) stabilizerable to prevent TTR tetramer dissociation. Therehave been a few encouraging studies onTafamidis efficacy in early-onset inheritedtransthyretin amyloidosis (ATTR) due toVal30Met mutation. However, less is knownabout its efficacy in later disease stages and innon-Val30Met mutations. We performed amulti-center observational study on symptomaticATTR patients prescribed to receive Tafamidis.We followed up patients according to astandardized protocol including general medical,cardiological and neurological assessments atbaseline and every 6 months up to 3 years.Sixty-one (42 males) patients were recruited.Only 28 % of enrolled subjects had the commonVal30Met mutation, mean age of onset wasremarkably late (59 years) and 18 % was inadvanced disease stage at study entry. Tafamidis", "metadata": {}}
+{"_id": "21330280", "title": "", "text": "The Spliceosome: Design Principles of a DynamicRNP MachineRibonucleoproteins (RNPs) mediatekey cellular functions such as gene expressionand its regulation. Whereas most RNP enzymesare stable in composition and harbor preformedactive sites, the spliceosome, which removesnoncoding introns from precursor messengerRNAs (pre-mRNAs), follows fundamentallydifferent strategies. In order to provide bothaccuracy to the recognition of reactive splicesites in the pre-mRNA and flexibility to the choiceof splice sites during alternative splicing, thespliceosome exhibits exceptional compositionaland structural dynamics that are exploited duringsubstrate-dependent complex assembly,catalytic activation, and active site remodeling.", "metadata": {}}
+{"_id": "21363424", "title": "", "text": "Blimp-1 attenuates Th1 differentiation byrepression of ifng, tbx21, and bcl6 geneexpression.T cell-specific deletion of Blimp-1causes abnormal T cell homeostasis andfunction, leading to spontaneous, fatal colitis inmice. Herein we explore the role of Blimp-1 inTh1/Th2 differentiation. Blimp-1 mRNA andprotein are more highly expressed in Th2 cellscompared with Th1 cells, and Blimp-1 attenuatesIFN-gamma production in CD4 cells activatedunder nonpolarizing conditions. AlthoughBlimp-1-deficient T cells differentiate normally toTh2 cytokines in vitro, Blimp-1 is required in vivofor normal Th2 humoral responses to NP-KLH(4-hydroxy-3-nitrophenylacetyl/keyholelymphocyte hemocyanin) immunization. Lack ofBlimp-1 in CD4 T cells causes increasedIFN-gamma, T-bet, and Bcl-6 mRNA. Bychromatin immunoprecipitation we show thatBlimp-1 binds directly to a distal regulatoryregion in the ifng gene and at multiple sites intbx21 and bcl6 genes. Our data provide evidence", "metadata": {}}
+{"_id": "21366394", "title": "", "text": "CX3CR1 is required for airway inflammation bypromoting T helper cell survival and maintenancein inflamed lungAllergic asthma is a T helper type2 (T(H)2)-dominated disease of the lung. Inpeople with asthma, a fraction of CD4(+) T cellsexpress the CX3CL1 receptor, CX3CR1, andCX3CL1 expression is increased in airway smoothmuscle, lung endothelium and epithelium uponallergen challenge. Here we found that untreatedCX3CR1-deficient mice or wild-type (WT) micetreated with CX3CR1-blocking reagents showreduced lung disease upon allergen sensitizationand challenge. Transfer of WT CD4(+) T cellsinto CX3CR1-deficient mice restored the cardinalfeatures of asthma, and CX3CR1-blockingreagents prevented airway inflammation inCX3CR1-deficient recipients injected with WTT(H)2 cells. We found that CX3CR1 signalingpromoted T(H)2 survival in the inflamed lungs,and injection of B cell leukemia/lymphoma-2protein (BCl-2)-transduced CX3CR1-deficientT(H)2 cells into CX3CR1-deficient mice restored", "metadata": {}}
+{"_id": "21369472", "title": "", "text": "TRPC6 is a glomerular slit diaphragm-associatedchannel required for normal renalfunctionProgressive kidney failure is a geneticallyand clinically heterogeneous group of disorders.Podocyte foot processes and the interposedglomerular slit diaphragm are essentialcomponents of the permeability barrier in thekidney. Mutations in genes encoding structuralproteins of the podocyte lead to the developmentof proteinuria, resulting in progressive kidneyfailure and focal segmental glomerulosclerosis.Here, we show that the canonical transientreceptor potential 6 (TRPC6) ion channel isexpressed in podocytes and is a component ofthe glomerular slit diaphragm. We identified fivefamilies with autosomal dominant focalsegmental glomerulosclerosis in which diseasesegregated with mutations in the gene TRPC6 onchromosome 11q. Two of the TRPC6 mutantshad increased current amplitudes. These datashow that TRPC6 channel activity at the slitdiaphragm is essential for proper regulation of", "metadata": {}}
+{"_id": "21372171", "title": "", "text": "Usefulness of high mobility group box 1 proteinas a plasma biomarker in patient with peripheralartery disease.Atherosclerosis is often associatedwith chronic vascular inflammation.High-mobility group box 1 protein (HMGB1) playsvarious roles, not only as a transcriptionalregulatory factor in the nucleus, but also as aninflammatory mediator. A previous studysuggested that fibrinogen is an important factorassociated with atherosclerosis progression. Thepresent study was performed to examine thelevels of plasma HMGB1 protein inatherosclerosis patients. We studied 24 patientswith peripheral artery disease (PAD) withatherosclerosis, and 10 healthy controls. Wefound that the concentrations of HMGB1 wereincreased in the plasma of the patients withatherosclerosis, and there were significantcorrelations between the plasma HMGB1 andfibrinogen levels. Plasma HMGB1 may play a keyrole in the pathogenesis of clinical andexperimental atherosclerosis.", "metadata": {}}
+{"_id": "21373240", "title": "", "text": "Functional specialization of Piwi proteins inParamecium tetraurelia from post-transcriptionalgene silencing to genome remodellingProteins ofthe Argonaute family are small RNA carriers thatguide regulatory complexes to their targets. Thefamily comprises two major subclades. Membersof the Ago subclade, which are present in mosteukaryotic phyla, bind different classes of smallRNAs and regulate gene expression at bothtranscriptional and post-transcriptional levels.Piwi subclade members appear to have been lostin plants and fungi and were mostly studied inmetazoa, where they bind piRNAs and haveessential roles in sexual reproduction. Theirpresence in ciliates, unicellular organismsharbouring both germline micronuclei andsomatic macronuclei, offers an interestingperspective on the evolution of their functions.Here, we report phylogenetic and functionalanalyses of the 15 Piwi genes from Parameciumtetraurelia. We show that four constitutivelyexpressed proteins are involved in siRNA", "metadata": {}}
+{"_id": "21373821", "title": "", "text": "A parasomnia overlap disorder involvingsleepwalking, sleep terrors, and REM sleepbehavior disorder in 33 polysomnographicallyconfirmed cases.A series of 33 patients withcombined (injurious) sleepwalking, sleep terrors,and rapid eye movement (REM) sleep behaviordisorder (viz. \"parasomnia overlap disorder\")was gathered over an 8-year period. Patientsunderwent clinical and polysomnographicevaluations. Mean age was 34 +/- 14 (SD)years; mean age of parasomnia onset was 15+/- 16 years (range 1-66); 70% (n = 23) weremales. An idiopathic subgroup (n = 22) had asignificantly earlier mean age of parasomniaonset (9 +/- 7 years) than a symptomaticsubgroup (n = 11) (27 +/- 23 years, p = 0.002),whose parasomnia began with either of thefollowing: neurologic disorders, n = 6 [congenitalMobius syndrome, narcolepsy, multiple sclerosis,brain tumor (and treatment), brain trauma,indeterminate disorder (exaggerated startleresponse/atypical cataplexy)]; nocturnal", "metadata": {}}
+{"_id": "21377587", "title": "", "text": "How can health care organizations be reliablycompared?: Lessons from a national survey ofpatient experience.BACKGROUND Patientexperience is increasingly used to assessorganizational performance, for example inpublic reporting or pay-for-performanceschemes. Conventional approaches using 95%confidence intervals are commonly used todetermine required survey samples or to reportperformance but these may result in unreliableorganizational comparisons. METHODS Weanalyzed data from 2.2 million patients whoresponded to the English 2009 General PracticePatient Survey, which included 45 patientexperience questions nested within 6 differentcare domains (access, continuity of care,communication, anticipatory care planning,out-of-hours care, and overall care satisfaction).For each question, unadjusted and case-mixadjusted (for age, sex, and ethnicity)organization-level reliability, and intraclasscorrelation coefficients were calculated. RESULTS", "metadata": {}}
+{"_id": "21380232", "title": "", "text": "Conservation of methylation reprogramming inmammalian development: aberrantreprogramming in cloned embryos.Mouseembryos undergo genome-wide methylationreprogramming by demethylation in earlypreimplantation development, followed byremethylation thereafter. Here we show thatgenome-wide reprogramming is conserved inseveral mammalian species and ask whether italso occurs in embryos cloned with the use ofhighly methylated somatic donor nuclei. Normalbovine, rat, and pig zygotes showed ademethylated paternal genome, suggestingactive demethylation. In bovine embryosmethylation was further reduced during cleavageup to the eight-cell stage, and this reduction inmethylation was followed by de novomethylation by the 16-cell stage. In clonedone-cell embryos there was a reduction inmethylation consistent with activedemethylation, but no further demethylationoccurred subsequently. Instead, de novo", "metadata": {}}
+{"_id": "21380348", "title": "", "text": "Intracellular transport of fat-soluble vitamins Aand E.Vitamins are compounds that are essentialfor the normal growth, reproduction andfunctioning of the human body. Of the 13 knownvitamins, vitamins A, D, E and K are lipophiliccompounds and are therefore called fat-solublevitamins. Because of their lipophilicity,fat-soluble vitamins are solubilized andtransported by intracellular carrier proteins toexert their actions and to be metabolizedproperly. Vitamin A and its derivatives,collectively called retinoids, are solubilized byintracellular retinoid-binding proteins such ascellular retinol-binding protein (CRBP), cellularretinoic acid-binding protein (CRABP) and cellularretinal-binding protein (CRALBP). These proteinsact as chaperones that regulate the metabolism,signaling and transport of retinoids.CRALBP-mediated intracellular retinoid transportis essential for vision in human. α-Tocopherol,the main form of vitamin E found in the body, istransported by α-tocopherol transfer protein", "metadata": {}}
+{"_id": "21382907", "title": "", "text": "Reduced Cytokine Release in Ex Vivo Responseto Cilengitide and Cetuximab Is a Marker forImproved Survival of Head and Neck CancerPatientsTargeting of αVβ3 and αVβ5 integrins bycilengitide may reduce growth of solid tumorsincluding head and neck squamous cellcarcinoma (HNSCC). Preclinical investigationssuggest increased activity of cilengitide incombination with other treatment modalities.The only published trial in HNSCC (ADVANTAGE)investigated cisplatin, 5-fluorouracil, andcetuximab (PFE) without or with once(PFE+CIL1W) or twice weekly cilengitide(PFE+CIL2W) in recurrent/metastatic HNSCC.ADVANTAGE showed good tolerability of thecilengitide arms and even lower adverse events(AEs) compared to PFE but not the benefit inoverall survival expected based on preclinicaldata. As we found in the FLAVINO assay, ashort-time ex vivo assay for prediction ofchemosensitivity, only a subgroup of HNSCC hadan increased suppressive effect of cilengitide", "metadata": {}}
+{"_id": "21383026", "title": "", "text": "Genes required for mycobacterial growth definedby high density mutagenesis.Despite over acentury of research, tuberculosis remains aleading cause of infectious death worldwide.Faced with increasing rates of drug resistance,the identification of genes that are required forthe growth of this organism should provide newtargets for the design of antimycobacterialagents. Here, we describe the use of transposonsite hybridization (TraSH) to comprehensivelyidentify the genes required by the causativeagent, Mycobacterium tuberculosis, for optimalgrowth. These genes include those that can beassigned to essential pathways as well as manyof unknown function. The genes important forthe growth of M. tuberculosis are largelyconserved in the degenerate genome of theleprosy bacillus, Mycobacterium leprae,indicating that non-essential functions have beenselectively lost since this bacterium divergedfrom other mycobacteria. In contrast, asurprisingly high proportion of these genes lack", "metadata": {}}
+{"_id": "21387297", "title": "", "text": "Production of de novo cardiomyocytes: humanpluripotent stem cell differentiation and directreprogramming.Cardiovascular disease is aleading cause of death worldwide. The limitedcapability of heart tissue to regenerate hasprompted methodological developments forcreating de novo cardiomyocytes, both in vitroand in vivo. Beyond uses in cell replacementtherapy, patient-specific cardiomyocytes mayfind applications in drug testing, drug discovery,and disease modeling. Recently, approaches forgenerating cardiomyocytes have expanded toencompass three major sources of starting cells:human pluripotent stem cells (hPSCs), adultheart-derived cardiac progenitor cells (CPCs),and reprogrammed fibroblasts. We discussstate-of-the-art methods for generating de novocardiomyocytes from hPSCs and reprogrammedfibroblasts, highlighting potential applicationsand future challenges.", "metadata": {}}
+{"_id": "21392223", "title": "", "text": "Within the hemopoietic system, LAR phosphataseis a T cell lineage-specific adhesion receptor-likeprotein whose phosphatase activity appearsdispensable for T cell development, repertoireselection and function.Expression of thereceptor-type tyrosine phosphatase LAR wasstudied in cells of the murine hemopoieticsystem. The gene is expressed in all cells of theT cell lineage but not in cells of any otherhemopoietic lineage and the level of expressionin T cells is developmentally regulated. TheCD4(-)8(-)44(+) early thymic immigrants andmature (CD4(+)8(-)/CD4(-)8(+)) thymocytesand T cells express low levels, whereas immature(CD4(-)8(-)44(-) and CD4(+)8(+)) thymocytesexpress high levels of LAR. Among bone marrowcells only uncommitted c-kit(+)B220(+)CD19(-)precursors, but not B cell lineage committedc-kit(+)B220(+)CD19(+) precursors, expresslow levels of LAR. In contrast to thec-kit(+)B220(+)CD19(+) pre-BI cells fromnormal mice, counterparts of pre-BI cells from", "metadata": {}}
+{"_id": "21392703", "title": "", "text": "Competition and the evolution of reproductiverestraint in malaria parasites.All organisms musttrade off resource allocation between differentlife processes that determine their survival andreproduction. Malaria parasites replicateasexually in the host but must produce sexualstages to transmit between hosts. Becausedifferent specialized stages are required for thesefunctions, the division of resources betweenthese life-history components is a key problemfor natural selection to solve. Despite themedical and economic importance of theseparasites, their reproductive strategies remainpoorly understood and often seemcounterintuitive. Here, we tested recent theorypredicting that in-host competition shapes howparasites trade off investment in in-hostreplication relative to between-hosttransmission. We demonstrate, across severalgenotypes, that Plasmodium chabaudi parasitesdetect the presence of competing genotypes andfacultatively respond by reducing their", "metadata": {}}
+{"_id": "21395936", "title": "", "text": "[Neutrophils and macrophages related to thepathogenesis and disease development ofchronic obstructive pulmonary disease by theinflammatory reaction].Chronic obstructivepulmonary disease (COPD) is a chronic airwaydisorder characterized by obstructive airflowlimitation which is not completely reversible withtreatment. Inflammatory changes in theperipheral airways, especially those with thediameter less than 2mm (so-called small airwaydisease) have been speculated to be initial stepsof COPD. And so it must be quite clear thatneutrophils and macrophages play an essentialrole in the pathogenesis of these lesions. Studieswith bronchoalveolar lavage demonstrated anincrease in neutrophil numbers and theneutrophil chemoattractant interleukin-8. Recentstudies demonstrated that neutrophils andmacrophages are increased and contain a varietyof proteases, which are involved in cellinfiltration and activation. Studies withgene-engineered animals and anti-cytokine", "metadata": {}}
+{"_id": "21414718", "title": "", "text": "Piezo1 Is as a Novel Trefoil Factor Family 1Binding Protein that Promotes Gastric Cancer CellMobility In VitroTrefoil factor family 1 (TFF1) is amember of the TFF-domain peptide familyinvolved in epithelial restitution and cell motility.Recently, we screened Piezo1 as a candidateTFF1-binding protein. We aimed to confirmPiezo1 as a novel TFF1 binding protein and toassess the role of this interaction in mediatinggastric cancer cell mobility. This interaction wasconfirmed by co-immunoprecipitation andco-localisation of TFF1 and Piezo1 in GES-1 cells.We used stable RNA interference to knockdownPiezo1 protein expression and restored theexpression of TFF1 in the gastric cancer cell linesSGC-7901 and BGC-823. Cell motility wasevaluated using invasion assay and migrationassay in vitro. The expression levels of theintegrin subunits β1, β5, α1 as well as theexpression of β-catenin and E-cadherin weredetected by Western blot. We demonstrate thatTFF1, but not TFF2 or TFF3, bind to and", "metadata": {}}
+{"_id": "21425864", "title": "", "text": "A conditionally lethal yeast mutant blocked at thefirst step in glycosyl phosphatidylinositol anchorsynthesis.Glycosyl phosphatidylinositols (GPIs)anchor many proteins to the surface ofeukaryotic cells and may also serve as sortingsignals on proteins and participate in signaltransduction. We have isolated a Saccharomycescerevisiae GPI anchoring mutant, gpi1, using acolony screen for cells blocked in [3H]inositolincorporation into protein. The gpi1 mutant isdefective in vitro in the synthesis ofN-acetylglucosaminyl phosphatidylinositol, thefirst intermediate in GPI synthesis, and is alsotemperature-sensitive for growth. Completion ofthe first step in GPI assembly is thereforerequired for growth of the unicellular eukaryoteS. cerevisiae. GPI synthesis could therefore beexploited as a target for antifungal orantiparasitic agents.", "metadata": {}}
+{"_id": "21439293", "title": "", "text": "Beyond pattern recognition: five immunecheckpoints for scaling the microbialthreatPattern recognition by the innate immunesystem enables the detection of microorganisms,but how the level of microbial threat is evaluated— a process that is crucial for eliciting measuredantimicrobial responses with minimalinflammatory tissue damage — is less wellunderstood. New evidence has shown thatfeatures of microbial viability can be detected bythe immune system and thereby induce robustresponses that are not warranted for deadmicroorganisms. Here, we propose five immunecheckpoints that, as defined here, collectivelydetermine the gravity of microbial encounters.", "metadata": {}}
+{"_id": "21439640", "title": "", "text": "Macrophages induce COX-2 expression in breastcancer cells: role of IL-1βautoamplification.Tumor-associatedmacrophages and high levels ofcyclooxygenase-2 (COX-2) are associated withpoor prognosis in breast cancer patients, buttheir potential interdependence has not beenevaluated. The objective of this study was todetermine whether macrophages regulate COX-2expression in breast cancer cells. For thispurpose, THP-1 cells were cocultured withHCC1954 breast cancer cells. Coculture led toincreased COX-2 expression in the HCC1954 cellsand elevated prostaglandin E(2) levels inconditioned media. Similar results were observedwhen THP-1 cells were incubated with HCC1937breast cancer cells or when humanmonocyte-derived macrophages were coculturedwith HCC1954 cells. Coculture triggeredproduction of reactive oxygen species (ROS) inHCC1954 cells. COX-2 induction was blocked incells preincubated with an reduced nicotinamide", "metadata": {}}
+{"_id": "21456232", "title": "", "text": "A graphene-based platform for inducedpluripotent stem cells culture anddifferentiation.Induced pluripotent stem cells(iPSCs) hold great promise as a cell source forregenerative medicine yet its culture,maintenance of pluripotency and induction ofdifferentiation remain challenging. Conversely,graphene (G) and graphene oxide (GO) havecaptured tremendous interests in the fields ofmaterials science, physics, chemistry andnanotechnology. Here we report on that G andGO can support the mouse iPSCs culture andallow for spontaneous differentiation.Intriguingly, G and GO surfaces led to distinctcell proliferation and differentiationcharacteristics. In comparison with the glasssurface, iPSCs cultured on the G surfaceexhibited similar degrees of cell adhesion andproliferation while iPSCs on the GO surfaceadhered and proliferated at a faster rate.Moreover, G favorably maintained the iPSCs inthe undifferentiated state while GO expedited the", "metadata": {}}
+{"_id": "21459247", "title": "", "text": "Aerobic capacity in black adolescent girls.Ourpurpose was to determine the aerobic capacities(VO2max) of a group of black female adolescents(age = 11.4-15.8 years) randomly chosen from asingle urban school. Of 91 girls selected, 64performed an incremental treadmill running testto volitional exhaustion and achieved VO2max asdetermined from expired gas measures. Othermeasures included height (m), weight (kg), andcalf and triceps skinfolds (for % fat estimates).Girls were also asked whether they had achievedmenarche. VO2max averaged 37.3 +/- 6.2ml.kg-1 x min-1 and was significantly correlated(r[62]) with height (-.32, p < .01), body massindex (-.63, p < .001), and % fat (-.65, p <.001) but not with age (-.16, p > .10).Postmenarchal girls were significantly taller andolder than premenarchal girls. Contrary toprevious studies, the girls' VO2max values werenot related to biological age. Our subjects'aerobic capacity values averaged 14% less thanthose of nonblack U.S. female adolescents", "metadata": {}}
+{"_id": "21465696", "title": "", "text": "Acetylation controls Notch3 stability and functionin T-cell leukemiaPost-translational modificationsof Notch3 and their functional role with respectto Notch3 overexpression in T-cell leukemia arestill poorly understood. We identify here aspecific novel property of Notch3 that isacetylated and deacetylated at lysines 1692 and1731 by p300 and HDAC1, respectively, abalance impaired by HDAC inhibitors (HDACi)that favor hyperacetylation. By using HDACi anda non-acetylatable Notch3 mutant carryingK/R1692−1731 mutations in the intracellulardomain, we show that Notch3 acetylation primesubiquitination and proteasomal-mediateddegradation of the protein. As a consequence,Notch3 protein expression and its transcriptionalactivity are decreased both in vitro and in vivo inNotch3 transgenic (tg) mice, thus impairingdownstream signaling upon target genes.Consistently, Notch3-induced T-cell proliferationis inhibited by HDACi, whereas it is enhanced bythe non-acetylatable Notch3-K/R1692−1731", "metadata": {}}
+{"_id": "21472388", "title": "", "text": "Hypoglycemia: incidence and clinical predictorsin a large population-based sample of childrenand adolescents with IDDM.OBJECTIVE Todetermine the frequency of moderate and severehypoglycemia and to identify clinical predictorsassociated with its occurrence in a largepopulation-based sample of children andadolescents with IDDM. RESEARCH DESIGN ANDMETHODS A total of 657 patients (age: 12.1 +/-4.4 years, mean +/- SD) were included in thestudy, yielding 1,449 patient-years of data. Aprospective assessment of severe hypoglycemia(an event resulting in a seizure or coma) andmoderate hypoglycemia (an event requiringassistance of another, excluding severeepisodes) was made over a 3-year period.Patients and caregivers detailed episodes ofsignificant hypoglycemia (moderate and severeevents) and these were recorded at each3-month clinic visit along with HbA1c. Data wereanalyzed using generalized estimating equationmodels fitted with the exchange correlation", "metadata": {}}
+{"_id": "21479231", "title": "", "text": "Efficacy of a 6-month versus 9-monthintermittent treatment regimen in HIV-infectedpatients with tuberculosis: a randomized clinicaltrial.RATIONALE The outcome of fullyintermittent thrice-weekly antituberculosistreatment of various durations in HIV-associatedtuberculosis is unclear. OBJECTIVES To comparethe efficacy of an intermittent 6-month regimen(Reg6M: 2EHRZ(3)/4HR(3) [ethambutol, 1,200mg; isoniazid, 600 mg; rifampicin, 450 or 600mg depending on body weight <60 or > or =60kg; and pyrazinamide, 1,500 mg for 2 mo;followed by 4 mo of isoniazid and rifampicin atthe same doses]) versus a 9-month regimen(Reg9M: 2EHRZ(3)/7HR(3)) in HIV/tuberculosis(TB). METHODS HIV-infected patients with newlydiagnosed pulmonary or extrapulmonary TB wererandomly assigned to Reg6M (n = 167) or Reg9M(n = 160) and monitored by determination ofclinical, immunological, and bacteriologicalparameters for 36 months. Primary outcomesincluded favorable responses at the end of", "metadata": {}}
+{"_id": "21479575", "title": "", "text": "High prevalence of evolutionarily conserved andspecies-specific genomic aberrations in mousepluripotent stem cells.Mouse pluripotent stemcells (PSCs) are the best studied pluripotentsystem and are regarded as the \"gold standard\"to which human PSCs are compared. However,while the genomic integrity of human PSCs hasrecently drawn much attention, mouse PSCshave not been systematically evaluated in thisregard. The genomic stability of PSCs is a matterof profound significance, as it affects theirpluripotency, differentiation, and tumorigenicity.We thus performed a thorough analysis of thegenomic integrity of 325 samples of mousePSCs, including 127 induced pluripotent stem cell(iPSC) samples. We found that genomicaberrations occur frequently in mouse embryonicstem cells of various mouse strains, add inmouse iPSCs of various cell origins andderivation techniques. Four hotspots ofchromosomal aberrations were detected: fulltrisomy 11 (with a minimally recurrent gain in", "metadata": {}}
+{"_id": "21487212", "title": "", "text": "Inhibition of cell proliferation and induction ofapoptosis by ExFABP gene targeting.Ex-FABP, anextracellular fatty acid binding lipocalin, isphysiologically expressed by differentiatingchicken chondrocytes and myoblasts. Itsexpression is enhanced after cell treatment withinflammatory stimuli and repressed byanti-inflammatory agents, behaving as an acutephase protein. Chicken liver fragments in cultureshow enhanced protein expression after bacterialendotoxin treatment. To investigate thebiological role of Ex-FABP, we stably transfectedproliferating chondrocytes with an expressionvector carrying antisense oriented Ex-FABPcDNA. We observed a dramatic loss of cellviability and a strong inhibition of cellproliferation and differentiation. Whenchondrocytes were transfected with theantisense oriented Ex-FABP cDNA we observedthat Ex-FABP down-modulation increasedapoptotic cell number. Myoblasts transfectedwith the same expression vector showed", "metadata": {}}
+{"_id": "21489324", "title": "", "text": "Profile of the Navrongo Health and DemographicSurveillance System.Located in theKassena-Nankana districts of northern Ghana,the Navrongo health and demographicsurveillance system (NHDSS) was established in1992 by the Navrongo health research centre(NHRC). The NHRC is one of three researchcentres of the Ghana health service. Theactivities and potential of the NHDSS forcollaborative research are described. The NHDSSmonitors health and demographic dynamics ofthe two Kassena-Nankana districts of northernGhana and facilitates evaluation of the morbidityand mortality impact of health and socialinterventions. The total population currentlyunder surveillance is 152 000 residing in 32 000households. Events monitored routinely includepregnancies, births, morbidity, deaths,migration, marriages and vaccination coverage.Data updates are done every 4 months bytrained fieldworkers. The NHRC also undertakesbiomedical and socio-economic studies.", "metadata": {}}
+{"_id": "21495419", "title": "", "text": "The impact of COPD on lung health worldwide:epidemiology and incidence.Information on theprevalence of COPD was obtained from vitalstatistics, health interview surveys, hospitalcharge records, national publications, and theWorld Health Organization (WHO). These dataindicate that COPD is a common disease withimplications for global health. In the UnitedStates, morbidity caused by COPD is 4%, makingCOPD the fourth leading cause of death,exceeded only by heart attacks, cancer, andstroke. Internationally, there is substantialvariation in death rates possibly reflectingsmoking behavior, type and processing oftobacco, pollution, climate, respiratorymanagement, and genetic factors. The GlobalObstructive Lung Disease Initiative, initiated bythe National Heart, Lung, and Blood Institute andthe WHO, aims to raise awareness of theincreasing burden of COPD, decrease morbidityand mortality, promote further study of thecondition, and implement programs to prevent", "metadata": {}}
+{"_id": "21498497", "title": "", "text": "TLR activation triggers the rapid differentiation ofmonocytes into macrophages and dendriticcellsLeprosy enables investigation ofmechanisms by which the innate immune systemcontributes to host defense against infection,because in one form, the disease progresses,and in the other, the infection is limited. Wereport that Toll-like receptor (TLR) activation ofhuman monocytes induces rapid differentiationinto two distinct subsets: DC-SIGN+ CD16+macrophages and CD1b+ DC-SIGN− dendriticcells. DC-SIGN+ phagocytic macrophages wereexpanded by TLR-mediated upregulation ofinterleukin (IL)-15 and IL-15 receptor. CD1b+dendritic cells were expanded by TLR-mediatedupregulation of granulocyte-macrophagecolony-stimulating factor (GM-CSF) and itsreceptor, promoted T cell activation and secretedproinflammatory cytokines. Whereas DC-SIGN+macrophages were detected in lesions and afterTLR activation in all leprosy patients, CD1b+dendritic cells were not detected in lesions or", "metadata": {}}
+{"_id": "21502234", "title": "", "text": "Mismatch repair status and clinical outcome inendometrial cancer: a systematic review andmeta-analysis.BACKGROUND The associationbetween the deficiency in mismatch repair(MMR) genes and prognosis in women withendometrial cancer is unclear. Here we report asystematic review and meta-analysis exploringthis association. METHODS We searchedliterature databases (MEDLINE, EMBASE, andCochrane) from 1980 until December 2011 toidentify studies evaluating the associationbetween MMR status and clinical outcome inendometrial cancer. The main outcome measureswere overall survival (OS) and disease-freesurvival (DFS). RESULTS Twenty-three studiesmet the inclusion criteria. The median samplesize of studies was 112, 74% were retrospectivecase-series and 70% performed microsatelliteinstability (MSI) analysis to evaluate the statusof MMR. Only 22% of studies used the panel offive microsatellite markers recommended by theNational Cancer Institute. Seven studies used", "metadata": {}}
+{"_id": "21521236", "title": "", "text": "p53 induces formation of NEAT1lncRNA-containing paraspeckles that modulatereplication stress response andchemosensitivityIn a search for mediators of thep53 tumor suppressor pathway, which inducespleiotropic and often antagonistic cellularresponses, we identified the long noncoding RNA(lncRNA) NEAT1. NEAT1 is an essentialarchitectural component of paraspeckle nuclearbodies, whose pathophysiological relevanceremains unclear. Activation of p53,pharmacologically or by oncogene-inducedreplication stress, stimulated the formation ofparaspeckles in mouse and human cells.Silencing Neat1 expression in mice, whichprevents paraspeckle formation, sensitizedpreneoplastic cells to DNA-damage-induced celldeath and impaired skin tumorigenesis. Weprovide mechanistic evidence that NEAT1promotes ATR signaling in response to replicationstress and is thereby engaged in a negativefeedback loop that attenuates", "metadata": {}}
+{"_id": "21535641", "title": "", "text": "Regulation of innate immunity by NADPHoxidase.NADPH oxidase is a critical regulator ofboth antimicrobial host defense andinflammation. Activated in nature by microbesand microbial-derived products, the phagocyteNADPH oxidase is rapidly assembled, andgenerates reactive oxidant intermediates (ROIs)in response to infectious threat. Chronicgranulomatous disease (CGD) is an inheriteddisorder of the NADPH oxidase characterized byrecurrent and severe bacterial and fungalinfections, and pathology related to excessiveinflammation. Studies in CGD patients and CGDmouse models indicate that NADPH oxidase playsa key role in modulating inflammation and injurythat is distinct from its antimicrobial function.The mechanisms by which NADPH oxidasemediates killing of pathogens and regulation ofinflammation have broad relevance to ourunderstanding of normal physiological immuneresponses and pathological states, such as acutelung injury and bacterial or fungal infections.", "metadata": {}}
+{"_id": "21547032", "title": "", "text": "Protection from olanzapine-induced metabolictoxicity in mice by acetaminophen andtetrahydroindenoindoleObjective:In mice and inhumans, treatment with the second-generationantipsychotic drug olanzapine (OLZ) producesexcessive weight gain, adiposity and secondarymetabolic complications, including loss of glucoseand insulin homeostasis. In mice consuming ahigh-fat (HF) diet, a similar phenotype develops,which is inhibited by the analgesicacetaminophen (APAP) and by the antioxidanttetrahydroindenoindole (THII). Therefore, weexamined the ability of APAP and THII to preventmetabolic changes in mice receiving OLZ.Designand Measurement:C57BL/6J mice received eithera normal diet or a HF diet, and wereadministered daily dosages of OLZ (3 mg kg−1body weight), alone or with APAP (30 mg kg−1body weight) or THII (4.5 mg kg−1 bodyweight), for 10 weeks. Parameters of bodycomposition and metabolism, including glucoseand insulin homeostasis and oxidative stress,", "metadata": {}}
+{"_id": "21550246", "title": "", "text": "Detection of prions in bloodPrion diseases arecaused by an unconventional infectious agenttermed prion, composed mainly of the misfoldedprion protein (PrPSc). The development of highlysensitive assays for biochemical detection ofPrPSc in blood is a top priority for minimizing thespread of the disease. Here we show that theprotein misfolding cyclic amplification (PMCA)technology can be automated and optimized forhigh-efficiency amplification of PrPSc. We showthat 140 PMCA cycles leads to a 6,600-foldincrease in sensitivity over standard detectionmethods. Two successive rounds of PMCA cyclesresulted in a 10 million–fold increase insensitivity and a capability to detect as little as8,000 equivalent molecules of PrPSc. Notably,serial PMCA enables detection of PrPSc in bloodsamples of scrapie-afflicted hamsters with 89%sensitivity and 100% specificity. These findingsrepresent the first time that PrPSc has beendetected biochemically in blood, offering promisefor developing a noninvasive method for early", "metadata": {}}
+{"_id": "21551568", "title": "", "text": "Genetic alterations and their relationship in thephosphatidylinositol 3-kinase/Akt pathway inthyroid cancer.PURPOSE To investigate theoverall occurrence and relationship of geneticalterations in the phosphatidylinositol 3-kinase(PI3K)/Akt pathway in thyroid tumors andexplore the scope of this pathway as atherapeutic target for thyroid cancer.EXPERIMENTAL DESIGN We examinedcollectively the major genetic alterations andtheir relationship in this pathway, includingPIK3CA copy number gain and mutation, Rasmutation, and PTEN mutation, in a large series ofprimary thyroid tumors. RESULTS Occurrence ofany of these genetic alterations was found in 25of 81 (31%) benign thyroid adenoma (BTA), 47of 86 (55%) follicular thyroid cancer (FTC), 21 of86 (24%) papillary thyroid cancer (PTC), and 29of 50 (58%) anaplastic thyroid cancer (ATC),with FTC and ATC most frequently harboringthese genetic alterations. PIK3CA copy gain wasassociated with increased PIK3CA protein", "metadata": {}}
+{"_id": "21553394", "title": "", "text": "Vitamin D and obesity: current perspectives andfuture directions.In recent years, new functionalroles of vitamin D beyond its traditional role incalcium homoeostasis and bone metabolismhave emerged linking the fat-soluble vitamin tovarious non-communicable diseases. Vitamin Ddeficiency (25-hydroxyvitamin D (25(OH)D) <25-30 nmol/l) and sub-optimal status (25(OH)D< 50-100 nmol/l) are increasingly associatedwith unfavourable metabolic phenotypes,including insulin resistance, type 2 diabetes andCVD; conditions also commonly linked withoverweight and obesity. Early studies reportedpoor vitamin D status in the morbidly obese.More recently, it has been observed that agraded relationship between vitamin D statusand BMI, or specifically adiposity, exists in thegeneral population. A number of hypotheseshave been proposed to explain the potentialmechanisms whereby alterations in the vitaminD endocrine system occur in the obese state.Plausible explanations include sequestration in", "metadata": {}}
+{"_id": "21557055", "title": "", "text": "Transcriptional regulation by p53 throughintrinsic DNA/chromatin binding and site-directedcofactor recruitment.The tumor suppressorprotein, p53, plays a critical role in mediatingcellular response to stress signals by regulatinggenes involved in cell cycle arrest and apoptosis.p53 is believed to be inactive for DNA bindingunless its C terminus is modified or structurallyaltered. We show that unmodified p53 activelybinds to two sites at -1.4 and -2.3 kb within thechromatin-assembled p21 promoter and requiresthe C terminus and the histoneacetyltransferase, p300, for transcription.Acetylation of the C terminus by p300 is notnecessary for binding or promoter activation.Instead, p300 acetylates p53-boundnucleosomes in the p21 promoter with spreadingto the TATA box. Thus, p53 is an active DNA andchromatin binding protein that may selectivelyregulate its target genes by recruitment ofspecific cofactors to structurally distinct bindingsites.", "metadata": {}}
+{"_id": "21557614", "title": "", "text": "Pleiotropic effects of statins.Statins are potentinhibitors of cholesterol biosynthesis. In clinicaltrials, statins are beneficial in the primary andsecondary prevention of coronary heart disease.However, the overall benefits observed withstatins appear to be greater than what might beexpected from changes in lipid levels alone,suggesting effects beyond cholesterol lowering.Indeed, recent studies indicate that some of thecholesterol-independent or \"pleiotropic\" effectsof statins involve improving endothelial function,enhancing the stability of atheroscleroticplaques, decreasing oxidative stress andinflammation, and inhibiting the thrombogenicresponse. Furthermore, statins have beneficialextrahepatic effects on the immune system,CNS, and bone. Many of these pleiotropic effectsare mediated by inhibition of isoprenoids, whichserve as lipid attachments for intracellularsignaling molecules. In particular, inhibition ofsmall GTP-binding proteins, Rho, Ras, and Rac,whose proper membrane localization and", "metadata": {}}
+{"_id": "21561474", "title": "", "text": "Increasing the efficiency of precise genomeediting with CRISPR-Cas9 by inhibition ofnonhomologous end joiningMethods to introducetargeted double-strand breaks (DSBs) into DNAenable precise genome editing by increasing therate at which externally supplied DNA fragmentsare incorporated into the genome throughhomologous recombination. The efficiency ofthese methods is limited by nonhomologous endjoining (NHEJ), an alternative DNA repairpathway that competes with homology-directedrepair (HDR). To promote HDR at the expense ofNHEJ, we targeted DNA ligase IV, a key enzymein the NHEJ pathway, using the inhibitor Scr7.Scr7 treatment increased the efficiency ofHDR-mediated genome editing, using Cas9 inmammalian cell lines and in mice for all fourgenes examined, up to 19-fold. This approachshould be applicable to other customizableendonucleases, such as zinc finger nucleases andtranscription activator–like effector nucleases,and to nonmammalian cells with sufficiently", "metadata": {}}
+{"_id": "21562657", "title": "", "text": "Molecular mechanism of BST2/tetherindownregulation by K5/MIR2 of Kaposi'ssarcoma-associated herpesvirus.K3/MIR1 andK5/MIR2 of Kaposi's sarcoma-associatedherpesvirus (KSHV) are viral members of themembrane-associated RING-CH (MARCH)ubiquitin ligase family and contribute to viralimmune evasion by directing the conjugation ofubiquitin to immunostimulatory transmembraneproteins. In a quantitative proteomic screen fornovel host cell proteins downregulated by viralimmunomodulators, we previously observed thatK5, as well as the human immunodeficiency virustype 1 (HIV-1) immunomodulator VPU, reducedsteady-state levels of bone marrow stromal cellantigen 2 (BST2; also called CD317 or tetherin),suggesting that BST2 might be a novel substrateof K5 and VPU. Recent work revealed that in theabsence of VPU, HIV-1 virions are tethered to theplasma membrane in BST2-expressing HeLacells. By targeting BST2, K5 might thus similarlyovercome an innate antiviral host defense", "metadata": {}}
+{"_id": "21564598", "title": "", "text": "Regulation of beta catenin signaling andparathyroid hormone anabolic effects in bone bythe matricellular protein periostin.Periostin(Postn) is a matricellular protein preferentiallyexpressed by osteocytes and periostealosteoblasts in response to mechanicalstimulation and parathyroid hormone (PTH).Whether and how periostin expression influencesbone anabolism, however, remains unknown. Weinvestigated the skeletal response of adultPostn(-/-) and Postn(+/+) mice to intermittentPTH. Compared with Postn(+/+), Postn(-/-) micehad a lower bone mass, cortical bone volume,and strength response to PTH. PTH-stimulatedbone-forming indices were all significantly lowerin Postn(-/-) mice, particularly at theperiosteum. Furthermore, in vivo stimulation ofWnt-β-catenin signaling by PTH, as evaluated inTOPGAL reporter mice, was inhibited in theabsence of periostin (TOPGAL;Postn(-/-) mice).PTH stimulated periostin and inhibited MEF2Cand sclerostin (Sost) expression in bone and", "metadata": {}}
+{"_id": "21571708", "title": "", "text": "Lipoprotein(a) concentration and the risk ofcoronary heart disease, stroke, and nonvascularmortality.CONTEXT Circulating concentration oflipoprotein(a) (Lp[a]), a large glycoproteinattached to a low-density lipoprotein-likeparticle, may be associated with risk of coronaryheart disease (CHD) and stroke. OBJECTIVE Toassess the relationship of Lp(a) concentrationwith risk of major vascular and nonvascularoutcomes. STUDY SELECTION Long-termprospective studies that recorded Lp(a)concentration and subsequent major vascularmorbidity and/or cause-specific mortalitypublished between January 1970 and March2009 were identified through electronic searchesof MEDLINE and other databases, manualsearches of reference lists, and discussion withcollaborators. DATA EXTRACTION Individualrecords were provided for each of 126,634participants in 36 prospective studies. During 1.3million person-years of follow-up, 22,076first-ever fatal or nonfatal vascular disease", "metadata": {}}
+{"_id": "21578627", "title": "", "text": "The biphasic behavior of incoherent feed-forwardloops in biomolecular regulatory networks.Anincoherent feed-forward loop (FFL) is one of themost-frequently observed motifs in biomolecularregulatory networks. It has been thought thatthe incoherent FFL is designed simply to induce atransient response shaped by a 'fast activationand delayed inhibition'. We find that thedynamics of various incoherent FFLs can befurther classified into two types: time-dependentbiphasic responses and dose-dependent biphasicresponses. Why do the structurally identicalincoherent FFLs play such different dynamicalroles? Through computational studies, we showthat the dynamics of the two types of incoherentFFLs are mutually exclusive. Following fromfurther computational results and experimentalobservations, we hypothesize that incoherentFFLs have been optimally designed to achievedistinct biological function arising from differentcellular contexts. Additional SupportingInformation may be found in the online version", "metadata": {}}
+{"_id": "21590125", "title": "", "text": "Antipsychotic prescribing patterns in Germany: aretrospective analysis using a large outpatientprescription database.Data of prescribingpractices for antipsychotics are of great interestwith respect to quality of care. Consequently, weanalysed all prescriptions under the statutoryhealth insurance redeemed at pharmacies inSouthern Germany between July 1999 andDecember 2001. The database coversprescriptions for approximately 25 millionpeople. Up to 6% of the population wereprescribed an antipsychotic at least once duringthe study period. Most prescriptions were forconventional antipsychotics and written bynon-specialists. Patients receiving secondgeneration antipsychotics were more likely toreceive continuous antipsychotic therapy. For alarge proportion of patients, antipsychoticpolypharmacy, as well as comedication forsomatic illnesses, were observed. In particular,drugs for the treatment of cardiovascular andmetabolic disorders were frequently", "metadata": {}}
+{"_id": "21598000", "title": "", "text": "Structural basis for the activation of microtubuleassembly by the EB1 and p150Gluedcomplex.Plus-end tracking proteins, such as EB1and the dynein/dynactin complex, regulatemicrotubule dynamics. These proteins arethought to stabilize microtubules by forming aplus-end complex at microtubule growing endswith ill-defined mechanisms. Here we report thecrystal structure of two plus-end complexcomponents, the carboxy-terminal dimerizationdomain of EB1 and the microtubule binding(CAP-Gly) domain of the dynactin subunitp150Glued. Each molecule of the EB1 dimercontains two helices forming a conservedfour-helix bundle, while also providingp150Glued binding sites in its flexible tail region.Combining crystallography, NMR, and mutationalanalyses, our studies reveal the criticalinteracting elements of both EB1 and p150Glued,whose mutation alters microtubulepolymerization activity. Moreover, removal of thekey flexible tail from EB1 activates microtubule", "metadata": {}}
+{"_id": "21601459", "title": "", "text": "Epigenetic regulation of NANOG by miR-302cluster-MBD2 completes induced pluripotentstem cell reprogramming.While most somaticcells undergoing induced pluripotent stem (iPS)cell reprogramming with Yamanaka factorsaccumulate at stable partially reprogrammedstages, the molecular mechanisms required toachieve full reprogramming are unknown.MicroRNAs (miRNAs) fine-tune mRNA translationand are implicated in reprogramming, but miRNAfunctional targets critical for complete iPS cellreprogramming remain elusive. We identifiedmethyl-DNA binding domain protein 2 (MBD2) asan epigenetic suppressor, blocking fullreprogramming of somatic to iPS cells throughdirect binding to NANOG promoter elementspreventing transcriptional activation. When weoverexpressed miR-302 cluster we observed asignificant increase in conversion of partial tofully reprogrammed iPS cells by suppressingMBD2 expression, thereby increasing NANOGexpression. Thus, expression of exogenous", "metadata": {}}
+{"_id": "21602220", "title": "", "text": "Complex physiology and compound stressresponses during fermentation ofalkali-pretreated corn stover hydrolysate by anEscherichia coli ethanologen.The physiology ofethanologenic Escherichia coli grownanaerobically in alkali-pretreated planthydrolysates is complex and not well studied. Togain insight into how E. coli responds to suchhydrolysates, we studied an E. coli K-12ethanologen fermenting a hydrolysate preparedfrom corn stover pretreated by ammonia fiberexpansion. Despite the high sugar content (\u00006%glucose, 3% xylose) and relatively low toxicity ofthis hydrolysate, E. coli ceased growth longbefore glucose was depleted. Nevertheless, thecells remained metabolically active andcontinued conversion of glucose to ethanol untilall glucose was consumed. Gene expressionprofiling revealed complex and changing patternsof metabolic physiology and cellular stressresponses during an exponential growth phase, atransition phase, and the glycolytically active", "metadata": {}}
+{"_id": "21616324", "title": "", "text": "Systemic arterial hypertension in childrenfollowing renal transplantation: prevalence andrisk factors.BACKGROUND Control of bloodpressure (BP) following renal transplantationmay improve allograft and patient survival. Ouraims were (i) to describe the distribution of BPand the prevalence of systolic and/or diastolichypertension in children over the first 5 yearsfollowing renal transplantation and (ii) toevaluate clinical risk factors and centre-specificfactors associated with hypertension in thispopulation. METHODS We conducted aretrospective case note review of all currentpaediatric kidney transplant patients in the UK,with data collected at 6 months, 1, 2 and 5 yearsfollowing transplantation in subjects withhypertension (systolic and/or diastolic BP > 95th> ) and non-hypertensive subjects BP ≤ 95th > .RESULTS In total, 27.3% (117/428), 27.6%(118/428), 26.0% (95/365) and 25.6% (50/195)of the patients were hypertensive (systolicand/or diastolic BP > 95th > ) at 6 months, 1, 2", "metadata": {}}
+{"_id": "21622715", "title": "", "text": "Coupling cAMP signaling to transcription in theliver: pivotal role of CREB andCREM.Transcriptional factors binding tocAMP-responsive elements (CREs) in thepromoters of various genes belong to the basicdomain-leucine zipper superfamily and arecomposed of three genes in mammals, CREB,CREM, and ATF-1. A large number of CREB,CREM, and ATF-1 proteins are generated byposttranscriptional events, mostly alternativesplicing, and regulate gene expression by actingas activators or repressors. Activation isclassically brought about by signaling-dependentphosphorylation of a key acceptor site (Ser133 inCREB) by a number of possible kinases, includingPKA, CamKIV, and Rsk-2. Phosphorylation is theprerequisite for the interaction of CBP(CREB-binding protein), a co-activator that hasalso histone acetyltransferase activity.Repression may involve dynamicdephosphorylation of the activators and thusdecreased association with CBP. Another", "metadata": {}}
+{"_id": "21623140", "title": "", "text": "Comparison of dietary assessment methods in aSouthern French population: use of weighedrecords, estimated-diet records and afood-frequency questionnaireObjective: Themain objective of the study was to developappropriate dietary assessment instruments forthe French Mediterranean region and to validatethe measurements they provide. Subjects andMethods: Three different assessment methodswere submitted to a sample of 150 male andfemale volunteers. 98 completed the protocol,which consisted of a 4 d weighed dietary record(PETRA) and a 7 d estimated-diet record (S7)based on a check list and a set of photographs,both these records being completed once in eachseason of the year, and a semi-quantitative(standard portion) food-frequency questionnaire(FFQ) including questions elicitingsocio-demographic and anthropometric data,which was completed once only. The days whenPETRA was used to evaluate food consumptioncoincided with the first 4 d of S7 (S4).Results:", "metadata": {}}
+{"_id": "21626639", "title": "", "text": "Substrate fate in activated macrophages: acomparison between innate, classic, andalternative activation.Macrophages play arelevant role in innate and adaptive immunitydepending on the balance of the stimuli received.From an analytical and functional point of view,macrophage stimulation can be segregated intothree main modes, as follows: innate, classic,and alternative pathways. These differentialactivations result in the expression of specificsets of genes involved in the release of pro- oranti-inflammatory stimuli. In the present work,we have analyzed whether specific metabolicpatterns depend on the signaling pathwayactivated. A [1,2-(13)C(2)]glucose tracer-basedmetabolomics approach has been used tocharacterize the metabolic flux distributions inmacrophages stimulated through the classic,innate, and alternative pathways. Using thismethodology combined with mass isotopomerdistribution analysis of the new formedmetabolites, the data show that activated", "metadata": {}}
+{"_id": "21636085", "title": "", "text": "The effect of folic acid supplementation onplasma homocysteine in an elderlypopulation.BACKGROUND Increased plasmahomocysteine is associated with coronary arterydisease, peripheral vascular disease and venousthrombosis. Folic acid is the most effectivetherapy for reducing homocysteine levels. Thelowest effective supplement of folic acid is notknown, particularly for the elderly who have thehighest prevalence of these conditions. AIM Toexplore the effects of daily supplements of 0, 50,100, 200, 400 and 600 microg folic acid onplasma homocysteine in an elderly population.DESIGN Randomized double-blindplacebo-controlled trial. METHODS Participants(n=368) aged 65-75 years were randomlyallocated to receive one of the treatments for 6weeks. Plasma homocysteine was recorded after3 weeks and 6 weeks of supplementation.RESULTS Only the 400 microg and 600 microggroups had significantly lower homocysteinelevels compared to placebo (p=0.038 and", "metadata": {}}
+{"_id": "21641088", "title": "", "text": "Central obesity and hyperinsulinaemia in womenare associated with polymorphism in the 5'flanking region of the human insulingene.Obesity is a multifactorial disease with amarked genetic component. The situation isfurther complicated by the heterogeneity ofobesity demonstrated by the topographicaldistribution of body fat, e.g. upper body (central)and lower body (gluteal) obesity. Furthermore,the distribution of fat shows a stronger heritabletendency compared with total body fat. Centralobesity is characterized by hyperinsulinaemiaand insulin resistance, a feature in common withnon-insulin dependent diabetes mellitus,hypertension and atherosclerosis. In order tostudy the molecular genetics of central obesitywe have examined 56 severely obese (meanbody mass index 40), unrelated BritishCaucasoid young non-diabetic women forassociations of restriction fragment lengthpolymorphism of candidate genes withanthropometric measurements and indices of", "metadata": {}}
+{"_id": "21644993", "title": "", "text": "Population density profiles of nasopharyngealcarriage of 5 bacterial species in pre-schoolchildren measured using quantitative PCR offerpotential insights into the dynamics oftransmission.Bacterial vaccines can reducecarriage rates. Colonization is usually a binaryendpoint. Real time quantitative PCR (qPCR) canquantify bacterial DNA in mucosal samples overa wide range. Using culture and single-genespecies-specific qPCRs for Streptococcuspneumoniae (lytA), Streptococcus pyogenes(ntpC), Moraxella catarrhalis (ompJ),Haemophilus influenzae (hdp) andStaphylococcus aureus (nuc) and standardcurves against log-phase reference strain brothcultures we described frequency and peakdensity distributions of carriage innasopharyngeal swabs from 161 healthy 2-4 yold children collected into STGG broth. Ingeneral, detection by qPCR and culture wasconsistent. Discordance mostly occurred at lowerdetection thresholds of both methods, although", "metadata": {}}
+{"_id": "21645205", "title": "", "text": "Circadian mechanisms in murine and humanbone marrow mesenchymal stem cells followingdexamethasone exposure.A core group ofregulatory factors control circadian rhythms inmammalian cells. While the suprachiasmaticnucleus in the brain serves as the central corecircadian oscillator, circadian clocks also existwithin peripheral tissues and cells. A growingbody of evidence has demonstrated that >20%of expressed mRNAs in bone and adipose tissuesoscillate in a circadian manner. The currentmanuscript reports evidence of the core circadiantranscriptional apparatus within primary culturesof murine and human bone marrow-derivedmesenchymal stem cells (BMSCs). Exposure ofconfluent, quiescent BMSCs to dexamethasonesynchronized the oscillating expression of themRNAs encoding the albumin D binding protein(dbp), brain-muscle arnt-like 1 (bmal1), period 3(per3), rev-erb alpha (Rev A), and rev-erb beta(Rev B). The genes displayed a mean oscillatoryperiod of 22.2 to 24.3 h. The acrophase or peak", "metadata": {}}
+{"_id": "21651116", "title": "", "text": "Herpesvirus-encoded GPCRs: neglected playersin inflammatory and proliferativediseases?Herpesviruses encodemembrane-associated G protein-coupledreceptors (GPCRs) in their viral genomes that arestructurally similar to chemokine receptors.These GPCRs hijack GPCR-mediated cellularsignalling networks of the host for survival,replication and pathogenesis. In particular theherpesvirus-encoded chemokine receptorsORF74, BILF1 and US28, which are present atinflammatory sites and tumour cells, provideimportant virus-specific targets for directedtherapies. Given the high druggability of GPCRsin general, these viral GPCRs can be consideredpromising antiviral drug targets.", "metadata": {}}
+{"_id": "21676556", "title": "", "text": "Midbody accumulation through evasion ofautophagy contributes to cellular reprogrammingand tumorigenicityThe midbody is a singularorganelle formed between daughter cells duringcytokinesis and required for their finalseparation. Midbodies persist in cells long afterdivision as midbody derivatives (MBds), but theirfate is unclear. Here we show that MBds areinherited asymmetrically by the daughter cellwith the older centrosome. They selectivelyaccumulate in stem cells, induced pluripotentstem cells and potential cancer ‘stem cells’ invivo and in vitro. MBd loss accompaniesstem-cell differentiation, and involves autophagicdegradation mediated by binding of theautophagic receptor NBR1 to the midbodyprotein CEP55. Differentiating cells and normaldividing cells do not accumulate MBds andpossess high autophagic activity. Stem cells andcancer cells accumulate MBds by evadingautophagosome encapsulation and exhibit lowautophagic activity. MBd enrichment enhances", "metadata": {}}
+{"_id": "21692235", "title": "", "text": "Integrated genomic analysis identifies clinicallyrelevant subtypes of glioblastoma characterizedby abnormalities in PDGFRA, IDH1, EGFR, andNF1.The Cancer Genome Atlas Network recentlycataloged recurrent genomic abnormalities inglioblastoma multiforme (GBM). We describe arobust gene expression-based molecularclassification of GBM into Proneural, Neural,Classical, and Mesenchymal subtypes andintegrate multidimensional genomic data toestablish patterns of somatic mutations and DNAcopy number. Aberrations and gene expressionof EGFR, NF1, and PDGFRA/IDH1 each define theClassical, Mesenchymal, and Proneural subtypes,respectively. Gene signatures of normal braincell types show a strong relationship betweensubtypes and different neural lineages.Additionally, response to aggressive therapydiffers by subtype, with the greatest benefit inthe Classical subtype and no benefit in theProneural subtype. We provide a framework thatunifies transcriptomic and genomic dimensions", "metadata": {}}
+{"_id": "21700295", "title": "", "text": "Chronic Hepatitis B Infection: AReviewImportance More than 240 millionindividuals worldwide are infected with chronichepatitis B virus (HBV). Among individuals withchronic HBV infection who are untreated, 15% to40% progress to cirrhosis, which may lead toliver failure and liver cancer. ObservationsPegylated interferon and nucleos(t)ide analogues(lamivudine, adefovir, entecavir, tenofovirdisoproxil, and tenofovir alafenamide) suppressHBV DNA replication and improve liverinflammation and fibrosis. Long-term viralsuppression is associated with regression of liverfibrosis and reduced risk of hepatocellularcarcinoma in cohort studies. The cure (defined ashepatitis B surface antigen loss withundetectable HBV DNA) rates after treatmentremain low (3%-7% with pegylated interferonand 1%-12% with nucleos[t]ide analoguetherapy). Pegylated interferon therapy can becompleted in 48 weeks and is not associated withthe development of resistance; however, its use", "metadata": {}}
+{"_id": "21719289", "title": "", "text": "CD64 expression distinguishes monocyte-derivedand conventional dendritic cells and reveals theirdistinct role during intramuscularimmunization.Although most vaccines areadministered i.m., little is known about thedendritic cells (DCs) that are present withinskeletal muscles. In this article, we show thatexpression of CD64, the high-affinity IgGreceptor FcγRI, distinguishes conventional DCsfrom monocyte-derived DCs (Mo-DCs). By usingsuch a discriminatory marker, we defined thedistinct DC subsets that reside in skeletalmuscles and identified their migratorycounterparts in draining lymph nodes (LNs). Wefurther used this capability to analyze thefunctional specialization that exists amongmuscle DCs. After i.m. administration of Agadsorbed to alum, we showed that alum-injectedmuscles contained large numbers of conventionalDCs that belong to the CD8α(+)- andCD11b(+)-type DCs. Both conventional DC typeswere capable of capturing Ag and of migrating to", "metadata": {}}
+{"_id": "21746539", "title": "", "text": "T-cell-antigen recognition and the immunologicalsynapseMuch excitement of the past five years inthe area of T-cell-antigen recognition has centredaround the immunological synapse — a complexcellular structure that forms at the interface of aT cell and a cell that expresses the appropriatepeptide–MHC complexes. Thanks to new imagingtechnologies, we are now beginning tounderstand the role of cell-surface molecules andsome of their attendant signalling modules in thecontext of cell-to-cell communication. Progresshas been so rapid that T-cell-antigen recognitionmight be the first system in which the molecularbasis of cell–cell recognition is understood.", "metadata": {}}
+{"_id": "21754541", "title": "", "text": "Key interactions by conserved polar amino acidslocated at the transmembrane helical boundariesin Class B GPCRs modulate activation, effectorspecificity and biased signalling in theglucagon-like peptide-1 receptor.Class B GPCRscan activate multiple signalling effectors with thepotential to exhibit biased agonism in responseto ligand stimulation. Previously, we highlightedkey TM domain polar amino acids that werecrucial for the function of the GLP-1 receptor, akey therapeutic target for diabetes and obesity.Using a combination of mutagenesis,pharmacological characterisation, mathematicaland computational molecular modelling, thisstudy identifies additional highly conserved polarresidues located towards the TM helicalboundaries of Class B GPCRs that are importantfor GLP-1 receptor stability and/or controllingsignalling specificity and biased agonism. Thisincludes (i) three positively charged residues(R3.30227, K4.64288, R5.40310) located at theextracellular boundaries of TMs 3, 4 and 5 that", "metadata": {}}
+{"_id": "21767325", "title": "", "text": "Influence of lifestyle modification on arterialstiffness and wave reflections.Arterial stiffnessand wave reflections exert a number of adverseeffects on cardiovascular function and diseaserisk and are associated with a greater rate ofmortality in patients with end-stage renal failureand essential hypertension. Accordingly, theprevention and treatment of arterial stiffness areof paramount importance. Because arterialstiffening is being recognized as a criticalprecursor of cardiovascular disease (CVD), it isessential to understand the role of lifestylemodifications on preventing and reversingarterial stiffening. Available evidence indicatesthat lifestyle modifications, in particular aerobicexercise and sodium restriction, appear to beclinically efficacious therapeutic interventions forpreventing and treating arterial stiffening. Thus,sufficient evidence is available to recommendlifestyle modifications as part of a first-linetherapeutic approach for arterial stiffening.However, more information is needed for a full", "metadata": {}}
+{"_id": "21789744", "title": "", "text": "Effect of exercise-induced ischemia on QTinterval dispersion.An increased spatialdispersion of ventricular repolarization duration(QT dispersion) is associated with an increasedvulnerability to arrhythmias. This study wasdesigned to examine the effect of exercise on QTdispersion in ischemic heart disease (IHD). QTdispersion, corrected QT dispersion, andpercentage change in uncorrected and correctedQT dispersion between rest and peak exercisewere examined in 14 members of a controlgroup, 17 patients with IHD, and 14 patientswith IHD who were receiving beta-blockers(IHD-B). All subjects had undergone a standardBruce protocol exercise test, and QT intervalswere measured at rest and peak exercise with adigitizing tablet interfaced to a personalcomputer. QT dispersion at rest was markedlyincreased in the IHD group compared with that inthe control and IHD-B groups, respectively(corrected QT dispersion in milliseconds), 74 +/-7, 40 +/- 4, 49 +/- 5, p < 0.03). The corrected", "metadata": {}}
+{"_id": "21790313", "title": "", "text": "Effects of powered mobility on self-initiatedbehaviors of very young children with locomotordisability.This study reports the effects ofpowered mobility on the self-initiated behavior ofsix children with various disabilities who,between 23 and 38 months of age, learnt to usemotorized wheelchairs in less than three weeks.Using a multiple baseline design, two-hourobservation periods were video-recorded at10-day intervals before and after they achievedindependent mobility. Frequency of self-initiatedinteraction with objects, spatial exploration andcommunication with care-giver were analyzed.Three children increased all three types ofbehavior; one increased in two types butdecreased in interaction with objects; and twoincreased in spatial exploration only.", "metadata": {}}
+{"_id": "21793890", "title": "", "text": "BCR/ABL modifies the kinetics and fidelity of DNAdouble-strand breaks repair in hematopoieticcells.The oncogenic BCR/ABL tyrosine kinasefacilitates the repair of DNA double-strandbreaks (DSBs). We find that aftergamma-irradiation BCR/ABL-positive leukemiacells accumulate more DSBs in comparison tonormal cells. These lesions are efficientlyrepaired in a time-dependent fashion byBCR/ABL-stimulated non-homologousend-joining (NHEJ) followed by homologousrecombination repair (HRR) mechanisms.However, mutations and large deletions weredetected in HRR and NHEJ products,respectively, in BCR/ABL-positive leukemia cells.We propose that unfaithful repair of DSBs maycontribute to genomic instability in thePhiladelphia chromosome-positive leukemias.", "metadata": {}}
+{"_id": "21804115", "title": "", "text": "Bone morphogenetic protein signaling in nephronprogenitor cellsBone morphogenetic protein(BMP) signaling plays an essential role in manyaspects of kidney development, and is a majordeterminant of outcome in kidney injury. BMPtreatment is also an essential component ofprotocols for differentiation of nephronprogenitors from pluripotent stem cells. Thisreview discusses the role of BMP signaling tonephron progenitor cells in each of thesecontexts.", "metadata": {}}
+{"_id": "21853444", "title": "", "text": "Computational analysis of 3'-ends of ESTs showsfour classes of alternative polyadenylation inhuman, mouse, and rat.Alternative initiation,splicing, and polyadenylation are keymechanisms used by many organisms togenerate diversity among mature mRNAtranscripts originating from the sametranscription unit. While previous computationalanalyses of alternative polyadenylation havefocused on polyadenylation activities within ordownstream of the normal 3'-terminal exons, wepresent the results of the first genome-wideanalysis of patterns of alternativepolyadenylation in the human, mouse, and ratgenomes occurring over the entire transcribedregions of mRNAs using 3'-ESTs with poly(A)tails aligned to genomic sequences. Four distinctclasses of patterns of alternative polyadenylationresult from this analysis: tandem poly(A) sites,composite exons, hidden exons, and truncatedexons. We estimate that at least 49% (human),31% (mouse), and 28% (rat) of polyadenylated", "metadata": {}}
+{"_id": "21855837", "title": "", "text": "Epigenetic instability in ES cells and clonedmice.Cloning by nuclear transfer (NT) is aninefficient process in which most clones diebefore birth and survivors often display growthabnormalities. In an effort to correlate geneexpression with survival and fetal overgrowth,we have examined imprinted gene expression inboth mice cloned by nuclear transfer and in theembryonic stem (ES) cell donor populations fromwhich they were derived. The epigenetic state ofthe ES cell genome was found to be extremelyunstable. Similarly, variation in imprinted geneexpression was observed in most cloned mice,even in those derived from ES cells of the samesubclone. Many of the animals survived toadulthood despite widespread genedysregulation, indicating that mammaliandevelopment may be rather tolerant toepigenetic aberrations of the genome. Thesedata imply that even apparently normal clonedanimals may have subtle abnormalities in geneexpression.", "metadata": {}}
+{"_id": "21859699", "title": "", "text": "Successful three-way kidney paired donationwith cross-country live donor allografttransport.Providing transplantation opportunitiesfor patients with incompatible live donorsthrough kidney paired donation (KPD) is seen asone of the important strategies for easing thecrisis in organ availability. It has been estimatedthat an additional 1000-2000 transplants peryear could be accomplished if a national KPDprogram were implemented in the United States.While most of these transplants could bearranged within the participants' local or regionalarea, patients with hard-to-match blood types orbroad HLA sensitization would benefit frommatching across larger geographic areas. In thiscase, either patients or organs would need totravel in order to obtain maximum benefit from anational program. In this study, we describe howa triple KPD enabled a highly sensitized patient(PRA 96%) to receive a well-matched kidneyfrom a live donor on the opposite coast. Thekidney was removed in San Francisco and", "metadata": {}}
+{"_id": "21866916", "title": "", "text": "Role of PACAP and VIP in astroglialfunctions.Astrocytes represent at least 50% ofthe volume of the human brain. Besides theirroles in various supportive functions, astrocytesare involved in the regulation of stem cellproliferation, synaptic plasticity andneuroprotection. Astrocytes also influenceneuronal physiology by responding toneurotransmitters and neuropeptides and byreleasing regulatory factors termedgliotransmitters. In particular, astrocytes expressthe PACAP-specific receptor PAC1-R and thePACAP/VIP mutual receptors VPAC1-R andVPAC2-R during development and/or in theadult. There is now clear evidence that PACAPand VIP modulate a number of astrocyteactivities such as proliferation, plasticity,glycogen production, and biosynthesis ofneurotrophic factors and gliotransmitters.", "metadata": {}}
+{"_id": "21868715", "title": "", "text": "A subset of 26S proteasomes is activated atcritically low ATP concentrations and contributesto myocardial injury during coldischemia.Molecular mechanisms leading tomyocardial injury during warm or cold ischemiaare insufficiently understood. Althoughproteasomes are thought to contribute tomyocardial ischemia-reperfusion injury, theirroles during the ischemic period remain elusive.Because donor hearts are commonly exposed toprolonged global cold ischemia prior to cardiactransplantation, we evaluated the role andregulation of the proteasome during coldischemic storage of rat hearts in context of themyocardial ATP content. When measured at theactual tissue ATP concentration, cardiacproteasome peptidase activity increased by225% as ATP declined during cold ischemicstorage of hearts in University of Wisconsin (UW)solution for up to 48h. Addition of the specificproteasome inhibitor epoxomicin to the UWsolution inhibited proteasome activity in the", "metadata": {}}
+{"_id": "21870716", "title": "", "text": "Coping and satisfaction with growth hormonetreatment among short-stature children.Theability of children to cope with a chronic medicalproblem requiring prolonged treatment has aneffect on the quality of life of these children andof their parents and serves as an index of thequality of treatment. This study deals with copingability and satisfaction with treatment of childrenwhose stature was two or more SD below theaverage for age and gender. The studypopulation included 96 patients, 53 of whomwere male, who were on growth hormone (GH)treatment for at least 1 year. 65 patients werewithout any underlying disease, 15 had classicalGH deficiency and 16 had Turner syndrome orrenal disease. All patients were treated with dailyinjections at home from 12 to 66 months. Usinga self-administered questionnaire, the ability tocope and the degree of satisfaction andcompliance with treatment were assessed. Nosignificant differences were found with respect togender, the presence of an underlying disease,", "metadata": {}}
+{"_id": "21874312", "title": "", "text": "Risk for breast cancer development determinedby mammographic parenchymal pattern.Aclassification of risk for developing breast cancerhas been devised based solely on the appearanceof the breast parenchyma by mammography.Four groups of patients were isolated. The studyencompassed a five-year period and was done byreviewing the mammograms of all women overthe age of 30 who had been examined at HutzelHospital, Detroit. The average time of followupwould be approximately 2 1/2 years. Four groupshad an incidence of developing breast cancer of0.1, 0.4, 1.7, and 2.2. These parenchymalpatterns are described and criteria for theiridentification are given.", "metadata": {}}
+{"_id": "21874414", "title": "", "text": "Accurate coarse-grained modeling of red bloodcells.We develop a systematic coarse-grainingprocedure for modeling red blood cells (RBCs)using arguments based on mean-field theory.The three-dimensional RBC membrane modeltakes into account the bending energy, in-planeshear energy, and constraints of fixed surfacearea and fixed enclosed volume. Thecoarse-graining procedure is general, it can beused for arbitrary level of coarse-graining anddoes not employ any fitting parameters. Thesensitivity of the coarse-grained model isinvestigated and its behavior is validated againstavailable experimental data and in dissipativeparticle dynamics (DPD) simulations of RBCs incapillary and shear flows.", "metadata": {}}
+{"_id": "21878751", "title": "", "text": "Mice deficient in CD4 T cells have only transientlydiminished levels of IFN-gamma, yet succumb totuberculosis.CD4 T cells are important in theprotective immune response againsttuberculosis. Two mouse models deficient in CD4T cells were used to examine the mechanism bywhich these cells participate in protection againstMycobacterium tuberculosis challenge.Transgenic mice deficient in either MHC class IIor CD4 molecules demonstrated increasedsusceptibility to M. tuberculosis, compared withwild-type mice. MHC class II-/- mice were moresusceptible than CD4-/- mice, as measured bysurvival following M. tuberculosis challenge, butthe relative resistance of CD4-/- mice did notappear to be due to increased numbers ofCD4-8- (double-negative) T cells. Analysis of invivo IFN-gamma production in the lungs ofinfected mice revealed that both mutant mousestrains were only transiently impaired in theirability to produce IFN-gamma following infection.At 2 wk postinfection, IFN-gamma production,", "metadata": {}}
+{"_id": "21884059", "title": "", "text": "Treatment and management of graft-versus-hostdisease: improving response andsurvival.Graft-versus-host disease (GVHD) is asignificant cause of morbidity and mortalityfollowing allogenic haematopoietic stem-celltransplantation and thus the focus of muchongoing research. Despite considerable advancesin our understanding of the pathophysiology,diagnosis and predisposing factors for both acuteand chronic forms of the disease, a standardisedtherapeutic strategy is still lacking. There is goodevidence for initial treatment of both acute andchronic forms of the disease with corticosteroidtherapy. However, the most effective approachto steroid-refractory disease remainscontroversial, with current practice based mainlyon smaller studies and varying considerablybetween local institutions. Timely diagnosis,multidisciplinary working and good supportivecare, including infection prophylaxis, are clearlyimportant in optimizing response and survival insuch patients. It is hoped that in the future", "metadata": {}}
+{"_id": "21884449", "title": "", "text": "The value of self-report assessment ofadherence, rhinitis and smoking in relation toasthma control.AIMS To explore the utility ofself-report measures of inhaled corticosteroid(ICS) adherence, degree of rhinitis and smokingstatus and their association with asthma control.METHODS Patients prescribed ICS for asthma at85 UK practices were sent validatedquestionnaire measures of control (AsthmaControl Questionnaire; ACQ) and adherence(Medication Adherence Report Scale), a two-itemmeasure of smoking status, and a single-itemmeasure of rhinitis. RESULTS Completeanonymised questionnaires were available for3916 participants. Poor asthma control (ACQ>1.5) was associated with reported rhinitis (OR= 4.62; 95% CI: 3.71-5.77), smoking (OR =4.33; 95% CI: 3.58-5.23) and low adherence toICS (OR = 1.35; 95% CI: 1.18-1.55). Thedegree of rhinitis was important, with thosereporting severe rhinitis exhibiting the worstasthma control, followed by those reporting mild", "metadata": {}}
+{"_id": "21891856", "title": "", "text": "Development of a syngeneic mouse model forevents related to ovarian cancer.Mouse ovariansurface epithelial cells (MOSEC) were obtainedfrom virgin, mature mice by mild trypsinizationand were repeatedly passaged in vitro. Earlypassage cells (<20 passages) exhibited acobblestone morphology and contact inhibition ofgrowth. After approximately 20 passages invitro, cobblestone morphology and contactinhibition of growth was lost. Tumor formingpotential was determined by s.c. and i.p.injection of early and late passage cells intoathymic and syngeneic C57BL6 mice.Subcutaneous tumors formed in approximately 4months and were present only at the injectionsite. Intraperitoneal injection of late passageMOSEC into athymic and syngeneic mice resultedin growth of tumor implants throughout theabdominal cavity, and production of hemorrhagicascitic fluid. Early passage MOSEC did not formtumors in vivo. Histopathologic analysis oftumors revealed a highly malignant neoplasm", "metadata": {}}
+{"_id": "21902400", "title": "", "text": "Hypoxia in cancer: significance and impact onclinical outcomeHypoxia, a characteristic featureof locally advanced solid tumors, has emerged asa pivotal factor of the tumor (patho-)physiomesince it can promote tumor progression andresistance to therapy. Hypoxia represents a“Janus face” in tumor biology because (a) it isassociated with restrained proliferation,differentiation, necrosis or apoptosis, and (b) itcan also lead to the development of anaggressive phenotype. Independent of standardprognostic factors, such as tumor stage andnodal status, hypoxia has been suggested as anadverse prognostic factor for patient outcome.Studies of tumor hypoxia involving the directassessment of the oxygenation status havesuggested worse disease-free survival forpatients with hypoxic cervical cancers or softtissue sarcomas. In head & neck cancers thestudies suggest that hypoxia is prognostic forsurvival and local control. Technical limitations ofthe direct O2 sensing technique have prompted", "metadata": {}}
+{"_id": "21902910", "title": "", "text": "Knowledge and Practice of Standard Precautionsand Awareness Regarding Post-ExposureProphylaxis for HIV among Interns of a MedicalCollege in West Bengal, India.OBJECTIVES Toassess the knowledge of interns on standardprecautions and post-exposure prophylaxis forHIV, and identify the gap between knowledgeand practice relating to standard precautions, aswell as determining the perceived barriersagainst adherence to standard precautions.METHODS The study was conducted on 130interns of 2010-11 batch from a government-runmedical college in Kolkata, India. All participantscompleted a self-administered questionnaire withitems relating to basic components of standardprecautions and post-exposure prophylaxis forHIV. The questionnaire also included open endedquestions relating to reasons for non-adherenceto the practice of standard precautions alongwith additional space for specific comments, ifany. RESULTS Poor adherence in the use ofpersonal protective equipment, hand washing,", "metadata": {}}
+{"_id": "21909315", "title": "", "text": "Viruses and microRNAsThe discovery of RNAinterference and cellular microRNAs (miRNAs)has not only affected how biological research isconducted but also revealed an entirely new levelof post-transcriptional gene regulation. Here, Idiscuss the potential functions of the virallyencoded miRNAs recently identified in severalpathogenic human viruses and propose thatcellular miRNAs may have had a substantialeffect on viral evolution and may continue toinfluence the in vivo tissue tropism of viruses.Our increasing knowledge of the role andimportance of virally encoded miRNAs willprobably offer new insights into how viruses thatestablish latent infections, such asherpesviruses, avoid elimination by the hostinnate or adaptive immune system. Researchinto viral miRNA function might also suggest newapproaches for treating some virally induceddiseases.", "metadata": {}}
+{"_id": "21914176", "title": "", "text": "Economic impact of primary open-angleglaucoma in Australia.BACKGROUND Glaucomais the World's leading cause of irreversibleblindness, and poses serious public health andeconomic concerns. DESIGN   Review. SAMPLESPublished randomized trials andpopulation-based studies since 1985. METHODSWe report the economic impact of primaryopen-angle glaucoma and model the effect ofchanges in detection rates and managementstrategies. MAIN OUTCOME MEASURES Thecost-effectiveness of different interventions toprevent vision loss from primary open-angleglaucoma was measured in terms of financialcost (Australian dollars) and disability-adjustedlife years. RESULTS The prevalence of glaucomain Australia is expected to increase from 208 000in 2005 to 379 000 in 2025 because of the agingpopulation. Health system costs over the sametime period are estimated to increase from$AU355 million to $AU784 million. Total costs(health system costs, indirect costs and costs of", "metadata": {}}
+{"_id": "21922424", "title": "", "text": "The LIM domain-containing homeo box geneXlim-1 is expressed specifically in the organizerregion of Xenopus gastrula embryos.A novelcysteine-rich motif, named LIM, has beenidentified in the homeo box genes lin-11, Isl-1,and mec-3; the mec-3 and lin-11 genesdetermine cell lineages in Caenorhabditiselegans. We isolated LIM class homeo box genesfrom Xenopus laevis that are closely related tolin-11 and mec-3 in the LIM and homeo domains.This paper deals with one of these genes, Xlim-1.Xlim-1 mRNA is found at low abundance in theunfertilized egg, has a major expression phase atthe gastrula stage, decreases, and rises againduring the tadpole stage. In adult tissues thebrain shows the highest abundance, by far, ofXlim-1 mRNA. The maternal and late expressionphases of the Xlim-1 gene suggest that it hasmultiple functions at different stages of theXenopus life cycle. In the gastrula embryo,Xlim-1 mRNA is localized in the dorsal lip and thedorsal mesoderm, that is, in the region of", "metadata": {}}
+{"_id": "21931005", "title": "", "text": "Signal transduction proteins that associate withthe platelet-derived growth factor (PDGF)receptor mediate the PDGF-induced release ofglucose-6-phosphate dehydrogenase frompermeabilized cells.Permeabilized rat kidney cellsrapidly released glucose 6-phosphatedehydrogenase (G6PD) following stimulation withpeptide growth factors (Stanton, R.C., Seifter,J.L., Boxer, D.C., Zimmerman, E., and Cantley,L. C. (1991) J. Biol. Chem. 266, 12442-12448).To evaluate the signal transduction pathwaysmediating release of G6PD, two cell linestransfected with wild type or mutantplatelet-derived growth factor (PDGF) receptors(PDGFR) were studied using twopermeabilization protocols. G6PD release wasevaluated by enzyme activity and Western blotanalysis. PDGF caused a significant increase inG6PD release in 1 min in cells transfected withwild type PDGFR. PDGF did not stimulate G6PDrelease in cells transfected with tyrosinekinase-deficient PDGFR. PDGF did not stimulate", "metadata": {}}
+{"_id": "21932050", "title": "", "text": "Microarrays for the study of viral geneexpression during human cytomegalovirus latentinfection.Human cytomegalovirus (HCMV) is oneof the largest known DNA viruses. It isubiquitous, and following resolution of primaryproductive infection, it persists in the humanhost by establishing a lifelong latent infection inmyeloid lineage cells such as monocytes andtheir progenitors. Most adults with HCMVinfection are healthy but it can cause neurologicdeficits in infants, and remains an importantcause of morbidity and mortality in theimmunosuppressed patient. Microarray-basedstudies of HCMV have provided usefulinformation about genes that aretranscriptionally active during both productiveand latent phases of infection. This chapterdescribes how to study genes in HCMV usingmicroarrays and two cell types (productivelyinfected human foreskin fibroblasts, and latentlyinfected primary human myeloid progenitorcells).", "metadata": {}}
+{"_id": "21932297", "title": "", "text": "Physiological implications of hydrogen sulfide: awhiff exploration that blossomed.The importantlife-supporting role of hydrogen sulfide (H(2)S)has evolved from bacteria to plants,invertebrates, vertebrates, and finally tomammals. Over the centuries, however, H(2)Shad only been known for its toxicity andenvironmental hazard. Physiological importanceof H(2)S has been appreciated for about adecade. It started by the discovery ofendogenous H(2)S production in mammaliancells and gained momentum by typifying thisgasotransmitter with a variety of physiologicalfunctions. The H(2)S-catalyzing enzymes aredifferentially expressed in cardiovascular,neuronal, immune, renal, respiratory,gastrointestinal, reproductive, liver, andendocrine systems and affect the functions ofthese systems through the production of H(2)S.The physiological functions of H(2)S aremediated by different molecular targets, such asdifferent ion channels and signaling proteins.", "metadata": {}}
+{"_id": "21943141", "title": "", "text": "TatC is a specificity determinant for proteinsecretion via the twin-arginine translocationpathway.The recent discovery of a ubiquitoustranslocation pathway, specifically required forproteins with a twin-arginine motif in their signalpeptide, has focused interest on itsmembrane-bound components, one of which isknown as TatC. Unlike most organisms of whichthe genome has been sequenced completely, theGram-positive eubacterium Bacillus subtiliscontains two tatC-like genes denoted tatCd andtatCy. The corresponding TatCd and TatCyproteins have the potential to be involved in thetranslocation of 27 proteins with putativetwin-arginine signal peptides of whichapproximately 6-14 are likely to be secreted intothe growth medium. Using a proteomicapproach, we show that PhoD of B. subtilis, aphosphodiesterase belonging to a novel proteinfamily of which all known members aresynthesized with typical twin-arginine signalpeptides, is secreted via the twin-arginine", "metadata": {}}
+{"_id": "21948782", "title": "", "text": "Function and regulation of SUMOproteasesCovalent attachment of smallubiquitin-like modifier (SUMO) to proteins ishighly dynamic, and both SUMO–proteinconjugation and cleavage can be regulated.Protein desumoylation is carried out by SUMOproteases, which control cellular mechanismsranging from transcription and cell division toribosome biogenesis. Recent advances includethe discovery of two novel classes of SUMOproteases, insights regarding SUMO proteasespecificity, and revelations of previouslyunappreciated SUMO protease functions inseveral key cellular pathways. Thesedevelopments, together with new connectionsbetween SUMO proteases and the recentlydiscovered SUMO-targeted ubiquitin ligases(STUbLs), make this an exciting period to studythese enzymes.", "metadata": {}}
+{"_id": "21956124", "title": "", "text": "Review article: prebiotics in the gastrointestinaltract.BACKGROUND Prebiotics are short-chaincarbohydrates that alter the composition, ormetabolism, of the gut microbiota in a beneficialmanner. It is therefore expected that prebioticswill improve health in a way similar to probiotics,whilst at the same time being cheaper, andcarrying less risk and being easier to incorporateinto the diet than probiotics. AIM To reviewpublished evidence for prebiotic effects on gutfunction and human health. METHODS Wesearched the Science Citation Index with theterms prebiotic, microbiota, gut bacteria, largeintestine, mucosa, bowel habit, constipation,diarrhoea, inflammatory bowel disease, Crohn'sdisease, ulcerative colitis, pouchitis, calcium andcancer, focussing principally on studies inhumans and reports in the English language.Search of the Cochrane Library did not identifyany clinical study or meta-analysis on this topic.RESULTS Three prebiotics, oligofructose,galacto-oligosaccharides and lactulose, clearly", "metadata": {}}
+{"_id": "21957231", "title": "", "text": "Pain catastrophizing and general health status ina large Dutch community sample.The aim of thepresent study was to examine the associationbetween pain catastrophizing and general healthstatus in a Dutch adult community sample,including various subgroups of people withmusculoskeletal pain in the analyses. Forexploratory reasons this study partly replicatedprevious studies of the factor structure,reliability, and validity of the PainCatastrophizing Scale (PCS). Resultsdemonstrated that across different painsubgroups, catastrophizing uniquely contributedvariance to the prediction of the various aspectsof general health status beyond the varianceexplained by pain intensity, age, gender, andchronicity. Across subgroups strongestassociations were found between catastrophizingand mental health, general health perception,social functioning, and vitality. Furthermore, theassociation between catastrophizing and thevarious aspects of general health status was not", "metadata": {}}
+{"_id": "21958900", "title": "", "text": "Variability in risk of gastrointestinalcomplications with individual non-steroidalanti-inflammatory drugs: results of acollaborative meta-analysis.OBJECTIVE Tocompare the relative risks of seriousgastrointestinal complications reported withindividual non-steroidal anti-inflammatory drugs.DESIGN Systematic review of controlledepidemiological studies that found a relationbetween use of the drugs and admission tohospital for haemorrhage or perforation.SETTING Hospital and community basedcase-control and cohort studies. MAIN OUTCOMEMEASURES (a) Estimated relative risks ofgastrointestinal complications with use ofindividual drugs, exposure to ibuprofen beingused as reference; (b) a ranking that bestsummarised the sequence of relative risksobserved in the studies. RESULTS 12 studies metthe inclusion criteria. 11 provided comparativedata on ibuprofen and other drugs. Ibuprofenranked lowest or equal lowest for risk in 10 of", "metadata": {}}
+{"_id": "21993510", "title": "", "text": "Accuracy of weighed dietary records in studies ofdiet and health.OBJECTIVE To provide anindependent evaluation of seven day weigheddietary records, which are currently accepted asthe most accurate technique for assessinghabitual dietary intake in studies investigatingthe links between diet and health. DESIGNSubjects who had previously participated in theNorthern Ireland diet and health study werereselected by stratified random sampling torepresent the range of energy intakes in thestudy as assessed by the seven day weigheddietary record. SETTING Northern Ireland.SUBJECTS 31 Free living adults (16 men and 15women). MAIN OUTCOME MEASURES Energyintake as measured by the seven day weigheddietary record and total energy expenditureestimated concurrently by the doubly labelledwater technique. RESULTS Average recordedenergy intakes were significantly lower thanmeasured expenditure in the group overall (9.66MJ/day v 12.15 MJ/day, 95% confidence interval", "metadata": {}}
+{"_id": "22003328", "title": "", "text": "A novel family of sequence-specificendoribonucleases associated with the clusteredregularly interspaced short palindromicrepeats.Clustered regularly interspaced shortpalindromic repeats (CRISPRs) together with theassociated CAS proteins protect microbial cellsfrom invasion by foreign genetic elements usingpresently unknown molecular mechanisms. AllCRISPR systems contain proteins of the CAS2family, suggesting that these uncharacterizedproteins play a central role in this process. Herewe show that the CAS2 proteins represent anovel family of endoribonucleases. Six purifiedCAS2 proteins from diverse organisms cleavedsingle-stranded RNAs preferentially within U-richregions. A representative CAS2 enzyme,SSO1404 from Sulfolobus solfataricus, cleavedthe phosphodiester linkage on the 3'-side andgenerated 5'-phosphate- and3'-hydroxyl-terminated oligonucleotides. Thecrystal structure of SSO1404 was solved at 1.6Aresolution revealing the first ribonuclease with a", "metadata": {}}
+{"_id": "22007333", "title": "", "text": "Menstrual and reproductive factors in relation tomammographic density: the Study of Women’sHealth Across the Nation (SWAN)Menstrual andreproductive factors may increase breast cancerrisk through a pathway that includes increasedmammographic density. We assessed whetherknown or suspected menstrual and reproductivebreast cancer risk factors were cross-sectionallyassociated with mammographic density, bymeasuring area of radiographic density and totalbreast area on mammograms from 801participants in the Study of Women’s HealthAcross the Nation (SWAN), a multi-ethnic cohortof pre- and early perimenopausal women. Frommultivariable linear regression, the followingmenstrual or reproductive factors wereindependently associated with percentmammographic density (area of densebreast/breast area): older age at menarche (β =10.3, P < 0.01, for >13 vs. <12 years),premenstrual cravings and bloating (β = −3.36,P = 0.02), younger age at first full-term birth (β", "metadata": {}}
+{"_id": "22023404", "title": "", "text": "Genetic and environmental determinants of25-hydroxyvitamin D and 1,25-dihydroxyvitaminD levels in Hispanic and AfricanAmericans.CONTEXT Vitamin D deficiency isassociated with many adverse health outcomes,yet little is known about the geneticepidemiology of vitamin D or its metabolites.OBJECTIVE Our objective was to examine therelationship among three vitamin D-relatedgenes and levels of 25-hydroxyvitamin D[25(OH)D] and 1,25-dihydroxyvitamin D[1,25(OH)2D] in Hispanics (HAs) and AfricanAmericans (AAs). DESIGN AND SETTING Thecross-sectional Insulin Resistance AtherosclerosisFamily Study recruited and examined subjectsin: Los Angeles, California (AAs; 513 individualsfrom 42 families); San Luis Valley (SLV),Colorado (HAs; 513 individuals from 30families); and San Antonio (SA), Texas (HAs;504 individuals from 58 families). MAINOUTCOME MEASURES Plasma levels of 25(OH)Dand 1,25(OH)2D were measured. RESULTS", "metadata": {}}
+{"_id": "22025252", "title": "", "text": "Changes in the levels of inositol phosphates afteragonist-dependent hydrolysis of membranephosphoinositides.The formation of inositolphosphates in response to agonists was studiedin brain slices, parotid gland fragments and inthe insect salivary gland. The tissues were firstincubated with [3H]inositol, which wasincorporated into the phosphoinositides. All thetissues were found to containglycerophosphoinositol, inositol 1-phosphate,inositol 1,4-bisphosphate and inositol1,4,5-trisphosphate, which were identified byusing anion-exchange and high-resolutionanion-exchange chromatography, high-voltagepaper ionophoresis and paper chromatography.There was no evidence for the existence ofinositol 1:2-cyclic phosphate. A simpleanion-exchange chromatographic method wasdeveloped for separating these inositolphosphates for quantitative analysis. Stimulationcaused no change in the levels ofglycerophosphoinositol in any of the tissues. The", "metadata": {}}
+{"_id": "22029384", "title": "", "text": "RNA editing in brain controls a determinant of ionflow in glutamate-gated channels.L-glutamate,the principal excitatory transmitter in the brain,gates ion channels mediating fastneurotransmission. Subunit components of tworelated classes of glutamate receptor channelshave been characterized by cDNA cloning andshown to carry either an arginine or a glutamineresidue in a defined position of their putativechannel-forming segment. The arginine residuein this segment profoundly alters, anddominates, the properties of ion flow, asdemonstrated for one channel class. We nowshow that the genomic DNA sequences encodingthe particular channel segment of all subunitsharbor a glutamine codon (CAG), even though anarginine codon (CGG) is found in mRNAs of threesubunits. Multiple genes and alternative exonswere excluded as sources for the arginine codon;hence, we propose that transcripts for threesubunits are altered by RNA editing. This processapparently edits subunit transcripts of the two", "metadata": {}}
+{"_id": "22036571", "title": "", "text": "Post-translational modifications of the beta-1subunit of AMP-activated protein kinase affectenzyme activity and cellular localization.TheAMP-activated protein kinase (AMPK) is aubiquitous mammalian protein kinase importantin the adaptation of cells to metabolic stress. Theenzyme is a heterotrimer, consisting of acatalytic alpha subunit and regulatory beta andgamma subunits, each of which is a member of alarger isoform family. The enzyme isallosterically regulated by AMP and byphosphorylation of the alpha subunit. The betasubunit is post-translationally modified bymyristoylation and multi-site phosphorylation. Inthe present study, we have examined the impactof post-translational modification of the beta-1subunit on enzyme activity, heterotrimerassembly and subcellular localization, usingsite-directed mutagenesis and expression ofsubunits in mammalian cells. Removal of themyristoylation site (G2A mutant) results in a4-fold activation of the enzyme and relocalization", "metadata": {}}
+{"_id": "22038539", "title": "", "text": "Caloric restriction delays age-related methylationdriftIn mammals, caloric restriction consistentlyresults in extended lifespan. Epigeneticinformation encoded by DNA methylation istightly regulated, but shows a striking driftassociated with age that includes both gains andlosses of DNA methylation at various sites. Here,we report that epigenetic drift is conservedacross species and the rate of drift correlateswith lifespan when comparing mice, rhesusmonkeys, and humans. Twenty-two to30-year-old rhesus monkeys exposed to 30%caloric restriction since 7-14 years of age showedattenuation of age-related methylation driftcompared to ad libitum-fed controls such thattheir blood methylation age appeared 7 yearsyounger than their chronologic age. Even morepronounced effects were seen in2.7-3.2-year-old mice exposed to 40% caloricrestriction starting at 0.3 years of age. Theeffects of caloric restriction on DNA methylationwere detectable across different tissues and", "metadata": {}}
+{"_id": "22042345", "title": "", "text": "Structural analysis of multiprotein complexes bycross-linking, mass spectrometry, and databasesearching.Most protein complexes areinaccessible to high resolution structuralanalysis. We report the results of a combinedapproach of cross-linking, mass spectrometry,and bioinformatics to two human complexescontaining large coiled-coil segments, the NDEL1homodimer and the NDC80 heterotetramer. Animportant limitation of the cross-linkingapproach, so far, was the identification ofcross-linked peptides from fragmentationspectra. Our novel approach overcomes the dataanalysis bottleneck of cross-linking and massspectrometry. We constructed a purpose-builtdatabase to match spectra with cross-linkedpeptides, define a score that expresses thequality of our identification, and estimate falsepositive rates. We show that our analysis shedslight on critical structural parameters such as thedirectionality of the homodimeric coiled coil ofNDEL1, the register of the heterodimeric coiled", "metadata": {}}
+{"_id": "22049489", "title": "", "text": "The long non-coding RNA H19-derived miR-675modulates human gastric cancer cell proliferationby targeting tumor suppressor RUNX1.ThelncRNA H19 has been recently shown to beupregulated and play important roles in gastriccancer tumorigenesis. However, the precisemolecular mechanism of H19 and its matureproduct miR-675 in the carcinogenesis of gastriccancer remains unclear. In this study, we foundthat miR-675 was positively expressed with H19and was a pivotal mediator in H19-inducedgastric cancer cell growth promotion.Subsequently, the tumor suppressor RuntDomain Transcription Factor1 (RUNX1) wasconfirmed to be a direct target of miR-675 usinga luciferase reporter assay and Western blottinganalyses. A series of rescue assays indicated thatRUNX1 mediated H19/miR-67-induced gastriccancer cell phenotypic changes. Moreover, theinverse relationship between the expression ofRUNX1 and H19/miR-675 was also revealed ingastric cancer tissues and gastric cancer cell", "metadata": {}}
+{"_id": "22057077", "title": "", "text": "Methylphenidate-induced erections in aprepubertal child.Methylphenidate is amedication used routinely in the management ofattention deficit hyperactivity disorder. We reporta case of a prepubertal child who developedunwanted erections after commencing aresponse-adjusted dosing regimen of sustainedrelease methylphenidate. Despite priapism beinga rare adverse reaction associated withmethylphenidate, physicians and parents need tobe aware as it can have significant long-termcomplications.", "metadata": {}}
+{"_id": "22059387", "title": "", "text": "Mechanism of NO-mediated oxidative andnitrative DNA damage in hamsters infected withOpisthorchis viverrini: a model ofinflammation-mediatedcarcinogenesis.Inflammation mediated byinfection is an important factor causingcarcinogenesis. Opisthorchis viverrini (OV)infection is a risk factor of cholangiocarcinoma(CHCA), probably through chronic inflammation.Formation of 8-nitroguanine and8-oxo-7,8-dihydro-2'-deoxyguanosine(8-oxodG), and expression of inducible nitricoxide synthase (iNOS) and heme oxygenase-1(HO-1) were assessed in the liver of hamstersinfected with OV. We newly produced specificanti-8-nitroguanine antibody withoutcross-reaction. Double immunofluorescencestaining revealed that 8-oxodG and8-nitroguanine were formed mainly in the sameinflammatory cells and epithelium of bile ductsfrom day 7 and showed the strongestimmunoreactivity on days 21 and 30,", "metadata": {}}
+{"_id": "22067786", "title": "", "text": "Monte Carlo tests for associations betweendisease and alleles at highly polymorphic loci.Inan association analysis comparing cases andcontrols with respect to allele frequencies at ahighly polymorphic locus, a potential problem isthat the conventional chi-squared test may notbe valid for a large, sparse contingency table.However, reliance on statistics with knownasymptotic distribution is now unnecessary, asMonte Carlo simulations can be performed toestimate the significance level of any teststatistic. We have implemented a Monte Carlomethod for four 'chi-squared' test statistics,three of which involved combination of alleles,and evaluated their performance on a real dataset. Combining rare alleles to avoid smallexpected cell counts, and considering each allelein turn against the rest, reduced the power todetect a genuine association when the number ofalleles was very large. We should either notcombine alleles at all, or combine them in such away that preserves the evidence for an", "metadata": {}}
+{"_id": "22080671", "title": "", "text": "KLF4-dependent phenotypic modulation ofsmooth muscle cells has a key role inatherosclerotic plaque pathogenesisPreviousstudies investigating the role of smooth musclecells (SMCs) and macrophages in thepathogenesis of atherosclerosis have providedcontroversial results owing to the use ofunreliable methods for clearly identifying each ofthese cell types. Here, using Myh11-CreERT2ROSA floxed STOP eYFP Apoe−/− mice toperform SMC lineage tracing, we find thattraditional methods for detecting SMCs based onimmunostaining for SMC markers fail to detect>80% of SMC-derived cells within advancedatherosclerotic lesions. These unidentifiedSMC-derived cells exhibit phenotypes of othercell lineages, including macrophages andmesenchymal stem cells (MSCs). SMC-specificconditional knockout of Krüppel-like factor 4(Klf4) resulted in reduced numbers ofSMC-derived MSC- and macrophage-like cells, amarked reduction in lesion size, and increases in", "metadata": {}}
+{"_id": "22107641", "title": "", "text": "Late-life depression and microstructuralabnormalities in dorsolateral prefrontal cortexwhite matter.OBJECTIVE The purpose of thisstudy was to determine whether microstructuralabnormalities in the white matter of thedorsolateral prefrontal cortex are associated withlate-life depression. METHOD Seventeen elderlydepressed subjects were compared with 16elderly subjects who were not depressed.Diffusion tensor imaging was used to measurethe fractional anisotropy of the white matter inthe dorsolateral prefrontal cortex's superior andmiddle frontal gyri bilaterally and in the leftoccipital lobe as a control region. The authorscompared results between groups whilecontrolling for age, sex, and comorbid medicaldisorders. RESULTS Even after controlling forage, sex, hypertension, and heart disease, theauthors found significantly lower fractionalanisotropy values in the right superior frontalgyrus white matter of depressed patients thancomparison subjects. CONCLUSIONS", "metadata": {}}
+{"_id": "22116439", "title": "", "text": "Pioglitazone prevents tau oligomerization.Tauaggregation and amyloid β protein (Aβ)deposition are the main causes of Alzheimer'sdisease (AD). Peroxisome proliferator-activatedreceptor γ (PPARγ) activation modulates Aβproduction. To test whether the PPARγ agonistpioglitazone (PIO) is also effective in preventingtau aggregation in AD, we used a cellular modelin which wild-type tau protein (4R0N) isoverexpressed (M1C cells) (Hamano et al., 2012)as well as primary neuronal cultures. PIOreduced both phosphorylated and total taulevels, and inactivated glycogen synthase kinase3β, a major tau kinase, associated withactivation of Akt. In addition, PIO decreasedcleaved caspase3 and C-terminal truncated tauspecies by caspase, which is expected todecrease tau aggregation. A fractionation studyshowed that PIO reduced high molecular-weight(120 kDa), oligomeric tau species in TrisInsoluble, sarkosyl-soluble fractions. Taudecrease was reversed by adding GW9662, a", "metadata": {}}
+{"_id": "22123421", "title": "", "text": "Prognostic impact of the mean plateletvolume/platelet count ratio in terms of survivalin advanced non-small cell lungcancer.BACKGROUND Mean platelet volume(MPV) is a platelet volume index. Classically,MPV was recognized as a hallmark of plateletactivation. Recent studies have revealed that theMPV and MPV/platelet count (PC) ratio canpredict long-term mortality in patients withischemic cardio-vascular disease. In addition,these indices were correlated with thepathophysiological characteristics of patientswith various disorders, including malignanttumors. PATIENTS AND METHODS Weretrospectively analyzed various hematologicalindices of patients with advanced non-small celllung cancer (NSCLC). The aim of this study wasto evaluate the contribution of platelet volumeindices to survival in these patients. RESULTS Atotal of 268 patients were enrolled in the study.The median age of the patients was 68 years(range: 31-87 years). We compared various", "metadata": {}}
+{"_id": "22130056", "title": "", "text": "Traceability of biologicals: present challenges inpharmacovigilance.INTRODUCTION Traceabilityis important in the postmarketing surveillance ofbiologicals, since changes in the manufacturingprocess may give rise to product- orbatch-specific risks. With the expected expansionof the biosimilar market, there have beenconcerns about the ability to trace individualproducts within pharmacovigilance databases.AREAS COVERED The authors discuss thepresent challenges in the traceability ofbiologicals in relation to pharmacovigilance, byexploring the processes involved in ensuringtraceability. They explore both the existingsystems that are in place for the recording ofexposure information in clinical practice, as wellas the critical steps involved in the transfer ofexposure data to various pharmacovigilancedatabases. EXPERT OPINION The existingsystems ensure the traceability of biologicalsdown to the manufacturer within pharmacyrecords, but do not support the routine recording", "metadata": {}}
+{"_id": "22134353", "title": "", "text": "Regulation of self-ligands for activating naturalkiller cell receptors.Natural killer (NK) cells areable to lyse infected and tumor cells whilesparing healthy cells. Recognition of diseasedcells by NK cells is governed by severalactivating and inhibitory receptors. We reviewnumerous pathways that have been implicated inthe regulation of self-ligands for activatingreceptors, including NKG2D, DNAM-1, LFA-1,NKp30, NKp44, NKp46, NKp65, and NKp80 foundon NK cells and some T cells. Understanding howthe regulation of self-encoded ligand expressionis regulated may provide novel avenues forfuture therapeutic approaches to infections andcancer.", "metadata": {}}
+{"_id": "22150633", "title": "", "text": "A core Klf circuitry regulates self-renewal ofembryonic stem cellsEmbryonic stem (ES) cellsare unique in their ability to self-renewindefinitely and maintain pluripotency. Theseproperties require transcription factors thatspecify the gene expression programme of EScells. It has been possible to reverse the highlydifferentiated state of somatic cells back to apluripotent state with a combination of fourtranscription factors: Klf4 is one of thereprogramming factors required, in conjunctionwith Oct4, Sox2 and c-Myc. Maintenance ofself-renewal and pluripotency of ES cells requiresOct4, Sox2 and c-Myc, but Klf4 is dispensable.Here, we show that Krüppel-like factors arerequired for the self-renewal of ES cells.Simultaneous depletion of Klf2, Klf4 and Klf5lead to ES cell differentiation. Chromatinimmunoprecipitation coupled to microarray assayreveals that these Klf proteins share manycommon targets of Nanog, suggesting a closefunctional relationship between these factors.", "metadata": {}}
+{"_id": "22153455", "title": "", "text": "A myeloid hypoxia-inducible factor1α-Krüppel-like factor 2 pathway regulatesgram-positive endotoxin-mediatedsepsis.Although gram-positive infections accountfor the majority of cases of sepsis, the molecularmechanisms underlying their effects remainspoorly understood. We investigated how cell wallcomponents of gram-positive bacteria contributeto the development of sepsis. Experimentalobservations derived from cultured primarymacrophages and the cell line indicate thatgram-positive bacterial endotoxins inducehypoxia-inducible factor 1α (HIF-1α) mRNA andprotein expression. Inoculation of live orheat-inactivated gram-positive bacteria withmacrophages induced HIF-1 transcriptionalactivity in macrophages. Concordant with theseresults, myeloid deficiency of HIF-1α attenuatedgram-positive bacterial endotoxin-inducedcellular motility and proinflammatory geneexpression in macrophages. Conversely,gram-positive bacteria and their endotoxins", "metadata": {}}
+{"_id": "22159299", "title": "", "text": "Autophagy controls Salmonella infection inresponse to damage to theSalmonella-containing vacuole.Salmonellaenterica serovar Typhimurium (S. Typhimurium)is a facultative intracellular pathogen that causesdisease in a variety of hosts. S. Typhimuriumactively invade host cells and typically residewithin a membrane-bound compartment calledthe Salmonella-containing vacuole (SCV). Thebacteria modify the fate of the SCV using twoindependent type III secretion systems (TTSS).TTSS are known to damage eukaryotic cellmembranes and S. Typhimurium has beensuggested to damage the SCV using itsSalmonella pathogenicity island (SPI)-1 encodedTTSS. Here we show that this damage gives riseto an intracellular bacterial population targetedby the autophagy system during in vitroinfection. Approximately 20% of intracellular S.Typhimurium colocalized with the autophagymarker GFP-LC3 at 1 h postinfection. Autophagyof S. Typhimurium was dependent upon the", "metadata": {}}
+{"_id": "22174015", "title": "", "text": "PI3K-Akt-mTORC1-S6K1/2 axis controls Th17differentiation by regulating Gfi1 expression andnuclear translocation of RORγ.ThePI3K-Akt-mTORC1 axis contributes to theactivation, survival, and proliferation of CD4(+) Tcells upon stimulation through TCR and CD28.Here, we demonstrate that the suppression ofthis axis by deletion of p85α or PI3K/mTORC1inhibitors as well as T cell-specific deletion ofraptor, an essential component of mTORC1,impairs Th17 differentiation in vitro and in vivo ina S6K1/2-dependent fashion. Inhibition ofPI3K-Akt-mTORC1-S6K1 axis impairs thedownregulation of Gfi1, a negative regulator ofTh17 differentiation. Furthermore, wedemonstrate that S6K2, a nuclear counterpart ofS6K1, is induced by the PI3K-Akt-mTORC1 axis,binds RORγ, and carries RORγ to the nucleus.These results point toward a pivotal role ofPI3K-Akt-mTORC1-S6K1/2 axis in Th17differentiation.", "metadata": {}}
+{"_id": "22178316", "title": "", "text": "Disrupted-in-schizophrenia 1 and neuregulin 1are required for the specification ofoligodendrocytes and neurones in the zebrafishbrain.Schizophrenia may arise from subtleabnormalities in brain development due toalterations in the functions of candidatesusceptibility genes such asDisrupted-in-schizophrenia 1 (DISC1) andNeuregulin 1 (NRG1). To provide novel insightsinto the functions of DISC1 in braindevelopment, we mapped the expression ofzebrafish disc1 and set out to characterize itsrole in early embryonic development usingmorpholino antisense methods. These studiesrevealed a critical requirement for disc1 inoligodendrocyte development by promotingspecification of olig2-positive cells in thehindbrain and other brain regions. Since NRG1has well-documented roles in myelination, wealso analyzed the roles of nrg1 and ErbBsignalling in zebrafish brain development and weobserved strikingly similar defects to those seen", "metadata": {}}
+{"_id": "22180793", "title": "", "text": "Monoclonal antibody targeting of N-cadherininhibits prostate cancer growth, metastasis andcastration resistanceThe transition fromandrogen-dependent to castration-resistantprostate cancer (CRPC) is a lethal event ofuncertain molecular etiology. Comparing geneexpression in isogenic androgen-dependent andCRPC xenografts, we found a reproducibleincrease in N-cadherin expression, which wasalso elevated in primary and metastatic tumorsof individuals with CRPC. Ectopic expression ofN-cadherin in nonmetastatic,androgen-dependent prostate cancer modelscaused castration resistance, invasion andmetastasis. Monoclonal antibodies against theectodomain of N-cadherin reduced proliferation,adhesion and invasion of prostate cancer cells invitro. In vivo, these antibodies slowed thegrowth of multiple established CRPC xenografts,blocked local invasion and metastasis and, athigher doses, led to complete regression.N-cadherin–specific antibodies markedly delayed", "metadata": {}}
+{"_id": "22185730", "title": "", "text": "PP2A regulates tau phosphorylation directly andalso indirectly via activatingGSK-3beta.Abnormal hyperphosphorylation oftau appears to be crucial in neurofibrillarydegeneration in Alzheimer's disease (AD).Previous studies suggest that a down-regulationof protein phosphatase 2A (PP2A), the major tauphosphatase in human brain, contributes to tauhyperphosphorylation in AD. However, theeffects of PP2A down-regulation on site-specifictau hyperphosphorylation is not well understood.In the present study, we showed that PP2Adephosphorylated tau at several phosphorylationsites with different efficiencies. Among the sitesstudied, Thr205, Thr212, Ser214, and Ser262were the most favorable sites, and Ser199 andSer404 were the least favorable sites for PP2A invitro. Inhibition of PP2A with okadaic acid inmetabolically active rat brain slices causedinhibition of glycogen synthase kinase-3beta(GSK-3beta) via an increase in itsphosphorylation at Ser9. GSK-3beta", "metadata": {}}
+{"_id": "22186938", "title": "", "text": "Human artificial chromosomes containingchromosome 17 alphoid DNA maintain an activecentromere in murine cells but are notstable.Human artificial chromosomes (HACs) areautonomous molecules that can function andsegregate as normal chromosomes in humancells. De novo HACs have successfully been usedas gene expression vectors to complementgenetic deficiencies in human cultured cells.HACs now offer the possibility of studying theregulation and expression of large genes in avariety of cell types from different tissues andcorrecting gene deficiencies caused by humaninherited diseases. Complementary geneexpression studies in mice, especially in mousemodels of human genetic diseases, are alsoimportant in determining if large humantransgenes can be expressed appropriately fromartificial chromosomes. Toward this aim we areestablishing artificial chromosomes in murinecells as novel gene expression vectors. Initiallywe transferred HAC vectors into murine cells, but", "metadata": {}}
+{"_id": "22190276", "title": "", "text": "How nascent phagosomes mature to becomephagolysosomes.Phagocytosis mediates theclearance of apoptotic bodies and also theelimination of microbial pathogens. The nascentphagocytic vacuole formed upon particleengulfment lacks microbicidal and degradativeactivity. These capabilities are acquired as thephagosome undergoes maturation; a progressiveremodeling of its membrane and contents thatculminates in the formation of phagolysosomes.Maturation entails orderly sequential fusion ofthe phagosomal vacuole with specializedendocytic and secretory compartments.Concomitantly, the phagosomal membraneundergoes both inward and outward vesiculationand tubulation followed by fission, therebyrecycling components and maintaining its overallsize. Here, we summarize what is known aboutthe molecular machinery that governs thiscomplex metamorphosis of phagosomematuration.", "metadata": {}}
+{"_id": "22191759", "title": "", "text": "Purification and structural characterization ofbovine cathelicidins, precursors of antimicrobialpeptides.Cathelicidins are a novel family ofantimicrobial peptide precursors frommammalian myeloid cells. They are characterizedby a conserved N-terminal region while theC-terminal antimicrobial domain can varyconsiderably in both primary sequence andlength. Four cathelicidins, proBac5, proBac7,prododecapeptide and proBMAP-28, have beenconcurrently purified from bovine neutrophils,using simple and rapid methodologies. Thecorrelation of ES-MS data from the purifiedproteins with their cDNA-deduced sequences hasrevealed several common features of theirprimary sequence, such as the presence ofN-terminal 5-oxoproline (pyroglutamate)residues and two disulfide bridges in a 1-2, 3-4arrangement. The N-terminal domains of thecathelicidins present one or two Asp-Pro bonds,which are particularly acid-labile in proBac5 andproBac7, but stable in prododecapeptide. This", "metadata": {}}
+{"_id": "22194407", "title": "", "text": "Tuberculosis mortality in England and Walesduring 1982-1992: its association with poverty,ethnicity and AIDS.This paper seeks to establishthe strength of association betweencontemporary tuberculosis (TB) in England andWales and several potential aetiological factors.It presents an ecological analysis of standardisedannual TB mortality rates for the 403 localauthority districts between 1982 and 1992,disaggregated by age and sex. Social,demographic and ethnicity measures from the1981 and 1991 censuses and standardisedannual AIDS-related mortality rates for youngmen are used to calculate Poisson regressionmodels. A strong association was found betweenall TB mortality groups and overcrowding at thehousehold level. For women, no other measuresimproved the explanatory power of the models.In multiple regressions, both poverty andAIDS-related mortality explained additionalvariation in the model for younger men. The linkbetween ethnicity and tuberculosis notifications", "metadata": {}}
+{"_id": "22198971", "title": "", "text": "Noncognate interaction with MHC class IImolecules is essential for maintenance of T cellmetabolism to establish optimal memory CD4 Tcell function.CD4 memory T cells surviving in theabsence of MHC class II contact lose theircharacteristic memory function. To investigatethe mechanisms underlying the impairedfunction of memory T cells in the absence of MHCclass II molecules, we analyzed gene expressionprofiles of resting memory T cells isolated fromMHC class II-competent or -deficient hosts. Theanalysis focused on five transcripts related to Tcell activation, metabolism, and survival that areunderexpressed in resting memory T cells fromMHC class II-deficient hosts compared with MHCclass II-competent hosts. CD4 memory cellsisolated from MHC class II-deficient hosts displayalterations in their degree of differentiation aswell as metabolic activity, and these changes arealready manifest in the effector phase despitethe presence of Ag-expressing dendritic cells.Our data suggest that the absence of interactions", "metadata": {}}
+{"_id": "22210434", "title": "", "text": "The kinase TAK1 integrates antigen and cytokinereceptor signaling for T cell development,survival and functionThe kinase TAK1 is criticalfor innate and B cell immunity. The function ofTAK1 in T cells is unclear, however. We showhere that T cell–specific deletion of the geneencoding TAK1 resulted in reduced developmentof thymocytes, especially of regulatory T cellsexpressing the transcription factor Foxp3. Inmature thymocytes, TAK1 was required forinterleukin 7–mediated survival and T cellreceptor–dependent activation of transcriptionfactor NF-κB and the kinase Jnk. In effector Tcells, TAK1 was dispensable for T cellreceptor–dependent NF-κB activation andcytokine production, but was important forproliferation and activation of the kinase p38 inresponse to interleukins 2, 7 and 15. Thus, TAK1is essential for the integration of T cell receptorand cytokine signals to regulate thedevelopment, survival and function of T cells.", "metadata": {}}
+{"_id": "22227889", "title": "", "text": "Caregiver burden in HIV-positive andHIV-negative partners of men with AIDS.Thisstudy examines factors associated with caregiverburden in 82 HIV-positive (HIV+) and 162HIV-negative (HIV-) partners of men with AIDS.We expected HIV+ caregivers to report moreburden than HIV- caregivers because of the tollof their disease on their resources. HIV+caregivers did report more burden and,compared with the HIV- caregivers, they weremore religious or spiritual, had less income, andcoped by using more positive reappraisal andcognitive escape-avoidance and by seeking socialsupport. Comparisons of HIV+ caregivers with 61HIV+ partners of healthy men indicated thatmost differences between HIV+ and HIV-caregivers were associated with HIVseropositivity rather than caregiving. However,of the variables associated with HIVseropositivity, only religiosity or spiritualitycontributed independently to burden in HIV+caregivers, suggesting a relatively weak link", "metadata": {}}
+{"_id": "22236223", "title": "", "text": "Renal Disease and PregnancyPregnancy inwomen with different renal diseases hasimportant consequences for the developing fetusand maternal health. Kidneys and the urinarytract have to adapt to the pregnancy status andtherefore suffer significant anatomical,hemodynamic and endocrine changes. Failure toadapt can aggravate the preexisting maternaldisease and can also create suboptimalenvironment for fetal development and increasethe risk of obstetric complications. Knowledgeand correct interpretation of the renal functionaltests is necessary for the modern obstetrician,avoiding an incorrect diagnosis for renal diseasewhere only specific renal changes duringpregnancy are present, but meanwhile a correctevaluation of the renal function and changes candetect a pathology that can aggravate both themother’s and the baby’s condition. Improvementand better understanding of the renalpathophysiology in pregnancy made possible thatpregnant woman look forward for a good", "metadata": {}}
+{"_id": "22241778", "title": "", "text": "Integrin beta1-mediated matrix assembly andsignaling are critical for the normal developmentand function of the kidney glomerulus.Thehuman kidneys filter 180 l of blood every day viaabout 2.5 million glomeruli. The three layers ofthe glomerular filtration apparatus consist offenestrated endothelium, specializedextracellular matrix known as the glomerularbasement membrane (GBM) and the podocytefoot processes with their modified adherensjunctions known as the slit diaphragm (SD). Inthis study we explored the contribution ofpodocyte beta1 integrin signaling for normalglomerular function. Mice with podocyte specificdeletion of integrin beta1 (podocin-Cre beta1-fl/flmice) are born normal but cannot completepostnatal renal development. They exhibitdetectable proteinuria on day 1 and die within aweek. The kidneys of podocin-Cre beta1-fl/flmice exhibit normal glomerular endothelium butshow severe GBM defects with multilaminationsand splitting including podocyte foot process", "metadata": {}}
+{"_id": "22264117", "title": "", "text": "The Aging Epigenome.During aging, themechanisms that normally maintain health andstress resistance strikingly decline, resulting indecrepitude, frailty, and ultimately death.Exactly when and how this decline occurs isunknown. Changes in transcriptional networksand chromatin state lie at the heart ofage-dependent decline. These epigenomicchanges are not only observed during aging butalso profoundly affect cellular function and stressresistance, thereby contributing to theprogression of aging. We propose that thedysregulation of transcriptional and chromatinnetworks is a crucial component of aging.Understanding age-dependent epigenomicchanges will yield key insights into how agingbegins and progresses and should lead to thedevelopment of new therapeutics that delay oreven reverse aging and age-related diseases.", "metadata": {}}
+{"_id": "22267225", "title": "", "text": "Cancer chemoprevention: Much has been done,but there is still much to do. State of the art andpossible new approaches.Over the past threedecades great efforts have been made in searchof cancer chemoprevention strategies. Theincrease in knowledge of the long process fromnormal to cancer cell has enabled interventionsin terms of lifestyle modifications, naturalcompounds or drugs to block or reverse theprocess. Great successes have been achieved,especially for breast and colorectal cancer.However, these strategies have yet to findclinical application on a large scale. In this articlewe identify the achievements, the pitfalls and thenext steps to be taken to improve the efficacyand applicability of chemoprevention strategies.Among the crucial key points to be implementedare educational activities for physicians toappropriately disseminate the aim and indeedthe culture of chemoprevention. It is essential toimprove the risk-benefit balance, seeking theminimal active doses, intermittent schedules, a", "metadata": {}}
+{"_id": "22281684", "title": "", "text": "Secreted Frizzled-related Protein 5 DiminishesCardiac Inflammation and Protects the Heartfrom Ischemia/Reperfusion Injury.Wnt signalinghas diverse actions in cardiovasculardevelopment and disease processes. Secretedfrizzled-related protein 5 (Sfrp5) has been shownto function as an extracellular inhibitor ofnon-canonical Wnt signaling that is expressed atrelatively high levels in white adipose tissue. Theaim of this study was to investigate the role ofSfrp5 in the heart under ischemic stress. Sfrp5KO and WT mice were subjected toischemia/reperfusion (I/R). Although Sfrp5-KOmice exhibited no detectable phenotype whencompared with WT control at baseline, theydisplayed larger infarct sizes, enhanced cardiacmyocyte apoptosis, and diminished cardiacfunction following I/R. The ischemic lesions ofSfrp5-KO mice had greater infiltration ofWnt5a-positive macrophages and greaterinflammatory cytokine and chemokine geneexpression when compared with WT mice. In", "metadata": {}}
+{"_id": "22309946", "title": "", "text": "Asymptomatic spinal cord lesions predict diseaseprogression in radiologically isolatedsyndrome.BACKGROUND Technologicaladvancements in neuroimaging and theincreased use of these diagnostic modalities areresponsible for the discovery of incidentallyidentified anomalies within the CNS. In additionto the identification of unanticipated brain MRIabnormalities suggestive of demyelinatingdisease in patients undergoing neuroimaging fora medical reason other than evaluation formultiple sclerosis (MS), asymptomatic spinalcord lesions are periodically identified.OBJECTIVE To determine if asymptomatic spinalcord lesions are associated with clinicalprogression in subjects with radiologicallyisolated syndrome (RIS). METHODS Aretrospective review of RIS cases at theUniversity of California, San Francisco MultipleSclerosis Center was performed. The presence ofasymptomatic cervical spinal cord MRI lesionswas analyzed as a potential predictor for clinical", "metadata": {}}
+{"_id": "22312627", "title": "", "text": "YqhC regulates transcription of the adjacentEscherichia coli genes yqhD and dkgA that areinvolved in furfural tolerancePrevious resultshave demonstrated that the silencing of adjacentgenes encoding NADPH-dependent furfuraloxidoreductases (yqhD dkgA) is responsible forincreased furfural tolerance in an E. coli strainEMFR9 [Miller et al., Appl Environ Microbiol75:4315–4323, 2009]. This gene silencing is nowreported to result from the spontaneous insertionof an IS10 into the coding region of yqhC, anupstream gene. YqhC shares homology withtranscriptional regulators belonging to theAraC/XylS family and was shown to act as apositive regulator of the adjacent operonencoding YqhD and DkgA. Regulation wasdemonstrated by constructing a chromosomaldeletion of yqhC, a firefly luciferase reporterplasmid for yqhC, and by a direct comparison offurfural resistance and NADPH-dependentfurfural reductase activity. Closely relatedbacteria contain yqhC, yqhD, and dkgA orthologs", "metadata": {}}
+{"_id": "22317868", "title": "", "text": "A direct role for Met endocytosis intumorigenesisCompartmentalization of signalsgenerated by receptor tyrosine kinase (RTK)endocytosis has emerged as a majordeterminant of various cell functions. Here, usingtumour-associated Met-activating mutations, wedemonstrate a direct link between endocytosisand tumorigenicity. Met mutants exhibitincreased endocytosis/recycling activity anddecreased levels of degradation, leading toaccumulation on endosomes, activation of theGTPase Rac1, loss of actin stress fibres andincreased levels of cell migration. Blockingendocytosis inhibited mutants’anchorage-independent growth, in vivotumorigenesis and metastasis while maintainingtheir activation. One mutant resistant toinhibition by a Met-specific tyrosine kinaseinhibitor was sensitive to endocytosis inhibition.Thus, oncogenicity of Met mutants results notonly from activation but also from their alteredendocytic trafficking, indicating that endosomal", "metadata": {}}
+{"_id": "22328290", "title": "", "text": "Immediate effects of droperidolThe subjectiveand behavioural responses of 20 healthyvolunteers taking droperidol 5 mg as part of acognitive challenge programme were catalogued.Some form of akathisia was universallyexperienced. Half of the subjects were dysphoric,but there appeared to be a number of differentinputs to their dysphoria and a range of othereffects were noted, including sedation,dissociative experiences, alterations in sensationand subtle changes in physiognomy. Theduration of these effects varied from a few hoursto over a week. In the acute phase, insight as tothe origin of what was happening was mixed.The results have implications for theinterpretation of cognitive challenge tests, thenature of akathisia, clinical therapeutics and drugdevelopment. © 1998 John Wiley & Sons, Ltd.", "metadata": {}}
+{"_id": "22334300", "title": "", "text": "Toxicity of Nerium oleander in the monkey(Cebus apella).The toxic effects of Neriumoleander were evaluated in capuchin monkeys(Cebus apella) by examination of clinical signs,hematologic and serum chemical values, andgross and microscopic lesions. Dried and groundoleander leaves were given at intervals of 48 h indoses of 30, 7.5, and 3 mg/kg body weight. Thecumulative lethal dose ranged from 30 to 60mg/kg body weight in monkeys that were givendoses of 30 and 7.5 mg/kg body weight.Monkeys that received doses of 3 mg/kg bodyweight (total cumulative dose: 60 mg/kg)survived. Clinical signs were vomiting, salivation,polyuria, bradycardia, vaginal hemorrhage,abortion, anorexia, constipation, loss of bodyweight, narcosis, restlessness, weakness, andshallow and rapid respirations. Changes in bloodvalues were leukocytosis; neutrophilia; increasedpotassium, glutamic-oxalacetic transaminase,glutamic-pyruvic transaminase, blood ureanitrogen and α-globulins; reticulo-cytopenia; and", "metadata": {}}
+{"_id": "22358449", "title": "", "text": "Plzf regulates limb and axial skeletalpatterningThe promyelocytic leukaemia zincfinger (Plzf) protein (encoded by the geneZfp145) belongs to the POZ/zinc-finger family oftranscription factors. Here we generateZfp145−/− mice and show that Plzf is essentialfor patterning of the limb and axial skeleton. Plzfinactivation results in patterning defects affectingall skeletal structures of the limb, includinghomeotic transformations of anterior skeletalelements into posterior structures. Wedemonstrate that Plzf acts as a growth-inhibitoryand pro-apoptotic factor in the limb bud. Theexpression of members of the abdominal b(Abdb) Hox gene complex, as well as genesencoding bone morphogenetic proteins (Bmps),is altered in the developing limb of Zfp145−/−mice. Plzf regulates the expression of thesegenes in the absence of aberrant polarizingactivity and independently of known patterninggenes. Zfp145−/− mice also exhibitanterior-directed homeotic transformation", "metadata": {}}
+{"_id": "22362025", "title": "", "text": "Requirement for the ERI/DICER complex inendogenous RNA interference and spermdevelopment in Caenorhabditis elegans.Smallregulatory RNAs are key regulators of geneexpression. One class of small regulatory RNAs,termed the endogenous small interfering RNAs(endo siRNAs), is thought to negatively regulatecellular transcripts via an RNA interference(RNAi)-like mechanism termed endogenous RNAi(endo RNAi). A complex of proteins composed ofERI-1/3/5, RRF-3, and DICER (the ERI/DICERcomplex) mediates endo RNAi processes inCaenorhabditis elegans. We conducted a geneticscreen to identify additional components of theendo RNAi machinery. Our screen recoveredalleles of eri-9, which encodes a novelDICER-interacting protein, and a missensemutation within the helicase domain of DICER[DCR-1(G492R)]. ERI-9(-) and DCR-1(G492)animals exhibit defects in endo siRNA expressionand a concomitant failure to regulate mRNAsthat exhibit sequence homology to these endo", "metadata": {}}
+{"_id": "22371455", "title": "", "text": "Drug-induced thrombocytopenia: pathogenesis,evaluation, and management.Although drugs area common cause of acute immune-mediatedthrombocytopenia in adults, the drug etiology isoften initially unrecognized. Most cases ofdrug-induced thrombocytopenia (DITP) arecaused by drug-dependent antibodies that arespecific for the drug structure and bind tightly toplatelets by their Fab regions but only in thepresence of the drug. A comprehensive databaseof 1301 published reports describing 317 drugs,available at www.ouhsc.edu/platelets, providesinformation on the level of evidence for a causalrelation to thrombocytopenia. Typically, DITPoccurs 1 to 2 weeks after beginning a new drugor suddenly after a single dose when a drug haspreviously been taken intermittently. However,severe thrombocytopenia can occur immediatelyafter the first administration of antithromboticagents that block fibrinogen binding to plateletGP IIb-IIIa, such as abciximab, tirofiban, andeptifibatide. Recovery from DITP usually begins", "metadata": {}}
+{"_id": "22401061", "title": "", "text": "Costs and financial feasibility of malariaeliminationThe marginal costs and benefits ofconverting malaria programmes from a control toan elimination goal are central to strategicdecisions, but empirical evidence is scarce. Wepresent a conceptual framework to assess theeconomics of elimination and analyse a centralcomponent of that framework-potentialshort-term to medium-term financial savings.After a review that showed a dearth of existingevidence, the net present value of elimination infive sites was calculated and compared witheffective control. The probability that eliminationwould be cost-saving over 50 years ranged from0% to 42%, with only one site achievingcost-savings in the base case. These findingsshow that financial savings should not be aprimary rationale for elimination, but thatelimination might still be a worthy investment iftotal benefits are sufficient to outweigh marginalcosts. Robust research into these eliminationbenefits is urgently needed.", "metadata": {}}
+{"_id": "22401720", "title": "", "text": "Expression of the angiogenic factors vascularendothelial cell growth factor, acidic and basicfibroblast growth factor, tumor growth factorbeta-1, platelet-derived endothelial cell growthfactor, placenta growth factor, and pleiotrophinin human primary breast cancer and its relationto angiogenesAngiogenesis is a significantprognostic factor in breast cancer, but thefactors that control angiogenesis in vivo are notwell defined. Multiple angiogenic polypeptidesare known, and we have determined theexpression of seven of these in primary humanbreast cancers; the relationship of expression toestrogen receptor and vascular density was alsoexamined. Vascular endothelial growth factor(VEGF) and its four isoforms (121, 165, 189, and206 amino acids), transforming growth factor(TGF)-beta1, pleiotrophin, acidic and basicfibroblast growth factor (FGF), placental growthfactor, and thymidine phosphorylase(platelet-derived endothelial cell growth factor)were quantitated by RNase protection analysis.", "metadata": {}}
+{"_id": "22405338", "title": "", "text": "Cnn1 inhibits the interactions between the KMNcomplexes of the yeast kinetochoreKinetochoresattach the replicated chromosomes to the mitoticspindle and orchestrate their transmission to thedaughter cells. Kinetochore–spindle binding andchromosome segregation are mediated by themulti-copy KNL1Spc105, MIS12Mtw1 andNDC80Ndc80 complexes that form the so-calledKMN network. KMN–spindle attachment isregulated by the Aurora BIpl1 and MPS1Mps1kinases. It is unclear whether other mechanismsexist that support KMN activity during the cellcycle. Using budding yeast, we show thatkinetochore protein Cnn1 localizes to the base ofthe Ndc80 complex and promotes a functionallycompetent configuration of the KMN network.Cnn1 regulates KMN activity in a spatiotemporalmanner by inhibiting the interaction between itscomplexes. Cnn1 activity peaks in anaphase andis driven by the Cdc28, Mps1 and Ipl1 kinases.", "metadata": {}}
+{"_id": "22406695", "title": "", "text": "Origin and functions of tissuemacrophages.Macrophages are distributed intissues throughout the body and contribute toboth homeostasis and disease. Recently, it hasbecome evident that most adult tissuemacrophages originate during embryonicdevelopment and not from circulatingmonocytes. Each tissue has its own compositionof embryonically derived and adult-derivedmacrophages, but it is unclear whethermacrophages of distinct origins are functionallyinterchangeable or have unique roles at steadystate. This new understanding also promptsreconsideration of the function of circulatingmonocytes. Classical Ly6c(hi) monocytes patrolthe extravascular space in resting organs, andLy6c(lo) nonclassical monocytes patrol thevasculature. Inflammation triggers monocytes todifferentiate into macrophages, but whetherresident and newly recruited macrophagespossess similar functions during inflammation isunclear. Here, we define the tools used for", "metadata": {}}
+{"_id": "22414304", "title": "", "text": "Treatment outcome of an unselected cohort oftuberculosis patients in relation to humanimmunodeficiency virus serostatus in ZombaHospital, Malawi.There is little information abouttreatment outcome in patients withsmear-negative pulmonary tuberculosis (PTB) orextrapulmonary tuberculosis (EPTB) treatedunder routine programme conditions insubsaharan Africa. A prospective study wascarried out to determine treatment outcome inan unselected cohort of TB patients admitted toZomba General Hospital, Malawi. Eight hundredand twenty-seven adult TB patients (451 menand 376 women) were registered between 1 Julyand 31 December 1995. Standardized treatmentoutcomes of treatment completion, death,default, and transfer to another district wereassessed in relation to type of TB, humanimmunodeficiency virus (HIV) serostatus, ageand gender. Two hundred and fifty-four patients(31%) died by the end of treatment, half of thedeaths occurring in the first month. Death rates", "metadata": {}}
+{"_id": "22420524", "title": "", "text": "Statin use and risk of gallstone disease followedby cholecystectomy.CONTEXT Gallstone diseaseis a leading cause of morbidity in westerncountries and carries a high economic burden.Statins decrease hepatic cholesterol biosynthesisand may therefore lower the risk of cholesterolgallstones by reducing the cholesterolconcentration in the bile. Data on this associationin humans are scarce. OBJECTIVE To study theassociation between the use of statins, fibrates,or other lipid-lowering agents and the risk ofincident gallstone disease followed bycholecystectomy. DESIGN, SETTING, ANDPARTICIPANTS Case-control analysis using theUK-based General Practice Research Database.Incident patients between 1994 and 2008 and 4controls per each patient were identified andmatched on age, sex, general practice, calendartime, and years of history in the database. Thestudy population was 76% women and the mean(SD) age was 53.4 (15.0) years at the indexdate. Conditional logistic regression was used to", "metadata": {}}
+{"_id": "22428640", "title": "", "text": "Chromatin remodeling in embryonic stem cells:regulating the balance between pluripotency anddifferentiation.Embryonic stem cells have anunlimited potential for self-renewal yet arepluripotent, capable of differentiating into threedifferent germ layers and ultimately into multiplecell lineages. Key pluripotency specific factorsmaintain an undifferentiated ES cell phenotypewhile lineage specific factors work in oppositionto promote cell specialization. In addition tothese important transcriptional regulators,epigenetic modifiers play a defining role inregulating the balance between pluripotency anddifferentiation by promoting changes inchromatin structure.", "metadata": {}}
+{"_id": "22431418", "title": "", "text": "The National Advisory Group on Immunization(NAGI) of the Republic of South Africa.TheNational Immunization Technical Advisory Group(NITAG) in South Africa, known as the NationalAdvisory Group on Immunization (NAGI), wasestablished in 1993 to advise the NationalDepartment of Health (DoH) on issues related tovaccination. Meetings are held as needed but atleast twice a year. The scope includes vaccinesand immunization and other relevant infectiousdisease issues. NAGI also makesrecommendations on vaccine schedules andformulations. Agendas are set by DoH and theChairman of NAGI. NAGI brings together expertsfrom a range of different fields relevant tovaccines and vaccinations and has been animportant resource for guiding the ExpandedProgram of Immunization (EPI) in South Africa.", "metadata": {}}
+{"_id": "22442133", "title": "", "text": "Effect of n-3 long chain polyunsaturated fattyacid supplementation in pregnancy on infants’allergies in first year of life: randomisedcontrolled trialOBJECTIVE To determine whetherdietary n-3 long chain polyunsaturated fatty acid(LCPUFA) supplementation of pregnant womenwith a fetus at high risk of allergic diseasereduces immunoglobulin E associated eczema orfood allergy at 1 year of age. DESIGN Follow-upof infants at high hereditary risk of allergicdisease in the Docosahexaenoic Acid to OptimiseMother Infant Outcome (DOMInO) randomisedcontrolled trial. SETTING Adelaide, SouthAustralia. PARTICIPANTS 706 infants at highhereditary risk of developing allergic diseasewhose mothers were participating in the DOMInOtrial. INTERVENTIONS The intervention group(n=368) was randomly allocated to receive fishoil capsules (providing 900 mg of n-3 LCPUFAdaily) from 21 weeks' gestation until birth; thecontrol group (n=338) received matchedvegetable oil capsules without n-3 LCPUFA. MAIN", "metadata": {}}
+{"_id": "22444939", "title": "", "text": "ModLoop: automated modeling of loops inprotein structures.SUMMARY ModLoop is a webserver for automated modeling of loops inprotein structures. The input is the atomiccoordinates of the protein structure in the ProteinData Bank format, and the specification of thestarting and ending residues of one or moresegments to be modeled, containing no morethan 20 residues in total. The output is thecoordinates of the non-hydrogen atoms in themodeled segments. A user provides the input tothe server via a simple web interface, andreceives the output by e-mail. The server relieson the loop modeling routine in MODELLER thatpredicts the loop conformations by satisfaction ofspatial restraints, without relying on a databaseof known protein structures. For a rapidresponse, ModLoop runs on a cluster of Linux PCcomputers. AVAILABILITY The server is freelyaccessible to academic users athttp://salilab.org/modloop", "metadata": {}}
+{"_id": "22446093", "title": "", "text": "What is the best way to help caregivers in cancerand palliative care? A systematic literaturereview of interventions and theireffectiveness.Informal carers in cancer andpalliative care are known to have high needs andpsychological morbidity, yet a literature reviewidentified few targeted interventions. Thissystematic review of interventions for carers ofpatients using home cancer and palliative careservices searched Medline, CancerLit, Psycinfoand Cinahl databases. The terms used werecarer(s), caregiver(s), palliative and cancer.Papers that reported interventions for adultsactively providing informal care fornoninstitutionalized cancer and palliative carepatients were reviewed. Twenty-twointerventions were identified, comprising homenursing care (four), respite services (three),social networks and activity enhancement (two),problem solving and education (three) and groupwork (10). Of these, nine were delivered solelyto carers (i.e., were targeted services). Only six", "metadata": {}}
+{"_id": "22467585", "title": "", "text": "Brief Internet-Based Intervention ReducesPosttraumatic Stress and Prolonged Grief inParents after the Loss of a Child duringPregnancy: A Randomized ControlledTrialBackground: The loss of a child duringpregnancy causes significant psychologicaldistress for many women and their partners, andmay lead to long-lasting psychiatric disorders.Internet-based interventions using exposuretechniques and cognitive restructuring haveproved effective for posttraumatic stress disorder(PTSD) and prolonged grief. This study comparedthe effects of an Internet-based intervention forparents after prenatal loss with a waiting listcondition (WLC). Methods: The Impact of EventScale - Revised assessed symptoms of PTSD; theInventory of Complicated Grief and the BriefSymptom Inventory assessed depression,anxiety, and general mental health. The 228participants (92% female) were randomlyallocated to a treatment group (TG; n = 115) ora WLC group (n = 113). The TG received a", "metadata": {}}
+{"_id": "22478394", "title": "", "text": "Up-regulation of PPAR-gamma mRNA expressionin the liver of obese patients: an additionalreinforcing lipogenic mechanism to SREBP-1cinduction.INTRODUCTION Triglycerideaccumulation in the liver is an early feature inthe development of nonalcoholic fatty liverdisease (NAFLD) associated with human obesity,which is a multifactorial syndrome and whoseunderlying mechanisms are beginning to beunderstood. OBJECTIVES Liver peroxisomeproliferator-activated receptor-γ (PPAR-γ) mRNAexpression was measured as a signalingmechanism related to steatosis in obese patientswith NAFLD. METHODS Liver PPAR-γ and sterolreceptor element-binding protein 1c (SREBP-1c)mRNA (real-time RT-PCR), serum totaladiponectin (RIA), and high molecular weight(HMW)-adiponectin (ELISA) levels, and insulinresistance (IR) evolution (homeostasis modelassessment-IR) were determined in 22 obeseNAFLD patients (16 with steatosis and six withsteatohepatitis) who underwent subtotal", "metadata": {}}
+{"_id": "22482024", "title": "", "text": "Ribosomal protein S17 gene (RPS17) is mutatedin Diamond-Blackfan anemia.Diamond-Blackfananemia (DBA) is a congenital erythroid aplasiacharacterized as a normochromic macrocyticanemia with a selective deficiency in red bloodcell precursors in otherwise normocellular bonemarrow. In 40% of DBA patients, variousphysical anomalies are also present. Currentlytwo genes are associated with the DBAphenotype--the ribosomal protein (RP) S19mutated in 25% of DBA patients and RPS24mutated in approximately 1.4% of DBA patients.Here we report the identification of a mutation inyet another ribosomal protein, RPS17. Themutation affects the translation initiation startcodon, changing T to G (c.2T>G), thuseliminating the natural start of RPS17 proteinbiosynthesis. RNA analysis revealed that themutated allele was expressed, and the nextdownstream start codon located at position +158should give rise to a short peptide of only fouramino acids (Met-Ser-Arg-Ile). The mutation", "metadata": {}}
+{"_id": "22482820", "title": "", "text": "An overview of the effective combinationtherapies for the treatment of breastcancer.Breast cancer (BC) is generally classifiedbased on the receptors overexpressed on the cellnucleus, which include hormone receptors suchas progesterone (PR) and estrogen (ER), andHER2. Triple-negative breast cancer (TNBC) is atype of cancer that lacks any of these threetypes of receptor proteins (ER/PR/HER2). Tumorcells exhibit drug resistant phenotypes thatdecrease the efficacy of chemotherapeutictreatments. Generally, drug resistance has agenetic basis that is caused by an abnormal geneexpression, nevertheless, there are several typesof drug resistance: efflux pumps reducing thecellular concentration of the drug, alterations inmembrane lipids that reduce cellular uptake,increased or altered drug targets, metabolicalteration of the drug, inhibition of apoptosis,repair of the damaged DNA, and alteration of thecell cycle checkpoints. The use of \"combinationtherapy\" is recognized as an efficient solution to", "metadata": {}}
+{"_id": "22483580", "title": "", "text": "Disturbed sleep in bipolar disorder is related toan elevation of IL-6 in peripheralmonocytes.Bipolar disorder is a severepsychiatric disorder that is associated withpersistent changes in the quality, duration andarchitecture of sleep. Currently there is nounifying hypothesis explaining the alterations insleep observable in patients with bipolar disorderand management is often difficult though vital.Sleep is modified by various cytokines includingIL-6. Elevated levels of IL-6 are associated witha poorer quality of sleep and changes in thearchitecture of sleep similar to those observed inbipolar disorder. Therapeutic administration ofInterferon causes elevations of intrathecal IL-6concentrations and appears to provoke adeteriorating quality of sleep. The blockade ofIL-6 with tocilizumab in rheumatoid arthritis isassociated with improvements in the quality ofsleep. Bipolar disorder is associated withelevated levels of IL-6 and in particular elevatedlevels of mRNA coding for IL-6 in peripheral", "metadata": {}}
+{"_id": "22488511", "title": "", "text": "Targeted blockade of TGF-β andIL-6/JAK2/STAT3 pathways inhibits lung cancergrowth promoted by bone marrow-derivedmyofibroblastsTo investigate the role of TGF-βand IL-6 in myofibroblasts (MFs) - lung cancercell interactions, lung cancer cells (Lewis andCTM-167 cell lines) were stimulated by IL-6,MF-conditioned medium (MF-CM) or MFs, with orwithout TGF-β signaling inhibitor - SB431542and/or JAK2/STAT3 inhibitor - JSI-124. MFs werestimulated by TGF-β, cancer cell-CM or cancercells, with or without SB431542 and JSI-124.Cell proliferation, the levels of cytokines,expression of mRNA and protein weredetermined. Mice bearing xenograft tumors wereintraperitoneally treated with SB431542 orJSI-124 and monitored for up to 45 days. Inco-culture systems, MFs secreted high levels ofIL-6, while cancer cells produced high levels ofTGF-β. Recombinant IL-6 and MF-CM activatedSTAT3 and upregulated TGF-β in cancer cells. Incontrast, cancer cell-CM or TGF-β stimulated MFs", "metadata": {}}
+{"_id": "22490293", "title": "", "text": "Production of cloned mice and ES cells from adultsomatic cells by nuclear transfer: how to improvecloning efficiency?Although it has now been 10years since the first cloned mammals weregenerated from somatic cells using nucleartransfer (NT), most cloned embryos usuallyundergo developmental arrest prior to or soonafter implantation, and the success rate forproducing live offspring by cloning remains below5%. The low success rate is believed to beassociated with epigenetic errors, includingabnormal DNA hypermethylation, but themechanism of \"reprogramming\" is unclear. Wehave been able to develop a stable NT method inthe mouse in which donor nuclei are directlyinjected into the oocyte using a piezo-actuatedmicromanipulator. Especially in the mouse, onlya few laboratories can make clones from adultsomatic cells, and cloned mice are neversuccessfully produced from most mouse strains.However, this technique promises to be animportant tool for future research in basic", "metadata": {}}
+{"_id": "22495397", "title": "", "text": "Recruitment of Tat to heterochromatin proteinHP1 via interaction with CTIP2 inhibits humanimmunodeficiency virus type 1 replication inmicroglial cells.The Tat protein of humanimmunodeficiency virus type 1 (HIV-1) plays akey role as inducer of viral gene expression. Wereport that Tat function can be potently inhibitedin human microglial cells by the recentlydescribed nuclear receptor cofactor chickenovalbumin upstream promoter transcriptionfactor-interacting protein 2 (CTIP2).Overexpression of CTIP2 leads to repression ofHIV-1 replication, as a result of inhibition ofTat-mediated transactivation. In contrast, therelated CTIP1 was unable to affect Tat functionand viral replication. Using confocal microscopyto visualize Tat subcellular distribution in thepresence of the CTIPs, we found thatoverexpression of CTIP2, and not of CTIP1, leadsto disruption of Tat nuclear localization andrecruitment of Tat within CTIP2-induced nuclearball-like structures. In addition, our studies", "metadata": {}}
+{"_id": "22500262", "title": "", "text": "Cryptochrome Mediates Circadian Regulation ofcAMP Signaling and HepaticGluconeogenesisDuring fasting, mammalsmaintain normal glucose homeostasis bystimulating hepatic gluconeogenesis. Elevationsin circulating glucagon and epinephrine, twohormones that activate hepatic gluconeogenesis,trigger the cAMP-mediated phosphorylation ofcAMP response element-binding protein (Creb)and dephosphorylation of the Creb-regulatedtranscription coactivator-2 (Crtc2)--two keytranscriptional regulators of this process.Although the underlying mechanism is unclear,hepatic gluconeogenesis is also regulated by thecircadian clock, which coordinates glucosemetabolism with changes in the externalenvironment. Circadian control of geneexpression is achieved by two transcriptionalactivators, Clock and Bmal1, which stimulatecryptochrome (Cry1 and Cry2) and Period (Per1,Per2 and Per3) repressors that feed back onClock-Bmal1 activity. Here we show that Creb", "metadata": {}}
+{"_id": "22505190", "title": "", "text": "Toll-like receptor 4 gene Asp299Glypolymorphism in myocardial infarction: ameta-analysis of 15,148 subjects.It remainscontroversial regarding the association betweentoll-like receptor 4 (TLR4) gene Asp299Gly(+896 A/G) polymorphism and myocardialinfarction (MI) risk. Thus, a large-scalemeta-analysis evaluating the potentialassociation between this gene variant and MI riskis required. PubMed, Embase, Web of Science,CBMdisc, CNKI, and Google Scholar weresearched until February 6, 2013. All thestatistical tests were performed using Stata 11.0.Nine articles involving 10 studies were includedin the final meta-analysis, covering a total of8299 MI cases and 6849 controls. Overall, nosignificant association was found between theTLR4 gene Asp299Gly polymorphism and MI risk(G allele vs. A allele: OR=0.95, 95%CI=0.74-1.22, p=0.71; G/G vs. A/A: OR=1.03,95% CI=0.54-1.98, p=0.93; G/G vs. A/G+A/A:OR=1.05, 95% CI=0.55-2.03, p=0.87; G/G+A/G", "metadata": {}}
+{"_id": "22505710", "title": "", "text": "Matrix metalloproteinase and proinflammatorycytokine production by chondrocytes of humanosteoarthritic cartilage: associations withdegenerative changes.OBJECTIVE To examine byimmunohistochemistry the relative distributionsof 6 matrix metalloproteinases (MMPs 1, 2, 3, 8,9, and 13) and the 2 proinflammatory cytokinesinterleukin-1beta (IL-1beta) and tumor necrosisfactor alpha (TNFalpha) in osteoarthritic (OA)cartilage compared with normal, age-matchedarticular cartilage. METHODS Articular cartilagesamples were obtained from the tibial plateau ofOA knees removed at arthroplasty and fromnormal, nonarthritic, knees obtained at autopsy.Specimens were promptly fixed in Carnoy'sfixative, processed, embedded in paraffin,sectioned, and examined byimmunohistochemistry for MMP and cytokineproduction. In addition, human articularchondrocytes (HAC) were treated in vitro witheither IL-1beta, TNFalpha, or phorbol myristateacetate (PMA) to assess their potential to", "metadata": {}}
+{"_id": "22509015", "title": "", "text": "β-catenin-independent WNT signaling inbasal-like breast cancer and brain metastasis.Arole of WNT signaling for primary breast cancersof the basal-like subtype and as a predictor ofbrain metastasis has been described. However, aresponsible WNT ligand has not been identified.To further clarify this question, we comparativelyinvestigated 22 human breast cancer brainmetastases as well as the highly invasive humanbreast cancer cell line MDA-MB-231 and theweakly motile MCF-7 as models for the basal-likeand the luminal A subtype. WNT5A and B werefound overexpressed in MDA-MB-231 cells ascompared with MCF-7. This corresponded toreduction of MDA-MB-231 invasiveness by WNTinhibitors, whereas MCF-7 invasion wasenhanced by recombinant WNT5B and abolishedby WNT and Jun-N-terminal kinase antagonists.Expression and subcellular distribution ofβ-catenin remained uninfluenced. Consistently,β-catenin was not localized in the nuclei of brainmetastases while there was strong nuclear c-Jun", "metadata": {}}
+{"_id": "22517564", "title": "", "text": "Retinal attenuates inflammatory arthritis byreciprocal regulation of IL-17-producing T cellsand Foxp3(+) regulatory T cells and theinhibition of osteoclastogenesis.Retinoids (e.g.,vitamin A and its derivatives) can regulateimmune responses. The aim of this study was todetermine whether all-trans retinaldehyde(retinal), a vitamin A derivative, can inhibitinflammatory responses and joint destruction inDBA/1J mice with collagen-induced arthritis(CIA). The arthritis score and incidence ofarthritis were lower in mice treated with retinalcompared to those treated with cottonseed oil.Histopathologic evidence of joint damage waslower in mice treated with retinal, correspondingwith a reduction in the infiltration of immunecells in mice treated with retinal type II collagen(CII)-stimulated spleen cells. In addition, theexpression of proinflammatory cytokines,oxidative stress proteins, and osteoclast markerswere significantly reduced in mice treated withretinal. In vitro, retinal induced increased Foxp3", "metadata": {}}
+{"_id": "22521091", "title": "", "text": "NRAGE promotes the malignant phenotype ofhepatocellular carcinoma.Hepatocellularcarcinoma (HCC) is a fatal disease, primarily dueto the limited effective therapies available forpatients with advanced or recurrent stages of thedisease. Therefore, in order to improve patientprognosis, it is important to identify aninformative biomarker for HCC progression, aswell as a molecular target for therapy.Neurotrophin receptor-interacting melanomaantigen-encoding protein (NRAGE), a member ofthe type II melanoma-associated antigen family,mediates apoptosis and cell death throughinteractions with a wide range of proteins, and isimplicated as a tumor suppressor or oncoproteindepending on cell type. However, the role ofNRAGE in HCC is currently unknown, therefore,the present study aimed to identify theunderlying function of NRAGE in HCCtumorigenesis. Resected tumor andnon-cancerous liver tissues from 151 patientswith HCC, alongside HCC cell lines, were", "metadata": {}}
+{"_id": "22522432", "title": "", "text": "Regulation of ISW2 by concerted action ofhistone H4 tail and extranucleosomal DNA.Thestable contact of ISW2 with nucleosomal DNAapproximately 20 bp from the dyad was shownby DNA footprinting and photoaffinity labelingusing recombinant histone octamers to requirethe histone H4 N-terminal tail. Efficient ISW2remodeling also required the H4 N-terminal tail,although the lack of the H4 tail can be mostlycompensated for by increasing the incubationtime or concentration of ISW2. Similarly, thelength of extranucleosomal DNA affected thestable contact of ISW2 with this same internalnucleosomal site, with the optimal length being70 to 85 bp. These data indicate the histone H4tail, in concert with a favorable length ofextranucleosomal DNA, recruits and properlyorients ISW2 onto the nucleosome for efficientnucleosome remodeling. One consequence ofthis property of ISW2 is likely its previouslyobserved nucleosome spacing activity.", "metadata": {}}
+{"_id": "22530842", "title": "", "text": "Embryonic Stem Cells for Severe Heart Failure:Why and How?The experience accumulated incardiac cell therapy suggests that regenerationof extensively necrotic myocardial areas isunlikely to be achieved by the sole paracrineeffects of the grafted cells but rather requires theconversion of these cells into cardiomyocytesfeaturing the capacity to substitute for thosewhich have been irreversibly lost. In this setting,the use of human pluripotent embryonic stemcells has a strong rationale. The experimentalresults obtained in animal models of myocardialinfarction are encouraging. However, the switchto clinical applications still requires to addresssome critical issues, among which theoptimization of the cardiac specification of theembryonic stem cells, the purification of theresulting progenitor cells so as to graft a purifiedpopulation devoid from any contamination byresidual pluripotent cells which carry the risk oftumorigenesis, and the control of the expectedallogeneic rejection by clinically acceptable", "metadata": {}}
+{"_id": "22534357", "title": "", "text": "A comparison of letrozole to gonadotropins forovulation induction, in subjects who failed toconceive with clomiphene citrate.OBJECTIVE Tocompare pregnancy rates (PR) for letrozole andgonadotropins in individuals who failed toconceive with clomiphene citrate (CC). DESIGNRetrospective cohort study. SETTING Universityreproductive center. PATIENT(S) Individualstreated with letrozole or gonadotropins whofailed to conceive with CC. INTERVENTION(S)Controlled ovarian hyperstimulation (COH),transvaginal ultrasound, ovulation induction, IUI.MAIN OUTCOME MEASURE(S) Pregnancy ratesper cycle. RESULT(S) Among patients who failedto conceive with at least three cycles of CC,gonadotropins had a higher PR per cycle thanletrozole. Among individuals who failed toconceive with less than three cycles of CC andwhose medications were changed because of thinuterine lining or intolerable side effects, averagePR per cycle for letrozole and gonadotropintreatments were equivalent. All patients", "metadata": {}}
+{"_id": "22543403", "title": "", "text": "Epigenetic mechanisms in neurologicaldiseaseThe exploration of brain epigenomes,which consist of various types of DNAmethylation and covalent histone modifications,is providing new and unprecedented insights intothe mechanisms of neural development,neurological disease and aging. Traditionally,chromatin defects in the brain were consideredstatic lesions of early development that occurredin the context of rare genetic syndromes, but it isnow clear that mutations and maladaptations ofthe epigenetic machinery cover a much widercontinuum that includes adult-onsetneurodegenerative disease. Here, we describehow recent advances in neuroepigenetics havecontributed to an improved mechanisticunderstanding of developmental anddegenerative brain disorders, and we discusshow they could influence the development offuture therapies for these conditions.", "metadata": {}}
+{"_id": "22544171", "title": "", "text": "Reversal of the cellular phenotype in thepremature aging disease Hutchinson-Gilfordprogeria syndromeHutchinson-Gilford progeriasyndrome (HGPS) is a childhood prematureaging disease caused by a spontaneous pointmutation in lamin A (encoded by LMNA), one ofthe major architectural elements of themammalian cell nucleus. The HGPS mutationactivates an aberrant cryptic splice site in LMNApre-mRNA, leading to synthesis of a truncatedlamin A protein and concomitant reduction inwild-type lamin A. Fibroblasts from individualswith HGPS have severe morphologicalabnormalities in nuclear envelope structure. Herewe show that the cellular disease phenotype isreversible in cells from individuals with HGPS.Introduction of wild-type lamin A protein doesnot rescue the cellular disease symptoms. Themutant LMNA mRNA and lamin A protein can beefficiently eliminated by correction of theaberrant splicing event using a modifiedoligonucleotide targeted to the activated cryptic", "metadata": {}}
+{"_id": "22545779", "title": "", "text": "Agouti-related peptide–expressing neurons aremandatory for feedingMultiple hormonescontrolling energy homeostasis regulate theexpression of neuropeptide Y (NPY) andagouti-related peptide (AgRP) in the arcuatenucleus of the hypothalamus. Nevertheless,inactivation of the genes encoding NPY and/orAgRP has no impact on food intake in mice. Herewe demonstrate that induced selective ablationof AgRP-expressing neurons in adult mice resultsin acute reduction of feeding, demonstratingdirect evidence for a critical role of these neuronsin the regulation of energy homeostasis.", "metadata": {}}
+{"_id": "22547508", "title": "", "text": "Predictors of survival after acute paraquatpoisoning.Acute paraquat poisoning is oftenfatal. Many studies have investigated successfultreatment modalities, but no standard treatmentyet exists. The purpose of this study was todetermine the predictors of survival after acuteparaquat poisoning in 602 patients. The paraquatexposure was assessed based on the amount ofingested paraquat and a semiquantitativemeasure of the urine level of paraquat. Initialclinical parameters including vital signs,hemoglobin, white-blood-cell count, pH, PaCO2,PaO2, blood urea nitrogen, creatinine, aspartateaminotransferase, alanine aminotransferase,total bilirubin, amylase, and glucose wereobtained at the time of arrival at the emergencyroom. Outcomes after acute paraquat poisoningwere categorized as survivors and nonsurvivors.Multiple logistic regression analysis was appliedto assess the predictors of survival after acuteparaquat poisoning. Some patients (55.5%)survived after oral ingestion of paraquat,", "metadata": {}}
+{"_id": "22549449", "title": "", "text": "Decreased neurogenesis after cholinergicforebrain lesion in the adult rat.Adultneurogenesis has been shown to be regulated bya multitude of extracellular cues, includinghormones, growth factors, andneurotransmitters. The cholinergic system of thebasal forebrain is one of the key transmittersystems for learning and memory. Because adultneurogenesis has been implicated in cognitiveperformance, the present work aims at definingthe role of cholinergic input for adultneurogenesis by using an immunotoxic lesionapproach. The immunotoxin 192IgG-saporin wasinfused into the lateral ventricle of adult rats toselectively lesion cholinergic neurons of thecholinergic basal forebrain (CBF), which projectto the two main regions of adult neurogenesis:the dentate gyrus and the olfactory bulb. Fiveweeks after lesioning, neurogenesis, defined bythe number of cells colocalized forbromodeoxyuridine (BrdU) and the neuronalnuclei marker NeuN, declined significantly in the", "metadata": {}}
+{"_id": "22551259", "title": "", "text": "DNA Methylation in Major DepressiveDisorder.Epigenetic mechanisms regulate geneexpression, influencing protein levels andultimately shaping phenotypes during life.However, both stochastic epigenetic variationsand environmental reprogramming of theepigenome might influence neurodevelopmentand ageing, and this may contribute to theorigins of mental ill-health. Studying the role ofepigenetic mechanisms is challenging, asgenotype-, tissue- and cell type-dependentepigenetic changes have to be taken intoaccount, while the nature of mental disordersalso poses significant challenges for linking themwith biological profiles. In this chapter, wesummarise the current evidence suggesting therole of DNA methylation as a key epigeneticmechanism in major depressive disorder.", "metadata": {}}
+{"_id": "22561064", "title": "", "text": "Consensus structural features of purifiedbacterial TatABC complexes.The twin-argininetranslocation (Tat) system transports foldedproteins across bacterial plasma membranes andthe chloroplast thylakoid membrane. Here, weinvestigate the composition and structuralorganization of three different purified Tatcomplexes from Escherichia coli, Salmonellatyphimurium and Agrobacterium tumefaciens.First, we demonstrate the functional activity ofthese Tat systems in vivo, since expression ofthe tatABC operons from S.typhimurium orA.tumefaciens in an E.coli tat null mutant strainresulted in efficient Tat-dependent export of anE.coli cofactor-containing substrate, TMAOreductase. The three isolated, affinity-tagged Tatcomplexes comprised TatA, TatB and TatC ineach case, demonstrating a strong interactionbetween these three subunits. Single-particleelectron microscopy studies of all threecomplexes revealed approximately oval-shaped,asymmetric particles with maximal dimensions", "metadata": {}}
+{"_id": "22613657", "title": "", "text": "Advances in graft-versus-host disease biologyand therapyAllogeneic haematopoietic stem celltransplantation is used to treat a variety ofdisorders, but its efficacy is limited by theoccurrence of graft-versus-host disease (GVHD).The past decade has brought impressiveadvances in our understanding of the role ofstimulatory and suppressive elements of theadaptive and innate immune systems from boththe donor and the host in GVHD pathogenesis.New insights from basic immunology, preclinicalmodels and clinical studies have led to novelapproaches for prevention and treatment. ThisReview highlights the recent advances inunderstanding the pathophysiology of GVHD andits treatment, with a focus on manipulations ofthe immune system that are amenable to clinicalapplication.", "metadata": {}}
+{"_id": "22621251", "title": "", "text": "Ly6Chi monocytes direct alternatively activatedprofibrotic macrophage regulation of lungfibrosis.RATIONALE Idiopathic pulmonary fibrosis(IPF) is a devastating disease. Antiinflammatorytherapies, including corticosteroids, are of nobenefit. The role of monocytes and macrophagesis therefore controversial. OBJECTIVES To definethe role of monocytes and macrophages duringlung fibrogenesis and resolution, and explore thephenotype of the cells involved. METHODS Weused multiple in vivo depletional strategies,backed up by adoptive transfer techniques.Further studies were performed on samples frompatients with IPF. MEASUREMENTS AND MAINRESULTS Depletion of lung macrophages duringfibrogenesis reduced pulmonary fibrosis asmeasured by lung collagen (P = 0.0079); fibrosisscore (P = 0.0051); and quantitative polymerasechain reaction for surrogate markers of fibrosisCol1 (P = 0.0083) and a-smooth muscle actin (P= 0.0349). There was an associated reduction inmarkers of the profibrotic alternative", "metadata": {}}
+{"_id": "22623275", "title": "", "text": "A single RNA-dependent RNA polymeraseassembles with mutually exclusive nucleotidyltransferase subunits to direct different pathwaysof small RNA biogenesis.Members of theconserved family of eukaryotic RNA-dependentRNA polymerases (Rdrs) synthesizedouble-stranded RNA (dsRNA) intermediates indiverse pathways of small RNA (sRNA)biogenesis and RNA-mediated silencing.Rdr-dependent pathways of sRNA production arepoorly characterized relative to Rdr-independentpathways, and the Rdr enzymes themselves arepoorly characterized relative to their viralRNA-dependent RNA polymerase counterparts.We previously described a physical andfunctional coupling of the Tetrahymenathermophila Rdr, Rdr1, and a Dicer enzyme,Dcr2, in the production of approximately24-nucleotide (nt) sRNA in vitro. Here wecharacterize the endogenous complexes thatharbor Rdr1, termed RDRCs. Distinct RDRCsassemble to contain Rdr1 and subsets of the", "metadata": {}}
+{"_id": "22632303", "title": "", "text": "Identification of T6SS-dependent effector andimmunity proteins by Tn-seq in Vibriocholerae.Type VI protein secretion system(T6SS) is important for bacterial competitionthrough contact-dependent killing ofcompetitors. T6SS delivers effectors toneighboring cells and corresponding antagonisticproteins confer immunity against effectors thatare delivered by sister cells. Although T6SS hasbeen found in more than 100 gram-negativebacteria including many important humanpathogens, few T6SS-dependent effector andimmunity proteins have been experimentallydetermined. Here we report a high-throughputapproach using transposon mutagenesis anddeep sequencing (Tn-seq) to identify T6SSimmunity proteins in Vibrio cholerae. Saturatingtransposon mutagenesis was performed in wildtype and a T6SS null mutant. Genes encodingimmunity proteins were predicted to be essentialin the wild type but dispensable in the T6SSmutant. By comparing the relative abundance of", "metadata": {}}
+{"_id": "22635278", "title": "", "text": "Immunotherapy of metastatic kidneycancer.From April 1986 to September 2000, 122MRCC patients were treated by monthlyintralymphatic injections (containing a mean of573 IL-2 U and 26 x 10(6) LAK cells) and i.m.administration of IFN and TF; 71 patients alsoreceived a 3-day cycle of monthly IL-2inhalations with a mean of 998 daily U. MRCCcases not treated by immunotherapy (n = 89)represent our historical controls. Adverse clinicalside effects related to treatment were negligible.CR (n = 11) and PR (n = 13) were noticed in24/122 patients. Of 24 responding patients, 17resumed progression, whereas 7 remain inremission 11-69 months later. The overallmedian survival of treated patients (28 months)was 3.5-fold higher than the median survival ofhistorical controls (7.5 months), and aKaplan-Meier curve showed 25% survival 11years after the beginning of immunotherapy.Apparently, the addition of IL-2 by inhalationimproved survival. The present immunotherapy", "metadata": {}}
+{"_id": "22647695", "title": "", "text": "Autoimmune T cell responses in the centralnervous systemAutoreactive T cell responseshave a crucial role in central nervous system(CNS) diseases such as multiple sclerosis. Recentdata indicate that CNS autoimmunity can bemediated by two distinct lineages of CD4+ T cellsthat are defined by the production of eitherinterferon-γ or interleukin-17. The activity ofthese CD4+ T cell subsets within the CNSinfluences the pathology and clinical course ofdisease. New animal models show thatmyelin-specific CD8+ T cells can also mediateCNS autoimmunity. This Review focuses onrecent progress in delineating the pathogenicmechanisms, regulation and interplay betweenthese different T cell subsets in CNSautoimmunity.", "metadata": {}}
+{"_id": "22674621", "title": "", "text": "Effects of FXR in foam-cell formation andatherosclerosis development.Farnesoid Xreceptor (FXR), a bile-acid-activated member ofthe nuclear receptor superfamily, is essential inregulating bile-acid, cholesterol, and triglyceridehomeostasis. Disruption of the FXR gene in miceresults in a proatherosclerotic lipid profile withincreased serum cholesterols and triglycerides.However, the role of FXR in foam-cell formationand atherosclerosis development remainsunclear. The current study showed that theperitoneal macrophages isolated from FXR-nullmice took up less oxidized LDL-cholesterol(oxLDL-C), which was accompanied by a markedreduction in CD36 expression in these cells. Thisresult appears to be FXR-independent, as FXRwas not detected in the peritoneal macrophages.To assess to what extent FXR modulatesatherosclerosis development, FXR/ApoEdouble-null mice were generated. Female micewere used for atherosclerosis analysis.Compared to ApoE-null mice, the FXR/ApoE", "metadata": {}}
+{"_id": "22682497", "title": "", "text": "Purkinje cell compartments in the reeler mutantmouse as revealed by Zebrin II and90-acetylated glycolipid antigen expressionThecerebellum is organized into a series ofparasagittally aligned bands that may berevealed histologically in the adult mouse bylargely complementary immunostaining ofPurkinje cell sets with the monoclonal antibodiesZebrin II (ZII; antigen:aldolase C) and P-path(PP; antigen:90-acetyl glycolipids). Wecompared the normal staining pattern usingthese markers and an antibody to calbindin withthat found in the reeler mutants (rl/rl), in whichmost Purkinje cell migration is halted beneaththe cerebellar white matter. The results revealedthat Purkinje cells in reeler mutants, despitetheir ectopic location in large subcortical masses,show a clear tendency to distribute intoalternating zones that either stain for Zebrin II orfor P-path, with variable transition zones ofmixed labeling. However, the estimated numberof zones was fewer than in the normal adult", "metadata": {}}
+{"_id": "22688699", "title": "", "text": "Awake craniotomy with brain mapping as theroutine surgical approach to treating patientswith supratentorial intraaxial tumors: aprospective trial of 200 cases.OBJECT Awakecraniotomy was performed as the standardsurgical approach to supratentorial intraaxialtumors, regardless of the involvement ofeloquent cortex, in a prospective trial of 200patients surgically treated by the same surgeonat a single institution. METHODS Patientpresentations, comorbid conditions, tumorlocations, and the histological characteristics oflesions were recorded. Brain mapping waspossible in 195 (97.5%) of 200 patients. Thetotal number of patients sustaining complicationswas 33 for an overall complication rate of 16.5%.There were two deaths in this series, for amortality rate of 1%. New postoperativeneurological deficits were seen in 13% of thepatients, but these were permanent in only 4.5%of them. Complication rates were higher inpatients who had gliomas or preoperative", "metadata": {}}
+{"_id": "22696649", "title": "", "text": "Reactive Oxygen Species Localization ProgramsInflammation to Clear Microbes of DifferentSizeHow the number of immune cells recruited tosites of infection is determined and adjusted todifferences in the cellular stoichiometry betweenhost and pathogen is unknown. Here, we haveuncovered a role for reactive oxygen species(ROS) as sensors of microbe size. By sensing thedifferential localization of ROS generated inresponse to microbes of different size,neutrophils tuned their interleukin (IL)-1βexpression via the selective oxidation of NF-κB,in order to implement distinct inflammatoryprograms. Small microbes triggered ROSintracellularly, suppressing IL-1β expression tolimit neutrophil recruitment as each phagocyteeliminated numerous pathogens. In contrast,large microbes triggered ROS extracellularly,amplifying IL-1β expression to recruit numerousneutrophils forming cooperative clusters. Defectsin ROS-mediated microbe size sensing resultedin large neutrophil infiltrates and clusters in", "metadata": {}}
+{"_id": "22703082", "title": "", "text": "Helicobacter pylori infection triggers aberrantexpression of activation-induced cytidinedeaminase in gastric epitheliumInfection withHelicobacter pylori (H. pylori) is a risk factor forthe development of gastric cancer. Here we showthat infection of gastric epithelial cells with 'cag'pathogenicity island (cagPAI)-positive H. pyloriinduced aberrant expression ofactivation-induced cytidine deaminase (AID), amember of the cytidine-deaminase family thatacts as a DNA- and RNA-editing enzyme, via theIκB kinase–dependent nuclear factor-κBactivation pathway. H. pylori–mediatedupregulation of AID resulted in the accumulationof nucleotide alterations in the TP53 tumorsuppressor gene in gastric cells in vitro. Ourfindings provide evidence that aberrant AIDexpression caused by H. pylori infection might bea mechanism of mutation accumulation in thegastric mucosa during H. pylori–associatedgastric carcinogenesis.", "metadata": {}}
+{"_id": "22705234", "title": "", "text": "The role of the immune response during SIVagminfection of the African green monkey naturalhost.The African green monkey (AGM) is one ofmany African species endemically infected withsimian immunodeficiency virus (SIV). Like theother natural hosts, AGMs do not succumb toAIDS and understanding the basis for thisresistance to disease progression would be ofenormous theoretical and practical importance.Early efforts by our group that concentrated onidentifying immune mechanisms presumed tokeep the virus under control failed to find anyobvious candidates. The presumption of viruscontrol was invalidated by the finding thatSIVagm replicates in AGMs with the same vigoras HIV-1 does in humans. Focus thereforeshifted to identifying possible immunopathologicfeatures present in disease susceptible hosts butabsent in the AGM natural host. The apparentimmunologic tolerance of AGMs to the SIVagmcore protein led to the development of ahypothesis implicating anti-Gag antibodies in the", "metadata": {}}
+{"_id": "22707413", "title": "", "text": "The S-LANSS score for identifying pain ofpredominantly neuropathic origin: validation foruse in clinical and postal research.This articledescribes the development and validation of theS-LANSS score, a self-report version of the LeedsAssessment of Neuropathic Symptoms and Signspain scale. The S-LANSS aims to identify pain ofpredominantly neuropathic origin, as distinctfrom nociceptive pain, without the need forclinical examination. Two hundred patients withchronic pain were asked to complete theS-LANSS unaided. A researcher thenadministered the S-LANSS scale and theNeuropathic Pain Scale (NPS) in interviewformat. An independent clinician determined thepain type (neuropathic versus nociceptive) andrated his or her certainty about diagnosis. TheS-LANSS scale was also incorporated into achronic pain questionnaire that was sent to 160community patients and 150 newly referredpatients waiting for pain clinic assessment. TheS-LANSS scale correctly identified 75% of pain", "metadata": {}}
+{"_id": "22711954", "title": "", "text": "Bias in meta-analysis detected by a simple,graphical test.OBJECTIVE Funnel plots (plots ofeffect estimates against sample size) may beuseful to detect bias in meta-analyses that werelater contradicted by large trials. We examinedwhether a simple test of asymmetry of funnelplots predicts discordance of results whenmeta-analyses are compared to large trials, andwe assessed the prevalence of bias in publishedmeta-analyses. DESIGN Medline search toidentify pairs consisting of a meta-analysis and asingle large trial (concordance of results wasassumed if effects were in the same directionand the meta-analytic estimate was within 30%of the trial); analysis of funnel plots from 37meta-analyses identified from a hand search offour leading general medicine journals 1993-6and 38 meta-analyses from the second 1996issue of the Cochrane Database of SystematicReviews. MAIN OUTCOME MEASURE Degree offunnel plot asymmetry as measured by theintercept from regression of standard normal", "metadata": {}}
+{"_id": "22712546", "title": "", "text": "Exploring Metabolic Configurations of Single Cellswithin Complex Tissue Microenvironments.Overthe past years, plenty of evidence has emergedillustrating how metabolism supports manyaspects of cellular function and how metabolicreprogramming can drive cell differentiation andfate. Here, we present a method to assess themetabolic configuration of single cells within theirnative tissue microenvironment via thevisualization and quantification of multipleenzymatic activities measured at saturatingsubstrate conditions combined with subsequentcell type identification. After careful validation ofthe approach and to demonstrate its potential,we assessed the intracellular metabolicconfiguration of different human immune cellpopulations in healthy and tumor colon tissue.Additionally, we analyzed the intercellularmetabolic relationship between cancer cells andcancer-associated fibroblasts in a breast cancertissue array. This study demonstrates that thedetermination of metabolic configurations in", "metadata": {}}
+{"_id": "22730024", "title": "", "text": "Twenty-four hour and early morning bloodpressure control of olmesartan vs. ramipril inelderly hypertensive patients: pooled individualdata analysis of two randomized, double-blind,parallel-group studies.OBJECTIVE To assess theantihypertensive efficacy of olmesartanmedoxomil and ramipril on 24-h ambulatoryblood pressure (ABP) in elderly hypertensivepatients by pooled data analysis of two studieswith identical designs (one Italian, oneEuropean). METHODS After a 2-week placebowash-out 1453 elderly hypertensive patients(65-89 years; sitting office DBP 90-109 mmHgand/or sitting office SBP 140-179 mmHg) wererandomized to a 12-week double-blind treatmentwith olmesartan medoxomil 10 mg or ramipril2.5 mg once-daily, up-titrated (20 and 40 mgolmesartan medoxomil; 5 and 10 mg ramipril)after 2 and 6 weeks in patients withoutnormalized office BP. 24-h ABP was recorded atrandomization and after 12 weeks. RESULTS In715 patients with valid baseline and", "metadata": {}}
+{"_id": "22767022", "title": "", "text": "Abi1 is essential for the formation and activationof a WAVE2 signalling complexWAVE2 belongs toa family of proteins that mediates actinreorganization by relaying signals from Rac tothe Arp2/3 complex, resulting in lamellipodiaprotrusion. WAVE2 displays Arp2/3-dependentactin nucleation activity in vitro, and does notbind directly to Rac. Instead, it formsmacromolecular complexes that have beenreported to exert both positive and negativemodes of regulation. How these complexes areassembled, localized and activated in vivoremains to be established. Here we use tandemmass spectrometry to identify an Abi1-basedcomplex containing WAVE2, Nap1(Nck-associated protein) and PIR121. Abi1interacts directly with the WHD domain ofWAVE2, increases WAVE2 actin polymerizationactivity and mediates the assembly of aWAVE2–Abi1–Nap1–PIR121 complex. TheWAVE2–Abi1–Nap1–PIR121 complex is as activeas the WAVE2–Abi1 sub-complex in stimulating", "metadata": {}}
+{"_id": "22791348", "title": "", "text": "The dendritic cell lineage: ontogeny and functionof dendritic cells and their subsets in the steadystate and the inflamed setting.Dendritic cells(DCs) form a remarkable cellular network thatshapes adaptive immune responses according toperipheral cues. After four decades of research,we now know that DCs arise from ahematopoietic lineage distinct from otherleukocytes, establishing the DC system as aunique hematopoietic branch. Recent work hasalso established that tissue DCs consist ofdevelopmentally and functionally distinct subsetsthat differentially regulate T lymphocytefunction. This review discusses major advancesin our understanding of the regulation of DClineage commitment, differentiation,diversification, and function in situ.", "metadata": {}}
+{"_id": "22800314", "title": "", "text": "IL-15 Receptor Deletion Results in CircadianChanges of Locomotor and MetabolicActivityInterleukin-15 (IL-15) is a cytokineproduced in the normal brain that acts on itsspecific receptor IL-15Rα and co-receptorsIL-2Rβ and IL-2Rγ in neuronal cells. Thefunctions of the cerebral IL-15 system, however,are not yet clear. To test the hypothesis thatIL-15Rα regulates metabolic activity and bodytemperature, we quantified the specific metabolicphenotype of IL-15Rα knockout mice. Thesenormal-appearing mice were leaner with lowerfat composition. During the entire circadiancycle, the knockout mice had a significantlyhigher acrophase in locomotor activity and heatdissipation. During the light phase, there wassignificantly greater food intake, oxygenconsumption, and carbon dioxide production. Thedifference in the dark and light phases suggeststhat IL-15Rα participates in circadian rhythmregulation. The higher oxygen consumption inthe light phase indicates adaptive thermogenesis", "metadata": {}}
+{"_id": "22815457", "title": "", "text": "Vaginal progesterone, cerclage or cervicalpessary for preventing preterm birth inasymptomatic singleton pregnant women with ahistory of preterm birth and a sonographic shortcervix.OBJECTIVE To compare the outcome ofpregnancy in cohorts of women with singletonpregnancy and history of preterm birth andsonographic short cervix managed with differenttreatment protocols, namely cerclage, vaginalprogesterone or cervical pessary. METHODS Thiswas a comparison of three managementprotocols for women with singleton pregnancyand a high risk of preterm birth because of aprior spontaneous preterm birth before 34 weeksand a shortened cervical length detected bytransvaginal ultrasound. The study included 142women who were initially treated with cerclage(USA), 59 with vaginal progesterone (UK) and 42with cervical pessary (Spain). Perinatal outcomeswere compared between the three cohorts.RESULTS There were no statistically significantdifferences in perinatal losses, neonatal", "metadata": {}}
+{"_id": "22820637", "title": "", "text": "The oxytocinase subfamily of M1aminopeptidases.The placental leucineaminopeptidase (P-LAP), adipocyte-derivedleucine aminopeptidase (A-LAP) andleukocyte-derived aminopeptidase (L-RAP)belong to one distinct group of the M1 family ofamimopeptidases, which we term the\"Oxytocinase subfamily\". They shareHEXXH(X)18E Zn-binding and GAMEN motifsessential for the enzymatic activities.Intracellular localization is the characteristicfeature of the subfamily members. While P-LAPis translocated from intracellular vesicles toplasma membrane in a stimulus-dependentmanner, both A-LAP and L-RAP are retained inthe endoplasmic reticulum. They containsequences necessary for the specific localizationin the cell. It is getting evident that thesubfamily members play important roles in themaintenance of homeostasis includingmaintenance of normal pregnancy, memoryretention, blood pressure regulation and antigen", "metadata": {}}
+{"_id": "22843616", "title": "", "text": "Myc represses primitive endoderm differentiationin pluripotent stem cells.The generation ofinduced pluripotent stem cells (iPSCs) provides anovel method to facilitate investigations into themechanisms that control stem cell pluripotencyand self-renewal. Myc has previously been shownto be critical for murine embryonic stem cell(mESC) maintenance, while also enhancingdirected reprogramming of fibroblasts byeffecting widespread changes in geneexpression. Despite several studies identifying invivo target genes, the precise mechanism bywhich Myc regulates pluripotency remainsunknown. Here we report that codeletion of c-and N-MYC in iPSCs and ESCs results in theirspontaneous differentiation to primitiveendoderm. We show that Myc sustainspluripotency through repression of the primitiveendoderm master regulator GATA6, while alsocontributing to cell cycle control by regulation ofthe mir-17-92 miRNA cluster. Our findingsdemonstrate the indispensable requirement for", "metadata": {}}
+{"_id": "22843838", "title": "", "text": "[Vitamin D and latitude as environmental factorsin multiple sclerosis].Multiple sclerosis (MS)shows a multifold increase in prevalence with anincrease in latitudes, both north and south of theequator. One of the potential factors related tothe difference of the prevalence is vitamin D,because the strength of ambient ultraviolet light,which is essential for vitamin D production,decreases with increasing latitude. It is knownthat vitamin D has immunomodulatory functionsand suppresses an animal model of MS. It is alsoconsidered that vitamin D-related genes arecritical susceptible genes for MS. An approachfrom environmental and genetic aspects isneeded to investigate the association betweenvitamin D and MS.", "metadata": {}}
+{"_id": "22852120", "title": "", "text": "Type 2 cytokines: mechanisms and therapeuticstrategiesType 2 immune responses are definedby the cytokines interleukin-4 (IL-4), IL-5, IL-9and IL-13, which can either be host protective orhave pathogenic activity. Type 2 immunitypromotes antihelminth immunity, suppressestype 1-driven autoimmune disease, neutralizestoxins, maintains metabolic homeostasis, andregulates wound repair and tissue regenerationpathways following infection or injury.Nevertheless, when type 2 responses aredysregulated, they can become important driversof disease. Type 2 immunity induces a complexinflammatory response characterized byeosinophils, mast cells, basophils, type 2 innatelymphoid cells, IL-4-and/or IL-13-conditionedmacrophages and T helper 2 (TH2) cells, whichare crucial to the pathogenesis of many allergicand fibrotic disorders. As chronic type 2 immuneresponses promote disease, the mechanismsthat regulate their maintenance are thought tofunction as crucial disease modifiers. This Review", "metadata": {}}
+{"_id": "22867765", "title": "", "text": "Implanted microvessels progress through distinctneovascularization phenotypes.We havepreviously demonstrated that implantedmicrovessels form a new microcirculation withminimal host-derived vessel investment. Ourobjective was to define the vascular phenotypespresent during neovascularization in theseimplants and identify post-angiogenesis events.Morphological, functional and transcriptionalassessments identified three distinct vascularphenotypes in the implants: sproutingangiogenesis, neovascular remodeling, andnetwork maturation. A sprouting angiogenicphenotype appeared first, characterized by highproliferation and low mural cell coverage. Thiswas followed by a neovascular remodelingphenotype characterized by a perfused, poorlyorganized neovascular network, reducedproliferation, and re-associated mural cells. Thelast phenotype included a vascular networkorganized into a stereotypical tree structurecontaining vessels with normal perivascular cell", "metadata": {}}
+{"_id": "22871664", "title": "", "text": "Characterization of a highly variable eutherianmicroRNA gene.Mouse microRNAs (miRNAs)miR-290-miR295 are encoded by a cluster ofpartially homologous pre-miRNA hairpins and arelikely to be functionally important in embryonicstem (ES) cells and preimplantation embryos.We present evidence that a spliced, capped, andpolyadenylated primary transcript spans thisentire Early Embryonic microRNA Cluster(EEmiRC). Partial Drosha processing yieldsadditional large nuclear RNA intermediates. Aconserved promoter element containing aTATA-box directs EEmiRC transcription.Sequence analysis shows that the EEmiRCtranscription unit is remarkably variable and canonly be identified bioinformatically in placental(eutherian) mammals. Consistent witheutherian-specific function, EEmiRC is expressedin trophoblastic stem (TS) cells. When analyzingevolutionary and functional relationships, theorganization of the entire miRNA loci should beconsidered in addition to the mature miRNA", "metadata": {}}
+{"_id": "22874817", "title": "", "text": "The function of follicular helper T cells isregulated by the strength of T cell antigenreceptor bindingHow follicular helper T cells (TFHcells) differentiate to regulate B cell immunity iscritical for effective protein vaccination. Here wedefine three transcription factorT-bet–expressing antigen-specific effector helperT cell subsets with distinguishable function,migratory properties and developmentalprogramming in vivo. Expression of thetranscriptional repressor Blimp-1 distinguished Tzone 'lymphoid' effector helper T cells(CD62LhiCCR7hi) from CXCR5lo 'emigrant'effector helper T cells and CXCR5hi 'resident' TFHcells expressing the transcriptional repressorBcl-6 (CD62LloCCR7lo). We then show byadoptive transfer and intact polyclonal responsesthat helper T cells with the highest specificbinding of peptide–major histocompatibilitycomplex class II and the most restricted T cellantigen receptor junctional diversity'preferentially' developed into the", "metadata": {}}
+{"_id": "22889972", "title": "", "text": "Disruption of tumor necrosis factor-alpha genediminishes the development of atherosclerosis inApoE-deficient mice.Inflammatory cytokines,including tumor necrosis factor-alpha(TNF-alpha) have been implicated inatherogenesis. However, the precise role ofTNF-alpha in atherogenesis is still unclear. Toexamine the effect of TNF-alpha onatherogenesis, we generated compound-deficientmice in apolipoprotein E (apoE) and TNF-alpha(apoE-/-/TNF-alpha-/-) and compared them withapoE-/- mice. Although serum total cholesterollevels were markedly elevated in bothapoE-/-/TNF-alpha-/- and apoE-/- micecompared to wild-type mice, no differences wereobserved between apoE-/-/TNF-alpha-/- andapoE-/- mice. The atherosclerotic plaque area inthe aortic luminal surface ofapoE-/-/TNF-alpha-/- mice (n=8, 3.1+/-0.4%)was significantly smaller than that of apoE-/-mice (n=7, 4.7+/-0.4%, p<0.001) despite thelack of difference in serum cholesterol levels. The", "metadata": {}}
+{"_id": "22890091", "title": "", "text": "Differential expression of bcl-2 and susceptibilityto anti-Fas-mediated cell death in peripheralblood lymphocytes, monocytes, andneutrophils.The recently identified Fas antigen(Ag) is a cell surface molecule that can mediateapoptosis. The cytoplasmic product ofproto-oncogene bcl-2 has been shown to prolongthe cellular survival by inhibiting apoptosis. Toelucidate the physiologic significance ofexpression of both molecules, we examined theexpression of Fas Ag and bcl-2 on bloodleukocyte populations and evaluated theirsensitivity to the cytolytic action of anti-Fasantibody. Although Fas Ag was expressed on afraction of lymphocytes, both neutrophils andmonocytes expressed Fas Ag constitutively. Incontrast, there was marked difference amongthese leukocytes regarding bcl-2 expression.Lymphocytes expressed bcl-2 intensely, butmonocytes showed weaker bcl-2 expression, andneutrophils were essentially absent for bcl-2expression. Seemingly reflecting this lack of", "metadata": {}}
+{"_id": "22896384", "title": "", "text": "Foxp2 and Foxp1 cooperatively regulate lung andesophagus development.The airways of the lungdevelop through a reiterative process ofbranching morphogenesis that gives rise to theintricate and extensive surface area required forpostnatal respiration. The forkhead transcriptionfactors Foxp2 and Foxp1 are expressed inmultiple foregut-derived tissues including thelung and intestine. In this report, we show thatloss of Foxp2 in mouse leads to defectivepostnatal lung alveolarization, contributing topostnatal lethality. Using in vitro and in vivoassays, we show that T1alpha, a lung alveolarepithelial type 1 cell-restricted gene crucial forlung development and function, is a direct targetof Foxp2 and Foxp1. Remarkably, loss of a singleFoxp1 allele in addition to complete loss of Foxp2results in increased severity of morphologicaldefects in mutant lungs and leads to perinatalloss of all Foxp2(-/-);Foxp1(+/-) mice.Expression of N-myc and Hop, crucial regulatorsof lung development, is compromised in", "metadata": {}}
+{"_id": "22896970", "title": "", "text": "Crystal structure of the eukaryotic 60S ribosomalsubunit in complex with initiation factor 6.Proteinsynthesis in all organisms is catalyzed byribosomes. In comparison to their prokaryoticcounterparts, eukaryotic ribosomes areconsiderably larger and are subject to morecomplex regulation. The large ribosomal subunit(60S) catalyzes peptide bond formation andcontains the nascent polypeptide exit tunnel. Wepresent the structure of the 60S ribosomalsubunit from Tetrahymena thermophila incomplex with eukaryotic initiation factor 6(eIF6), cocrystallized with the antibioticcycloheximide (a eukaryotic-specific inhibitor ofprotein synthesis), at a resolution of 3.5angstroms. The structure illustrates the complexfunctional architecture of the eukaryotic 60Ssubunit, which comprises an intricate network ofinteractions between eukaryotic-specificribosomal protein features and RNA expansionsegments. It reveals the roles of eukaryoticribosomal protein elements in the stabilization of", "metadata": {}}
+{"_id": "22901758", "title": "", "text": "Hedgehog signaling regulates braintumor-initiating cell proliferation and portendsshorter survival for patients withPTEN-coexpressing glioblastomas.Theidentification of brain tumor stem-like cells(BTSCs) has implicated a role of biologicalself-renewal mechanisms in clinical brain tumorinitiation and propagation. The molecularmechanisms underlying the tumor-formingcapacity of BTSCs, however, remain unknown.Here, we have generated molecular signatures ofglioblastoma multiforme (GBM) using geneexpression profiles of BTSCs and have identifiedboth Sonic Hedgehog (SHH) signaling-dependentand -independent BTSCs and their respectiveglioblastoma surgical specimens. BTSCproliferation could be abrogated in apathway-dependent fashion in vitro and in anintracranial tumor model in athymic mice. BothSHH-dependent and -independent brain tumorgrowth required phosphoinositide3-kinase-mammalian target of rapamycin", "metadata": {}}
+{"_id": "22908536", "title": "", "text": "Stress and host immunity amplify Mycobacteriumtuberculosis phenotypic heterogeneity andinduce nongrowing metabolically activeforms.Nonreplicating and metabolically quiescentbacteria are implicated in latent tuberculosisinfections and relapses following \"sterilizing\"chemotherapy. However, evidence linkingbacterial dormancy and persistence in vivo islargely inconclusive. Here we measure thesingle-cell dynamics of Mycobacteriumtuberculosis replication and ribosomal activityusing quantitative time-lapse microscopy and areporter of ribosomal RNA gene expression.Single-cell dynamics exhibit heterogeneity understandard growth conditions, which is amplified bystressful conditions such as nutrient limitation,stationary phase, intracellular replication, andgrowth in mouse lungs. Additionally, the lungs ofchronically infected mice harbor a subpopulationof nongrowing but metabolically active bacteria,which are absent in mice lacking interferon-γ, acytokine essential for antituberculosis immunity.", "metadata": {}}
+{"_id": "22914228", "title": "", "text": "Proteomic analysis reveals Warburg effect andanomalous metabolism of glutamine inpancreatic cancer cells.In this present work, wecharacterized the proteomes of pancreatic ductaladenocarcinoma (PDAC) cell line PANC-1 andnormal pancreatic duct cells by massspectrometry using LTQ-Orbitrap and identifiedmore than 1700 proteins from each sample. Onthe basis of the spectra count label-freequantification approach, we identified a largenumber of differentially expressed metabolicenzymes and proteins involved in cytoskeleton,cell adhesion, transport, transcription,translation, and cell proliferation as well. Thedata demonstrated that metabolic pathwayswere altered in PANC-1, consistent with theWarburg effect. In addition, the comparative MSanalysis unveiled anomalous metabolism ofglutamine, suggesting that glutamine was largelyconsumed as a nitrogen donor in nucleotide andamino acid biosynthesis in PANC-1. Our analysisprovides a potentially comprehensive picture of", "metadata": {}}
+{"_id": "22922353", "title": "", "text": "Prevalence of attempting weight loss andstrategies for controlling weight.CONTEXTOverweight and obesity are increasing in theUnited States. Changes in diet and physicalactivity are important for weight control.OBJECTIVES To examine the prevalence ofattempting to lose or to maintain weight and todescribe weight control strategies among USadults. DESIGN The Behavioral Risk FactorSurveillance System, a random-digit telephonesurvey conducted in 1996 by state healthdepartments. Setting The 49 states (and theDistrict of Columbia) that participated in thesurvey. PARTICIPANTS Adults aged 18 years andolder (N = 107 804). MAIN OUTCOMEMEASURES Reported current weights and goalweights, prevalence of weight loss ormaintenance attempts, and strategies used tocontrol weight (eating fewer calories, eating lessfat, or using physical activity) by populationsubgroup. RESULTS The prevalence ofattempting to lose and maintain weight was", "metadata": {}}
+{"_id": "22937651", "title": "", "text": "Antibodies specific for Epstein-Barr virus nuclearantigen-1 cross-react with human heterogeneousnuclear ribonucleoprotein L.Epstein-Barr virus(EBV) is associated with multiple sclerosis (MS),and antibodies to the EBV nuclear antigen-1(EBNA-1) are consistently increased in MSpatients. The hypothesis of this study is thatanti-EBNA-1 antibodies cross-react with a selfantigen in MS patients. We affinity purifiedanti-EBNA-1 antibodies from human plasma,used the anti-EBNA-1 to immunoprecipitateantigens from human brain, and identified boundantigens with mass spectrometry. Anti-EBNA-1consistently bound heterogeneous nuclearribonucleoprotein L (HNRNPL). We expressedboth the long and short isoforms of this protein,and verified with Western blots and ELISA thatthe long isoform cross-reacts with EBNA-1.Immunohistochemistry demonstrated thatanti-EBNA-1 bound to an antigen in the nucleusof cultured rat central nervous system cells.ELISA demonstrated the presence of antibodies", "metadata": {}}
+{"_id": "22937815", "title": "", "text": "Roles of chromatin remodellers in DNA doublestrand break repair.Now that we have a goodunderstanding of the DNA double strand break(DSB) repair mechanisms and DSB-induceddamage signalling, attention is focusing on thechanges to the chromatin environment neededfor efficient DSB repair. Mutations in chromatinremodelling complexes have been identified incancers, making it important to evaluate howthey impact upon genomic stability. Our currentunderstanding of the DSB repair pathwayssuggests that each one has distinct requirementsfor chromatin remodelling. Moreover, restrictingthe extent of chromatin modifications could be asignificant factor regulating the decision ofpathway usage. In this review, we evaluate thedistinct DSB repair pathways for their potentialneed for chromatin remodelling and review theroles of ATP-driven chromatin remodellers in thepathways.", "metadata": {}}
+{"_id": "22938539", "title": "", "text": "Epstein-Barr virus and virus human proteininteraction maps.A comprehensive mapping ofinteractions among Epstein-Barr virus (EBV)proteins and interactions of EBV proteins withhuman proteins should provide specifichypotheses and a broad perspective on EBVstrategies for replication and persistence.Interactions of EBV proteins with each other andwith human proteins were assessed by using astringent high-throughput yeast two-hybridsystem. Overall, 43 interactions between EBVproteins and 173 interactions between EBV andhuman proteins were identified. EBV-EBV andEBV-human protein interaction, or \"interactome\"maps provided a framework for hypotheses ofprotein function. For example, LF2, an EBVprotein of unknown function interacted with theEBV immediate early R transactivator (Rta) andwas found to inhibit Rta transactivation. From abroader perspective, EBV genes can be dividedinto two evolutionary classes, \"core\" genes,which are conserved across all herpesviruses and", "metadata": {}}
+{"_id": "22942787", "title": "", "text": "Relation between Medicare screeningreimbursement and stage at diagnosis for olderpatients with colon cancer.CONTEXT Medicare'sreimbursement policy was changed in 1998 toprovide coverage for screening colonoscopies forpatients with increased colon cancer risk, andexpanded further in 2001 to cover screeningcolonoscopies for all individuals. OBJECTIVE Todetermine whether the Medicare reimbursementpolicy changes were associated with an increasein either colonoscopy use or early stage coloncancer diagnosis. DESIGN, SETTING, ANDPARTICIPANTS Patients in the Surveillance,Epidemiology, and End Results Medicare linkeddatabase who were 67 years of age and olderand had a primary diagnosis of colon cancerduring 1992-2002, as well as a group ofMedicare beneficiaries who resided inSurveillance, Epidemiology, and End Resultsareas but who were not diagnosed with cancer.MAIN OUTCOME MEASURES Trends incolonoscopy and sigmoidoscopy use among", "metadata": {}}
+{"_id": "22948960", "title": "", "text": "Direct visualization of the endomitotic cell cyclein living megakaryocytes: differential patterns inlow and high ploidy cells.Endomitosis inmegakaryocytes (MKs) involves repeated DNAreplication in the absence of cytokinesis and is acrucial part of MK development. However,chromosomal dynamics have never beenobserved in living MKs. We developed a newtransgenic mouse model in which the expressionof human histone H2B fused in-frame to greenfluorescent protein is targeted to MKs. Ex vivotime-lapse microscopy analysis indicated thatchromosomal condensation occurs at earlymitosis in all MKs. In high ploidy MKs (>or=8N),late anaphase was marked by a ring-typealignment of chromosomes with multipleterritories formed between them. By contrast, inlow ploidy MKs mitotic chromosomes segregatedto form two groups separated by a clear spacebefore re-joining to one cluster. This is the firststudy to document chromosomal segregationpatterns during endomitosis ex vivo and to", "metadata": {}}
+{"_id": "22963769", "title": "", "text": "Aberrant expression and altered cellularlocalization of desmosomal and hemidesmosomalproteins are associated with aggressiveclinicopathological features of oral squamous cellcarcinomaDisruption of cell adhesion plays acentral role in dedifferentiation, invasion, andmetastasis of various cancers. The desmosomeand hemidesmosome are anchoring junctionsthat control cell-cell and cell-matrix adhesion,respectively. To clarify their contributions inmediating the biological properties of oralcancer, we immunohistochemically examined theexpression of desmoglein 1 (DSG1), DSG2,DSG3, desmocollin 2 (DSC2), integrin beta 4(ITGB4), laminin gamma chain 2 (LAMC2), andcollagen type 17 alpha 1 (COL17A1) in 51 casesof oral squamous cell carcinoma. On normal oralepithelial cells, DSG1, DSG3, DSC2, andCOL17A1 were expressed on the plasmamembrane, while ITGB4 and mature LAMC2 werepresent at the basement membrane. In cancer,the expression of DSG1, DSG3, DSC2, and", "metadata": {}}
+{"_id": "22968257", "title": "", "text": "Histone/protein deacetylase inhibitors increasesuppressive functions of human FOXP3+Tregs.Histone/protein deacetylases (HDACs)decrease histone and protein acetylation,typically leading to suppression of genetranscription and modulation of various proteinfunctions. We found significant differences inexpression of HDAC before and after stimulationof human T regulatory (Treg) and T effectorcells, suggesting the potential for future selectivetargeting of Tregs with HDAC inhibitors (HDACi).Use of various HDACi small molecules enhanced,by up to 4.5-fold (average 2-fold), thesuppressive functions of both freshly isolated andexpanded human Tregs, consistent with ourprevious murine data. HDACi use increased Tregexpression of CTLA-4, a key negative regulatorof immune response, and we found a direct andsignificant correlation between CTLA-4expression and Treg suppression. Hence, HDACicompounds are promising pharmacologic tools toincrease Treg suppressive functions, and this", "metadata": {}}
+{"_id": "22972632", "title": "", "text": "Enhanced pathological angiogenesis in micelacking β3 integrin or β3 and β5integrinsInhibition of αvβ3 or αvβ5 integrinfunction has been reported to suppressneovascularization and tumor growth, suggestingthat these integrins are critical modulators ofangiogenesis. Here we report that mice lackingβ3 integrins or both β3 and β5 integrins not onlysupport tumorigenesis, but have enhanced tumorgrowth as well. Moreover, the tumors in theseintegrin-deficient mice display enhancedangiogenesis, strongly suggesting that neither β3nor β5 integrins are essential forneovascularization. We also observed thatangiogenic responses to hypoxia and vascularendothelial growth factor (VEGF) are augmentedsignificantly in the absence of β3 integrins. Wefound no evidence that the expression orfunctions of other integrins were altered as aconsequence of the β3 deficiency, but we didobserve elevated levels of VEGF receptor-2 (alsocalled Flk-1) in β3-null endothelial cells. These", "metadata": {}}
+{"_id": "22973574", "title": "", "text": "A lineage of myeloid cells independent of Myband hematopoietic stem cells.Macrophages anddendritic cells (DCs) are key components ofcellular immunity and are thought to originateand renew from hematopoietic stem cells(HSCs). However, some macrophages develop inthe embryo before the appearance of definitiveHSCs. We thus reinvestigated macrophagedevelopment. We found that the transcriptionfactor Myb was required for development ofHSCs and all CD11b(high) monocytes andmacrophages, but was dispensable for yolk sac(YS) macrophages and for the development ofYS-derived F4/80(bright) macrophages in severaltissues, such as liver Kupffer cells, epidermalLangerhans cells, and microglia--cell populationsthat all can persist in adult mice independently ofHSCs. These results define a lineage of tissuemacrophages that derive from the YS and aregenetically distinct from HSC progeny.", "metadata": {}}
+{"_id": "22975806", "title": "", "text": "Heterogenic Loss of the Wild-Type BRCA Allele inHuman Breast TumorigenesisFor individualsgenetically predisposed to breast and ovariancancer through inheritance of a mutant BRCAallele, somatic loss of heterozygosity affectingthe wild-type allele is considered obligatory forcancer initiation and/or progression. However,several lines of evidence suggest that phenotypiceffects may result from BRCA haploinsufficiency.Archival fixed and embedded tissue specimensfrom women with germ line deleteriousmutations in BRCA1 or BRCA2 were identified.After pathologic review, focal areas of normalbreast epithelium, atypical ductal hyperplasia,ductal carcinoma-in-situ, and invasive ductalcarcinoma were identified from 14 BRCA1-linkedand 9 BRCA2-linked breast cancers. TenBRCA-linked prophylactic mastectomy specimensand 12 BRCA-linked invasive ovarian carcinomaswere also studied. Laser catapult microdissectionwas used to isolate cells from the variouspathologic lesions and corresponding normal", "metadata": {}}
+{"_id": "22980205", "title": "", "text": "Targeted therapies in urothelialcarcinoma.PURPOSE OF REVIEW Greaterunderstanding of the biology and genetics ofurothelial carcinoma is helping to identify anddefine the role of molecules and pathwaysappropriate for novel-targeted therapies. Here,we review the targeted therapies that have beenreported or are in ongoing urothelial carcinomaclinical trials, and highlight molecular targetscharacterized in preclinical and clinical studies.RECENT FINDINGS Trials in nonmuscle-invasivebladder cancer are evaluating the role ofimmunotherapy and agents targeting vascularendothelial growth factor (VEGF) or fibroblastgrowth factor receptor-3. In muscle-invasivebladder cancer, neoadjuvant studies havefocused on combining VEGF agents withchemotherapy; adjuvant studies are testingvaccines and agents targeting the humanepidermal growth factor receptor 2, p53, andHsp27. In the first-line treatment of metastaticurothelial carcinoma, tubulin, cytotoxic", "metadata": {}}
+{"_id": "22995164", "title": "", "text": "H2S and HS− donor NaHS releases nitric oxidefrom nitrosothiols, metal nitrosyl complex, brainhomogenate and murine L1210 leukaemiacellsNitrosoglutathione [(GSNO), 500 nmol/l]relaxed the norepinephrine precontracted rataortic rings. The relaxation effect waspronouncedly enhanced by H2S- and HS−-donorNaHS (30 μmol/l) at 7.5 pH but not at 6.3 pH. Tostudy molecular mechanism of this effect, weinvestigated whether NaHS can release NO fromNO donors. Using an electron paramagneticresonance spectroscopy method of spin trap andby measuring the NO oxidation product, which isnitrite, by the Griess reaction, we report thatNaHS released NO from nitrosothiols, namelyfrom GSNO, S-nitroso-N-acetyl-dl-penicillamine(SNAP), from metal nitrosyl complexnitroprusside (SNP) and from rat brainhomogenate and murine L1210 leukaemia cells.From the observation that the releasing effectwas more pronounced at 8.0 pH than 6.0 pH, wesuppose that HS−, rather than H2S, is", "metadata": {}}
+{"_id": "22995579", "title": "", "text": "Amitriptyline is effective in chronic but not inepisodic tension-type headache: pathogeneticimplications.The tricyclic antidepressant,amitriptyline, is an effective drug for thetreatment of chronic tension-type headache andfor other chronic pain syndromes, but it is alsoeffective in the prophylaxis of an episodic type ofheadache such as migraine. However, its efficacyin episodic tension-type headache has not yetbeen clarified. We compared the efficacy ofamitriptyline (25 mg/day) in 82 nondepressedpatients with either chronic or episodictension-type headache in an open-label study.Amitriptyline significantly reduced (P < 0.05)frequency and duration of headache as well asanalgesic consumption in chronic, but not inepisodic, tension-type headache. Furtherplacebo-controlled trials, possibly with higherdoses of amitriptyline, might confirm if thedifferent pattern of response to amitriptyline canbe explained in terms of different involvement ofcentral nociception and of peripheral myofascial", "metadata": {}}
+{"_id": "22997657", "title": "", "text": "Kruppel-like factor 2 is required for traffickingbut not quiescence in postactivated T cells.Thetranscription factor Kruppel-like factor 2 (KLF2)was proposed to regulate genes involved in cellcycle entry and T cell trafficking; however, thephysiological role of its expression inpostactivated T cells is not well defined. Previousstudies suggested that the cytokines IL-2 andIL-15 differentially regulate KLF2 re-expressionin postactivation T cells and that these cytokinesalso influence effector versus memory T celldifferentiation. Using conditional and inducibleKLF2-knockout model systems, we tested thespecific role of KLF2 expression in activatedCD8(+) T cells cultured with these cytokines.KLF2 was required for effective transcription ofsphingosine-1-phosphate receptor-1 (S1P(1))and CD62L in postactivation T cells. However,although different cytokines dramatically alteredthe expression of cell-cycle-related genes,endogenous KLF2 had a minimal impact.Correspondingly, KLF2-deficient T cells showed", "metadata": {}}
+{"_id": "23013317", "title": "", "text": "Hypoalbuminemia in acute illness: is there arationale for intervention? A meta-analysis ofcohort studies and controlled trials.OBJECTIVETo determine whether hypoalbuminemia is anindependent risk factor for poor outcome in theacutely ill, and to assess the potential ofexogenous albumin administration for improvingoutcomes in hypoalbuminemic patients.SUMMARY BACKGROUND DATAHypoalbuminemia is associated with pooroutcomes in acutely ill patients, but whether thisassociation is causal has remained unclear. Trialsinvestigating albumin therapy to correcthypoalbuminemia have proven inconclusive.METHODS A meta-analysis was conducted of 90cohort studies with 291,433 total patientsevaluating hypoalbuminemia as an outcomepredictor by multivariate analysis and,separately, of nine prospective controlled trialswith 535 total patients on correctinghypoalbuminemia. RESULTS Hypoalbuminemiawas a potent, dose-dependent independent", "metadata": {}}
+{"_id": "23017040", "title": "", "text": "Methionine restriction decreases visceral fatmass and preserves insulin action in aging maleFischer 344 rats independent of energyrestriction.Reduced dietary methionine intake(0.17% methionine, MR) and calorie restriction(CR) prolong lifespan in male Fischer 344 rats.Although the mechanisms are unclear, bothregimens feature lower body weight andreductions in adiposity. Reduced fat deposition inCR is linked to preservation of insulinresponsiveness in older animals. These studiesexamine the relationship between insulinresponsiveness and visceral fat in MR and testwhether, despite lower food intake observed inMR animals, decreased visceral fat accretion andpreservation of insulin sensitivity is notsecondary to CR. Accordingly, rats pair fed (pf)control diet (0.86% methinone, CF) to match thefood intake of MR for 80 weeks exhibit insulin,glucose, and leptin levels similar to control-fedanimals and comparable amounts of visceral fat.Conversely, MR rats show significantly reduced", "metadata": {}}
+{"_id": "23032247", "title": "", "text": "Generation of T cell receptor–retrogenic mice:improved retroviral-mediated stem cell genetransferThe use of retrogenic mice offers a rapidand flexible approach to T cell receptor(TCR)-transgenic mice. By transducing bonemarrow progenitor cells with a retrovirus thatencodes a given TCR-α/β subunit, TCR-retrogenicmice can be generated in as few as 4–6 weeks,whereas conventional TCR transgenics can take 6months or longer. In this updated protocol, wehave increased the efficiency of the bone marrowtransduction and bone marrow reconstitutioncompared with our previously published protocol.The main departure from the previous protocol isthe implementation of spin transduction with theviral supernatant instead of coculture with theviral producer cell line. The changes in thisprotocol improve bone marrow viability, increaseconsistency of the bone marrow transduction andbone marrow engraftment, and they reduce theratio of bone marrow donor mice to bone marrowrecipients.", "metadata": {}}
+{"_id": "23036207", "title": "", "text": "Transient delivery of modified mRNA encodingTERT rapidly extends telomeres in humancells.Telomere extension has been proposed as ameans to improve cell culture and tissueengineering and to treat disease. However,telomere extension by nonviral, nonintegratingmethods remains inefficient. Here we report thatdelivery of modified mRNA encoding TERT tohuman fibroblasts and myoblasts increasestelomerase activity transiently (24-48 h) andrapidly extends telomeres, after which telomeresresume shortening. Three successivetransfections over a 4 d period extendedtelomeres up to 0.9 kb in a cell type-specificmanner in fibroblasts and myoblasts andconferred an additional 28 ± 1.5 and 3.4 ± 0.4population doublings (PDs), respectively.Proliferative capacity increased in adose-dependent manner. The second and thirdtransfections had less effect on proliferativecapacity than the first, revealing a refractoryperiod. However, the refractory period was", "metadata": {}}
+{"_id": "23052989", "title": "", "text": "The death receptor CD95 activates adult neuralstem cells for working memory formation andbrain repair.Adult neurogenesis persists in thesubventricular zone and the dentate gyrus andcan be induced upon central nervous systeminjury. However, the final contribution ofnewborn neurons to neuronal networks islimited. Here we show that in neural stem cells,stimulation of the \"death receptor\" CD95 doesnot trigger apoptosis but unexpectedly leads toincreased stem cell survival and neuronalspecification. These effects are mediated viaactivation of the Src/PI3K/AKT/mTOR signalingpathway, ultimately leading to a global increasein protein translation. Induction of neurogenesisby CD95 was further confirmed in the ischemicCA1 region, in the naive dentate gyrus, and afterforced expression of CD95L in the adultsubventricular zone. Lack of hippocampal CD95resulted in a reduction in neurogenesis andworking memory deficits. Following globalischemia, CD95-mediated brain repair rescued", "metadata": {}}
+{"_id": "23073816", "title": "", "text": "Umbilical Cord Blood Therapy Potentiated withErythropoietin for Children with Cerebral Palsy: ADouble-blind, Randomized, Placebo-ControlledTrialAllogeneic umbilical cord blood (UCB) hastherapeutic potential for cerebral palsy (CP).Concomitant administration of recombinanthuman erythropoietin (rhEPO) may boost theefficacy of UCB, as it has neurotrophic effects.The objectives of this study were to assess thesafety and efficacy of allogeneic UCB potentiatedwith rhEPO in children with CP. Children with CPwere randomly assigned to one of three parallelgroups: the pUCB group, which receivedallogeneic UCB potentiated with rhEPO; the EPOgroup, which received rhEPO and placebo UCB;and the Control group, which received placeboUCB and placebo rhEPO. All participants receivedrehabilitation therapy. The main outcomes werechanges in scores on the following measuresduring the 6 months treatment period: the grossmotor performance measure (GMPM), grossmotor function measure, and Bayley scales of", "metadata": {}}
+{"_id": "23076291", "title": "", "text": "Pituitary adenylate cyclase-activatingpolypeptide (PACAP(1-38)) enhancesN-methyl-D-aspartate receptor function andbrain-derived neurotrophic factor expression viaRACK1.We recently identified a novel mechanismfor modulation of the phosphorylation state andfunction of the N-methyl-d-aspartate (NMDA)receptor via the scaffolding protein RACK1. Wefound that RACK1 binds both the NR2B subunitof the NMDA receptor and the nonreceptorprotein-tyrosine kinase, Fyn. RACK1 inhibits Fynphosphorylation of NR2B and decreases NMDAreceptor-mediated currents in CA1 hippocampalslices (Yaka, R., Thornton, C., Vagts, A. J.,Phamluong, K., Bonci, A., and Ron, D. (2002)Proc. Natl. Acad. Sci. U. S. A. 99, 5710-5715).Here, we identified the signaling cascade bywhich RACK1 is released from the NMDA receptorcomplex and identified the consequences of thedissociation. We found that activation of thecAMP/protein kinase A pathway in hippocampalslices induced the release of RACK1 from NR2B", "metadata": {}}
+{"_id": "23078022", "title": "", "text": "MUC1 oncoprotein activates the IκB kinase βcomplex and constitutive NF-κB signallingNuclearfactor-κB (NF-κB) is constitutively activated indiverse human malignancies by mechanisms thatare not understood. The MUC1 oncoprotein isaberrantly overexpressed by most humancarcinomas and, similarly to NF-κB, blocksapoptosis and induces transformation. This studydemonstrates that overexpression of MUC1 inhuman carcinoma cells is associated withconstitutive activation of NF-κB p65. We showthat MUC1 interacts with thehigh-molecular-weight IκB kinase (IKK) complexin vivo and that the MUC1 cytoplasmic domainbinds directly to IKKβ and IKKγ. Interaction ofMUC1 with both IKKβ and IKKγ is necessary forIKKβ activation, resulting in phosphorylation anddegradation of IκBα. Studies in non-malignantepithelial cells show that MUC1 is recruited to theTNF-R1 complex and interacts with IKKβ–IKKγ inresponse to TNFα stimulation. TNFα-inducedrecruitment of MUC1 is dependent on TRADD and", "metadata": {}}
+{"_id": "23100220", "title": "", "text": "Lipoxins: novel series of biologically activecompounds formed from arachidonic acid inhuman leukocytes.Trihydroxytetraenes, a novelseries of oxygenated derivatives formed fromarachidonic acid in human leukocytes, wererecently isolated [Serhan, C. N., Hamberg, M. &Samuelsson, B. (1984) Biochem. Biophys. Res.Commun. 118, 943-949]. The structure of themajor compound was established--i.e.,5,6,15L-trihydroxy-7,9,11,13-icosatetraenoicacid. The present study reports the structure of asecond member of the trihydroxytetraene seriesof compounds--i.e.,5D,14,15L-trihydroxy-6,8,10,12-icosatetraenoicacid. When added to human neutrophils,5,6,15L-trihydroxy-7,9,11,13-icosatetraenoicacid stimulated superoxide anion generation anddegranulation at submicromolar concentrationswithout provoking a substantial aggregationresponse. With respect to superoxide aniongeneration,5,6,15L-trihydroxy-7,9,11,13-icosatetraenoic", "metadata": {}}
+{"_id": "23100962", "title": "", "text": "Nitric oxide synthase generates superoxide andnitric oxide in arginine-depleted cells leading toperoxynitrite-mediated cellular injury.Besidessynthesizing nitric oxide (NO), purified neuronalNO synthase (nNOS) can produce superoxide(.O2-) at lower L-Arg concentrations. By usingelectron paramagnetic resonance spin-trappingtechniques, we monitored NO and .O2- formationin nNOS-transfected human kidney 293 cells. Incontrol transfected cells, the Ca2+ ionophoreA23187 triggered NO generation but no .O2- wasseen. With cells in L-Arg-free medium, weobserved .O2- formation that increased as thecytosolic L-Arg levels decreased, while NOgeneration declined. .O2- formation was virtuallyabolished by the specific NOS blocker,N-nitro-L-arginine methyl ester (L-NAME).Nitrotyrosine, a specific nitration product ofperoxynitrite, accumulated in L-Arg-depletedcells but not in control cells. Activation byA23187 was cytotoxic to L-Arg-depleted, but notto control cells, with marked lactate", "metadata": {}}
+{"_id": "23117378", "title": "", "text": "Sudden infant death syndrome and unclassifiedsudden infant deaths: a definitional anddiagnostic approach.The definition of suddeninfant death syndrome (SIDS) originallyappeared in 1969 and was modified 2 decadeslater. During the following 15 years, anenormous amount of additional information hasemerged, justifying additional refinement of thedefinition of SIDS to incorporate epidemiologicfeatures, risk factors, pathologic features, andancillary test findings. An expert panel ofpediatric and forensic pathologists andpediatricians considered these issues anddeveloped a new general definition of SIDS foradministrative and vital statistics purposes. Thenew definition was then stratified to facilitateresearch into sudden infant death. Anothercategory, defined as unclassified sudden infantdeaths, was introduced for cases that do notmeet the criteria for a diagnosis of SIDS and forwhich alternative diagnoses of natural orunnatural conditions were equivocal. It is", "metadata": {}}
+{"_id": "23117928", "title": "", "text": "Inter-viral conflicts that exploit host CRISPRimmune systems of Sulfolobus.Infection ofSulfolobus islandicus REY15A with mixtures ofdifferent Sulfolobus viruses, including STSV2, didnot induce spacer acquisition by the host CRISPRimmune system. However, coinfection with thetailed fusiform viruses SMV1 and STSV2generated hyperactive spacer acquisition in bothCRISPR loci, exclusively from STSV2, with theresultant loss of STSV2 but not SMV1. SMV1 wasshown to activate adaptation while itself beingresistant to CRISPR-mediated adaptation andDNA interference. Exceptionally, a single cloneS-1 isolated from an SMV1 + STSV2-infectedculture, that carried STSV2-specific spacers andhad lost STSV2 but not SMV1, acquired spacersfrom SMV1. This effect was also reproducible onreinfecting wild-type host cells with a variantSMV1 isolated from the S-1 culture. The SMV1variant lacked a virion protein ORF114 that wasshown to bind DNA. This study also providedevidence for: (i) limits on the maximum sizes of", "metadata": {}}
+{"_id": "23122306", "title": "", "text": "Lung Carcinogenesis by Diesel Exhaust Particlesand the Carcinogenic Mechanism Via ActiveOxygens.In an experiment to clarify theinvolvement of oxygen radicals in lungcarcinogenesis induced by diesel exhaustparticles (DEP), we found that there is a strongrelation between lung tumor response andformation of 8-hydroxydeoxyguanosine(8-OHdG) in lung DNA of mice administered DEPby repeated intratracheal instillation. Repeatedintratracheal instillation of DEP also induced theactivity of cytochrome P-450 reductase in thelungs as a representative enzyme of superoxidegeneration, and two types of nitric oxide (NO)synthase, cNOS and iNOS, in the lungs. On theother hand, activities of CuZn-superoxidedismutase (SOD) and Mn-SOD antioxidantenzymes were depressed by the instillation ofDEP. These results suggest that generation ofsuperoxide, hydroxyI radical, and nitric oxide areincreased in epithelial cells in airways, and thatthe increased superoxide and nitric oxide react", "metadata": {}}
+{"_id": "23124332", "title": "", "text": "Prion-induced amyloid heart disease with highblood infectivity in transgenic mice.Weinvestigated extraneural manifestations inscrapie-infected transgenic mice expressingprion protein lacking theglycophosphatydylinositol membrane anchor. Inthe brain, blood, and heart, both abnormalprotease-resistant prion protein (PrPres) andprion infectivity were readily detected byimmunoblot and by inoculation intonontransgenic recipients. The titer of infectiousscrapie in blood plasma exceeded 10(7) 50%infectious doses per milliliter. The hearts of thesetransgenic mice contained PrPres-positiveamyloid deposits that led to myocardial stiffnessand cardiac disease.", "metadata": {}}
+{"_id": "23126677", "title": "", "text": "Circulating plasma microRNAs as a screeningmethod for detection of colorectaladenomas.BACKGROUND MicroRNAs (miRNAs)are small non-coding RNA molecules. Reduced orincreased levels of specific miRNAs are observedin colon and other cancers, supporting their rolein carcinogenesis. Detection of colorectal polypsis the cornerstone of the Bowel Cancer ScreeningProgramme in the UK. However, uptake ofscreening nationally remains under 60%. Weaimed to see whether circulating plasma miRNAscan be used to screen for patients with colorectalpolyps, adenomas, or both. METHODS Bloodsamples were taken from patients from theBowel Cancer Screening Programme(asymptomatic but faecal occult blood testing[FOBt] positive). Plasma RNA was extracted,target miRNAs (19a, 98, 146b, 186, 191, 222*,331-5p, 452, 625, 664, 1247) were identified onpooled case miRNA assay cards, and miRNAfraction was quantified by quantitative RT-PCRassay. Results were compared with endoscopy", "metadata": {}}
+{"_id": "23136735", "title": "", "text": "Short term persistence of human papillomavirusand risk of cervical precancer and cancer:population based cohort studyOBJECTIVE Toevaluate the cumulative incidence of cervicalintraepithelial neoplasia II or worse (grade II+)or cervical intraepithelial neoplasia grade III+after short term persistence of prevalentlydetected carcinogenic human papillomavirus(HPV). DESIGN Population based cohort study.SETTING Guanacaste, Costa Rica. PARTICIPANTS2282 sexually active women actively followedafter enrolment. MAIN OUTCOME MEASURESPrimary end points: three year and five yearcumulative incidence of histologically confirmedcervical intraepithelial neoplasia grade II+(n=70). Cervical specimens collected at eachvisit tested for more than 40 HPV genotypes.HPV 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 56,58, 59, 66, 68, 73, and 82 were considered theprimary carcinogenic genotypes. RESULTSWomen who tested positive for a carcinogenicHPV at enrolment and after about one year (9-21", "metadata": {}}
+{"_id": "23141360", "title": "", "text": "Nature and anisotropy of cortical forces orientingDrosophila tissue morphogenesisThemorphogenesis of developing embryos andorgans relies on the ability of cells to remodeltheir contacts with neighbouring cells. Usingquantitative modelling and laser nano-dissection,we probed the mechanics of a morphogeneticprocess, the elongation of Drosophilamelanogaster embryos, which results frompolarized cell neighbour exchanges. We showthat anisotropy of cortical tension at apical celljunctions is sufficient to drive tissue elongation.We estimated its value through comparisonsbetween in silico and in vivo data using varioustissue descriptors. Nano-dissection of theactomyosin network indicates that tension isanisotropically distributed and depends onmyosin II accumulation. Junction relaxation afternano-dissection also suggests that cortical elasticforces are dominant in this process.Interestingly, fluctuations in vertex position(points where three or more cells meet) facilitate", "metadata": {}}
+{"_id": "23148978", "title": "", "text": "The influence of some metabolic inhibitors onphagocytic activity of mouse macrophages invitro.The action of different metabolic inhibitorson phagocytosis by macrophages from mouseperitoneal exudate cultured in vitro was studied.The following metabolic inhibitors were tested:sodium iodoacetate, sodium fluoride, sodiumfluoroacetate, sodium malonate,2-4-dinitrophenol, sodium azide, ouabain andcycloheximide, all at the concentration of 10(-3)M. Iodoacetate caused a strong inhibitory effecton phagocytosis; this observation confirms thatglycolysis is the main source of energy for thephagocytic process. On the contrary, fluoride,although it is an effective inhibitor of glycolysis,did not exert any effect. This difference may beexplained by the fact that sodium fluoride blocksanaerobic glycolysis only in vitro at anunphysiological temperature (0 degrees C).Fluoroacetate and malonate, two compoundswhich interfere with the Krebs cycle, did notinhibit phagocytosis, but it is known that the", "metadata": {}}
+{"_id": "23160444", "title": "", "text": "Two-tiered coupling between flowing actin andimmobilized N-cadherin/catenin complexes inneuronal growth cones.Neuronal growth conesmove forward by dynamically connectingactin-based motility to substrate adhesion, butthe mechanisms at the individual molecular levelremain unclear. We cultured primary neurons onN-cadherin-coated micropatterned substrates,and imaged adhesion and cytoskeletal proteinsat the ventral surface of growth cones usingsingle particle tracking combined tophotoactivated localization microscopy(sptPALM). We demonstrate transientinteractions in the second time scale betweenflowing actin filaments and immobilizedN-cadherin/catenin complexes, translating into alocal reduction of the actin retrograde flow.Normal actin flow on micropatterns was rescuedby expression of a dominant negative N-cadherinconstruct competing for the coupling betweenactin and endogenous N-cadherin. Fluorescencerecovery after photobleaching (FRAP)", "metadata": {}}
+{"_id": "23180075", "title": "", "text": "Cloning of factors related to HIV-inducible LBPproteins that regulate steroidogenicfactor-1-independent human placentaltranscription of the cholesterol side-chaincleavage enzyme, P450scc.The cholesterolside-chain cleavage enzyme, cytochromeP450scc, initiates the biosynthesis of all steroidhormones. Adrenal and gonadal strategies forP450scc gene transcription are essentiallyidentical and depend on the orphan nuclearreceptor steroidogenic factor-1, but the placentalstrategy for transcription of P450scc employscis-acting elements different from those used inthe adrenal strategy and is independent ofsteroidogenic factor-1. Because placentalexpression of P450scc is required for humanpregnancy, we sought factors that bind to the-155/-131 region of the human P450sccpromoter, which participates in its placental butnot adrenal or gonadal transcription. A yeastone-hybrid screen of 2.4 x 10(6) cDNA clonesfrom human placental JEG-3 cells yielded two", "metadata": {}}
+{"_id": "23190392", "title": "", "text": "Functional reprogramming of polyploidization inmegakaryocytes.Polyploidization is a naturalprocess that frequently accompaniesdifferentiation; its deregulation is linked togenomic instability and cancer. Despite itsrelevance, why cells select differentpolyploidization mechanisms is unknown. Herewe report a systematic genetic analysis ofendomitosis, a process in which megakaryocytesbecome polyploid by entering mitosis butaborting anaphase. Whereas ablation of theAPC/C cofactor Cdc20 results in mitotic arrestand severe thrombocytopenia, lack of thekinases Aurora-B, Cdk1, or Cdk2 does not affectmegakaryocyte polyploidization or platelet levels.Ablation of Cdk1 forces a switch to endocycleswithout mitosis, whereas polyploidization in theabsence of Cdk1 and Cdk2 occurs in thepresence of aberrant re-replication events.Importantly, ablation of these kinases rescuesthe defects in Cdc20 null megakaryocytes. Thesefindings suggest that endomitosis can be", "metadata": {}}
+{"_id": "23195302", "title": "", "text": "Histone methyltransferase activity associatedwith a human multiprotein complex containingthe Enhancer of Zeste protein.Enhancer of Zeste[E(z)] is a Polycomb-group transcriptionalrepressor and one of the founding members ofthe family of SET domain-containing proteins.Several SET-domain proteins possess intrinsichistone methyltransferase (HMT) activity.However, recombinant E(z) protein was found tobe inactive in a HMT assay. Here we report theisolation of a multiprotein E(z) complex thatcontains extra sex combs, suppressor ofzeste-12 [Su(z)12], and the histone bindingproteins RbAp46/RbAp48. This complex, whichwe termed Polycomb repressive complex (PRC)2, possesses HMT activity with specificity for Lys9 (K9) and Lys 27 (K27) of histone H3. The HMTactivity of PRC2 is dependent on an intact SETdomain in the E(z) protein. We hypothesize thattranscriptional repression by the E(z) proteininvolves methylation-dependent recruitment ofPRC1. The presence of Su(z)12, a strong", "metadata": {}}
+{"_id": "23195674", "title": "", "text": "Simvastatin reduces platelet-endocardiumadhesion in atrial fibrillation.OBJECTIVES Toevaluate the relationship between CD40/CD40Lsystem and increased thrombogenesis in AF, andto test the effects of simvastatin treatment.METHODS In vitro study using human tissue,University Hospital (tertiary referral center).Experiments on right atrial segments obtainedbefore the onset of cardiopulmonary bypass weredone in either presence or absence of 5 microMsimvastatin. Two groups of patients in eitherchronic atrial fibrillation or sinus rhythm at thetime of cardiac surgery. The endocardialexpression of CD40, the release of CD40L, andadhesion of platelets to endocardium.Additionally, the thickness of platelet aggregatesand the platelet distribution on the endocardiumwere also evaluated. RESULTS Atrial fibrillationwas associated with a significant increase ofendocardial CD40 expression (293.1+/-55.1pg/ml vs. 230.9+/-53.3 pg/ml, p<0.01), andplatelet-endocardial adhesion compared with", "metadata": {}}
+{"_id": "23203102", "title": "", "text": "Transmission of sporadic Creutzfeldt-Jakobdisease by blood transfusion: risk factor orpossible biases.BACKGROUND The occurrence oftransfusion transmissions of variantCreutzfeldt-Jakob disease (CJD) cases hasreawakened attention to the possible similar riskposed by other forms of CJD. STUDY DESIGNAND METHODS CJD with a definite or probablediagnosis (sporadic CJD, n = 741; genetic CJD, n= 175) and no-CJD patients with definitealternative diagnosis (n = 482) with availableblood transfusion history were included in thestudy. The risk of exposure to blood transfusionoccurring more than 10 years before diseaseonset and for some possible confounding factorswas evaluated by calculating crude odds ratios(ORs). Variables with significant ORs inunivariate analyses were included in multivariatelogistic regression analyses. RESULTS In theunivariate model, blood transfusion occurringmore than 10 years before clinical onset is4.1-fold more frequent in sporadic CJD than in", "metadata": {}}
+{"_id": "23206239", "title": "", "text": "Advantages and pitfalls of fructosamine andglycated albumin in the diagnosis and treatmentof diabetes.The efficient diagnosis and accuratemonitoring of diabetic patients are cornerstonesfor reducing the risk of diabetic complications.The current diagnostic and prognostic strategiesin diabetes are mainly based on two tests,plasma (or capillary) glucose and glycatedhemoglobin (HbA1c). Nevertheless, thesemeasures are not foolproof, and their clinicalusefulness is biased by a number of clinical andanalytical factors. The introduction of otherindices of glucose homeostasis in clinical practicesuch as fructosamine and glycated albumin (GA)may be regarded as an attractive alternative,especially in patients in whom the measurementof HbA1c may be biased or even unreliable.These include patients with rapid changes ofglucose homeostasis and larger glycemicexcursions, and patients with red blood celldisorders and renal disease. According toavailable evidence, the overall diagnostic", "metadata": {}}
+{"_id": "23208167", "title": "", "text": "Catalytic-Independent Functions of PARP-1Determine Sox2 Pioneer Activity at IntractableGenomic Loci.Pioneer transcription factors (TFs)function as genomic first responders, binding toinaccessible regions of chromatin to promoteenhancer formation. The mechanism by whichpioneer TFs gain access to chromatin remains animportant unanswered question. Here we showthat PARP-1, a nucleosome-binding protein,cooperates with intrinsic properties of thepioneer TF Sox2 to facilitate its binding tointractable genomic loci in embryonic stem cells.These actions of PARP-1 occur independently ofits poly(ADP-ribosyl) transferase activity.PARP-1-dependent Sox2-binding sites reside ineuchromatic regions of the genome withrelatively high nucleosome occupancy and lowco-occupancy by other transcription factors.PARP-1 stabilizes Sox2 binding to nucleosomesat suboptimal sites through cooperativeinteractions on DNA. Our results define intrinsicand extrinsic features that determine Sox2", "metadata": {}}
+{"_id": "23237995", "title": "", "text": "Steroid regulation of C. elegans diapause,developmental timing, and longevity.Hormonesplay a critical role in driving major stagetransitions and developmental timing events inmany species. In the nematode C. elegans thesteroid hormone receptor, DAF-12, works at theconfluence of pathways regulatingdevelopmental timing, stage specification, andlongevity. DAF-12 couples environmental andphysiologic signals to life history regulation, andit is embedded in a rich architecture governingdiverse processes. Here, we highlight themolecular insights, extraordinary circuitry, andsignaling pathways governing life stagetransitions in the worm and how they haveyielded fundamental insights into steroidregulation of biological time.", "metadata": {}}
+{"_id": "23244529", "title": "", "text": "A core subunit of Polycomb repressive complex 1is broadly conserved in function but not primarysequence.Polycomb Group (PcG) proteinsmediate heritable gene silencing by modifyingchromatin structure. An essential PcG complex,PRC1, compacts chromatin and inhibitschromatin remodeling. In Drosophilamelanogaster, the intrinsically disorderedC-terminal region of PSC (PSC-CTR) mediatesthese noncovalent effects on chromatin, and isessential for viability. Because the PSC-CTRsequence is poorly conserved, the significance ofits effects on chromatin outside of Drosophilawas unclear. The absence of folded domains alsomade it difficult to understand how the sequenceof PSC-CTR encodes its function. To determinethe mechanistic basis and extent of conservationof PSC-CTR activity, we identified 17 metazoanPSC-CTRs spanning chordates to arthropods, andexamined their sequence features andbiochemical properties. PSC-CTR sequences arepoorly conserved, but are all highly charged and", "metadata": {}}
+{"_id": "23245050", "title": "", "text": "Dietary status of trained female cyclists.Dietarystatus was evaluated in eight highly trainedfemale cyclists. Each cyclist kept a 3-dayweighed food record. Diets were analyzed fornutrient content using a computerized softwarepackage. Blood was also obtained and evaluatedfor hemoglobin, hematocrit, and albumin. For anathletic group, the cyclists' diets were found tobe low in energy (85% RDA) and carbohydrate(4.4 gm/kg body weight per day). Mean dailydietary intakes were well below the RDAs forfolacin (76% RDA), magnesium (81%), iron(59%), and zinc (48%). In addition, more thanone-third of the cyclists failed to consume 67%of the RDA for the following micronutrients:pyridoxine, folacin, cobalamin, vitamin E,magnesium, iron, and zinc. Hemoglobin (135gm/L), hematocrit (0.39), and albumin (45gm/L) values were all normal, although mosthemoglobin values were in the lower 50% ofnormal range. Foods such as meats, poultry,fish, beans, peas, and nuts were low or absent", "metadata": {}}
+{"_id": "23253955", "title": "", "text": "Regulation of Pax-3 expression in thedermomyotome and its role in muscledevelopment.The segmented mesoderm invertebrates gives rise to a variety of cell types inthe embryo including the axial skeleton andmuscle. A number of transcription factorscontaining a paired domain (Pax proteins) areexpressed in the segmented mesoderm duringembryogenesis. These include Pax-3 and aclosely related gene, Pax-7, both of which areexpressed in the segmental plate and in thedermomyotome. In this paper, we show thatsignals from the notochord pattern theexpression of Pax-3, Pax-7 and Pax-9 in somitesand the subsequent differentiation of cell typesthat arise from the somitic mesoderm. Wedirectly assess the role of the Pax-3 gene in thedifferentiation of cell types derived from thedermomyotome by analyzing the development ofmuscle in splotch mouse embryos which lack afunctional Pax-3 gene. A population ofPax-3-expressing cells derived from the", "metadata": {}}
+{"_id": "23260700", "title": "", "text": "Angiopoietin 2 is a partial agonist/antagonist ofTie2 signaling in the endothelium.Angiopoietin 2(Ang2) was originally shown to be a competitiveantagonist for Ang1 of the receptor tyrosinekinase Tie2 in endothelial cells (ECs). Since then,reports have conflicted on whether Ang2 is anagonist or antagonist of Tie2. Here we show thatAng2 functions as an agonist when Ang1 isabsent but as a dose-dependent antagonist whenAng1 is present. Exogenous Ang2 activates Tie2and the promigratory, prosurvival PI3K/Aktpathway in ECs but with less potency and loweraffinity than exogenous Ang1. ECs produce Ang2but not Ang1. This endogenous Ang2 maintainsTie2, phosphatidylinositol 3-kinase, and Aktactivities, and it promotes EC survival, migration,and tube formation. However, when ECs arestimulated with Ang1 and Ang2, Ang2dose-dependently inhibits Ang1-induced Tie2phosphorylation, Akt activation, and EC survival.We conclude that Ang2 is both an agonist and anantagonist of Tie2. Although Ang2 is a weaker", "metadata": {}}
+{"_id": "23262027", "title": "", "text": "Bacteremia caused by a strain of Desulfovibriorelated to the provisionally named Desulfovibriofairfieldensis.Eight isolates of Desulfovibrio spp.have been obtained over 5 years from abdominalor brain abscesses or blood. Seven isolates werepart of a mixed flora [corrected]. One strain wasisolated in pure culture from the blood of apatient with peritonitis of appendicular origin.According to the 16S rRNA gene sequences, thisstrain was close to Desulfovibrio fairfieldensis.The present report describes the fourth isolate ofthis recently described species to be isolated inpure culture or as a predominant part of the floraand to be associated with infectious processes.Thus, D. fairfieldensis may possess a higherpathogenic potential than other Desulfovibriospecies.", "metadata": {}}
+{"_id": "23267371", "title": "", "text": "Vitamin D: The \"sunshine\" vitamin.Vitamin Dinsufficiency affects almost 50% of thepopulation worldwide. An estimated 1 billionpeople worldwide, across all ethnicities and agegroups, have a vitamin D deficiency (VDD). Thispandemic of hypovitaminosis D can mainly beattributed to lifestyle (for example, reducedoutdoor activities) and environmental (forexample, air pollution) factors that reduceexposure to sunlight, which is required forultraviolet-B (UVB)-induced vitamin D productionin the skin. High prevalence of vitamin Dinsufficiency is a particularly important publichealth issue because hypovitaminosis D is anindependent risk factor for total mortality in thegeneral population. Current studies suggest thatwe may need more vitamin D than presentlyrecommended to prevent chronic disease. As thenumber of people with VDD continues toincrease, the importance of this hormone inoverall health and the prevention of chronicdiseases are at the forefront of research. VDD is", "metadata": {}}
+{"_id": "23269537", "title": "", "text": "Cyclin D1 activation in B-cell malignancy:association with changes in histone acetylation,DNA methylation, and RNA polymerase II bindingto both promoter and distal sequences.Cyclin D1expression is deregulated by chromosometranslocation in mantle cell lymphoma and asubset of multiple myeloma. The molecularmechanisms involved in long-distance genederegulation remain obscure, although changesin acetylated histones and methylated CpGdinucleotides may be important. The patterns ofDNA methylation and histone acetylation weredetermined at the cyclin D1 locus onchromosome 11q13 in B-cell malignancies. Thecyclin D1 promoter was hypomethylated andhyperacetylated in expressing cell lines andpatient samples, and methylated andhypoacetylated in nonexpressing cell lines.Domains of hyperacetylated histones andhypomethylated DNA extended over 120 kbupstream of the cyclin D1 gene. Interestingly,hypomethylated DNA and hyperacetylated", "metadata": {}}
+{"_id": "23273454", "title": "", "text": "The physiological regulation of toll-like receptorexpression and function in humans.Elevenmammalian toll-like receptors (TLRs 1-11) havebeen identified to date and are known to play acrucial role in the regulation of immuneresponses; however, the factors that regulateTLR expression and function in vivo are poorlyunderstood. Therefore, in the present study, weinvestigated the physiological regulation of TLRexpression and function in humans. To examinethe influence of diurnal rhythmicity on TLRexpression and function, peripheral venous bloodsamples were collected from healthy volunteers(n = 8) at time points coinciding with the peakand nadir in the endogenous circulating cortisolconcentration. While no diurnal rhythmicity inthe expression of TLRs 1, 2, 4 or 9 wasobserved, the upregulation of costimulatory(CD80 and CD86) and antigen-presenting (MHCclass II) molecules on CD14(+) monocytesfollowing activation with specific TLR ligands wasgreater (P < 0.05) in samples obtained in the", "metadata": {}}
+{"_id": "23284774", "title": "", "text": "A review of psychosocial needs of breast-cancerpatients and their relatives.AIM To identify thepsychosocial needs of breast-cancer patients andtheir relatives along with factors affecting theseneeds and to develop a tentative model to guidefurther research and need assessments in clinicalpractice. BACKGROUND Women experiencingbreast cancer must deal with the diagnosis of alife-threatening illness. Treatment and therecovery process can be demanding for patientsand their relatives. Need assessment may helpclinicians focus on providing appropriate help.DESIGN Literature review. METHOD Undertakenusing electronic databases and specific researchterms; 20 articles were identified and analysed.RESULTS The needs identified by patients involve(1) treatment-related physical and socialimpairment like fatigue, menopausal symptomsand a changed body image and (2) emotionaldistress like fear of recurrence, anxiety anddepression. Partners need help to protectthemselves and the patient from different", "metadata": {}}
+{"_id": "23286603", "title": "", "text": "Poly(ADP-ribose) Polymerase 1 Represses Liver XReceptor-mediated ABCA1 Expression andCholesterol Efflux in Macrophages.Liver Xreceptors (LXR) are oxysterol-activated nuclearreceptors that play a central role in reversecholesterol transport through up-regulation ofATP-binding cassette transporters (ABCA1 andABCG1) that mediate cellular cholesterol efflux.Mouse models of atherosclerosis exhibit reducedatherosclerosis and enhanced regression ofestablished plaques upon LXR activation.However, the coregulatory factors that affectLXR-dependent gene activation in macrophagesremain to be elucidated. To identify novelregulators of LXR that modulate its activity, weused affinity purification and mass spectrometryto analyze nuclear LXRα complexes and identifiedpoly(ADP-ribose) polymerase-1 (PARP-1) as anLXR-associated factor. In fact, PARP-1 interactedwith both LXRα and LXRβ. Both depletion ofPARP-1 and inhibition of PARP-1 activityaugmented LXR ligand-induced ABCA1", "metadata": {}}
+{"_id": "23294314", "title": "", "text": "Emergency contraception: advance provision in ayoung, high-risk clinic population.OBJECTIVE Toassess whether advance provision of emergencycontraception increases its use and whether ithas secondary effects on regular contraceptiveuse. METHODS We conducted a controlled trial offemale clients, aged 16-24 years, who attendeda publicly funded family planning clinic. Womenwere systematically assigned to receive anadvance provision of emergency contraceptionand education (treatment) or education only(control). Among 263 participants enrolled (133treatment, 130 control), follow-up wascompleted in 213 (111 treatment, 102 control).The main outcome measures were emergencycontraception knowledge and use, frequency ofunprotected sex, and pattern of contraceptiveuse in the past 4 months. RESULTS Participantswere aware of emergency contraception atfollow-up, but the treatment group was threetimes as likely to use it (P =.006). Although thetreatment group did not report higher", "metadata": {}}
+{"_id": "23304931", "title": "", "text": "Immunophenotypic analysis of AIDS-relateddiffuse large B-cell lymphoma and clinicalimplications in patients from AIDS malignanciesconsortium clinical trials 010 and 034PURPOSEDiffuse large B-cell lymphoma (DLBCL)represents a clinically heterogeneous disease.Models based on immunohistochemistry predictclinical outcome. These include subdivision intogerminal center (GC) versus non-GC subtypes;proliferation index (measured by expression ofKi-67), and expression of BCL-2, FOXP1, orB-lymphocyte-induced maturation protein(Blimp-1)/PRDM1. We sought to determinewhether immunohistochemical analyses ofbiopsies from patients with DLBCL having HIVinfection are similarly relevant for prognosis.PATIENTS AND METHODS We examined 81DLBCLs from patients with AIDS in AMC010(cyclophosphamide, doxorubicin, vincristine, andprednisone [CHOP] v CHOP-rituximab) andAMC034 (etoposide, doxorubicin, vincristine,prednisone, and dose-adjusted", "metadata": {}}
+{"_id": "23305547", "title": "", "text": "Prion-like activity of Cu/Zn superoxidedismutase: implications for amyotrophic lateralsclerosis.Neurodegenerative diseases belong to alarger group of protein misfolding disorders,known as proteinopathies. There is increasingexperimental evidence implicating prion-likemechanisms in many commonneurodegenerative disorders, includingAlzheimer disease, Parkinson disease, thetauopathies, and amyotrophic lateral sclerosis(ALS), all of which feature the aberrantmisfolding and aggregation of specific proteins.The prion paradigm provides a mechanism bywhich a mutant or wild-type protein candominate pathogenesis through the initiation ofself-propagating protein misfolding. ALS, a lethaldisease characterized by progressivedegeneration of motor neurons is understood asa classical proteinopathy; the disease is typifiedby the formation of inclusions consisting ofaggregated protein within and around motorneurons that can contribute to neurotoxicity. It is", "metadata": {}}
+{"_id": "23305884", "title": "", "text": "Analysis of Epstein-Barr virus-regulated hostgene expression changes through primary B-celloutgrowth reveals delayed kinetics of latentmembrane protein 1-mediated NF-κBactivation.Epstein-Barr virus (EBV) is anoncogenic human herpesvirus that dramaticallyreorganizes host gene expression to immortalizeprimary B cells. In this study, we analyzedEBV-regulated host gene expression changesfollowing primary B-cell infection, both duringinitial proliferation and through transformationinto lymphoblastoid cell lines (LCLs). While mostEBV-regulated mRNAs were changed during thetransition from resting, uninfected B cellsthrough initial B-cell proliferation, a substantialnumber of mRNAs changed uniquely from earlyproliferation through LCL outgrowth. Weidentified constitutively and dynamicallyEBV-regulated biological processes, proteinclasses, and targets of specific transcriptionfactors. Early after infection, genes associatedwith proliferation, stress responses, and the p53", "metadata": {}}
+{"_id": "23326722", "title": "", "text": "Clinical and laboratory features of adult T-cellleukaemia lymphoma in Barbados.We describethe clinical and pathological features of 23Afro-Caribbean patients with adult T-cellleukaemia/lymphoma admitted to the QueenElizabeth Hospital, Barbados over a 5 yearperiod. There were 9 males and 14 females, witha median age of 38 years (range 14-84). Twelvehad acute leukaemia, 10 lymphoma (including 4with solitary extra nodal lesions) and 1smouldering subtype. Two patients had a pasthistory of tropical spastic paraparesis/HTLV Iassociated myelopathy (TSP/HAM). Theprognosis was poor, with only 3 completeresponses to chemotherapy (CHOP) lasting from9 to 36 months. We conclude that ATLL inBarbados is similar to the disease in the otherCaribbean islands and Japan, except that inBarbados the age of onset is over a decadeyounger than in Japan.", "metadata": {}}
+{"_id": "23331269", "title": "", "text": "Acoustic landmarks drive delta-theta oscillationsto enable speech comprehension by facilitatingperceptual parsing.A growing body of researchsuggests that intrinsic neuronal slow (<10 Hz)oscillations in auditory cortex appear to trackincoming speech and other spectro-temporallycomplex auditory signals. Within this framework,several recent studies have identifiedcritical-band temporal envelopes as the specificacoustic feature being reflected by the phase ofthese oscillations. However, how this alignmentbetween speech acoustics and neural oscillationsmight underpin intelligibility is unclear. Here wetest the hypothesis that the 'sharpness' oftemporal fluctuations in the critical bandenvelope acts as a temporal cue to speechsyllabic rate, driving delta-theta rhythms to trackthe stimulus and facilitate intelligibility. Weinterpret our findings as evidence that sharpevents in the stimulus cause cortical rhythms tore-align and parse the stimulus intosyllable-sized chunks for further decoding. Using", "metadata": {}}
+{"_id": "23342686", "title": "", "text": "Crystal structures of complexes of the smallribosomal subunit with tetracycline, edeine andIF3.The small ribosomal subunit is responsiblefor the decoding of genetic information and playsa key role in the initiation of protein synthesis.We analyzed by X-ray crystallography thestructures of three different complexes of thesmall ribosomal subunit of Thermus thermophiluswith the A-site inhibitor tetracycline, theuniversal initiation inhibitor edeine and theC-terminal domain of the translation initiationfactor IF3. The crystal structure analysis of thecomplex with tetracycline revealed thefunctionally important site responsible for theblockage of the A-site. Five additionaltetracycline sites resolve most of thecontroversial biochemical data on the location oftetracycline. The interaction of edeine with thesmall subunit indicates its role in inhibitinginitiation and shows its involvement with P-sitetRNA. The location of the C-terminal domain ofIF3, at the solvent side of the platform, sheds", "metadata": {}}
+{"_id": "23342845", "title": "", "text": "Plasmid-encoded proinsulin preserves C-peptidewhile specifically reducing proinsulin-specificCD8\u0000 T cells in type 1 diabetes.In type 1diabetes (T1D), there is an intense inflammatoryresponse that destroys the β cells in thepancreatic islets of Langerhans, the site whereinsulin is produced and released. A therapy forT1D that targets the specific autoimmuneresponse in this disease while leaving theremainder of the immune system intact, has longbeen sought. Proinsulin is a major target of theadaptive immune response in T1D. Wehypothesized that an engineered DNA plasmidencoding proinsulin (BHT-3021) would preserveβ cell function in T1D patients through reductionof insulin-specific CD8\u0000 T cells. We studied 80subjects over 18 years of age who werediagnosed with T1D within the past 5 years.Subjects were randomized 2:1 to receiveintramuscular injections of BHT-3021 orBHT-placebo, weekly for 12 weeks, and thenmonitored for safety and immune responses in a", "metadata": {}}
+{"_id": "23349986", "title": "", "text": "Dexamethasone and risk of nausea and vomitingand postoperative bleeding after tonsillectomy inchildren: a randomized trial.CONTEXTDexamethasone is widely used to preventpostoperative nausea and vomiting (PONV) inpediatric tonsillectomy. OBJECTIVE To assesswhether dexamethasone dose-dependentlyreduces the risk of PONV at 24 hours aftertonsillectomy. DESIGN, SETTING, AND PATIENTSRandomized placebo-controlled trial conductedamong 215 children undergoing electivetonsillectomy at a major public teaching hospitalin Switzerland from February 2005 to December2007. INTERVENTIONS Children were randomlyassigned to receive dexamethasone (0.05, 0.15,or 0.5 mg/kg) or placebo intravenously afterinduction of anesthesia. Acetaminophen-codeineand ibuprofen were given as postoperativeanalgesia. Follow-up continued until the 10thpostoperative day. MAIN OUTCOME MEASURESThe primary end point was prevention of PONVat 24 hours; secondary end points were decrease", "metadata": {}}
+{"_id": "23351136", "title": "", "text": "Detection of sweet and umami taste in theabsence of taste receptor T1r3.The tastes ofsugars (sweet) and glutamate (umami) arethought to be detected by T1r receptorsexpressed in taste cells. Molecular genetics andheterologous expression implicate T1r2 plus T1r3as a sweet-responsive receptor,and T1r1 plusT1r3,as well as a truncated form of the type 4metabotropic glutamate receptor(taste-mGluR4),as umami-responsive receptors.Here,we show that mice lacking T1r3 showed nopreference for artificial sweeteners and haddiminished but not abolished behavioral andnerve responses to sugars and umamicompounds. These results indicate thatT1r3-independent sweet- and umami-responsivereceptors and/or pathways exist in taste cells.", "metadata": {}}
+{"_id": "23356816", "title": "", "text": "Cyclin A1 is required for meiosis in the malemouseThe mammalian A-type cyclin familyconsists of two members, cyclin A1 (encoded byCcna1) and cyclin A2 (encoded by Ccna2). CyclinA2 promotes both G1/S and G2/M transitions,and targeted deletion of Ccna2 in mouse isembryonic lethal. Cyclin A1 is expressed in miceexclusively in the germ cell lineage and isexpressed in humans at highest levels in thetestis and certain myeloid leukaemia cells. Toinvestigate the role of cyclin A1 and possibleredundancy among the cyclins in vivo, wegenerated mice bearing a null mutation ofCcna1. Ccna1-/- males were sterile due to ablock of spermatogenesis before the first meioticdivision, whereas females were normal. Meiosisarrest in Ccna1–/– males was associated withincreased germ cell apoptosis, desynapsisabnormalities and reduction of Cdc2 kinaseactivation at the end of meiotic prophase. CyclinA1 is therefore essential for spermatocytepassage into the first meiotic division in male", "metadata": {}}
+{"_id": "23369842", "title": "", "text": "Metabolic effects of isoenergetic nutrientexchange over 24 hours in relation to obesity inwomen.Twenty-four hour whole body indirectcalorimetry has been used to study the effects offeeding, during a sedentary test day,isoenergetic diets which varied in fat (3 or 40 percent of total energy) and carbohydrate (82 or 45per cent) content. Three groups of women werestudied: lean, obese and 'post-obese' afterslimming. Energy expenditure was greater inabsolute terms in the obese women. Twenty-fourhour energy expenditure was lower by only 3-7per cent when fasting compared to that when fedto achieve energy balance. There were no largedifferences in energy expenditure between thetwo diets or between the groups but thethermogenic effect of the high carbohydrate dietwas significantly greater than that of the high fatdiet (5.8 vs 3.5 per cent of energy expenditure:P less than 0.01). The post-obese tended to havelower energy expenditure per kg FFM thancontrols when fasting and when high-fat fed, but", "metadata": {}}
+{"_id": "23377475", "title": "", "text": "Acute kidney injury and chronic kidney disease:an integrated clinical syndrome.The previousconventional wisdom that survivors of acutekidney injury (AKI) tend to do well and fullyrecover renal function appears to be flawed. AKIcan cause end-stage renal disease (ESRD)directly, and increase the risk of developingincident chronic kidney disease (CKD) andworsening of underlying CKD. In addition,severity, duration, and frequency of AKI appearto be important predictors of poor patientoutcomes. CKD is an important risk factor for thedevelopment and ascertainment of AKI.Experimental data support the clinicalobservations and the bidirectional nature of therelationships between AKI and CKD. Reductionsin renal mass and nephron number, vascularinsufficiency, cell cycle disruption, andmaladaptive repair mechanisms appear to beimportant modulators of progression in patientswith and without coexistent CKD. Distinctionbetween AKI and CKD may be artificial.", "metadata": {}}
+{"_id": "23388442", "title": "", "text": "Fatty acids as modulators of the immuneresponse.Research describing fatty acids asmodulators of inflammation and immuneresponses abounds. Many of these studies havefocused on one particular group of fatty acids,omega-3. The data from animal studies haveshown that these fatty acids can have powerfulanti-inflammatory and immunomodulatoryactivities in a wide array of diseases (e.g.,autoimmunity, arthritis, and infection). However,the evidence from human trials is moreequivocal. In this review, a historical frameworkfor understanding how and why fatty acids mayaffect the immune system is provided. Second,highlights of two recent landmark reports fromthe Agency for Healthcare Research and Qualityare presented. These reports critically evaluatethe evidence from human clinical trials ofomega-3 fatty acids and rheumatoid arthritis,asthma, and a few other immune-mediateddiseases. Third, the data from human clinicaltrials investigating the impact of various", "metadata": {}}
+{"_id": "23389795", "title": "", "text": "Common and rare variants in multifactorialsusceptibility to common diseasesHere, we givea historical overview of the search for geneticvariants that influence the susceptibility of anindividual to a chronic disease, from RA Fisher'sseminal work to the current excitement ofwhole-genome association studies (WGAS). Wethen discuss the concepts behind theidentification of common variants as diseasecausal factors and contrast them to the basicideas that underlie the rare variant hypothesis.The identification of rare variants involves thecareful selection of candidate genes to examine,the availability of highly efficient resequencingtechniques and the appropriate assessment ofthe functional consequences of the implicatedvariant. We believe that this strategy can besuccessfully applied at present in order tounravel the contribution of rare variants to themultifactorial inheritance of common diseases,which could lead to the implementation of muchneeded preventative screening schemes.", "metadata": {}}
+{"_id": "23393712", "title": "", "text": "Cell-cell adhesion and signalling.Signallingpathways activated by Rho small GTPases haverecently been identified that coordinate junctionassembly, stability and function, as well asinteractions of adhesive complexes with theunderlying cortical cytoskeleton. Particularlyexciting is the interplay between adherensjunctions, activation of Rho proteins and thedynamics of microtubule, actin and intermediatefilaments. This interplay has importantimplications for functional regulation of cell-celladhesion, and points to a more integrated viewof signalling processes.", "metadata": {}}
+{"_id": "23397658", "title": "", "text": "Fibroblast growth factor 21 as an emergingmetabolic regulator: clinicalperspectives.Fibroblast growth factor 21(FGF21), a metabolic hormone predominantlyproduced by the liver, is also expressed inadipocytes and the pancreas. It regulatesglucose and lipid metabolism through pleiotropicactions in these tissues and the brain. In mice,fasting leads to increased PPAR-α mediatedexpression of FGF21 in the liver where itstimulates gluconeogenesis, fatty acid oxidation,and ketogenesis, as an adaptive response tofasting and starvation. In the fed state, FGF21acts as an autocrine factor in adipocytes,regulating the activity of PPAR-γ through afeed-forward loop mechanism. Administration ofrecombinant FGF21 has been shown to confermultiple metabolic benefits on insulin sensitivity,blood glucose, lipid profile and body weight inobese mice and diabetic monkeys, withoutmitogenic or other side effects. Such findingshighlight the potential role of FGF21 as a", "metadata": {}}
+{"_id": "23400191", "title": "", "text": "Assessment of the cerebral circulation in adultswith coarctation of the aorta.AIMS There is afivefold increase in the frequency of intracranialaneurysm (IA) in adults with coarctation of theaorta (CoA). Current guidelines for managementof adults with CoA recommend computedtomography angiography (CTA) or magneticresonance imaging of the intracranial vessels.However, this recommendation has not beenuniversally accepted. The purpose of our studywas to prospectively perform CTA of theintracranial vessels in adults with CoA toevaluate the prevalence and identify high-riskfeatures of this complication. METHODS ANDRESULTS From January 2008 to February 2011,adults ≥18 years of age with CoA wereprospectively enrolled in a screening programwith CTA of the intracranial vessels. Analyses ofprognostic variables were performed with bothFisher's exact and two sample t-test. Forty-threepatients (58% female, 33.55 ± 10.21 years) withCoA completed CTA of the intracranial vessels.", "metadata": {}}
+{"_id": "23403754", "title": "", "text": "Bioenergetic aspects of apoptosis, necrosis andmitoptosisIn this review I summarizeinterrelations between bioenergetic processesand such programmed death phenomena as cellsuicide (apoptosis and necrosis) andmitochondrial suicide (mitoptosis). The followingconclusions are made. (I) ATP and rather oftenmitochondrial hyperpolarization (i.e. an increasein membrane potential, ΔΨ) are required forcertain steps of apoptosis and necrosis. (II)Apoptosis, even if it is accompanied by ΔΨ and[ATP] increases at its early stage, finally resultsin a ΔΨ collapse and ATP decrease. (III)Moderate (about three-fold) lowering of [ATP] forshort and long periods of time induces apoptosisand necrosis, respectively. In some types ofapoptosis and necrosis, the cell death ismediated by a ΔΨ-dependent overproduction ofROS by the initial (Complex I) and the middle(Complex III) spans of the respiratory chain.ROS initiate mitoptosis which is postulated to ridthe intracellular population of mitochondria from", "metadata": {}}
+{"_id": "23418635", "title": "", "text": "Embryonic stem cells require Wnt proteins toprevent differentiation to epiblast stemcellsPluripotent stem cells exist in naive andprimed states, epitomized by mouse embryonicstem cells (ESCs) and the developmentally moreadvanced epiblast stem cells (EpiSCs; ref. ). Inthe naive state of ESCs, the genome has anunusual open conformation and possesses aminimum of repressive epigenetic marks. Incontrast, EpiSCs have activated the epigeneticmachinery that supports differentiation towardsthe embryonic cell types. The transition fromnaive to primed pluripotency thereforerepresents a pivotal event in cellulardifferentiation. But the signals that control thisfundamental differentiation step remain unclear.We show here that paracrine and autocrine Wntsignals are essential self-renewal factors forESCs, and are required to inhibit theirdifferentiation into EpiSCs. Moreover, we findthat Wnt proteins in combination with thecytokine LIF are sufficient to support ESC", "metadata": {}}
+{"_id": "23420615", "title": "", "text": "CLIP identifies Nova-regulated RNA networks inthe brain.Nova proteins are neuron-specificantigens targeted in paraneoplastic opsoclonusmyoclonus ataxia (POMA), an autoimmuneneurologic disease characterized by abnormalmotor inhibition. Nova proteins regulate neuronalpre-messenger RNA splicing by directly bindingto RNA. To identify Nova RNA targets, wedeveloped a method to purify protein-RNAcomplexes from mouse brain with the use ofultraviolet cross-linking and immunoprecipitation(CLIP).Thirty-four transcripts were identifiedmultiple times by Nova CLIP.Three-quarters ofthese encode proteins that function at theneuronal synapse, and one-third are involved inneuronal inhibition. Splicing targets confirmed inNova-/- mice include c-Jun N-terminal kinase 2,neogenin, and gephyrin; the latter encodes aprotein that clusters inhibitorygamma-aminobutyric acid and glycine receptors,two previously identified Nova splicing targets.Thus, CLIP reveals that Nova coordinately", "metadata": {}}
+{"_id": "23420807", "title": "", "text": "Anti-Angiogenic Activity of Selected ReceptorTyrosine Kinase Inhibitors, PD166285 andPD173074: Implications for CombinationTreatment with PhotodynamicTherapyAngiogenesis, the formation of newblood vessels from an existing vasculature, isrequisite for tumor growth. It entails intercellularcoordination of endothelial and tumor cellsthrough angiogenic growth factor signaling.Interruption of these events has implications inthe suppression of tumor growth. PD166285, abroad-spectrum receptor tyrosine kinase (RTK)inhibitor, and PD173074, a selective FGFR1TKinhibitor, were evaluated for theiranti-angiogenic activity and anti-tumor efficacyin combination with photodynamic therapy(PDT). To evaluate the anti-angiogenic andanti-tumor activities of these compounds, RTKassays, in vitro tumor cell growth andmicrocapillary formation assays, in vivo murineangiogenesis and anti-tumor efficacy studiesutilizing RTK inhibitors in combination with", "metadata": {}}
+{"_id": "23423230", "title": "", "text": "The VirB type IV secretion system of Bartonellahenselae mediates invasion, proinflammatoryactivation and antiapoptotic protection ofendothelial cells.Bartonella henselae is anarthropod-borne zoonotic pathogen causingintraerythrocytic bacteraemia in the felinereservoir host and a broad range of clinicalmanifestations in incidentally infected humans.Remarkably, B. henselae can specifically colonizethe human vascular endothelium, resulting ininflammation and the formation ofvasoproliferative lesions known as bacillaryangiomatosis and bacillary peliosis. Culturedhuman endothelial cells provide an in vitrosystem to study this intimate interaction of B.henselae with the vascular endothelium.However, little is known about the bacterialvirulence factors required for this pathogenicprocess. Recently, we identified the type IVsecretion system (T4SS) VirB as an essentialpathogenicity factor in Bartonella, required toestablish intraerythrocytic infection in the", "metadata": {}}
+{"_id": "23439808", "title": "", "text": "Serum Cystatin C Is Related to Pulse WaveVelocity Even in Subjects with Normal SerumCreatinineWe hypothesized that serum cystatin Ccan be a more predictable marker of arterialstiffness than serum creatinine andcreatinine-based glomerular filtration rate (GFR).The aim of this study is to evaluate whetherserum cystatin C is related to arterial stiffnessindependently of serum creatinine in subjects forwhom serum creatinine is normal. A total of2,018 individuals (1,120 males, 898 females)were enrolled. Mean brachial-ankle pulse wavevelocity (baPWV) was used as a marker ofarterial stiffness and sex-specific analysis wasperformed. A positive relationship betweenbaPWV and serum cystatin C(Y=1109.0548+329.9102X, r2=0.056, p<0.001)was found in males. Stepwise multivariateregression analysis in males showed that age,waist circumference, heart rate, cystatin C level,triglyceride level, and fasting glucose wereindependent contributors to baPWV. In females,", "metadata": {}}
+{"_id": "23440856", "title": "", "text": "Screening for inhibition of Vibrio choleraeVipA-VipB interaction identifies small-moleculecompounds active against type VI secretion.Thetype VI secretion system (T6SS) is the mostprevalent bacterial secretion system and animportant virulence mechanism utilized byGram-negative bacteria, either to targeteukaryotic cells or to combat other microbes.The components show much variability, butsome appear essential for the function, and twohomologues, denoted VipA and VipB in Vibriocholerae, have been identified in all T6SSsdescribed so far. Secretion is dependent onbinding of an α-helical region of VipA to VipB,and in the absence of this binding, bothcomponents are degraded within minutes andsecretion is ceased. The aim of the study was toinvestigate if this interaction could be blocked,and we hypothesized that such inhibition wouldlead to abrogation of T6S. A library of 9,600small-molecule compounds was screened fortheir ability to block the binding of VipA-VipB in a", "metadata": {}}
+{"_id": "23460562", "title": "", "text": "Early life compartmentalization of human T celldifferentiation and regulatory function in mucosaland lymphoid tissuesIt is unclear how theimmune response in early life becomesappropriately stimulated to provide protectionwhile also avoiding excessive activation as aresult of diverse new antigens. T cells areintegral to adaptive immunity; mouse studiesindicate that tissue localization of T cell subsetsis important for both protective immunity andimmunoregulation. In humans, however, theearly development and function of T cells intissues remain unexplored. We present here ananalysis of lymphoid and mucosal tissue T cellsderived from pediatric organ donors in the firsttwo years of life, as compared to adult organdonors, revealing early compartmentalization ofT cell differentiation and regulation. Whereasadult tissues contain a predominance of memoryT cells, in pediatric blood and tissues the mainsubset consists of naive recent thymicemigrants, with effector memory T cells (T(EM))", "metadata": {}}
+{"_id": "23471400", "title": "", "text": "Circulating microRNAs as biomarkers forhepatocellular carcinoma.GOALS We investigatedwhether measurement of serum levels of themicroRNAs (miRNAs) miR-16, miR-195, andmiR-199a, alone or in combination withconventional serum markers, can help todifferentiate hepatocellular carcinoma (HCC)from chronic liver diseases (CLDs).BACKGROUND Recent reports suggest a linkbetween aberrant expression of miRNA, andHCC. STUDY This retrospective analysis wasconducted using sera from 105 HCC patients,107 CLD patients, and 71 normal controlsubjects. The miRNAs were measured usingreal-time reverse transcription-polymerase chainreaction. The conventional HCC markersα-fetoprotein (AFP), lens culinarisagglutinin-reactive AFP (AFP-L3%), anddes-γ-carboxyprothrombin (DCP) were measuredwith commercial kits. RESULTS Serum levels ofmiR-16 and miR-199a were significantly lower inHCC than in CLD patients or control subjects", "metadata": {}}
+{"_id": "23495058", "title": "", "text": "Mitochondrial haplogroups and hypervariableregion polymorphisms in schizophrenia: acase-control study.Previous studies havedetected associations between mitochondrialhaplogroups and schizophrenia (SZ). However,no study has examined the relationship betweenmajor mitochondrial DNA (mtDNA) haplogroupsand SZ in the Chinese population. The aim of thisstudy was to assess the association betweenmtDNA haplogroups and SZ genesis in theChinese Han population. We used a case-controlstudy and sequenced the mtDNA hypervariableregions (HVR1, HVR2, and HVR3) in the Hanpopulation. We analyzed mtDNA haplogroupsand HVR polymorphisms in 298 SZ patients and298 controls. The haplotypes were classified into10 major haplogroups: A, B, CZ, D, F, G, M, N,N9a, and R. Statistical analysis revealed thatonly N9a showed a nominally significantassociation with protection from SZ [1.68% vs.6.38%, p=0.004, OR=0.251 (0.092-0.680);after adjustment for age and sex: p=0.006,", "metadata": {}}
+{"_id": "23509113", "title": "", "text": "Resolution of acute inflammation in thelung.Acute inflammation in the lung is essentialto health. So too is its resolution. In response toinvading microbes, noxious stimuli, or tissueinjury, an acute inflammatory response ismounted to protect the host. To limitinflammation and prevent collateral injury ofhealthy, uninvolved tissue, the lung orchestratesthe formation of specialized proresolvingmediators, specifically lipoxins, resolvins,protectins, and maresins. Theseimmunoresolvents are agonists for resolutionthat interact with specific receptors onleukocytes and structural cells to blunt furtherinflammation and promote catabasis. Thisprocess appears to be defective in severalcommon lung diseases that are characterized byexcess or chronic inflammation. Here, we reviewthe molecular and cellular effectors of resolutionof acute inflammation in the lung.", "metadata": {}}
+{"_id": "23509593", "title": "", "text": "The calcium sensor STIM1 is regulated byandrogens in prostate stromalcells.BACKGROUND Prostate development andmaintenance in the adult results from aninteraction of stromal and glandular components.Androgens can drive this process by direct actionon the stroma. We investigated whether therewas a direct link between androgens and anotherkey regulator of stromal cells, intracellular Ca2+([Ca2+ ]i ). METHODS Prostate stromal cellswere freshly obtained and cultures derived frompatients with benign prostatic hyperplasia. Geneexpression in dihydrotestosterone treated anduntreated cells was compared using Affymetrixgene expression arrays and Ca2+ regulatedfeatures were identified by Gene Ontology (GO).Changes in [Ca2+]i were determined in Fluo-4loaded cells. Androgen regulation was confirmedby chromatin immunoprecipitaion. RESULTSStromal cell cultures were sorted for expressionof integrin α1 β1 , which enriched for cellsexpressing the androgen receptor (AR). We", "metadata": {}}
+{"_id": "23513718", "title": "", "text": "Role of soluble guanylate cyclase in dilatorresponses of the cerebralmicrocirculation.Responses of cerebral bloodvessels to nitric oxide (NO) are mediated bysoluble guanylate cyclase (sGC)-dependent andpotentially by sGC-independent mechanisms.One sGC-independent mechanism by which NOmay produce vasodilatation is inhibition offormation of a vasoconstrictor metaboliteproduced through the cytochrome P450pathway. In these experiments, we examinedthe hypothesis that dilatation of cerebralmicrovessels in response to NO is dependent onactivation of sGC. Diameters of cerebralarterioles (baseline diameter=94+/-5micrometers, mean+/-S.E.) were measuredusing a closed cranial window in anesthetizedrabbits. Under control conditions, YC-1[3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole], an NO-independent activator of sGC,produced vasodilation that was blocked by ODQ(1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one)(", "metadata": {}}
+{"_id": "23513818", "title": "", "text": "Noxa controls Mule-dependent Mcl-1ubiquitination through the regulation of theMcl-1/USP9X interaction.The level of the Mcl-1pro-survival protein is highly regulated, and thedown-regulation of Mcl-1 expression favors theapoptotic process. Mcl-1 physically interacts withdifferent BH3-only proteins; particularly, Noxa isinvolved in the modulation of Mcl-1 expression.In this study, we demonstrated that Noxatriggers the degradation of Mcl-1 at themitochondria according to the exclusive locationof Noxa at this compartment. The Noxa-induceddegradation of Mcl-1 required the E3 ligase Mule,which is responsible for the polyubiquitination ofMcl-1. Because the USP9X deubiquitinase wasrecently demonstrated to be involved in Mcl-1protein turnover by preventing its degradationthrough the removal of conjugated ubiquitin, weinvestigated whether Noxa affected thedeubiquitination process. Interestingly, Noxaover-expression caused a decrease in theUSP9X/Mcl-1 interaction associated with an", "metadata": {}}
+{"_id": "23531592", "title": "", "text": "Paediatric HIV infection.By the year 2000 therewill be six million pregnant women and five toten million children infected with HIV-1.Intervention strategies have been planned and insome instances already started. A timely andcost-effective strategy needs to take into accountthat most HIV-1 infected individuals reside indeveloping countries. Further studies are neededon immunological and virological factors affectingHIV-1 transmission from mother to child, ondifferential disease progression in affectedchildren, and on transient infection.", "metadata": {}}
+{"_id": "23535770", "title": "", "text": "Potential role of NF-kappaB in adult neural stemcells: the underrated steersman?Neural stemcells are precursors of neurons and glial cells.During brain development, these cellsproliferate, migrate and differentiate into specificlineages. Recently neural stem cells within theadult central nervous system were identified.Informations are now emerging about regulationof stem cell proliferation, migration anddifferentiation by numerous soluble factors suchas chemokines and cytokines. However, thesignal transduction mechanisms downstream ofthese factors are less clear. Here, we reviewpotential evidences for a novel central role of thetranscription factor nuclear factor kappa B(NF-kappaB) in these crucial signal transductionprocesses. NF-kappaB is an inducibletranscription factor detected in neurons, glia andneural stem cells. NF-kappaB was discovered byDavid Baltimore's laboratory as a transcriptionfactor in lymphocytes. NF-kappaB is involved inmany biological processes such as inflammation", "metadata": {}}
+{"_id": "23557241", "title": "", "text": "Intrauterine factors and risk of breast cancer: asystematic review and meta-analysis of currentevidence.BACKGROUND Emerging evidencesuggests an association between female prenatalexperience and her subsequent risk ofdeveloping breast cancer. Potential underlyingmechanisms include variation in amounts ofmaternal endogenous sex hormones and growthhormones, germ-cell mutations, formation ofcancer stem-cells, and other genetic orepigenetic events. We reviewed and summarisedquantitatively the available data on intrauterineexposures and risk of breast cancer. METHODSWe systematically searched for studies thatassessed association between perinatal factorsand risk of breast cancer. We reviewedseparately each of the perinatal factors, includingbirthweight, birth length, parental age atdelivery, gestational age, intrauterine exposureto diethylstilbestrol, twin membership, maternalpre-eclampsia or eclampsia, and other factors.FINDINGS We identified 57 studies published", "metadata": {}}
+{"_id": "23573229", "title": "", "text": "Helicobacter hepaticus does not induce orpotentiate colitis in interleukin-10-deficientmice.Helicobacter hepaticus has been reported toinduce colitis, hepatitis, and hepatocellularcarcinoma in several different murine models.The aim of this study was to determine if H.hepaticus will cause colitis in monoassociatedmice lacking the interleukin-10 gene (IL-10(-/-)mice) and potentiate colitis inspecific-pathogen-free (SPF) IL-10(-/-) mice.Germfree IL-10(-/-) mice on either a mixed(C57BL/6 x 129/Ola) or inbred (129/SvEv)genetic background were monoassociated withH. hepaticus ATCC 51448 by oral feeding andrectal enemas. In a second experiment,germfree IL-10(-/-) mice were colonized withstool from SPF mice that harbored or did notharbor endogenous H. hepaticus. After 7 to 9weeks of colonization, weight loss and mortalitywere assessed, the colon was isolated forhistology and IL-12 secretion, and mesentericlymph node cells were assessed for T-cell", "metadata": {}}
+{"_id": "23576165", "title": "", "text": "Metabolic interplay between glycolysis andmitochondrial oxidation: The reverse Warburgeffect and its therapeutic implication.Aerobicglycolysis, i.e., the Warburg effect, maycontribute to the aggressive phenotype ofhepatocellular carcinoma. However, increasingevidence highlights the limitations of theWarburg effect, such as high mitochondrialrespiration and low glycolysis rates in cancercells. To explain such contradictory phenomenawith regard to the Warburg effect, a metabolicinterplay between glycolytic and oxidative cellswas proposed, i.e., the \"reverse Warburg effect\".Aerobic glycolysis may also occur in the stromalcompartment that surrounds the tumor; thus,the stromal cells feed the cancer cells withlactate and this interaction prevents the creationof an acidic condition in the tumormicroenvironment. This concept provides greatheterogeneity in tumors, which makes thedisease difficult to cure using a single agent.Understanding metabolic flexibility by lactate", "metadata": {}}
+{"_id": "23576726", "title": "", "text": "Enhanced waterlogging tolerance in barley bymanipulation of expression of the N\u0000end rulepathway E3 ligase PROTEOLYSIS6Increasedtolerance of crops to low oxygen (hypoxia)during flooding is a key target for food security.In Arabidopsis thaliana (L.) Heynh., the N-endrule pathway of targeted proteolysis controlsplant responses to hypoxia by regulating thestability of group VII ethylene response factor(ERFVII) transcription factors, controlled by theoxidation status of amino terminal (Nt)-cysteine(Cys). Here, we show that the barley (Hordeumvulgare L.) ERFVII BERF1 is a substrate of theN-end rule pathway in vitro. Furthermore, weshow that Nt-Cys acts as a sensor for hypoxia invivo, as the stability of the oxygen-sensorreporter protein MCGGAIL-GUS increased inwaterlogged transgenic plants. Transgenic RNAibarley plants, with reduced expression of theN-end rule pathway N-recognin E3 ligasePROTEOLYSIS6 (HvPRT6), showed increasedexpression of hypoxia-associated genes and", "metadata": {}}
+{"_id": "23577014", "title": "", "text": "A SUMO-Dependent Protein Network RegulatesChromosome Congression during OocyteMeiosisDuring Caenorhabditis elegans oocytemeiosis, a multi-protein ring complex (RC)localized between homologous chromosomes,promotes chromosome congression through theaction of the chromokinesin KLP-19. While someRC components are known, the mechanism of RCassembly has remained obscure. We show thatSUMO E3 ligase GEI-17/PIAS is required forKLP-19 recruitment to the RC, and proteomicanalysis identified KLP-19 as a SUMO substratein vivo. In vitro analysis revealed that KLP-19 isefficiently sumoylated in a GEI-17-dependentmanner, while GEI-17 undergoes extensiveauto-sumoylation. GEI-17 and another RCcomponent, the kinase BUB-1, contain functionalSUMO interaction motifs (SIMs), allowing themto recruit SUMO modified proteins, includingKLP-19, into the RC. Thus, dynamic SUMOmodification and the presence of SIMs in RCcomponents generate a SUMO-SIM network that", "metadata": {}}
+{"_id": "23577867", "title": "", "text": "Prediagnostic levels of C-peptide, IGF-I, IGFBP-1, -2 and -3 and risk of endometrialcancer.Conditions related to chronichyperinsulinemia, such as obesity, noninsulindependent diabetes mellitus and polycystic ovarysyndrome, are associated with an increased riskof endometrial cancer. Elevated plasma IGF-Iand decreased levels of IGF-binding proteinshave been shown to be associated with increasedrisk of several cancer types that are frequent inaffluent societies. We investigated for the firsttime in a prospective study the association ofpre-diagnostic blood concentrations of C-peptide(a marker of pancreatic insulin production),IGF-I, IGFBP-1, -2 and -3 with endometrialcancer risk. A case-control study was nestedwithin 3 cohorts in New York (USA), Umeå(Sweden) and Milan (Italy). It included 166women with primary invasive endometrial cancerand 315 matched controls, of which 44 case and78 control subjects were premenopausal atrecruitment. Endometrial cancer risk increased", "metadata": {}}
+{"_id": "23581096", "title": "", "text": "Interactions between SRY and SOX genes inmammalian sex determination.The SRY gene onthe mammalian Y chromosome undoubtedly actsto determine testis, but it is still quite unclearhow. It was originally supposed that SRY actsdirectly to activate other genes in thetestis-determining pathway. This paper presentsan alternative hypothesis that SRY functionsindirectly, by interacting with related genesSOX3 (from which SRY evolved) and SOX9(which appears to be intimately involved invertebrate gonad differentiation). Specifically, Ipropose that in females SOX3 inhibits SOX9function, but in males, SRY inhibits SOX3 andpermits SOX9 to enact its testis-determiningrole. This hypothesis makes testable predictionsof the phenotypes of XX and XY individuals withdeficiencies or overproduction of any of the threegenes, and is able to account for the difficultcases of XX(SRY-) males and transdifferentiationin the absence of SRY. The hypothesis alsosuggests a way that the dominant SRY", "metadata": {}}
+{"_id": "23586085", "title": "", "text": "Chromatin immunoprecipitation andmicroarray-based analysis of proteinlocationGenome-wide location analysis, alsoknown as ChIP-Chip, combines chromatinimmunoprecipitation and DNA microarrayanalysis to identify protein-DNA interactions thatoccur in living cells. Protein-DNA interactions arecaptured in vivo by chemical crosslinking. Celllysis, DNA fragmentation and immunoaffinitypurification of the desired protein will co-purifyDNA fragments that are associated with thatprotein. The enriched DNA population is thenlabeled, combined with a differentially labeledreference sample and applied to DNAmicroarrays to detect enriched signals. Variouscomputational and bioinformatic approaches arethen applied to normalize the enriched andreference channels, to connect signals to theportions of the genome that are represented onthe DNA microarrays, to provide confidencemetrics and to generate maps of protein-genomeoccupancy. Here, we describe the experimental", "metadata": {}}
+{"_id": "23594156", "title": "", "text": "Spatial and temporal clusters of Barmah Forestvirus disease in Queensland,Australia.OBJECTIVE To identify the spatial andtemporal clusters of Barmah Forest virus (BFV)disease in Queensland in Australia, usinggeographical information systems and spatialscan statistic (SaTScan). METHODS We obtainedBFV disease cases, population and statisticallocal areas (SLAs) boundary data fromQueensland Health and Australian Bureau ofStatistics, respectively, during 1992-2008 forQueensland. A retrospective Poisson-basedanalysis using SaTScan software and methodwas conducted to identify both purely spatial andspace-time BFV disease high-rate clusters. Aspatial cluster size of a proportion of thepopulation and a 200 km radius and varying timewindows from 1 to 12 months were chosen (forthe space-time analysis). RESULTS The spatialscan statistic detected a most likely significantpurely spatial cluster (including 23 SLAs) and amost likely significant space-time cluster", "metadata": {}}
+{"_id": "23599024", "title": "", "text": "Surfactant Protein B Suppresses Lung CancerProgression by Inhibiting SecretoryPhospholipase A2 Activity and Arachidonic AcidProductionBackground/Aims: Radiotherapy isapplied to patients with inoperable cancer typesincluding advanced stage non-small cell lungcancer (NSCLC) and radioresistance functions asa critical obstacle in radiotherapy. This study wasaimed to investigate the mechanism ofradioresistance regulated by surfactant protein B(SP-B). Methods: To investigate the role of SP-Bin radioresistance, ΔSFTPB A549 cell line wasestablished and SP-B expression was analyzed.In response to ionizing radiation (IR), the changeof SP-B expression was analyzed in A549 andNCI-H441 cell lines. Conditioned media (CM)from NSCLC cells were utilized to evaluate thedownstream signaling pathway. The in vivoeffects of SP-B were assessed through mousexenograft model with intratumoral injection ofCM. Results: In response to IR, NSCLC cell linesshowed decreased SP-B regulated by the TGF-β", "metadata": {}}
+{"_id": "23601616", "title": "", "text": "Liraglutide improves hippocampal synapticplasticity associated with increased expression ofMash1 in ob/ob miceObjective:Consumption ofhigh-fat diet exerts adverse effects on learningand memory formation, which is linked toimpaired hippocampal function. Activation ofglucagon-like peptide-1 (GLP-1) signallingameliorates detrimental effects ofobesity-diabetes on cognitive function; however,mechanisms underlying these beneficial actionsremain unclear. This study examined effects ofdaily subcutaneous treatment with GLP-1mimetic, Liraglutide, on synaptic plasticity,hippocampal gene expression and metaboliccontrol in adult obese diabetic (ob/ob) mice.Results:Long-term potentiation (LTP) induced byarea CA1 was completely abolished in ob/obmice compared with lean controls. Deleteriouseffects on LTP were rescued (P<0.001) withLiraglutide. Indeed, Liraglutide-treated miceexhibited superior LTP profile compared with leancontrols (P<0.01). Expression of hippocampal", "metadata": {}}
+{"_id": "23604601", "title": "", "text": "Post-transcriptional regulation of IME1determines initiation of meiosis inSaccharomyces cerevisiae.The IME1 gene ofSaccharomyces cerevisiae is required forinitiation of meiosis. Transcription of IME1 isdetected under conditions which are known toinduce initiation of meiosis, namely starvation fornitrogen and glucose, and the presence of MATa1and MAT alpha 2 gene products. In this paper weshow that IME1 is also subject to translationalregulation. Translation of IME1 mRNA is achievedeither upon nitrogen starvation, or upon G1arrest. In the presence of nutrients,constitutively elevated transcription of IME1 isalso sufficient for the translation of IME1 RNA.Four different conditions were found to causeexpression of Ime1 protein in vegetativecultures: elevated transcription levels due to thepresence of IME1 on a multicopy plasmid;elevated transcription provided by a Gal-IME1construct; G1 arrest due to alpha-factortreatment; G1 arrest following mild heat-shock", "metadata": {}}
+{"_id": "23618826", "title": "", "text": "Targeted proteomics reveals compositionaldynamics of 60S pre-ribosomes after nuclearexportConstruction and intracellular targeting ofeukaryotic pre-ribosomal particles involve amultitude of diverse transiently associatingtrans-acting assembly factors,energy-consuming enzymes, and transportfactors. The ability to rapidly and reliablymeasure co-enrichment of multiple factors withmaturing pre-ribosomal particles presents amajor biochemical bottleneck towards revealingtheir function and the precise contribution of >50energy-consuming steps that drive ribosomeassembly. Here, we devised a workflow thatcombines genetic trapping, affinity-capture, andselected reaction monitoring mass spectrometry(SRM-MS), to overcome this deficiency. Weexploited this approach to interrogate thedynamic proteome of pre-60S particles afternuclear export. We uncovered assembly factorsthat travel with pre-60S particles to thecytoplasm, where they are released before", "metadata": {}}
+{"_id": "23627419", "title": "", "text": "Obstructive sleep apnea-hypopnea and incidentstroke: the sleep heart health study.RATIONALEAlthough obstructive sleep apnea is associatedwith physiological perturbations that increaserisk of hypertension and are proatherogenic, it isuncertain whether sleep apnea is associated withincreased stroke risk in the general population.OBJECTIVES To quantify the incidence ofischemic stroke with sleep apnea in acommunity-based sample of men and womenacross a wide range of sleep apnea. METHODSBaseline polysomnography was performedbetween 1995 and 1998 in a longitudinal cohortstudy. The primary exposure was the obstructiveapnea-hypopnea index (OAHI) and outcome wasincident ischemic stroke. MEASUREMENTS ANDMAIN RESULTS A total of 5,422 participantswithout a history of stroke at the baselineexamination and untreated for sleep apnea werefollowed for a median of 8.7 years. One hundredninety-three ischemic strokes were observed. Incovariate-adjusted Cox proportional hazard", "metadata": {}}
+{"_id": "23633726", "title": "", "text": "Reproducibility of 31P cardiac magneticresonance spectroscopy at 3 T.The purpose ofthis work was to take advantage of the newclinical field strength of 3 T to implement andoptimize a chemical shift imaging (CSI)acquisition protocol to produce spectra of highquality with high specificity to the myocardiumwithin a clinically feasible scan time. Further, ananalysis method was implemented dependentpurely on anatomical location of spectra, and assuch free from any potential user bias caused byinference from spectral information. Twentyhealthy male subjects were scanned on twoseparate occasions using the optimized CSIprotocol at 3 T. Data were analyzed for intra-and inter-subject variability, as well as intra- andinter-observer variability. The averagephosphocreatine (PCr)/adenosine triphosphate(ATP) value for scan 1 was 2.07 +/- 0.38 and forscan 2 was 2.14 +/- 0.46, showing no significantdifference between scans. Intra-subjectvariability was 0.43 +/- 0.35 (percentage", "metadata": {}}
+{"_id": "23634484", "title": "", "text": "Nuclear HuR accumulation throughphosphorylation by Cdk1.A predominantlynuclear RNA-binding protein, HuR translocates tothe cytoplasm in response to stress andproliferative signals, where it stabilizes ormodulates the translation of target mRNAs.Here, we present evidence that HuRphosphorylation at S202 by the G2-phase kinaseCdk1 influences its subcellular distribution. HuRwas specifically phosphorylated in synchronousG2-phase cultures; its cytoplasmic levelsincreased by Cdk1-inhibitory interventions anddeclined in response to Cdk1-activatinginterventions. In keeping with the prominentlycytoplasmic location of the nonphosphorylatablepoint mutant HuR(S202A), phospho-HuR(S202)was shown to be predominantly nuclear using anovel anti-phospho-HuR(S202) antibody. Theenhanced cytoplasmic presence ofunphosphorylated HuR was linked to itsdecreased association with 14-3-3 and to itsheightened binding to target mRNAs. Our", "metadata": {}}
+{"_id": "23639838", "title": "", "text": "Surgical Resection for Patients with Solid BrainMetastases: Current StatusBrain metastasesoccur in up to 40% of patients with cancer. Theirmanagement has been revolutionized in the lastdecade by three developments: improvedimaging and detection of metastases, bettertreatment of systemic disease with the resultthat metastases occur more often; and improvedsurgical techniques including image-guidedsurgery to treat metastatic lesions. Class 1 datasuggest that surgery is a better treatment formetastases than whole brain radiation. Otherdata suggest that metastases even in eloquentcortex can be removed safely. The complicationrate is low and the recurrence rate is less than10%. In general, indications for surgery includea mass with an unknown primary; asymptomatic mass including one in eloquentareas; a mass with considerable edema requiringhigh dose steroids; a mass greater than 3 cm; orpatient preference when radiosurgery may alsobe an option. The question of radiosurgery or", "metadata": {}}
+{"_id": "23649163", "title": "", "text": "Clinical features and treatment of peristomalpyoderma gangrenosum.CONTEXT Peristomalpyoderma gangrenosum (PPG), an unusualvariant of pyoderma gangrenosum, has beenreported almost exclusively in patients withinflammatory bowel disease (IBD) and isfrequently misdiagnosed. OBJECTIVE To bettercharacterize the clinical manifestations,diagnosis, and management of PPG. DESIGN,SETTING, AND PATIENTS Retrospective analysisof 7 patients with PPG observed in auniversity-affiliated community setting between1988 and December 1999. MAIN OUTCOMEMEASURES Clinical and histopathologic features,associated disorders, and microbiologic findings.RESULTS Two patients had Crohn disease, 2 hadulcerative colitis, and 3 had abdominal cancer.Five patients had at least 1 relapse of PPG afterinitial healing. Although 3 of 4 patients with IBDhad active bowel disease, a parallel course withPPG occurred in only 1 patient. Both patientswhose stoma was relocated developed an ulcer", "metadata": {}}
+{"_id": "23664875", "title": "", "text": "The Tof1p-Csm3p protein complex counteractsthe Rrm3p helicase to control replicationtermination of Saccharomycescerevisiae.Termination of replication forks at thenatural termini of the rDNA of Saccharomycescerevisiae is controlled in a sequence-specificand polar mode by the interaction of the Fob1preplication terminator protein with the tandemTer sites located in the nontranscribed spacers.Here we show, by both 2D gel analyses andchromatin immunoprecipitations (ChIP), thatthere exists a second level of global controlmediated by the intra-S-phase checkpointprotein complex of Tof1p and Csm3p that protectstalled forks at Ter sites against the activity ofthe Rrm3p helicase (\"sweepase\"). The sweepasetends to release arrested forks presumably bythe transient displacement of the Ter-boundFob1p. Consistent with this mechanism, very fewreplication forks were arrested at the naturalreplication termini in the absence of the twocheckpoint proteins. In the absence of the Rrm3p", "metadata": {}}
+{"_id": "23665162", "title": "", "text": "Association of hypomethylation of LINE-1repetitive element in blood leukocyte DNA withan increased risk of hepatocellularcarcinomaGlobal DNA hypomethylation has beenassociated with increased risk for cancers of thecolorectum, bladder, breast, head and neck, andtesticular germ cells. The aim of this study wasto examine whether global hypomethylation inblood leukocyte DNA is associated with the riskof hepatocellular carcinoma (HCC). A total of 315HCC cases and 356 age-, sex- and HBsAgstatus-matched controls were included. Globalmethylation in blood leukocyte DNA wasestimated by analyzing long interspersedelement-1 (LINE-1) repeats usingbisulfite-polymerase chain reaction (PCR) andpyrosequencing. We observed that the medianmethylation level in HCC cases (percentage of5-methylcytosine (5mC)=77.7%) wassignificantly lower than that in controls (79.5%5mC) (P=0.004, Wilcoxon rank-sum test). Theodds ratios (ORs) of HCC for individuals in the", "metadata": {}}
+{"_id": "23670644", "title": "", "text": "The ketogenic diet for the treatment of childhoodepilepsy: a randomised controlledtrial.BACKGROUND The ketogenic diet has beenwidely and successfully used to treat childrenwith drug-resistant epilepsy since the 1920s. Theaim of this study was to test the efficacy of theketogenic diet in a randomised controlled trial.METHODS 145 children aged between 2 and 16years who had at least daily seizures (or morethan seven seizures per week), had failed torespond to at least two antiepileptic drugs, andhad not been treated previously with theketogenic diet participated in a randomisedcontrolled trial of its efficacy to control seizures.Enrolment for the trial ran between December,2001, and July, 2006. Children were seen at oneof two hospital centres or a residential centre foryoung people with epilepsy. Children wererandomly assigned to receive a ketogenic diet,either immediately or after a 3-month delay,with no other changes to treatment (controlgroup). Neither the family nor investigators were", "metadata": {}}
+{"_id": "23686039", "title": "", "text": "Building-in biosafety for synthetic biology.As thefield of synthetic biology develops, real-worldapplications are moving from the realms of ideasand laboratory-confined research towardsimplementation. A pressing concern, particularlywith microbial systems, is that self-replicatingre-engineered cells may produce undesiredconsequences if they escape or overwhelm theirintended environment. To address this biosafetyissue, multiple mechanisms for constrainingmicrobial replication and horizontal gene transferhave been proposed. These include the use ofhost-construct dependencies such astoxin-antitoxin pairs, conditional plasmidreplication or the requirement for a specificmetabolite to be present for cellular function.While refactoring of the existing genetic code ortailoring of orthogonal systems, e.g. xeno nucleicacids, offers future promise of more stringent'firewalls' between natural and synthetic cells,here we focus on what can be achieved usingexisting technology. The state-of-the-art in", "metadata": {}}
+{"_id": "23698769", "title": "", "text": "Sustained active site rigidity during synthesis byhuman DNA polymerase μDNA polymerase μ (Polμ) is the only template-dependent human DNApolymerase capable of repairing double-strandDNA breaks (DSBs) with unpaired 3′ ends innonhomologous end joining (NHEJ). To probethis function, we structurally characterized Polμ's catalytic cycle for single-nucleotideincorporation. These structures indicate that,unlike other template-dependent DNApolymerases, Pol μ shows no large-scaleconformational changes in protein subdomains,amino acid side chains or DNA upon dNTPbinding or catalysis. Instead, the only majorconformational change is seen earlier in thecatalytic cycle, when the flexible loop 1 regionrepositions upon DNA binding. Pol μ variants withchanges in loop 1 have altered catalyticproperties and are partially defective in NHEJ.The results indicate that specific loop 1 residuescontribute to Pol μ's unique ability to catalyzetemplate-dependent NHEJ of DSBs with unpaired", "metadata": {}}
+{"_id": "23700330", "title": "", "text": "Angiopoietin-1 requires p190 RhoGAP to protectagainst vascular leakage in vivo.Angiopoietin-1(Ang-1), a ligand of the endothelium-specificreceptor Tie-2, inhibits permeability in themature vasculature, but the mechanism remainsunknown. Here we show that Ang-1 signals Rhofamily GTPases to organize the cytoskeleton intoa junction-fortifying arrangement that enhancesthe permeability barrier function of theendothelium. Ang-1 phosphorylates Tie-2 and itsdownstream effector phosphatidylinositol3-kinase. This induces activation of oneendogenous GTPase, Rac1, and inhibition ofanother, RhoA. Loss of either part of this dualeffect abrogates the cytoskeletal andanti-permeability actions of Ang-1, suggestingthat coordinated GTPase regulation is necessaryfor the vessel-sealing effects of Ang-1. p190RhoGAP, a GTPase regulatory protein, providesthis coordinating function as it is phosphorylatedby Ang-1 treatment, requires Rac1 activation,and is necessary for RhoA inhibition. Ang-1", "metadata": {}}
+{"_id": "23702805", "title": "", "text": "Vesicular trafficking of semaphorin 3A isactivity-dependent and differs between axonsand dendrites.Secreted semaphorins act asguidance cues in the developing nervous systemand may have additional functions in matureneurons. How semaphorins are transported andsecreted by neurons is poorly understood. Wefind that endogenous semaphorin 3A (Sema3A)displays a punctate distribution in axons anddendrites of cultured cortical neurons.GFP-Sema3A shows a similar distribution andco-localizes with secretory vesicle cargo proteins.Live-cell imaging reveals highly dynamictrafficking of GFP-Sema3A vesicles with distinctproperties in axons and dendrites regardingdirectionality, velocity, mobility and pausingtime. In axons, most GFP-Sema3A vesicles movefast without interruption, almost exclusively inthe anterograde direction, while in dendritesmany GFP-Sema3A vesicles are stationary andmove equally frequent in both directions.Disruption of microtubules, but not of actin", "metadata": {}}
+{"_id": "23704559", "title": "", "text": "Frequency of Intracranial Aneurysms Determinedby Magnetic Resonance Angiography in Children(Mean Age 16) Having Operative or EndovascularTreatment of Coarctation of the Aorta (Mean Age3).Coarctation of the aorta (CofA) has beenassociated with an increased risk of intracranialaneurysm (IA). This magnetic resonanceangiography (MRA) study investigates theprevalence of IAs in 80 children treated in earlylife for CofA. MRA was performed at mean age of15.7 ± 7.1 years, and surgical or endovasculartreatment for CofA occurred at a mean age of2.6 ± 4.4 years. No IA was found. In contrastwith earlier findings in adult patients with latetreatment for CofA, this first systematic study ofvery early treated patients for CofA failed toconfirm the association between CofA and IAs.Our results call the abnormal developmentalrelation between CofA and IAs into question andsuggest that modifiable risk factors likehypertension may be responsible for IAdevelopment in patients with CofA with adult", "metadata": {}}
+{"_id": "23716150", "title": "", "text": "Transcriptional profiling of the heart revealschamber-specific gene expressionpatterns.Cardiac chamber-specific geneexpression is critical for the normal developmentand function of the heart. To investigate thegenetic basis of cardiac anatomicalspecialization, we have undertaken a nearlygenome-wide transcriptional profiling of the fourheart chambers and the interventricular septum.Rigorous statistical analysis has allowed theidentification of known and novel members ofgene families that are felt to be important incardiac development and function, including LIMproteins, homeobox proteins, wnt and T-boxpathway proteins, as well as structural proteinslike actins and myosins. In addition, thesestudies have allowed the identification ofthousands of additional differentially expressedgenes, for which there is little structural orfunctional information. Clustering of genes withknown and unknown functions provides insightsinto signaling pathways that are essential for", "metadata": {}}
+{"_id": "23727313", "title": "", "text": "CD34+ hematopoietic stem-progenitor cellmicroRNA expression and function: a circuitdiagram of differentiation control.MicroRNAs(miRNAs) are a recently identified class ofepigenetic elements consisting of smallnoncoding RNAs that bind to the 3' untranslatedregion of mRNAs and down-regulate theirtranslation to protein. miRNAs play critical rolesin many different cellular processes includingmetabolism, apoptosis, differentiation, anddevelopment. We found 33 miRNAs expressed inCD34+ hematopoietic stem-progenitor cells(HSPCs) from normal human bone marrow andmobilized human peripheral blood stem cellharvests. We then combined these data withhuman HSPC mRNA expression data and withmiRNA-mRNA target predictions, into apreviously undescribed miRNA:mRNA interactiondatabase called the Transcriptome InteractionDatabase. The in silico predictions from theTranscriptome Interaction Database pointed tomiRNA control of hematopoietic differentiation", "metadata": {}}
+{"_id": "23737024", "title": "", "text": "Acute exercise activates nuclear factor(NF)-kappaB signaling pathway in rat skeletalmuscle.Two studies were performed toinvestigate the effects of an acute bout ofphysical exercise on the nuclear protein kappaB(NF-kappaB) signaling pathway in rat skeletalmuscle. In Study 1, a group of rats (n=6) wasrun on the treadmill at 25 m/min, 5% grade, for1 h or until exhaustion (Ex), and compared witha second group (n=6) injected with two doses ofpyrrolidine dithiocarbamate (PDTC, 100 mg/kg,i.p.) 24 and 1 h prior to the acute exercise bout.Three additional groups of rats (n=6) wereinjected with either 8 mg/kg (i.p.) oflipopolysaccharide (LPS), 1 mmol/kg (i.p.)t-butylhydroperoxide (tBHP), or saline (C) andkilled at resting condition. Ex rats showed higherlevels of NF-kappaB binding and P50 proteincontent in muscle nuclear extracts comparedwith C rats. Cytosolic IkappaBalpha and IkappaBkinase (IKK) contents were decreased, whereasphospho-IkappaBalpha and phospho-IKK", "metadata": {}}
+{"_id": "23746313", "title": "", "text": "Staphylococcus aureus RNAIII and theendoribonuclease III coordinately regulate spagene expression.Staphylococcus aureus RNAIII isone of the largest regulatory RNAs, whichcontrols several virulence genes encodingexoproteins and cell-wall-associated proteins.One of the RNAIII effects is the repression of spagene (coding for the surface protein A)expression. Here, we show that spa repressionoccurs not only at the transcriptional level butalso by RNAIII-mediated inhibition of translationand degradation of the stable spa mRNA by thedouble-strand-specific endoribonuclease III(RNase III). The 3' end domain of RNAIII,partially complementary to the 5' part of spamRNA, efficiently anneals to spa mRNA throughan initial loop-loop interaction. Although thisannealing is sufficient to inhibit in vitro theformation of the translation initiation complex,the coordinated action of RNase III is essential invivo to degrade the mRNA and irreversibly arresttranslation. Our results further suggest that", "metadata": {}}
+{"_id": "23746332", "title": "", "text": "Fast calcium and voltage-sensitive dye imagingin enteric neurones reveal calcium peaksassociated with single action potentialdischarge.Slow changes in [Ca(2+)](i) reflectincreased neuronal activity. Our studydemonstrates that single-trial fast [Ca(2+)](i)imaging (≥200 Hz sampling rate) revealed peakseach of which are associated with single spikedischarge recorded by consecutivevoltage-sensitive dye (VSD) imaging in entericneurones and nerve fibres. Fast [Ca(2+)](i)imaging also revealed subthreshold fastexcitatory postsynaptic potentials.Nicotine-evoked [Ca(2+)](i) peaks were reducedby -conotoxin and blocked by ruthenium red ortetrodotoxin. Fast [Ca(2+)](i) imaging can beused to directly record single action potentials inenteric neurones. [Ca(2+)](i) peaks requiredopening of voltage-gated sodium and calciumchannels as well as Ca(2+) release fromintracellular stores.", "metadata": {}}
+{"_id": "23763738", "title": "", "text": "New colorimetric cytotoxicity assay foranticancer-drug screening.We have developed arapid, sensitive, and inexpensive method formeasuring the cellular protein content ofadherent and suspension cultures in 96-wellmicrotiter plates. The method is suitable forordinary laboratory purposes and for verylarge-scale applications, such as the NationalCancer Institute's disease-oriented in vitroanticancer-drug discovery screen, which requiresthe use of several million culture wells per year.Cultures fixed with trichloroacetic acid werestained for 30 minutes with 0.4% (wt/vol)sulforhodamine B (SRB) dissolved in 1% aceticacid. Unbound dye was removed by four washeswith 1% acetic acid, and protein-bound dye wasextracted with 10 mM unbuffered Tris base [tris(hydroxymethyl)aminomethane] fordetermination of optical density in acomputer-interfaced, 96-well microtiter platereader. The SRB assay results were linear withthe number of cells and with values for cellular", "metadata": {}}
+{"_id": "23777820", "title": "", "text": "A murine model of human myeloma bonedisease.Myeloma causes a devastating andunique form of osteolytic bone disease. Althoughosteoclast activation is responsible for bonedestruction, the precise mechanisms by whichmyeloma cells increase osteoclast activity havenot been defined. An animal model of humanmyeloma bone disease would help in clarificationof these mechanisms. Multiple myeloma occursspontaneously in aging C57 BL/KaLwRij mice andhas all of the features of the disease in humans,including the characteristic bone lesions. Thedisease can be induced in normal C57BL/KaLwRij mice by inoculation of freshmarrow-derived cells from mice with myeloma,but this model is difficult to study because ofvariability in the number of myeloma cells inmarrow-derived preparations. To develop abetter animal model of human myeloma bonedisease, we have established and subcloned acell line from this murine myeloma and foundthat it causes osteolytic bone lesions in mice", "metadata": {}}
+{"_id": "23783727", "title": "", "text": "Ticagrelor vs. clopidogrel in patients with acutecoronary syndromes and diabetes: a substudyfrom the PLATelet inhibition and patientOutcomes (PLATO) trialAIMS patients withdiabetes mellitus (DM) have high plateletreactivity and are at increased risk of ischaemicevents and bleeding post-acute coronarysyndromes (ACS). In the PLATelet inhibition andpatient Outcomes (PLATO) trial, ticagrelorreduced the primary composite endpoint ofcardiovascular death, myocardial infarction, orstroke, but with similar rates of major bleedingcompared with clopidogrel. We aimed toinvestigate the outcome with ticagrelor vs.clopidogrel in patients with DM or poor glycaemiccontrol. METHODS AND RESULTS we analysedpatients with pre-existing DM (n = 4662),including 1036 patients on insulin, those withoutDM (n = 13 951), and subgroups based onadmission levels of haemoglobin A1c (HbA1c; n= 15 150). In patients with DM, the reduction inthe primary composite endpoint (HR: 0.88, 95%", "metadata": {}}
+{"_id": "23785605", "title": "", "text": "Cardiovascular risk factors and migraine: theGEM population-based study.BACKGROUNDMigraine, particularly with aura, is a risk factorfor early-onset ischemic stroke. The underlyingmechanisms are unknown, but may in part bedue to migraineurs having an increased riskprofile for cardiovascular disease. In this study,the authors compare the cardiovascular riskprofile of adult migraineurs to that ofnonmigraineurs. METHODS Participants (n =5,755, 48% men, age 20 to 65 years) are fromthe Genetic Epidemiology of Migraine (GEM)study, a population-based study in theNetherlands. A total of 620 current migraineurswere identified: 31% with aura (MA), 64%without aura (MO), and 5% unclassified. Controlswere 5,135 individuals without lifetime migraine.Measured cardiovascular risk factors includedblood pressure (BP), serum total andhigh-density lipoprotein cholesterol (TC, HDL),smoking, oral contraceptive use, and theFramingham risk score for myocardial infarction", "metadata": {}}
+{"_id": "23801039", "title": "", "text": "Th2-mediated host protective immunity tointestinal nematode infections.Despite manyyears of study, relatively little is known about theeffector mechanisms that operate againstintestine-dwelling nematodes. Most of thecurrent understanding comes from studies oflaboratory model systems in rodents. It is clearthat when an intestinal helminth infection takesplace the immune system generates a strongTh2-mediated response, which regulates avariety of responses characteristic of helminthinfections such as eosinophilia, intestinalmastocytosis and elevated IgE production. Theability to modulate the host's immune responsein vivo with cytokine-specific monoclonalantibodies and recombinant cytokines, togetherwith the use of animals with disruption of keygenes involved in the immune response, haveprovided powerful tools with which to dissect thepotential effector mechanisms operating. In theabsence of a T-cell compartment the host isunable to expel the parasite. If a Th1-dominated", "metadata": {}}
+{"_id": "23804187", "title": "", "text": "Wnt/β-catenin signaling defines organizingcenters that orchestrate growth anddifferentiation of the regenerating zebrafishcaudal fin.Zebrafish regenerate their fins via theformation of a population of progenitor cells, theblastema. Wnt/β-catenin signaling is essential forblastemal cell proliferation and patterning of theoverlying epidermis. Yet, we find that β-cateninsignaling is neither active in the epidermis northe majority of the proliferative blastemal cells.Rather, tissue-specific pathway interferenceindicates that Wnt signaling in thenonproliferative distal blastema is required forcell proliferation in the proximal blastema, andsignaling in cells lining the osteoblasts directsosteoblast differentiation. Thus, Wnt signalingregulates epidermal patterning, blastemal cellproliferation, and osteoblast maturationindirectly via secondary signals. Gene expressionprofiling, chromatin immunoprecipitation, andfunctional rescue experiments suggest thatWnt/β-catenin signaling acts through Fgf and", "metadata": {}}
+{"_id": "23816832", "title": "", "text": "The utility of cerebrospinal fluid analysis inpatients with multiple sclerosisDiagnosis ofmultiple sclerosis (MS) requires the exclusion ofother possible diagnoses. For this reason, thecerebrospinal fluid (CSF) should be routinelyanalysed in patients with a first clinical eventsuggestive of MS. CSF analysis is no longermandatory for diagnosis of relapsing–remittingMS, as long as MRI diagnostic criteria arefulfilled. However, caution is required indiagnosing MS in patients with negative MRIfindings or in the absence of CSF analysis, asCSF investigation is useful to eliminate othercauses of disease. The detection of oligoclonalIgG bands in CSF has potential prognostic valueand is helpful for clinical decision-making. Inaddition, CSF analysis is important for researchinto the pathogenesis of MS. Pathophysiologicaland neurodegenerative findings of inflammationin MS have been derived from CSFinvestigations. Novel CSF biomarkers, thoughnot yet validated, have been identified for", "metadata": {}}
+{"_id": "23830488", "title": "", "text": "Expression of circadian genes correlates withliver metastasis and outcomes in colorectalcancer.Circadian rhythms are daily oscillations invarious biological processes, generated by thefeedback loops of eight core circadian genes:Period1 (Per1), Period2 (Per2), Period3 (Per3),Cryptochrome1 (Cry1), Cryptochrome2 (Cry2),Clock, Bmal1 and Casein Kinase I ε (CKIε).Recent studies have suggested that circadiangenes participate in the growth and developmentof various cancers. This study examined therelations of circadian gene expression toclinicopathological factors and outcomes inpatients with colorectal cancer. We studiedsurgical specimens of cancer tissue and adjacentnormal mucosa obtained from 202 patients withuntreated colorectal cancer. The relativeexpression levels of the circadian genes in thespecimens were measured by quantitativereal-time, reverse-transcription polymerasechain reaction. Expression of the Clock gene andthe CKIε gene in cancer tissue were significantly", "metadata": {}}
+{"_id": "23841828", "title": "", "text": "The Danish prescription registries.The extensivecomputerisation of Danish pharmacies haspermitted the establishment of two largeprescription registries: The Odense UniversityPharmacoepidemiological Database (OPED) andthe Pharmacoepidemiological PrescriptionDatabase of North Jutland (PDNJ). The Danishprescription registries content, coverage,completeness and the quality of the data arediscussed in this article. Furthermore, conditionsfor access to the data are presented. The twoprescription registries cover a backgroundpopulation of approximately one million or 18%of the Danish population. The populationscovered by the registries are stable andrepresentative of the Danish population ingeneral. The registries cover all reimbursedmedicine at the level of the individual user.Registration of a unique and permanent personalidentifier enables the compilation of longitudinaldrug histories and allows the linking ofprescription data to other population-based", "metadata": {}}
+{"_id": "23848916", "title": "", "text": "Oridonin, a diterpenoid purified from Rabdosiarubescens, inhibits the proliferation of cells fromlymphoid malignancies in association withblockade of the NF-kappa B signal pathways.Thisstudy found that oridonin, a natural diterpenoidpurified from Rabdosia rubescens, inhibitedgrowth of multiple myeloma (MM; U266,RPMI8226), acute lymphoblastic T-cell leukemia(Jurkat), and adult T-cell leukemia (MT-1) cellswith an effective dose that inhibited 50% oftarget cells (ED50) ranging from 0.75 to 2.7microg/mL. Terminaldeoxynucleotidyltransferase-mediated dUTP nickend labeling staining showed that oridonincaused apoptosis of MT-1 cells in atime-dependent manner. We explored effects oforidonin on antiapoptotic Bcl-2 family membersand found that it down-regulated levels of Mcl-1and BCL-x(L), but not Bcl-2 protein, in both MT-1and RPMI8226 cells. Further studies found thatoridonin inhibited nuclear factor-kappa B(NF-kappa B) DNA-binding activity in these cells", "metadata": {}}
+{"_id": "23851261", "title": "", "text": "Uncertainty in integrative structuralmodeling.Integrative structural modeling usesmultiple types of input information and proceedsin four stages: (i) gathering information, (ii)designing model representation and convertinginformation into a scoring function, (iii) samplinggood-scoring models, and (iv) analyzing modelsand information. In the first stage, uncertaintyoriginates from data that are sparse, noisy,ambiguous, or derived from heterogeneoussamples. In the second stage, uncertainty canoriginate from a representation that is too coarsefor the available information or a scoring functionthat does not accurately capture the information.In the third stage, the major source ofuncertainty is insufficient sampling. In the fourthstage, clustering, cross-validation, and othermethods are used to estimate the precision andaccuracy of the models and information.", "metadata": {}}
+{"_id": "23862975", "title": "", "text": "Moist occlusive dressing (Aquacel(®) Ag) versusmoist open dressing (MEBO(®)) in themanagement of partial-thickness facial burns: acomparative study in Ain ShamsUniversity.INTRODUCTION The face is the centralpoint of the physical features; it transmitsexpressions and emotions, communicatesfeelings and allows for individual identity. Facialburns are very common and are devastating tothe affected patient and results into numerousphysical, emotional and psychosocial sequels.Partial thickness facial burns are very commonespecially among children. This study comparesthe effect of standard moist open techniquemanagement and a moist closed technique forpartial thickness burns of the face. PATIENTSAND METHODS Patients with partial-thicknessfacial burns admitted in the burn unit, Ain ShamsUniversity, Cairo, Egypt in the period from April2009 to December 2009 were included in thisstudy. They were divided into two groups toreceive either open treatment with MEBO(®)", "metadata": {}}
+{"_id": "23863551", "title": "", "text": "Feedback upregulation of HER3 (ErbB3)expression and activity attenuates antitumoreffect of PI3K inhibitors.We examined the effectsof an inhibitor of PI3K, XL147, against humanbreast cancer cell lines with constitutive PI3Kactivation. Treatment with XL147 resulted indose-dependent inhibition of cell growth andlevels of pAKT and pS6, signal transducers in thePI3K/AKT/TOR pathway. In HER2-overexpressingcells, inhibition of PI3K was followed byup-regulation of expression and phosphorylationof multiple receptor tyrosine kinases, includingHER3. Knockdown of FoxO1 and FoxO3atranscription factors suppressed the induction ofHER3, InsR, IGF1R, and FGFR2 mRNAs uponinhibition of PI3K. In HER2(+) cells, knockdownof HER3 with siRNA or cotreatment with theHER2 inhibitors trastuzumab or lapatinibenhanced XL147-induced cell death andinhibition of pAKT and pS6. Trastuzumab andlapatinib each synergized with XL147 forinhibition of pAKT and growth of established", "metadata": {}}
+{"_id": "23863576", "title": "", "text": "Developmental RacGAP α2-Chimaerin SignalingIs a Determinant of the Morphological Featuresof Dendritic Spines in Adulthood.UNLABELLEDMorphological characteristics of dendritic spinesform the basis of cognitive ability. However,molecular mechanisms involved in fine-tuning ofspine morphology during development are notfully understood. Moreover, it is unclear whether,and to what extent, these developmentalmechanisms determine the normal adult spinemorphological features. Here, we provideevidence that α2-isoform of Rac-specificGTPase-activating protein α-chimaerin(α2-chimaerin) is involved in spine morphologicalrefinement during late postnatal period, andfurthermore show that this developmentalα2-chimaerin function affects adult spinemorphologies. We used a series of mice withglobal and conditional knock-out of α-chimaerinisoforms (α1-chimaerin and α2-chimaerin).α2-Chimaerin disruption, but not α1-chimaerindisruption, in the mouse results in an increased", "metadata": {}}
+{"_id": "23865182", "title": "", "text": "Efficacy and tolerability of amitriptylinoxide inthe treatment of chronic tension-type headache:a multi-centre controlled study.Amitriptyline isthe medication of first choice in the treatment ofchronic tension-type headache. In 197 patientswith chronic tension-type headache (87M and110F with a mean age of 38 +/- 13 (18-68))efficacy and tolerability of 60-90 mgamitriptylinoxide (AO) were compared with50-75 mg amitriptyline (AM) and placebo (PL) ina double-blind, parallel-group trial consisting of afour weeks' baseline phase and 12 weeks oftreatment. The primary study endpoint was areduction of at least 50% of the product ofheadache duration and frequency and areduction of at least 50% in headache intensity.Statistics used were Fisher's exact test andanalysis of variance. No significant differenceemerged between AO, AM and PL with respect tothe primary study endpoint. Treatment responseoccurred in 30.3% of the AO, 22.4% of the AMand 21.9% of the PL group. A reduction in", "metadata": {}}
+{"_id": "23868856", "title": "", "text": "Downregulation of Superoxide Dismutase Activityand Gene Expression in Cultured Rat BrainAstrocytes after Incubation with VitaminCReactive oxygen species have been linked withneuropathological changes in the central nervoussystem. Epidemiological studies supported thebeneficial effect of supplementation ofantioxidants. Superoxide dismutase (SOD) is anendogenous enzyme which can scavengereactive oxygen species. This study investigatedthe effect of supplementation with ascorbic acid(vitamin C) on the changes of SOD in culturedneurological cells. Rat brain astrocytes (RBA-1cells) were incubated with vitamin C and dividedinto four groups: a control group (withoutvitamin C) and three treatment groups withvitamin C at 40, 80, and 160 µmol/l. Aftershort-term (2 days) and long-term (7 days)incubation, SOD activity, SOD mRNA level byNorthern blotting, and SOD protein amounts byWestern blotting were measured. After 2 days ofincubation, vitamin C resulted in a decrease in", "metadata": {}}
+{"_id": "23869951", "title": "", "text": "Lateral Hypothalamic Area GlutamatergicNeurons and Their Projections to the LateralHabenula Regulate Feeding andReward.UNLABELLED The overconsumption ofcalorically dense, highly palatable foods isthought to be a major contributor to theworldwide obesity epidemic; however, theprecise neural circuits that directly regulatehedonic feeding remain elusive. Here, we showthat lateral hypothalamic area (LHA)glutamatergic neurons, and their projections tothe lateral habenula (LHb), negatively regulatethe consumption of palatable food. Geneticablation of LHA glutamatergic neurons increaseddaily caloric intake and produced weight gain inmice that had access to a high-fat diet, while notaltering general locomotor activity. Anterior LHAglutamatergic neurons send a functionalglutamatergic projection to the LHb, a brainregion involved in processing aversive stimuliand negative reward prediction outcomes.Pathway-specific, optogenetic stimulation of", "metadata": {}}
+{"_id": "23887844", "title": "", "text": "Glucose Metabolism Inhibits Apoptosis inNeurons and Cancer Cells by Redox Inactivationof Cytochrome cNeurons and cancer cells useglucose extensively, yet the precise advantage ofthis adaptation remains unclear. These twoseemingly disparate cell types also show anincreased regulation of the apoptotic pathway,which allows for their long-term survival. Herewe show that both neurons and cancer cellsstrictly inhibit cytochrome c-mediated apoptosisby a mechanism dependent on glucosemetabolism. We report that the pro-apoptoticactivity of cytochrome c is influenced by its redoxstate and that increases in reactive oxygenspecies (ROS) following an apoptotic insult leadto the oxidation and activation of cytochrome c.In healthy neurons and cancer cells, however,cytochrome c is reduced and held inactive byintracellular glutathione (GSH), generated as aresult of glucose metabolism by the pentosephosphate pathway. These results uncover astriking similarity in apoptosis regulation", "metadata": {}}
+{"_id": "23895668", "title": "", "text": "mTORC2 Regulates Amino Acid Metabolism inCancer by Phosphorylation of theCystine-Glutamate Antiporter xCT.Mutations incancer reprogram amino acid metabolism todrive tumor growth, but the molecularmechanisms are not well understood. Using anunbiased proteomic screen, we identifiedmTORC2 as a critical regulator of amino acidmetabolism in cancer via phosphorylation of thecystine-glutamate antiporter xCT. mTORC2phosphorylates serine 26 at the cytosolic Nterminus of xCT, inhibiting its activity. Geneticinhibition of mTORC2, or pharmacologicinhibition of the mammalian target of rapamycin(mTOR) kinase, promotes glutamate secretion,cystine uptake, and incorporation intoglutathione, linking growth factor receptorsignaling with amino acid uptake and utilization.These results identify an unanticipatedmechanism regulating amino acid metabolism incancer, enabling tumor cells to adapt to changingenvironmental conditions.", "metadata": {}}
+{"_id": "23897346", "title": "", "text": "Bayesian models leveraging bioactivity andcytotoxicity information for drugdiscovery.Identification of unique leadsrepresents a significant challenge in drugdiscovery. This hurdle is magnified in neglecteddiseases such as tuberculosis. We haveleveraged public high-throughput screening(HTS) data to experimentally validate a virtualscreening approach employing Bayesian modelsbuilt with bioactivity information (single-eventmodel) as well as bioactivity and cytotoxicityinformation (dual-event model). We virtuallyscreened a commercial library andexperimentally confirmed actives with hit ratesexceeding typical HTS results by one to twoorders of magnitude. This initial dual-eventBayesian model identified compounds withantitubercular whole-cell activity and lowmammalian cell cytotoxicity from a published setof antimalarials. The most potent hit exhibits thein vitro activity and in vitro/in vivo safety profileof a drug lead. These Bayesian models offer", "metadata": {}}
+{"_id": "23901235", "title": "", "text": "A role for interleukin-1β in determining thelineage fate of embryonic rat hippocampal neuralprecursor cells.Neurogenesis occurs in thehippocampus of the developing and adult braindue to the presence of multipotent stem cellsand restricted precursor cells at different stagesof differentiation. It has been proposed that theymay be of potential benefit for use in celltransplantation approaches forneurodegenerative disorders and trauma.Prolonged release of interleukin-1β (IL-1β) fromactivated microglia has a deleterious effect onhippocampal neurons and is implicated in theimpaired neurogenesis and cognitive dysfunctionassociated with aging, Alzheimer's disease anddepression. This study assessed the effect ofIL-1β on the proliferation and differentiation ofembryonic rat hippocampal NPCs in vitro. Weshow that IL-1R1 is expressed on proliferatingNPCs and that IL-1β treatment decreases cellproliferation and neurosphere growth. WhenNPCs were differentiated in the presence of", "metadata": {}}
+{"_id": "23908217", "title": "", "text": "Bone disease in pediatric patients undergoingdialysis with CAPD or CCPD.The histologicfeatures of renal osteodystrophy and theprevalence of bone aluminum deposition inchildren receiving regular dialysis have not beendescribed. Forty-four pediatric patientsundergoing continuous ambulatory (CAPD) orcycling (CCPD) peritoneal dialysis had bonebiopsies and deferoxamine (DFO) infusion tests;all were receiving oral calcitriol. Osteitis fibrosa(OF) was found in 39%, mild lesions (M) in 25%,normal histology (NH) in 16%, aplastic lesions(AP) in 11%, and osteomalacia (OM) in 9%.Bone surface aluminum (SA) was present byhistochemical staining in 10 out of 20 givenaluminum-containing phosphate-binding agentsand in 0 of 24 treated with calcium carbonate;chi 2 = 15.5, P less than 0.0001. Serumbiochemistries and DFO infusion tests failed topredict bone histology, but plasma aluminumlevels were markedly elevated and bonealuminum content was highest in patients with", "metadata": {}}
+{"_id": "23912923", "title": "", "text": "Disruption of the immune-checkpoint VISTA geneimparts a proinflammatory phenotype withpredisposition to the development ofautoimmunity.V domain-containing Igsuppressor of T-cell activation (VISTA) is anegative checkpoint regulator that suppresses Tcell-mediated immune responses. Previousstudies using a VISTA-neutralizing monoclonalantibody show that VISTA blockade enhancesT-cell activation. The current study describes acomprehensive characterization of mice in whichthe gene for VISTA has been deleted. Despite theapparent normal hematopoietic development inyoung mice, VISTA genetic deficiency leads to agradual accumulation of spontaneously activatedT cells, accompanied by the production of aspectrum of inflammatory cytokines andchemokines. Enhanced T-cell responsiveness wasalso observed upon immunization withneoantigen. Despite the presence of multiorganchronic inflammation, aged VISTA-deficient micedid not develop systemic or organ-specific", "metadata": {}}
+{"_id": "23913146", "title": "", "text": "Molecular mechanisms that funnel RNAprecursors into endogenous small-interferingRNA and microRNA biogenesis pathways inDrosophila.In Drosophila, three types ofendogenous small RNAs-microRNAs (miRNAs),PIWI-interacting RNAs (piRNAs), andendogenous small-interfering RNAs (endo-siRNAsor esiRNAs)-function as triggers in RNA silencing.Although piRNAs are produced independently ofDicer, miRNA and esiRNA biogenesis pathwaysrequire Dicer1 and Dicer2, respectively. Recentstudies have shown that among the fourisoforms of Loquacious (Loqs), Loqs-PB andLoqs-PD are involved in miRNA and esiRNAprocessing pathways, respectively. However,how these Loqs isoforms function in theirrespective small RNA biogenesis pathwaysremains elusive. Here, we show that Loqs-PDassociates specifically with Dicer2 through itsC-terminal domain. The Dicer2-Loqs-PD complexcontains R2D2, another known Dicer2 partner,and excises both exogenous siRNAs and esiRNAs", "metadata": {}}
+{"_id": "23915841", "title": "", "text": "Neutralizing antibody responses in acute humanimmunodeficiency virus type 1 subtype Cinfection.The study of the evolution andspecificities of neutralizing antibodies during thecourse of human immunodeficiency virus type 1(HIV-1) infection may be important in thediscovery of possible targets for vaccine design.In this study, we assessed the autologous andheterologous neutralization responses of 14HIV-1 subtype C-infected individuals, usingenvelope clones obtained within the first 2months postinfection. Our data show that potentbut relatively strain-specific neutralizingantibodies develop within 3 to 12 months ofHIV-1 infection. The magnitude of this responsewas associated with shorter V1-to-V5 envelopelengths and fewer glycosylation sites, particularlyin the V1-V2 region. Anti-MPER antibodies weredetected in 4 of 14 individuals within a year ofinfection, while antibodies to CD4-induced (CD4i)epitopes developed to high titers in 12participants, in most cases before the", "metadata": {}}
+{"_id": "23918031", "title": "", "text": "The cell cycle in polyploid megakaryocytes isassociated with reduced activity of cyclinB1-dependent cdc2 kinase.The plateletprecursor, the megakaryocyte, matures to apolyploid cell as a result of DNA replication in theabsence of mitosis (endomitosis). The factorscontrolling endomitosis are accessible to analysisin our megakaryocytic cell line, MegT, generatedby targeted expression of temperature-sensitivesimian virus 40 large T antigen tomegakaryocytes of transgenic mice. We aimed todefine whether endomitosis consists of acontinuous phase of DNA synthesis (S) or of Sphases interrupted by gaps. Analysis of the cellcycle in MegT cells revealed that, uponinactivation of large T antigen, the cells shiftedfrom a mitotic cell cycle to an endomitotic cellcycle consisting of S/Gap phases. The level of theG1/S cyclin, cyclin A, as well as of the G1 phasecyclin, cyclin D3, were elevated at the onset ofDNA synthesis, either in MegT cells undergoing amitotic cell cycle or during endomitosis. In", "metadata": {}}
+{"_id": "23929297", "title": "", "text": "Ghrelin secretion stimulated by{beta}1-adrenergic receptors in culturedghrelinoma cells and in fasted mice.Ghrelin, anoctanoylated peptide hormone produced in thestomach, rises dramatically in mouse plasmaduring chronic severe calorie deprivation, anevent that is essential to maintain life. Themechanism for this increase is not understood.Here, we study the control of ghrelin secretion intissue culture cells derived from mice bearingghrelinomas induced by a tissue-specific SV40T-antigen transgene. We found that theghrelin-secreting cells express high levels ofmRNA encoding beta(1)-adrenergic receptors.Addition of norepinephrine or epinephrine to theculture medium stimulated ghrelin secretion, andthis effect was blocked by atenolol, a selectivebeta(1)-adrenergic antagonist. When WT micewere treated with reserpine to depleteadrenergic neurotransmitters from sympatheticneurons, the fasting-induced increase in plasmaghrelin was blocked. Inhibition was also seen", "metadata": {}}
+{"_id": "23932173", "title": "", "text": "Dominance relationships between S-alleles inself-incompatible Brassica campestrisL.Dominance relationships were studied for 249out of 276 possible pair-wise combinationsbetween 24 S-alleles of Brassica campestris thathad been isolated from two natural populationsfrom Turkey and Japan. Each F1 hybrid wastest-crossed reciprocally against its respectiveparental S-homozygotes to determine thedominance relationships between the pair ofS-alleles it contained. The 24 S-alleles wereclassified into two groups on the stigma side andthree groups on the pollen side. In the stigma,codominance occurred frequently, anddominance or recessiveness seemed to appearaccording to the combination of S-alleles. In thepollen, codominance was less frequent, andthere seemed to be a certain hierarchy of thedominance relationships as a whole, althoughdominance appeared with certain specificcombinations of S-alleles. Interactions among 24S-alleles were different in the stigma and in the", "metadata": {}}
+{"_id": "23934390", "title": "", "text": "MicroRNA-203 inhibits cellular proliferation andinvasion by targeting Bmi1 in non-small cell lungcancer.MicroRNAs are proposed to serve vitalfunctions in the regulation of tumor progressionand invasion. However, the expression levels ofmiR-203 in non-small cell lung cancer (NSCLC)and its clinical significance remain unknown. Inthe present study, the association betweenB-cell-specific moloney murine leukemia virusinsertion site 1 (Bmi1) and miR-203 wasinvestigated. miR-203 was demonstrated to actas a tumor suppressor by regulating theexpression of Bmi1. miR-203 expression levelswere downregulated in NSCLC tissues while Bmi1expression was upregulated in NSCLC tissuesand cell lines. Furthermore, downregulated Bmi1or enhanced miR-203 expression inhibitedNSCLC cell proliferation and invasion in vitro. Inaddition, a dual-luciferase reporter assay wasperformed, which identified Bmi1 as a noveltarget of miR-203. In conclusion, the presentstudy demonstrated that miR-203 functions as a", "metadata": {}}
+{"_id": "23938319", "title": "", "text": "Characterization of the interaction betweenretinoic acid receptor/retinoid X receptor(RAR/RXR) heterodimers and transcriptionalcoactivators through structural and fluorescenceanisotropy studies.Retinoid receptors (RARs andRXRs) are ligand-activated transcription factorsthat regulate the transcription of target genes byrecruiting coregulator complexes at cognatepromoters. To understand the effects ofheterodimerization and ligand binding oncoactivator recruitment, we solved the crystalstructure of the complex between theRARbeta/RXRalpha ligand-binding domainheterodimer, its 9-cis retinoic acid ligand, and anLXXLL-containing peptide (termed NR box 2)derived from the nuclear receptor interactiondomain (NID) of the TRAP220 coactivator. Inparallel, we measured the binding affinities ofthe isolated NR box 2 peptide or the full-lengthNID of the coactivator SRC-1 for retinoidreceptors in the presence of various types ofligands. Our correlative analysis of", "metadata": {}}
+{"_id": "23959496", "title": "", "text": "PRC2 complexes with JARID2, MTF2, andesPRC2p48 in ES cells to modulate ES cellpluripotency and somatic cellreprogramming.Polycomb repressive complextwo (PRC2) has been implicated in embryonicstem (ES) cell pluripotency; however, themechanistic roles of this complex are unclear. Itwas assumed that ES cells contain PRC2 with thesame subunit composition as that identified inHeLa cells and Drosophila embryos. Here, wereport that PRC2 in mouse ES cells contains atleast three additional subunits: JARID2, MTF2,and a novel protein denoted esPRC2p48. JARID2,MTF2, and esPRC2p48 are highly expressed inmouse ES cells compared to differentiated cells.Importantly, knockdowns of JARID2, MTF2, oresPRC2p48 alter the level of PRC2-mediatedH3K27 methylation and result in the expressionof differentiation-associated genes in ES cells.Interestingly, expression of JARID2, MTF2, andesPRC2p48 together, but not individually,enhances Oct4/Sox2/Klf4-mediated", "metadata": {}}
+{"_id": "23967973", "title": "", "text": "General and abdominal adiposity and risk ofdeath in Europe.BACKGROUND Previous studieshave relied predominantly on the body-massindex (BMI, the weight in kilograms divided bythe square of the height in meters) to assess theassociation of adiposity with the risk of death,but few have examined whether the distributionof body fat contributes to the prediction of death.METHODS We examined the association of BMI,waist circumference, and waist-to-hip ratio withthe risk of death among 359,387 participantsfrom nine countries in the European ProspectiveInvestigation into Cancer and Nutrition (EPIC).We used a Cox regression analysis, with age asthe time variable, and stratified the modelsaccording to study center and age atrecruitment, with further adjustment foreducational level, smoking status, alcoholconsumption, physical activity, and height.RESULTS During a mean follow-up of 9.7 years,14,723 participants died. The lowest risks ofdeath related to BMI were observed at a BMI of", "metadata": {}}
+{"_id": "23972114", "title": "", "text": "Phosphorylation of the autophagy receptoroptineurin restricts Salmonella growth.Selectiveautophagy can be mediated via receptormolecules that link specific cargoes to theautophagosomal membranes decorated byubiquitin-like microtubule-associated proteinlight chain 3 (LC3) modifiers. Although severalautophagy receptors have been identified, littleis known about mechanisms controlling theirfunctions in vivo. In this work, we found thatphosphorylation of an autophagy receptor,optineurin, promoted selective autophagy ofubiquitin-coated cytosolic Salmonella enterica.The protein kinase TANK binding kinase 1 (TBK1)phosphorylated optineurin on serine-177,enhancing LC3 binding affinity and autophagicclearance of cytosolic Salmonella. Conversely,ubiquitin- or LC3-binding optineurin mutants andsilencing of optineurin or TBK1 impairedSalmonella autophagy, resulting in increasedintracellular bacterial proliferation. We proposethat phosphorylation of autophagy receptors", "metadata": {}}
+{"_id": "23974474", "title": "", "text": "PKD1 Inhibits AMPKα2 through Phosphorylationof Serine 491 and Impairs Insulin Signaling inSkeletal Muscle Cells.AMP-activated proteinkinase (AMPK) is an energy-sensing enzymewhose activity is inhibited in settings of insulinresistance. Exposure to a high glucoseconcentration has recently been shown toincrease phosphorylation of AMPK atSer(485/491) of its α1/α2 subunit; however, themechanism by which it does so is not known.Diacylglycerol (DAG), which is also increased inmuscle exposed to high glucose, activates anumber of signaling molecules including proteinkinase (PK)C and PKD1. We sought to determinewhether PKC or PKD1 is involved in inhibition ofAMPK by causing Ser(485/491) phosphorylationin skeletal muscle cells. C2C12 myotubes weretreated with the PKC/D1 activator phorbol12-myristate 13-acetate (PMA), which acts as aDAG mimetic. This caused dose- andtime-dependent increases in AMPK Ser(485/491)phosphorylation, which was associated with a", "metadata": {}}
+{"_id": "23983289", "title": "", "text": "Accuracy of ICD-9-CM codes for identifyingcardiovascular and stroke riskfactors.OBJECTIVES We sought to determinewhich ICD-9-CM codes in Medicare Part A dataidentify cardiovascular and stroke risk factors.DESIGN AND PARTICIPANTS This was across-sectional study comparing ICD-9-CM datato structured medical record review from 23,657Medicare beneficiaries aged 20 to 105 years whohad atrial fibrillation. MEASUREMENTS Qualityimprovement organizations used standardizedabstraction instruments to determine thepresence of 9 cardiovascular and stroke riskfactors. Using the chart abstractions as the goldstandard, we assessed the accuracy of ICD-9-CMcodes to identify these risk factors. MAINRESULTS ICD-9-CM codes for all risk factors hadhigh specificity (>0.95) and low sensitivity (< or=0.76). The positive predictive values weregreater than 0.95 for 5 common, chronic riskfactors-coronary artery disease, stroke/transientischemic attack, heart failure, diabetes, and", "metadata": {}}
+{"_id": "23985464", "title": "", "text": "Modulation of cellular and viral promoters bymutant human p53 proteins found in tumorcells.Wild-type p53 has recently been shown torepress transcription from several cellular andviral promoters. Since p53 mutations are themost frequently reported genetic defects inhuman cancers, it becomes important to studythe effects of mutations of p53 on promoterfunctions. We, therefore, have studied theeffects of wild-type and mutant human p53 onthe human proliferating-cell nuclear antigen(PCNA) promoter and on several viral promoters,including the herpes simplex virus type 1 UL9promoter, the human cytomegalovirus majorimmediate-early promoter-enhancer, and thelong terminal repeat promoters of Rous sarcomavirus and human T-cell lymphotropic virus type I.HeLa cells were cotransfected with a wild-type ormutant p53 expression vector and a plasmidcontaining a chloramphenicol acetyltransferasereporter gene under viral (or cellular) promotercontrol. As expected, expression of the wild-type", "metadata": {}}
+{"_id": "24003461", "title": "", "text": "Valvular interstitial cells suppress calcification ofvalvular endothelial cells.BACKGROUND Calcificaortic valve disease (CAVD) is the most commonheart valve disease in the Western world. Wepreviously proposed that valvular endothelialcells (VECs) replenish injured adult valve leafletsvia endothelial-to-mesenchymal transformation(EndMT); however, whether EndMT contributesto valvular calcification is unknown. Wehypothesized that aortic VECs undergoosteogenic differentiation via an EndMT processthat can be inhibited by valvular interstitial cells(VICs). APPROACH AND RESULTS VEC clonesunderwent TGF-β1-mediated EndMT, shown bysignificantly increased mRNA expression of theEndMT markers α-SMA (5.3 ± 1.2), MMP-2 (13.5± 0.6) and Slug (12 ± 2.1) (p < 0.05),(compared to unstimulated controls). To studythe effects of VIC on VEC EndMT, clonalpopulations of VICs were derived from the samevalve leaflets, placed in co-culture with VECs,and grown in control/TGF-β1 supplemented", "metadata": {}}
+{"_id": "24005548", "title": "", "text": "The HMG-CoA reductase inhibitor simvastatinactivates the protein kinase Akt and promotesangiogenesis in normocholesterolemicanimals.Recent studies suggest that statins canfunction to protect the vasculature in a mannerthat is independent of their lipid-loweringactivity. We show here that statins rapidlyactivate the protein kinase Akt/PKB in endothelialcells. Accordingly, simvastatin enhancedphosphorylation of the endogenous Akt substrateendothelial nitric oxide synthase (eNOS),inhibited apoptosis and accelerated vascularstructure formation in vitro in an Akt-dependentmanner. Similar to vascular endothelial growthfactor (VEGF) treatment, both simvastatinadministration and enhanced Akt signaling in theendothelium promoted angiogenesis in ischemiclimbs of normocholesterolemic rabbits.Therefore, activation of Akt represents amechanism that can account for some of thebeneficial side effects of statins, including thepromotion of new blood vessel growth.", "metadata": {}}
+{"_id": "24019260", "title": "", "text": "Varenicline, an alpha4beta2 nicotinicacetylcholine receptor partial agonist, selectivelydecreases ethanol consumption andseeking.Alcohol dependence is a disease thatimpacts millions of individuals worldwide. Therehas been some progress with pharmacotherapyfor alcohol-dependent individuals; however,there remains a critical need for the developmentof novel and additional therapeutic approaches.Alcohol and nicotine are commonly abusedtogether, and there is evidence that neuronalnicotinic acetylcholine receptors (nAChRs) play arole in both alcohol and nicotine dependence.Varenicline, a partial agonist at the alpha4beta2nAChRs, reduces nicotine intake and wasrecently approved as a smoking cessation aid.We have investigated the role of varenicline inthe modulation of ethanol consumption andseeking using three different animal models ofdrinking. We show that acute administration ofvarenicline, in doses reported to reduce nicotinereward, selectively reduced ethanol but not", "metadata": {}}
+{"_id": "24042363", "title": "", "text": "Targeting TLR4 signaling by TLR4 Toll/IL-1receptor domain-derived decoy peptides:identification of the TLR4 Toll/IL-1 receptordomain dimerization interface.Agonist-induceddimerization of TLR4 Toll/IL-1R (TIR) domainsinitiates intracellular signaling. Therefore,identification of the TLR4-TIR dimerizationinterface is one key to the rational design oftherapeutics that block TLR4 signaling. A libraryof cell-permeating decoy peptides, each of whichrepresents a nonfragmented patch of the TLR4TIR surface, was designed such that the peptidesentirely encompass the TLR4 TIR surface. Eachpeptide was synthesized in tandem with acell-permeating Antennapedia homeodomainsequence and tested for the ability to inhibitearly cytokine mRNA expression and MAPKactivation in LPS-stimulated primary murinemacrophages. Five peptides--4R1, 4R3, 4BB,4R9, and 4αE--potently inhibited allmanifestations of TLR4, but not TLR2 signaling.When tested for their ability to bind directly to", "metadata": {}}
+{"_id": "24042919", "title": "", "text": "A paediatric case of sideroblastic anaemia.Ultrastructural studies of erythroblasts culturedfrom marrow BFU-E in a methylcellulosemicromethod.We examined the morphologicaland functional characteristics of erythroblastsderived from marrow erythroid progenitor cellsgrown in a methylcellulose microculture, whichwere taken from a female child with rare atypicalsideroblastic anaemia (SA) partially responsiveto pyridoxine. Colony formation was within thenormal range in three successive cultures(median values: 82.25 CFU-E and 16.4 BFU-Ederived colonies/6.6 X 10(4) cells) compared togrowth by normal cells (65-315 CFU-E and 9-40BFU-E). We evaluated in vitro differentiation bybiochemical microassay of a cytosol enzymeinvolved in the haem pathway: uroporphyrinogenI synthase (UROS). The UROS values in theerythroid colonies from SA marrow were at thelowere end of the normal range (median values:6.7 +/- 0.3 and 14.4 +/- 3.8 pmoluroporphyrinogen/h in CFU-E and BFU-E-derived", "metadata": {}}
+{"_id": "24044977", "title": "", "text": "Innate lymphoid cells: emerging insights indevelopment, lineage relationships, andfunction.Innate lymphoid cells (ILCs) areimmune cells that lack a specific antigen receptoryet can produce an array of effector cytokinesthat in variety match that of T helper cellsubsets. ILCs function in lymphoidorganogenesis, tissue remodeling, antimicrobialimmunity, and inflammation, particularly atbarrier surfaces. Their ability to promptlyrespond to insults inflicted by stress-causingmicrobes strongly suggests that ILCs are criticalin first-line immunological defenses. Here, wereview current data on developmentalrequirements, lineage relationships, and effectorfunctions of two families of ILCs: (a)Rorγt-expressing cells involved in lymphoidtissue formation, mucosal immunity, andinflammation and (b) type 2 ILCs that areimportant for helminth immunity. We alsodiscuss the potential roles of ILCs in thepathology of immune-mediated inflammatory", "metadata": {}}
+{"_id": "24049225", "title": "", "text": "No net renal extraction of homocysteine infasting humans.BACKGROUND Thepathophysiological mechanism ofhyperhomocysteinemia in chronic renal failure inhumans is unknown. The loss of a putative renalhomocysteine extraction in chronic renal failurehas been hypothesized as significanthomocysteine uptake has been demonstrated inthe normal rat kidney. We studied homocysteineextraction in the normal human kidney.METHODS We measured plasma total (free andprotein-bound) and free homocysteine (tHcy andfHcy, respectively) in arterial and renal venousblood sampled from the aorta and right-siderenal vein during cardiac catheterization in 20fasting patients with normal renal function. Renalhomocysteine extraction was calculated as thearteriovenous difference divided by the arteriallevels times 100%. RESULTS No significant renalextraction was demonstrated either for tHcy:0.9% (SD 5.8; 95% CI -1.8 to +3.6) or for fHcy:-0.2% (11.0; -5.4 to +4.9). CONCLUSIONS We", "metadata": {}}
+{"_id": "24055603", "title": "", "text": "Traditional Chinese acupuncture in tension-typeheadache: a controlled study.Thirty patients withtension-type headache were randomly chosen toundergo a trial of traditional Chineseacupuncture and sham acupuncture. Fivemeasures were used to assess symptom severityand treatment response: intensity, duration andfrequency of headache pain episodes, headacheindex and analgesic intake. The five measureswere assessed during a 4 week baseline period,after 4 and 8 weeks of treatment, and 1, 6 and12 months thereafter. Before the start of thestudy, each patient was administered the MMPI.Split-plot ANOVAs showed that, compared tobaseline, at 1 month after the end of treatmentand for the 12 month follow-up, the frequency ofheadache episodes, analgesic consumption andthe headache index (but not the duration orintensity of headache episodes) significantlydecreased over time; however, no differencebetween acupuncture and placebo treatment wasfound. No single MMPI scale predicted the", "metadata": {}}
+{"_id": "24069089", "title": "", "text": "TCR stimulation with modified anti-CD3 mAbexpands CD8+ T cell population and inducesCD8+CD25+ Tregs.Modified anti-CD3 mAbs areemerging as a possible means of inducingimmunologic tolerance in settings includingtransplantation and autoimmunity such as intype 1 diabetes. In a trial of a modified anti-CD3mAb [hOKT3gamma1(Ala-Ala)] in patients withtype 1 diabetes, we identified clinical respondersby an increase in the number of peripheral bloodCD8+ cells following treatment with the mAb.Here we show that the anti-CD3 mAb causedactivation of CD8+ T cells that was similar invitro and in vivo and induced regulatoryCD8+CD25+ T cells. These cells inhibited theresponses of CD4+ cells to the mAb itself and toantigen. The regulatory CD8+CD25+ cells wereCTLA4 and Foxp3 and required contact forinhibition. Foxp3 was also induced on CD8+ Tcells in patients during mAb treatment, whichsuggests a potential mechanism of the anti-CD3mAb immune modulatory effects involving", "metadata": {}}
+{"_id": "24077493", "title": "", "text": "Interactions between Non-Physician Cliniciansand Industry: A SystematicReviewBACKGROUND With increasing restrictionsplaced on physician-industry interactions,industry marketing may target other healthprofessionals. Recent health policy developmentsconfer even greater importance on the decisionmaking of non-physician clinicians. The purposeof this systematic review is to examine the typesand implications of non-physicianclinician-industry interactions in clinical practice.METHODS AND FINDINGS We searched MEDLINEand Web of Science from January 1, 1946,through June 24, 2013, according to PRISMAguidelines. Non-physician clinicians eligible forinclusion were: Registered Nurses, nurseprescribers, Physician Assistants, pharmacists,dieticians, and physical or occupationaltherapists; trainee samples were excluded.Fifteen studies met inclusion criteria. Data weresynthesized qualitatively into eight outcomedomains: nature and frequency of industry", "metadata": {}}
+{"_id": "24082820", "title": "", "text": "Emtricitabine-tenofovir concentrations andpre-exposure prophylaxis efficacy in men whohave sex with men.Drug concentrationsassociated with protection from HIV-1 acquisitionhave not been determined. We evaluated drugconcentrations among men who have sex withmen in a substudy of the iPrEx trial (1). In thisrandomized placebo-controlled trial, daily oraldoses of emtricitabine/tenofovir disoproxilfumarate were used as pre-exposure prophylaxis(PrEP) in men who have sex with men. Drug wasdetected less frequently in blood plasma and inviable cryopreserved peripheral bloodmononuclear cells (PBMCs) in HIV-infected casesat the visit when HIV was first discoveredcompared with controls at the matched timepoint of the study (8% versus 44%; P < 0.001)and in the 90 days before that visit (11% versus51%; P < 0.001). An intracellular concentrationof the active form of tenofovir,tenofovir-diphosphate (TFV-DP), of 16 fmol permillion PBMCs was associated with a 90%", "metadata": {}}
+{"_id": "24088502", "title": "", "text": "Clinical outcomes following institution of theCanadian universal leukoreduction program forred blood cell transfusions.CONTEXT A number ofcountries have implemented a policy of universalleukoreduction of their blood supply, but thepotential role of leukoreduction in decreasingpostoperative mortality and infection is unclear.OBJECTIVE To evaluate clinical outcomesfollowing adoption of a national universalprestorage leukoreduction program for bloodtransfusions. DESIGN, SETTING, ANDPOPULATION Retrospective before-and-aftercohort study conducted from August 1998 toAugust 2000 in 23 academic and communityhospitals throughout Canada, enrolling 14 786patients who received red blood cell transfusionsfollowing cardiac surgery or repair of hipfracture, or who required intensive care followinga surgical intervention or multiple trauma.INTERVENTION Universal prestorageleukoreduction program introduced by 2Canadian blood agencies. A total of 6982", "metadata": {}}
+{"_id": "24097933", "title": "", "text": "Failure of continuous venovenous hemofiltrationto prevent death in paraquat poisoning.Paraquatpoisoning is characterized by multiorgan failureand pulmonary fibrosis with respiratory failure.Multiorgan failure with circulatory collapse is amajor cause of early death within 3 days ofparaquat ingestion. Recent studies suggestedthat continuous venovenous hemofiltration(CVVH) had a role in the treatment of multiorganfailure by promoting hemodynamic stability. Wetherefore evaluated the effect of prophylacticCVVH in 80 patients with paraquat poisoning(August 1996 to February 1999). The amountingested was 2.1 +/- 1.0 mouthfuls (as 20%concentrate). All patients were treated withhemoperfusion (HP; duration, 6.4 +/- 3.0 hours)within 24 hours of ingestion and then randomlyassigned to the HP-alone or HP-CVVH group.Forty-four patients underwent HP only, and 36patients underwent CVVH (duration, 57.4 +/-31.3 hours; ultrafiltration volume, 40.2 +/- 4.8L/d) after HP. Although time to death after", "metadata": {}}
+{"_id": "24101431", "title": "", "text": "The antidiabetic effect of mesenchymal stemcells is unrelated to their transdifferentiationpotential but to their capability to restoreTh1/Th2 balance and to modify the pancreaticmicroenvironment.Type 1 diabetes mellitus(T1DM) is a chronic metabolic disease thatresults from cell-mediated autoimmunedestruction of insulin-producing cells. In T1DManimal models, it has been shown that thesystemic administration of multipotentmesenchymal stromal cells, also referred as tomesenchymal stem cells (MSCs), results in theregeneration of pancreatic islets. Mechanismsunderlying this effect are still poorly understood.Our aims were to assess whether donor MSCs (a)differentiate into pancreatic β-cells and (b)modify systemic and pancreatic pathophysiologicmarkers of T1DM. After the intravenousadministration of 5 × 10(5) syngeneic MSCs, weobserved that mice with T1DM reverted theirhyperglycemia and presented no donor-derivedinsulin-producing cells. In contrast, 7 and 65", "metadata": {}}
+{"_id": "24142891", "title": "", "text": "Tmem27: a cleaved and shed plasma membraneprotein that stimulates pancreatic beta cellproliferation.The signals and molecularmechanisms that regulate the replication ofterminally differentiated beta cells are unknown.Here, we report the identification andcharacterization of transmembrane protein 27(Tmem27, collectrin) in pancreatic beta cells.Expression of Tmem27 is reduced in Tcf1(-/-)mice and is increased in islets of mouse modelswith hypertrophy of the endocrine pancreas.Tmem27 forms dimers and its extracellulardomain is glycosylated, cleaved and shed fromthe plasma membrane of beta cells. Thiscleavage process is beta cell specific and doesnot occur in other cell types. Overexpression offull-length Tmem27, but not the truncated orsoluble protein, leads to increased thymidineincorporation, whereas silencing of Tmem27using RNAi results in a reduction of cellreplication. Furthermore, transgenic mice withincreased expression of Tmem27 in pancreatic", "metadata": {}}
+{"_id": "24144677", "title": "", "text": "The ATM missense mutation p.Ser49Cys(c.146C>G) and the risk of breastcancer.Homozygous mutation in the ATM genecauses ataxia telangiectasia and heterozygousmutation carriers may be at increased risk ofbreast cancer. We studied a total of 22 ATMvariants; 18 variants were analyzed in one of twolarge population-based studies from the U.S. andPoland, and four variants were analyzed in all2,856 breast cancer cases and 3,344 controlsfrom the two studies. The missense mutationSer49Cys (c.146C>G, p. S49C), carried byapproximately 2% of subjects, was morecommon in cases than controls in both studypopulations, combined odds ratio (OR) 1.69(95% CI, 1.19-2.40; P=0.004). Anothermissense mutation at approximately 2%frequency, Phe858Leu (c.2572T>C, p. F858L),was associated with a significant increased risk inthe U.S. study but not in Poland, and had acombined OR of 1.44 (95% CI, 0.98-2.11;P=0.06). These analyses provide the most", "metadata": {}}
+{"_id": "24148722", "title": "", "text": "A diffusion tensor magnetic resonance imagingstudy of corpus callosum from adult patients withmigraine complicated with depressive/anxiousdisorder.OBJECTIVE The aim of this study was toinvestigate the possible microstructuralabnormalities of the corpus callosum (CC) inadult patients with migraine without auracomplicated with depressive/anxious disorder.BACKGROUND Emotional disorders, especiallydepression and anxiety, are with relatively higherincidence in migraine population. However, themechanism of migraine complicated withdepressive/anxious disorder remains unclear.METHODS Diffusion tensor magnetic resonanceimaging was carried out in 12 adult patients withsimple migraine (without aura and withoutdepressive/anxious disorder) (S-M group), 12adult patients with complicated migraine(without aura but complicated withdepressive/anxious disorder) (Co-M group), and12 age- and sex-matched healthy subjects(Control group). Fractional anisotropy (FA) and", "metadata": {}}
+{"_id": "24150328", "title": "", "text": "Peroxisome proliferator-activated receptorgamma agonists for the Prevention of Adverseevents following percutaneous coronaryRevascularization--results of the PPARstudy.BACKGROUND Patients with metabolicsyndrome are at increased risk for cardiovascularcomplications. We sought to determine whetherperoxisome proliferator-activated receptorgamma agonists had any beneficial effect onpatients with metabolic syndrome undergoingpercutaneous coronary intervention (PCI).METHODS A total of 200 patients with metabolicsyndrome undergoing PCI were randomized torosiglitazone or placebo and followed for 1 year.Carotid intima-medial thickness (CIMT),inflammatory markers, lipid levels, brainnatriuretic peptide, and clinical events weremeasured at baseline, 6 months, and 12 months.RESULTS There was no significant difference inCIMT between the 2 groups. There was nodifference in the 12-month composite end pointof death, myocardial infarction (MI), stroke, or", "metadata": {}}
+{"_id": "24155601", "title": "", "text": "Accumulation of hydroxyethyl starch in humanand animal tissues: a systematic reviewTosystematically review clinical and preclinical dataon hydroxyethyl starch (HES) tissue storage.MEDLINE (PubMed) was searched and abstractswere screened using defined criteria to identifyarticles containing original data on HES tissueaccumulation. Forty-eight studies were included:37 human studies with a total of 635 patientsand 11 animal studies. The most frequentindication for fluid infusion was surgeryaccounting for 282 patients (45.9 %). HESlocalization in skin was shown by 17 studies, inkidney by 12, in liver by 8, and in bone marrowby 5. Additional sites of HES deposition werelymph nodes, spleen, lung, pancreas, intestine,muscle, trophoblast, and placental stroma.Among major organs the highest measuredtissue concentration of HES was in the kidney.HES uptake into intracellular vacuoles wasobserved by 30 min after infusion. Storage wascumulative, increasing in proportion to dose,", "metadata": {}}
+{"_id": "24157077", "title": "", "text": "Cationic host defense (antimicrobial)peptides.Members of the cationic host defense(antimicrobial) peptide family are widelydistributed in nature, existing in organisms frominsects to plants to mammals andnon-mammalian vertebrates. Although manydemonstrate direct antimicrobial activity againstbacteria, fungi, eukaryotic parasites and/orviruses, it has been established that cationicpeptides have a key modulatory role in theinnate immune response. More recent evidencesuggests that host defense peptides are effectiveadjuvants, are synergistic with other immuneeffectors, polarize the adaptive response, andsupport wound healing. In addition, themechanisms of action are being unraveled, whichsupport more effective implementation ofderivatives of these endogenous peptides astherapeutic agents.", "metadata": {}}
+{"_id": "24159217", "title": "", "text": "A mental health intervention for schoolchildrenexposed to violence: a randomized controlledtrial.CONTEXT No randomized controlled studieshave been conducted to date on theeffectiveness of psychological interventions forchildren with symptoms of posttraumatic stressdisorder (PTSD) that has resulted frompersonally witnessing or being personallyexposed to violence. OBJECTIVE To evaluate theeffectiveness of a collaboratively designedschool-based intervention for reducing children'ssymptoms of PTSD and depression that hasresulted from exposure to violence. DESIGN Arandomized controlled trial conducted during the2001-2002 academic year. SETTING ANDPARTICIPANTS Sixth-grade students at 2 largemiddle schools in Los Angeles who reportedexposure to violence and had clinical levels ofsymptoms of PTSD. INTERVENTION Studentswere randomly assigned to a 10-sessionstandardized cognitive-behavioral therapy (theCognitive-Behavioral Intervention for Trauma in", "metadata": {}}
+{"_id": "24163770", "title": "", "text": "Knowledge gaps and misconceptions aboutcoronary heart disease among U.S. SouthAsians.BACKGROUND Although South Asians areat higher risk for coronary heart disease (CHD)than most other U.S. racial/ethnic groups, verylittle research has addressed this disparity.PURPOSE As a first step in developing culturallytargeted CHD prevention messages for thisrapidly growing community, this study examinedSouth Asians' knowledge and beliefs about CHD.METHODS Analyses, conducted in 2009, werebased on data collected from January to July2008 in a cross-sectional study population of 270South Asian adults in Illinois. Interviews wereconducted in English, Hindi, or Urdu using astandardized questionnaire. Multivariateregression models were used to examine theassociations between sociodemographics andCHD knowledge and attitudes aboutpreventability. RESULTS Eighty-one percent ofrespondents had one or more CHD risk factors.Most participants (89%) said they knew little or", "metadata": {}}
+{"_id": "24177706", "title": "", "text": "Innate host defense requires TFEB-mediatedtranscription of cytoprotective and antimicrobialgenes.Animal host defense against infectionrequires the expression of defense genes at theright place and the right time. Understandingsuch tight control of host defense requires theelucidation of the transcription factors involved.By using an unbiased approach in the modelCaenorhabditis elegans, we discovered thatHLH-30 (known as TFEB in mammals) is a keytranscription factor for host defense. HLH-30 wasactivated shortly after Staphylococcus aureusinfection, and drove the expression of close to80% of the host response, includingantimicrobial and autophagy genes that wereessential for host tolerance of infection. TFEBwas also rapidly activated in murinemacrophages upon S. aureus infection and wasrequired for proper transcriptional induction ofseveral proinflammatory cytokines andchemokines. Thus, our data suggest that TFEB isa previously unappreciated, evolutionarily", "metadata": {}}
+{"_id": "24185667", "title": "", "text": "DAP kinase regulates JNK signaling by bindingand activating protein kinase D under oxidativestressThe stress-activated kinase JNK mediateskey cellular responses to oxidative stress. Herewe show that DAP kinase (DAPk), a cell deathpromoting Ser/Thr protein kinase, plays a mainrole in oxidative stress-induced JNK signaling.We identify protein kinase D (PKD) as a novelsubstrate of DAPk and demonstrate that DAPkphysically interacts with PKD in response tooxidative stress. We further show that DAPkactivates PKD in cells and that induction of JNKphosphorylation by ectopically expressed DAPkcan be attenuated by knocking down PKDexpression or by inhibiting its catalytic activity.Moreover, knockdown of DAPk expression causeda marked reduction in JNK activation underoxidative stress, indicating that DAPk isindispensable for the activation of JNK signalingunder these conditions. Finally, DAPk is shown tobe required for cell death under oxidative stressin a process that displays the characteristics of", "metadata": {}}
+{"_id": "24186125", "title": "", "text": "The changes of antioxidant defense systemcaused by quercetin administration do not leadto DNA damage and apoptosis in the spleen andbone marrow cells of rats.Quercetin may havethe opposite effect, namely anti- as well aspro-oxidant. The aim of this study was to assessthe results of quercetin anti- and/or pro-oxidantactivity in the bone marrow and spleen cells ofrats. The experimental rats were treated daily,with quercetin in a dose of 8 or 80mg/kg b.w. bygavage for 40 days. The intracellular redox statein cells were assessed by measuring the ferricion reducing antioxidant power (FRAP) level andmalonodialdehyde concentration. HO-1 mRNAexpression was examined with real-time PCR.The extent of DNA damage was determined bythe alkaline-labile comet assay. A potentialpro-apoptotic quercetin action was determinedusing the FITC-Annexin V kit. The quercetin andisorhamnetin concentrations in serum wereanalyzed by HPLC-ECD. MDA concentration andFRAP values, were significantly decreased in the", "metadata": {}}
+{"_id": "24190159", "title": "", "text": "Mutated KRAS results in overexpression ofDUSP4, a MAP-kinase phosphatase, and SMYD3,a histone methyltransferase, in rectalcarcinomas.Mutations of the KRAS oncogene arepredictive for resistance to treatment withantibodies against the epithelial growth factorreceptor in patients with colorectal cancer.Overcoming this therapeutic dilemma couldpotentially be achieved by the introduction ofdrugs that inhibit signaling pathways that areactivated by KRAS mutations. To identifycomprehensively such signaling pathways, weprofiled pretreatment biopsies and normalmucosa from 65 patients with locally advancedrectal cancer-30 of which carried mutatedKRAS-using global gene expression microarrays.By comparing all tumor tissues exclusively tomatched normal mucosa, we could improveassay sensitivity, and identified a total of 22,297features that were differentially expressed(adjusted P-value <0.05) between normalmucosa and cancer, including several novel", "metadata": {}}
+{"_id": "24205118", "title": "", "text": "Clinicopathological and prognostic significance ofBmi-1 expression in human cervicalcancer.OBJECTIVE To investigate the clinicalsignificance of Bmi-1 expression as a prognosticmarker for cervical cancer. Design.Retrospectively collected data from apopulation-based cohort. SETTING JiangsuProvince Hospital. Population. Eighty-eightwomen diagnosed with cervical carcinomabetween 2000 and 2003. METHODS RT-PCRassay was performed to determine Bmi-1 mRNAexpression in 18 cervical cancer andnoncancerous tissue samples andimmunohistochemistry to detect Bmi-1 proteinexpression in 88 cervical cancer samples. Thecorrelation between Bmi-1 expression andclinicopathological factors was analyzed.Additionally, statistical analyses were applied totest for prognostic associations. RNA interferencewas used to downregulate Bmi-1 expression in acervical cancer cell line (HeLa). In vitrocytotoxicity was measured by the", "metadata": {}}
+{"_id": "24211561", "title": "", "text": "Dexamethasone decreases vomiting by childrenafter tonsillectomy.We evaluated the effect ofdexamethasone on vomiting after electivetonsillectomy in 133 healthy children aged 2-12yr in a randomized, stratified, blocked,double-blind, placebo-controlled study. Generalanesthesia was induced by inhalation of N2O andhalothane or intravenously (IV) with propofol.Anesthesia was maintained with N2O andhalothane. Dexamethasone 150 micrograms/kgup to a maximum dose of 8 mg, or placebo, wasadministered IV before surgery. All patientsreceived 1.5 mg/kg codeine intramuscularly (IM)intraoperatively. Perioperative IV fluids,management of emesis, postoperative pain andhospital discharge criteria were all standardized.The groups were similar with respect to number,age, weight, length of surgery, and estimatedintraoperative blood loss. Dexamethasonereduced the overall incidence of vomiting from72% (placebo) to 40% (P < 0.001). Vomiting,both in-hospital and postdischarge, was", "metadata": {}}
+{"_id": "24221369", "title": "", "text": "A Conserved Histidine in the RNA Sensor RIG-IControls Immune Tolerance toN1-2'O-Methylated Self RNA.The cytosolichelicase retinoic acid-inducible gene-I (RIG-I)initiates immune responses to most RNA virusesby detecting viral 5'-triphosphorylated RNA(pppRNA). Although endogenous mRNA is also5'-triphosphorylated, backbone modifications andthe 5'-ppp-linked methylguanosine ((m7)G) capprevent immunorecognition. Here we show thatthe methylation status of endogenous cappedmRNA at the 5'-terminal nucleotide (N1) wascrucial to prevent RIG-I activation. Moreover, weidentified a single conserved amino acid (H830)in the RIG-I RNA binding pocket as the mediatorof steric exclusion of N1-2'O-methylated RNA.H830A alteration (RIG-I(H830A)) restoredbinding of N1-2'O-methylated pppRNA.Consequently, endogenous mRNA activated theRIG-I(H830A) mutant but not wild-type RIG-I.Similarly, knockdown of the endogenousN1-2'O-methyltransferase led to considerable", "metadata": {}}
+{"_id": "24234341", "title": "", "text": "lumi: a pipeline for processing Illuminamicroarray.UNLABELLED Illumina microarray isbecoming a popular microarray platform. TheBeadArray technology from Illumina makes itspreprocessing and quality control different fromother microarray technologies. Unfortunately,most other analyses have not taken advantageof the unique properties of the BeadArraysystem, and have just incorporatedpreprocessing methods originally designed forAffymetrix microarrays. lumi is a Bioconductorpackage especially designed to process theIllumina microarray data. It includes data input,quality control, variance stabilization,normalization and gene annotation portions. Inspecific, the lumi package includes avariance-stabilizing transformation (VST)algorithm that takes advantage of the technicalreplicates available on every Illumina microarray.Different normalization method options andmultiple quality control plots are provided in thepackage. To better annotate the Illumina data, a", "metadata": {}}
+{"_id": "24237492", "title": "", "text": "Large scale replication and meta-analysis ofvariants on chromosome 4q25 associated withatrial fibrillation.AIMS A recent genome-wideassociation study identified a haplotype block onchromosome 4q25 associated with atrialfibrillation (AF). We sought to replicate thisassociation in four independent cohorts.METHODS AND RESULTS The Framingham HeartStudy and Rotterdam Study arecommunity-based longitudinal studies. TheVanderbilt AF Registry and German AF Network(AFNet) are case-control studies. Participantswith AF (n = 3508) were more likely to be maleand were older than referent participants (n = 12173; Framingham 82 +/- 10 vs. 71 +/- 13 years;Rotterdam 73 +/- 8 vs. 69 +/- 9 years;Vanderbilt 54 +/- 14 vs. 57 +/- 14 years; AFNet62 +/- 12 vs. 49 +/- 14 years). Single nucleotidepolymorphism (SNP) rs2200733 was associatedwith AF in all four cohorts, with odds ratios (ORs)ranging from 1.37 in Rotterdam [95% confidenceinterval (CI) 1.18-1.59; P = 3.1 x 10(-5)] to", "metadata": {}}
+{"_id": "24241932", "title": "", "text": "Ecological analysis of ethnic differences inrelation between tuberculosis andpoverty.OBJECTIVE To examine the effect ofethnicity on the relation between tuberculosisand deprivation. DESIGN Retrospectiveecological study comparing incidence oftuberculosis in white and south Asian residents ofthe 39 electoral wards in Birmingham with ethnicspecific indices of deprivation. SETTINGBirmingham, 1989-93. SUBJECTS 1516 notifiedcases of tuberculosis. MAIN OUTCOMEMEASURES Rates of tuberculosis and measuresof deprivation. RESULTS Univariate analysisshowed significant associations of tuberculosisrates for the whole population with severalindices of deprivation (P<0.01) and with theproportion of the population of south Asian origin(P<0.01). All deprivation covariates werepositively associated with each other but onmultiple regression, higher level of overcrowdingwas independently associated with tuberculosisrates. For the white population, overcrowding", "metadata": {}}
+{"_id": "24249915", "title": "", "text": "Reduced expression of oestrogen receptor betain invasive breast cancer and its re-expressionusing DNA methyl transferase inhibitors in a cellline model.To gain insights into the possible roleof oestrogen receptor (ER) beta in breastcarcinogenesis, immunohistochemical analysis ofER beta was performed on 512 breast specimensencompassing normal (n = 138), pure ductalcarcinoma in situ (n = 16), invasive cancers (n =319), lymph node metastases (n = 31), andrecurrences (n = 8). Real-time polymerase chainreaction (PCR) was used to investigate themethylation status of the ER beta gene in the ERbeta negative breast cancer cell lines SkBr3 andMDA-MB-435. A gradual reduction in, but not acomplete loss of, ER beta expression wasobserved during the transition from normal andpre-invasive lesions to invasive cancers, whereER beta was lost in 21% of cases. This was morepronounced in invasive ductal than in lobularcarcinomas, a significantly higher proportion ofwhich were ER beta-positive (74% compared", "metadata": {}}
+{"_id": "24269361", "title": "", "text": "Atopy risk in infants and children in relation toearly exposure to fish, oily fish, or long-chainomega-3 fatty acids: a systematic review.Thereare two main families of polyunsaturated fattyacids (PUFAs), the n-6 and the n-3 families. Ithas been suggested that there is a causalrelationship between n-6 PUFA intake andallergic disease, and there are biologicallyplausible mechanisms, involving eicosanoidmediators of the n-6 PUFA arachidonic acid, thatcould explain this. Fish and fish oils are sourcesof long-chain n-3 PUFAs and these fatty acids actto oppose the actions of n-6 PUFAs. Thus, it isconsidered that n-3 PUFAs will protect againstatopic sensitization and against the clinicalmanifestations of atopy. Evidence to examinethis has been acquired from epidemiologicstudies investigating associations between fishintake in pregnancy, lactation, infancy, andchildhood, and atopic outcomes in infants andchildren and from intervention studies with fishoil supplements in pregnancy, lactation, infancy,", "metadata": {}}
+{"_id": "24273592", "title": "", "text": "Dietary quality among men and women in 187countries in 1990 and 2010: a systematicassessmentBACKGROUND Healthy dietarypatterns are a global priority to reducenon-communicable diseases. Yet neitherworldwide patterns of diets nor their trends withtime are well established. We aimed tocharacterise global changes (or trends) in dietarypatterns nationally and regionally and to assessheterogeneity by age, sex, national income, andtype of dietary pattern. METHODS In thissystematic assessment, we evaluated globalconsumption of key dietary items (foods andnutrients) by region, nation, age, and sex in1990 and 2010. Consumption data wereevaluated from 325 surveys (71·7% nationallyrepresentative) covering 88·7% of the globaladult population. Two types of dietary patternwere assessed: one reflecting greaterconsumption of ten healthy dietary items and theother based on lesser consumption of sevenunhealthy dietary items. The mean intakes of", "metadata": {}}
+{"_id": "24276304", "title": "", "text": "The epidemiology of major depressive disorder:results from the National Comorbidity SurveyReplication (NCS-R).CONTEXT Uncertainties existabout prevalence and correlates of majordepressive disorder (MDD). OBJECTIVE Topresent nationally representative data onprevalence and correlates of MDD by Diagnosticand Statistical Manual of Mental Disorders,Fourth Edition (DSM-IV) criteria, and on studypatterns and correlates of treatment andtreatment adequacy from the recently completedNational Comorbidity Survey Replication(NCS-R). DESIGN Face-to-face household surveyconducted from February 2001 to December2002. SETTING The 48 contiguous United States.PARTICIPANTS Household residents ages 18years or older (N = 9090) who responded to theNCS-R survey. MAIN OUTCOME MEASURESPrevalence and correlates of MDD using theWorld Health Organization's (WHO) CompositeInternational Diagnostic Interview (CIDI),12-month severity with the Quick Inventory of", "metadata": {}}
+{"_id": "24276902", "title": "", "text": "The Pain Catastrophizing Scale: FurtherPsychometric Evaluation with AdultSamplesPrevious studies with undergraduateshave provided support for the reliability andoblique three-factor structure of a new scale, thePain Catastrophizing Scale (PCS). We examinedthe reliability and validity of the PCS in adultcommunity and pain outpatient samples. ThePCS showed a high internal consistency in bothgroups. Using data from the community sample,confirmatory factor analyses showed that thePCS taps a single construct characterized bythree related dimensions. Gender differenceswere obtained on the PCS total score in thecommunity and the outpatient samples. Theanalyses also showed significant differencesbetween the community and the outpatientsamples on the PCS total and subscales. Overall,the results showed strong evidence ofcriterion-related, concurrent, and discriminantvalidity for the PCS in the community sample.Limitations of the present study are discussed.", "metadata": {}}
+{"_id": "24278870", "title": "", "text": "Temsirolimus, interferon alfa, or both foradvanced renal-cell carcinoma.BACKGROUNDInterferon alfa is widely used for metastaticrenal-cell carcinoma but has limited efficacy andtolerability. Temsirolimus, a specific inhibitor ofthe mammalian target of rapamycin kinase, maybenefit patients with this disease. METHODS Inthis multicenter, phase 3 trial, we randomlyassigned 626 patients with previously untreated,poor-prognosis metastatic renal-cell carcinomato receive 25 mg of intravenous temsirolimusweekly, 3 million U of interferon alfa (with anincrease to 18 million U) subcutaneously threetimes weekly, or combination therapy with 15mg of temsirolimus weekly plus 6 million U ofinterferon alfa three times weekly. The primaryend point was overall survival in comparisons ofthe temsirolimus group and thecombination-therapy group with the interferongroup. RESULTS Patients who receivedtemsirolimus alone had longer overall survival(hazard ratio for death, 0.73; 95% confidence", "metadata": {}}
+{"_id": "24282306", "title": "", "text": "Macrophage Diversity Enhances TumorProgression and MetastasisThere is persuasiveclinical and experimental evidence thatmacrophages promote cancer initiation andmalignant progression. During tumor initiation,they create an inflammatory environment that ismutagenic and promotes growth. As tumorsprogress to malignancy, macrophages stimulateangiogenesis, enhance tumor cell migration andinvasion, and suppress antitumor immunity. Atmetastatic sites, macrophages prepare the targettissue for arrival of tumor cells, and then adifferent subpopulation of macrophagespromotes tumor cell extravasation, survival, andsubsequent growth. Specialized subpopulationsof macrophages may represent important newtherapeutic targets.", "metadata": {}}
+{"_id": "24285403", "title": "", "text": "Ankle brachial index as a predictor of cognitiveimpairment in the general population: ten-yearfollow-up of the Edinburgh ArteryStudy.OBJECTIVES To determine whether theankle brachial index (ABI, a marker ofgeneralized atherosclerosis) is associated withcognitive impairment after 10 years in olderpeople. DESIGN Cohort study (Edinburgh ArteryStudy). SETTING Eleven general practices inEdinburgh, Scotland. PARTICIPANTS Sevenhundred seventeen men and women aged 55 to74 from the general population, followed for 10years. MEASUREMENTS ABI measured atbaseline and major cognitive functions (includingpremorbid function using the National AdultReading Test, NART) tested after 10 years.RESULTS After adjustment for age and sex, a lowABI was associated with lower scoring (bottomtertile vs top tertile) on Raven's Matrices (oddsratio (OR)=1.6, 95% confidence interval (CI)=1.0-2.6), Verbal Fluency (OR =1.8, 95% CI=1.1-3.0), and Digit Symbol Test (OR =2.3, 95%", "metadata": {}}
+{"_id": "24294572", "title": "", "text": "PTEN Regulates PI(3,4)P2 Signaling Downstreamof Class I PI3KThe PI3K signaling pathwayregulates cell growth and movement and isheavily mutated in cancer. Class I PI3Kssynthesize the lipid messenger PI(3,4,5)P3.PI(3,4,5)P3 can be dephosphorylated by 3- or5-phosphatases, the latter producing PI(3,4)P2.The PTEN tumor suppressor is thought tofunction primarily as a PI(3,4,5)P33-phosphatase, limiting activation of thispathway. Here we show that PTEN also functionsas a PI(3,4)P2 3-phosphatase, both in vitro andin vivo. PTEN is a major PI(3,4)P2 phosphatasein Mcf10a cytosol, and loss of PTEN and INPP4B,a known PI(3,4)P2 4-phosphatase, leads tosynergistic accumulation of PI(3,4)P2, whichcorrelated with increased invadopodia inepidermal growth factor (EGF)-stimulated cells.PTEN deletion increased PI(3,4)P2 levels in amouse model of prostate cancer, and it inverselycorrelated with PI(3,4)P2 levels across severalEGF-stimulated prostate and breast cancer lines.", "metadata": {}}
+{"_id": "24307695", "title": "", "text": "Genetic analysis of an ARS element from thefission yeast Schizosaccharomyces pombe.ARS(autonomously replicating sequence) elementsare DNA fragments that can function as origins ofDNA replication in yeast. We report the firstfine-structure analysis of ars1, an ARS elementof the fission yeast Schizosaccharomyces pombe.Characterization of a series of nested deletionmutations indicated that the minimal fragment ofDNA encompassing ars1 is surprisingly large. Nofragment < 650 bp retained significant ARSactivity. Analysis of deletion and substitutionmutations scanning the entire minimal ars1identified a single essential 50 bp fragment(segment 1). Only one other 50 bp mutationreduced activity as much as 5-fold and mostdeletions were without effect. Thus, the minimalars1 is composed of two general types of geneticelements, a small segment that is absolutelyrequired for efficient ARS activity and a muchlarger region that is tolerant of internal structuralalterations. Higher resolution analysis of", "metadata": {}}
+{"_id": "24311787", "title": "", "text": "N terminus of Swr1 binds to histone H2AZ andprovides a platform for subunit assembly in thechromatin remodeling complex.Variant histoneH2AZ-containing nucleosomes are involved inthe regulation of gene expression. InSaccharomyces cerevisiae, chromatin depositionof histone H2AZ is mediated by thefourteen-subunit SWR1 complex, which catalyzesATP-dependent exchange of nucleosomal histoneH2A for H2AZ. Previous work defined the role ofseven SWR1 subunits (Swr1 ATPase, Swc2,Swc3, Arp6, Swc5, Yaf9, and Swc6) inmaintaining complex integrity and H2AZ histonereplacement activity. Here we examined thefunction of three additional SWR1 subunits,bromodomain containing Bdf1, actin-relatedprotein Arp4 and Swc7, by analyzingaffinity-purified mutant SWR1 complexes. Weobserved that depletion of Arp4 (arp4-td)substantially impaired the association of Bdf1,Yaf9, and Swc4. In contrast, loss of either Bdf1or Swc7 had minimal effects on overall complex", "metadata": {}}
+{"_id": "24315156", "title": "", "text": "Role of the cytoskeleton during leukocyteresponsesThe cytoskeleton is a cellular networkof structural, adaptor and signalling moleculesthat regulates most cellular functions that arerelated to the immune response, includingmigration, extravasation, antigen recognition,activation and phagocytosis by different subsetsof leukocytes. Recently, a large number ofregulatory elements and structural constituentsof the leukocyte cytoskeleton have beenidentified. In this review, we discuss thecomposition and regulation of the differentcytoskeletal elements and their role in immuneresponses.", "metadata": {}}
+{"_id": "24318630", "title": "", "text": "Integration of mental health into primaryhealthcare in low-income countries: avoidingmedicalization.Since 2008 the World HealthOrganization (WHO), through its mental healthGap Action Programme, has attempted torevitalize efforts to integrate mental health intonon-specialized (e.g. primary) healthcare. Whilethis has led to renewed interest in this potentialmethod of mental health service delivery, it hasalso prompted criticism. Some concerns raisedare that it would contribute to the medicalizationof social and psychological problems, andnarrowly focus on primary care without sufficientattention given to strengthening other levels ofthe healthcare system, notablycommunity-based care and care on districtlevels. This paper discusses seven elements thatmay be critical to preventing inadvertentlycontributing to increasing a narrow biomedicalapproach to mental healthcare when integratingmental health into non-specialized healthcare:(1) using task shifting approaches within a", "metadata": {}}
+{"_id": "24323369", "title": "", "text": "Comparison of clomiphene citrate, metformin, orthe combination of both for first-line ovulationinduction and achievement of pregnancy in 154women with polycystic ovarysyndrome.OBJECTIVE To determine whichfirst-line medication is more effective inpolycystic ovary syndrome (PCOS) patients forovulation induction and pregnancy achievementand to verify whether any patient characteristicis associated with a better response to therapy.DESIGN Observational comparative study.SETTING Fertility clinic. PATIENT(S) Onehundred fifty-four infertile women witholigomenorrhea and hyperandrogenism.INTERVENTION(S) Group 1 (56 patients)received clomiphene citrate (CC) 50 mg fromdays 5-9 of the cycle. Group 2 (57 patients)received 500 mg of metformin 3 times a day.Group 3 (41 patients) received both medications.MAIN OUTCOME MEASURE(S) Ovulation andpregnancy. RESULT(S) Patients receivingmetformin alone had an increased ovulation rate", "metadata": {}}
+{"_id": "24323695", "title": "", "text": "Pulmonologist involvement, stage-specifictreatment, and survival in adults with non-smallcell lung cancer and chronic obstructivepulmonary disease.RATIONALE Up to 80% ofpatients with lung cancer have comorbid chronicobstructive pulmonary disease (COPD). Many ofthem are poor candidates for stage-specific lungcancer treatment due to diminished lung functionand poor functional status, and many foregotreatment. The negative effect of COPD may bemoderated by pulmonologist-guidedmanagement. OBJECTIVES This study examinedthe association between pulmonologistmanagement and the probability of receiving therecommended stage-specific treatment modalityand overall survival among patients withnon-small cell lung cancer (NSCLC) withpreexisting COPD. METHODS Early- andadvanced-stage NSCLC cases diagnosed between2002 and 2005 with a prior COPD diagnosis(3-24 months before NSCLC diagnosis) wereidentified in Surveillance, Epidemiology, and End", "metadata": {}}
+{"_id": "24335068", "title": "", "text": "Divalent cations differentially regulate integrinalphaIIb cytoplasmic tail binding to beta3 and tocalcium- and integrin-binding protein.We haveused recombinant or synthetic alphaIIb andbeta3 integrin cytoplasmic peptides to studytheir in vitro complexation and ligand bindingcapacity by surface plasmon resonance.alpha.beta heterodimerization occurred in a 1:1stoichiometry with a weak KD in the micromolarrange. Divalent cations were not required for thisassociation but stabilized the alpha.beta complexby decreasing the dissociation rate. alpha.betacomplexation was impaired by the R995Asubstitution or the KVGFFKR deletion in alphaIIbbut not by the beta3 S752P mutation.Recombinant calcium- and integrin-bindingprotein (CIB), an alphaIIb-specific ligand, boundto the alphaIIb cytoplasmic peptide in a Ca2+- orMn2+-independent, one-to-one reaction with aKD value of 12 microM. In contrast, in vitro liquidphase binding of CIB to intact alphaIIbbeta3occurred preferentially with Mn2+-activated", "metadata": {}}
+{"_id": "24338780", "title": "", "text": "Lethal autoimmune myocarditis ininterferon-gamma receptor-deficient mice:enhanced disease severity by impaired induciblenitric oxide synthase induction.BACKGROUNDInterferon-gamma (IFN-gamma) is an essentialcytokine in the regulation of inflammatoryresponses in autoimmune diseases. Little isknown about its role in inflammatory heartdisease. METHODS AND RESULTS We showedthat IFN-gamma receptor-deficient mice(IFN-gammaR(-/-)) on a BALB/c backgroundimmunized with a peptide derived from cardiacalpha-myosin heavy chain develop severemyocarditis with high mortality. Althoughmyocarditis subsided in wild-type mice after 3weeks, IFN-gammaR(-/-) mice showedpersistent disease. The persistent inflammationwas accompanied by vigorous in vitro CD4 T-cellresponses and impaired inducible nitric oxidesynthase expression, together with evidence ofimpaired nitric oxide production inIFN-gammaR(-/-) hearts. Treatment of wild-type", "metadata": {}}
+{"_id": "24341590", "title": "", "text": "Association between CYP2D6 polymorphisms andoutcomes among women with early stage breastcancer treated with tamoxifen.CONTEXT Thegrowth inhibitory effect of tamoxifen, which isused for the treatment of hormonereceptor-positive breast cancer, is mediated byits metabolites, 4-hydroxytamoxifen andendoxifen. The formation of active metabolites iscatalyzed by the polymorphic cytochrome P4502D6 (CYP2D6) enzyme. OBJECTIVE To determinewhether CYP2D6 variation is associated withclinical outcomes in women receiving adjuvanttamoxifen. DESIGN, SETTING, AND PATIENTSRetrospective analysis of German and US cohortsof patients treated with adjuvant tamoxifen forearly stage breast cancer. The 1325 patients haddiagnoses between 1986 and 2005 of stage Ithrough III breast cancer and were mainlypostmenopausal (95.4%). Last follow-up was inDecember 2008; inclusion criteria were hormonereceptor positivity, no metastatic disease atdiagnosis, adjuvant tamoxifen therapy, and no", "metadata": {}}
+{"_id": "24346598", "title": "", "text": "Long-term, nightly benzodiazepine treatment ofinjurious parasomnias and other disorders ofdisrupted nocturnal sleep in 170 adults.PURPOSETo assess the efficacy, dose stability, safety, andabuse potential of long-term, nightlybenzodiazepine treatment of chronic disorders ofdisrupted nocturnal sleep. PATIENTS ANDMETHODS During a 12-year period, one authorevaluated and treated 170 adult referrals for >or = 6 months with nightly benzodiazepinetherapy for longstanding, sleep-disruptivedisorders: injurious sleepwalking and sleepterrors (69); rapid eye movement sleep behaviordisorder (52); chronic, severe insomnia (25);and restless legs syndrome/periodic limbmovement disorder (24). RESULTSComplete/substantial control of the sleepdisorders was achieved by 146 patients (86%);8% had adverse effects requiring medicationchanges; 2% had relapses of alcohol or chemicalabuse requiring hospitalization; another 2% attimes misused their medications. A total of 136", "metadata": {}}
+{"_id": "24347647", "title": "", "text": "Decreased proteasomal activity causesage-related phenotypes and promotes thedevelopment of metabolic abnormalities.Theproteasome is a multicatalytic enzyme complexresponsible for the degradation of both normaland damaged proteins. An age-related decline inproteasomal activity has been implicated invarious age-related pathologies. The relevance ofdecreased proteasomal activity to aging andage-related diseases remains unclear, however,because suitable animal models are notavailable. In the present study, we established atransgenic (Tg) mouse model with decreasedproteasomal chymotrypsin-like activity. Tg miceexhibited a shortened life span and developedage-related phenotypes. In Tg mice,polyubiquitinated and oxidized proteinsaccumulated, and the expression levels ofcellular proteins such as Bcl-xL and RNase L werealtered. When Tg mice were fed a high-fat diet,they developed more pronounced obesity andhepatic steatosis than did wild-type mice.", "metadata": {}}
+{"_id": "24349430", "title": "", "text": "Orai1/CRACM1 overexpression suppresses cellproliferation via attenuation of thestore-operated calcium influx-mediated signallingpathway in A549 lung cancer cells.BACKGROUNDOrai1/CRACM1 is a principal component of thestore-operated calcium channels. Store-operatedcalcium influx is highly correlated withinflammatory reactions, immunologicalregulation, and cell proliferation. Epidermalgrowth factor (EGF), which plays an importantrole in the regulation of cell proliferation, canactivate store-operated calcium channels.However, the consequences of Orai1/CRACM1overexpression in EGF-mediated lung cancercells growth are not known. METHODS Toinvestigate the role of Orai1/CRACM1 inEGF-mediated lung cancer cell proliferation,Orai1/CRACM1 plasmids were transfected intocells by lipofection. A cell proliferation assay,immunofluorescence staining, flow cytometry,and real-time polymerase chain reaction wereemployed to monitor cell proliferation. The", "metadata": {}}
+{"_id": "24349992", "title": "", "text": "Oxidative stress in cancer associated fibroblastsdrives tumor-stroma co-evolution: A newparadigm for understanding tumor metabolism,the field effect and genomic instability in cancercells.Loss of stromal fibroblast caveolin-1(Cav-1) is a powerful single independentpredictor of poor prognosis in human breastcancer patients, and is associated with earlytumor recurrence, lymph node metastasis andtamoxifen-resistance. We developed a novelco-culture system to understand themechanism(s) by which a loss of stromalfibroblast Cav-1 induces a \"lethal tumormicro-environment. \" Here, we propose a newparadigm to explain the powerful prognosticvalue of stromal Cav-1. In this model, cancercells induce oxidative stress in cancer-associatedfibroblasts, which then acts as a \"metabolic\" and\"mutagenic\" motor to drive tumor-stromaco-evolution, DNA damage and aneuploidy incancer cells. More specifically, we show that anacute loss of Cav-1 expression leads to", "metadata": {}}
+{"_id": "24351680", "title": "", "text": "Telomeres and telomerase: more than the end ofthe lineEarly studies of telomerase suggestedthat telomeres are maintained by an elegant butrelatively simple and highly conservedmechanism of telomerase-mediated replication.As we learn more, it has become clear that themechanism is elegant but not as simple as firstthought. It is also evident that, although manyspecies use similar, sometimes identical, DNAsequences for telomeres, these species expresstheir own individuality in the way they regulatethese sequences and, perhaps, in the additionaltasks that they have imposed on their telomericDNA. The striking similarities between telomeresin different species have revealed much aboutchromosome ends; the differences are proving tobe equally informative. In addition to thedifferences between species that use telomerase,there are also a few exceptional organisms withatypical telomeres for which no telomeraseactivity has been detected. This reviewaddresses recent studies, the insights they offer,", "metadata": {}}
+{"_id": "24356383", "title": "", "text": "Reduced osteoblastic population and defectivemineralization in osteopetrotic (op/op)mice.Osteopetrotic (op/op) mice fail to exhibitbone remodeling because of a defectiveosteoclast formation due to a lack of macrophagecolony-stimulating factor. In this study, weinvestigated the femora of op/op mice to clarifywhether the osteoblastic population and bonemineralization are involved in osteoclasts or theirbone resorption. The op/op mice extended themeshwork of trabecular bones from thechondro-osseous junction to the diaphysealregion. In the femoral metaphyses of op/opmice, intense alkaline phosphatase(ALPase)-positive osteoblasts were observed onthe metaphyseal bone in close proximity to theerosion zone of the growth plates. Von Kossa'sstaining revealed scattered mineralized nodulesand a fine meshwork of mineralized bonematrices while the wild-type littermatesdeveloped well-mineralized trabeculae parallel tothe longitudinal axis. In contrast to the", "metadata": {}}
+{"_id": "24384587", "title": "", "text": "Interleukin 18 function in atherosclerosis ismediated by the interleukin 18 receptor and theNa-Cl co-transporterInterleukin-18 (IL18)participates in atherogenesis through severalputative mechanisms. Interruption of IL18 actionreduces atherosclerosis in mice. Here, we showthat absence of the IL18 receptor (IL18r) doesnot affect atherosclerosis in apolipoproteinE–deficient (Apoe−/−) mice, nor does it affectIL18 cell surface binding to or signaling inendothelial cells. As identified initially byco-immunoprecipitation with IL18, we found thatIL18 interacts with the Na-Cl co-transporter(NCC; also known as SLC12A3), a12-transmembrane-domain ion transporterprotein preferentially expressed in the kidney.NCC is expressed in atherosclerotic lesions,where it colocalizes with IL18r. In Apoe−/−mice, combined deficiency of IL18r and NCC, butnot single deficiency of either protein, protectsmice from atherosclerosis. Peritonealmacrophages from Apoe−/− mice or from", "metadata": {}}
+{"_id": "24387017", "title": "", "text": "Notch promotes survival of pre–T cells at theβ-selection checkpoint by regulating cellularmetabolismNotch signals are necessary for thefunctional outcomes of T cell receptorβ-selection, including differentiation, proliferationand rescue from apoptosis. The mechanismunderlying this requirement for T celldevelopment is unknown. Here we show thatNotch receptor and Delta-like 1 ligandinteractions promoted the survival of CD4−CD8−pre–T cells through the maintenance of cell size,glucose uptake and metabolism. Furthermore,the trophic effects of Notch signaling weremediated by the pathway ofphosphatidylinositol-3-OH kinase and the kinaseAkt, such that expression of active Atk overcamethe requirement for Notch in β-selection.Collectively, our results demonstrateinvolvement of Notch receptor–ligandinteractions in the regulation of cellularmetabolism, thus enabling the autonomoussignaling capacity of the pre–T cell receptor", "metadata": {}}
+{"_id": "24396137", "title": "", "text": "Blood pressure, salivary cortisol, andinflammatory cytokine outcomes in senior femalecancer survivors enrolled in a tai chi chihrandomized controlled trialOlder cancer survivorsare a vulnerable population due to an increasedrisk for chronic diseases (e.g., cardiovasculardisease) compounded with treatment late-effectsand declines in physical functioning. Therefore,interventions that reduce chronic disease riskfactors (i.e., blood pressure, chronicinflammation, and cortisol) are important in thispopulation. Tai chi chih (TCC) is a mind-bodyexercise associated with reductions in chronicdisease risk factors, but has not been examinedwith older cancer survivors. In a feasibilityrandomized controlled trial of TCC, we examinedsecondary outcomes of blood pressure, salivarycortisol, and inflammatory cytokines (interleukin(IL)-6, IL-12, tumor necrosis factor-α, IL-10,IL-4) due to their implications in chronicdiseases. Sixty-three senior female cancersurvivors (M age = 67 years, SD = 7.15) with", "metadata": {}}
+{"_id": "24408040", "title": "", "text": "Heart failure admissions in adults with congenitalheart disease; risk factors andprognosis.BACKGROUND Heart failure (HF) is aserious complication and often the cause ofdeath in adults with congenital heart disease(CHD). Therefore, our aims were to determinethe frequency of HF-admissions, and to assessrisk factors of first HF-admission and of mortalityafter first HF-admission in adults with CHD.METHODS The Dutch CONCOR registry waslinked to the Hospital Discharge Registry andNational Mortality Registry to obtain data onHF-admissions and mortality. Risk factors forboth HF-admission and mortality were assessedusing Cox regression models. RESULTS Of10,808 adult patients (49% male), 274 (2.5%)were admitted for HF during a median follow-upperiod of 21 years. The incidence of firstHF-admission was 1.2 per 1000 patient-years,but the incidence of HF itself will be higher. Maindefect, multiple defects, and surgicalinterventions in childhood were identified as", "metadata": {}}
+{"_id": "24414345", "title": "", "text": "New pathologic classification of lung cancer:relevance for clinical practice and clinicaltrials.We summarize significant changes inpathologic classification of lung cancer resultingfrom the 2011 International Association for theStudy of Lung Cancer/American ThoracicSociety/European Respiratory Society(IASLC/ATS/ERS) lung adenocarcinomaclassification. The classification was developedby an international core panel of expertsrepresenting IASLC, ATS, and ERS withoncologists/pulmonologists, pathologists,radiologists, molecular biologists, and thoracicsurgeons. Because 70% of patients with lungcancer present with advanced stages, a newapproach to small biopsies and cytology withspecific terminology and criteria focused on theneed for distinguishing squamous cell carcinomafrom adenocarcinoma and on molecular testingfor EGFR mutations and ALK rearrangement.Tumors previously classified as non-small-cellcarcinoma, not otherwise specified, because of", "metadata": {}}
+{"_id": "24423427", "title": "", "text": "Polymorphisms in EGFR and IL28B are associatedwith spontaneous clearance in an HCV-infectediranian populationAlthough most hepatitis C virus(HCV)-infected individuals develop chronicinfection, about 25% of them are able to clearthe virus spontaneously without any therapeuticintervention. The aim of the present study was toidentify genes associated with spontaneous HCVclearance in a population of Iranian patients. Wegenotyped 110 single-nucleotide polymorphisms(SNPs) in 59 selected—candidate—genes in acohort of 107 HCV-infected participants whospontaneously cleared the infection and 176participants whose infection persisted. Three outof the 110 SNPs were found to be associatedwith HCV outcome (P-values<0.03). rs11506105in EGFR (epidermal growth factor receptor gene),and rs11881222 and rs12979860 in IL28B(interferon-λ3 gene). Multivariate logisticregression of the three markers showed that theA/A genotypes in both rs11506105 (EFGR) andrs11881222 (IL28B), and the C/C genotype in", "metadata": {}}
+{"_id": "24443043", "title": "", "text": "Cardiopulmonary exercise testing variablesreflect the degree of diastolic dysfunction inpatients with heart failure-normal ejectionfraction.PURPOSE Previous investigations havereported a relationship between variablesobtained from echocardiography with tissueDoppler imaging (TDI) and cardiopulmonaryexercise testing (CPX) in systolic heart failure(HF) cohorts. The purpose of the presentinvestigation was to perform a comparativeanalysis between echocardiography with TDI andCPX in patients with HF and normal ejectionfraction (NEF). METHODS Patients with HF-NEF(N = 32) underwent echocardiography with TDIand CPX to determine the following variables: (1)the ratio between mitral early velocity (E) andmitral annular velocity (E'), (2) ejection fraction,(3) left ventricular (LV) mass, (4) left ventricularend systolic volume, (5) peak oxygen uptake(.VO2), (6) ventilatory efficiency, (7) the partialpressure of end-tidal carbon dioxide (P(ET)CO2)at rest and peak exercise, and (8) heart rate", "metadata": {}}
+{"_id": "24450344", "title": "", "text": "Radical prostatectomy for pathological Gleason 8or greater prostate cancer: influence ofconcomitant pathological variables.PURPOSE Weevaluated the long-term outcome of radicalprostatectomy for pathological Gleason score 8or greater prostate cancer and characterized theprognostic significance of other pathologicalvariables. MATERIALS AND METHODS A total of6,419 patients underwent radical prostatectomybetween 1987 and 1996. There were 407patients classified as having pathological Gleason8 or greater, including 8 in 48%, 9 in 49% and10 in 3%. Adjuvant treatment was used in 45%of patients and adjuvant hormonal therapy wasadministered to 155 (38%). Progression-free,including local or systemic, and/or prostatespecific antigen (PSA) 0.4 ng./ml. or greater, andcancer specific survival were determined by theKaplan-Meier method. The effect of pathologicalgrade and stage, preoperative PSA, DNA ploidy,margin status, tumor dimension, seminal vesicleinvasion, and adjuvant treatment was assessed", "metadata": {}}
+{"_id": "24466904", "title": "", "text": "Successful establishment of long-term bonemarrow cultures in 103 patients withmyelodysplastic syndromes.We used bonemarrow biopsies instead of mononuclear cells tomaintain long-term cultures from 103 patientsbelonging to all five sub-categories ofmyelodysplastic syndromes (MDS), as well as 12normal controls. By week 4, 30-50% confluencywas reached and could be maintained for up to12 weeks with 100% confluency. The fourprominent cells were fibroblasts, macrophages,endothelial cells and adipocytes.Immunohistochemical and electron microscopicstudies provided lineage confirmation. Normalhematopoiesis was well supported by MDSstroma. Neither the FAB nor cytogenetics wasco-related with the potency of growth. MDSstroma appears to be both morphologically andfunctionally normal.", "metadata": {}}
+{"_id": "24494539", "title": "", "text": "[Acupuncture combined with auricular pointsticking therapy for post stroke depression:arandomized controlled trial].OBJECTIVE Toobserve the clinical effects of acupuncturecombined with auricular point sticking based onthe western medication for post strokedepression (PSD). METHODS Sixty patients withPSD were randomly assigned into anacupuncture plus auricular application group (acombination group) and a medication group, 30cases in each one. 20 mg paroxetinehydrochloride was prescribed orally in themedication group, once a day for continuous 8weeks. Based on the above treatment,30-minute acupuncture was used in thecombination group for 8 weeks at Baihui (GV20), Sishencong (EX-HN 1), Shenting (GV 24),Yintang (GV 29), Shenmen (HT 7), Neiguan (PC6), Taichong (LR 3), Hegu (LI 4), Zusanli (ST36), Sanyinjiao (SP 6) and Fenglong (ST 40),once the other day and three times a week.Auricular point sticking therapy for 8 weeks was", "metadata": {}}
+{"_id": "24496245", "title": "", "text": "Selective enhancement of endothelial BMPR-IIwith BMP9 reverses pulmonary arterialhypertensionGenetic evidence implicates the lossof bone morphogenetic protein type II receptor(BMPR-II) signaling in the endothelium as aninitiating factor in pulmonary arterialhypertension (PAH). However, selective targetingof this signaling pathway using BMP ligands hasnot yet been explored as a therapeutic strategy.Here, we identify BMP9 as the preferred ligandfor preventing apoptosis and enhancingmonolayer integrity in both pulmonary arterialendothelial cells and blood outgrowth endothelialcells from subjects with PAH who bear mutationsin the gene encoding BMPR-II, BMPR2. Micebearing a heterozygous knock-in allele of ahuman BMPR2 mutation, R899X, which wegenerated as an animal model of PAH caused byBMPR-II deficiency, spontaneously developedPAH. Administration of BMP9 reversedestablished PAH in these mice, as well as in twoother experimental PAH models, in which PAH", "metadata": {}}
+{"_id": "24498673", "title": "", "text": "Coordinated actions of SLX1-SLX4 andMUS81-EME1 for Holliday junction resolution inhuman cells.Holliday junctions (HJs) arefour-way DNA intermediates that form duringhomologous recombination, and their efficientresolution is essential for chromosomesegregation. Here, we show that threestructure-selective endonucleases, namelySLX1-SLX4, MUS81-EME1, and GEN1, define twopathways of HJ resolution in human cells. Onepathway is mediated by GEN1, whereasSLX1-SLX4 and MUS81-EME1 provide a secondand genetically distinct pathway (SLX-MUS).Cells depleted for SLX-MUS or GEN1 pathwayproteins exhibit severe defects in chromosomesegregation and reduced survival. In response toCDK-mediated phosphorylation, SLX1-SLX4 andMUS81-EME1 associate at the G2/M transition toform a stable SLX-MUS holoenzyme, which canbe reconstituted in vitro. Biochemical studiesshow that SLX-MUS is a HJ resolvase thatcoordinates the active sites of two distinct", "metadata": {}}
+{"_id": "24510595", "title": "", "text": "Prevalence of frequent headache in a populationsample.PURPOSE Patients with daily ornear-daily headaches are commonly seen inneurology practices and in headache subspecialtycenters, but there is little information on theprevalence of this condition in the generalpopulation. We present the first US-based studydescribing the prevalence and characteristics offrequent headache in the general population.METHODS In Baltimore County, Maryland, 13343 individuals 18 to 65 years of age wereselected by random-digit dialing and interviewedby telephone about their headaches. Subjectsreporting 180 or more headaches per year wereclassified as having frequent headache. Threemutually exclusive subtypes of frequentheadache were identified: frequent headachewith migrainous features, chronic tension-typeheadache, and unclassified frequent headache.RESULTS The overall prevalence of frequentheadache was 4.1% (5.0% female, 2.8% male;1.8:1 female to male ratio). Frequent headache", "metadata": {}}
+{"_id": "24512064", "title": "", "text": "HTLV-I/II associated disease in England andWales, 1993-7: retrospective review of serologyrequests.Apart from HIV two exogenousretroviruses (human T cell leukaemia virusestype I (HTLV-I) and type II (HTLV-II)) infecthumans. HTLV-I infection is endemic in Japan,the Caribbean, Africa, and Melanesia and isfound among immigrants from these regions inEurope. HTLV-I infection is associated with a1-5% lifetime risk of adult T cellleukaemia/lymphoma, 1 a 0.25% lifetime risk ofHTLV-I associated myelopathy, 2 and otherinflammatory conditions (uveitis, alveolitis, andarthritis).1 HTLV-II infection is endemic in somenative American and African peoples and amonginjecting drug users and has been associatedwith neurological disease.1 Between 1986 and1992, 100 cases of HTLV-I associatedmyelopathy and 44 cases of adult T cellleukaemia/lymphoma were diagnosed in theUnited Kingdom.3 Adult T cellleukaemia/lymphoma was first described in 1977", "metadata": {}}
+{"_id": "24512417", "title": "", "text": "Lentiviral vector design and imaging approachesto visualize the early stages of cellularreprogramming.Induced pluripotent stem cells(iPSCs) can be derived from somatic cells bygene transfer of reprogramming transcriptionfactors. Expression levels of these factorsstrongly influence the overall efficacy to formiPSC colonies, but additional contribution ofstochastic cell-intrinsic factors has beenproposed. Here, we present engineeredcolor-coded lentiviral vectors in whichcodon-optimized reprogramming factors areco-expressed by a strong retroviral promoterthat is rapidly silenced in iPSC, and imaged theconversion of fibroblasts to iPSC. We combinedfluorescence microscopy with long-term singlecell tracking, and used live-cell imaging toanalyze the emergence and composition of earlyiPSC clusters. Applying our engineered lentiviralvectors, we demonstrate that vector silencingtypically occurs prior to or simultaneously withthe induction of an Oct4-EGFP pluripotency", "metadata": {}}
+{"_id": "24521894", "title": "", "text": "EIF2AK3, encoding translation initiation factor2-α kinase 3, is mutated in patients withWolcott-Rallison syndromeWolcott-Rallisonsyndrome (WRS) is a rare, autosomal recessivedisorder characterized by permanent neonatal orearly infancy insulin-dependent diabetes.Epiphyseal dysplasia, osteoporosis and growthretardation occur at a later age. Other frequentmultisystemic manifestations include hepatic andrenal dysfunction, mental retardation andcardiovascular abnormalities. On the basis of twoconsanguineous families, we mapped WRS to aregion of less than 3 cM on chromosome 2p12,with maximal evidence of linkage andhomozygosity at 4 microsatellite markers withinan interval of approximately 1 cM. The geneencoding the eukaryotic translation initiationfactor 2-α kinase 3 (EIF2AK3) resides in thisinterval; thus we explored it as a candidate. Weidentified distinct mutations of EIF2AK3 thatsegregated with the disorder in each of thefamilies. The first mutation produces a truncated", "metadata": {}}
+{"_id": "24523573", "title": "", "text": "Beta oscillations in a large-scale sensorimotorcortical network: directional influences revealedby Granger causality.Previous studies haveshown that synchronized beta frequency (14-30Hz) oscillations in the primary motor cortex areinvolved in maintaining steady contractions ofcontralateral arm and hand muscles. However,little is known about the role of postcentralcortical areas in motor maintenance and theirpatterns of interaction with motor cortex. Weinvestigated the functional relations ofbeta-synchronized neuronal assemblies in pre-and postcentral areas of two monkeys as theypressed a hand lever during the wait period of avisual discrimination task. By using power andcoherence spectral analysis, we identified abeta-synchronized large-scale network linkingpre- and postcentral areas. We then usedGranger causality spectra to measure directionalinfluences among recording sites. In bothmonkeys, strong Granger causal influences wereobserved from primary somatosensory cortex to", "metadata": {}}
+{"_id": "24524403", "title": "", "text": "Aging, frailty and age-related diseasesTheconcept of frailty as a medically distinctsyndrome has evolved based on the clinicalexperience of geriatricians and is clinically wellrecognizable. Frailty is a nonspecific state ofvulnerability, which reflects multisystemphysiological change. These changes underlyingfrailty do not always achieve disease status, sosome people, usually very elderly, are frailwithout a specific life threatening illness. Currentthinking is that not only physical but alsopsychological, cognitive and social factorscontribute to this syndrome and need to betaken into account in its definition andtreatment. Together, these signs and symptomsseem to reflect a reduced functional reserve andconsequent decrease in adaptation (resilience) toany sort of stressor and perhaps even in theabsence of extrinsic stressors. The overallconsequence is that frail elderly are at higherrisk for accelerated physical and cognitivedecline, disability and death. All these", "metadata": {}}
+{"_id": "24525112", "title": "", "text": "A case of paraquat intoxication caused byintravenous injection.Paraquat intoxication is afatal problem. Most paraquat intoxicationshappen through oral administration. We report acase of death after intravenous paraquatinjection. There is little clinical data on parenteralparaquat exposure, and we describe this caseand fatal progression. Toxic symptoms andsevere organ function impairment developedsoon after injection. Treatment with repeatedactivated charcoal hemoperfusion with pulsesteroids, cyclophosphamide, and antioxidantswas attempted. The patient died from multipleorgan failure 3 days after intoxication. This caseindicates that paraquat intoxication viaintravenous injection, even in very smallamounts, has an extremely poor prognosis.", "metadata": {}}
+{"_id": "24530130", "title": "", "text": "Genome-wide association study identifiesvariants at CLU and CR1 associated withAlzheimer's diseaseThe gene encodingapolipoprotein E (APOE) on chromosome 19 isthe only confirmed susceptibility locus forlate-onset Alzheimer's disease. To identify otherrisk loci, we conducted a large genome-wideassociation study of 2,032 individuals fromFrance with Alzheimer's disease (cases) and5,328 controls. Markers outside APOE withsuggestive evidence of association (P < 10−5)were examined in collections from Belgium,Finland, Italy and Spain totaling 3,978Alzheimer's disease cases and 3,297 controls.Two loci gave replicated evidence of association:one within CLU (also called APOJ), encodingclusterin or apolipoprotein J, on chromosome 8(rs11136000, OR = 0.86, 95% CI 0.81–0.90, P =7.5 × 10−9 for combined data) and the otherwithin CR1, encoding the complementcomponent (3b/4b) receptor 1, on chromosome1 (rs6656401, OR = 1.21, 95% CI 1.14–1.29, P", "metadata": {}}
+{"_id": "24530633", "title": "", "text": "Identification and characterization ofsubpopulations in undifferentiated ES cellculture.Embryonic stem (ES) cells are pluripotentcells derived from the inner cell mass (ICM) andthe epiblast, and have been suggested to be ahomogeneous population with characteristicsintermediate between them. These cells expressOct3/4 and Rex1 genes, which have been usedas markers to indicate the undifferentiated stateof ES cells. Whereas Oct3/4 is expressed intotipotent and pluripotent cells in the mouse lifecycle, Rex1 expression is restricted to the ICM,and is downregulated in pluripotent cellpopulations in the later stages, i.e. the epiblastand primitive ectoderm (PrE). To addresswhether ES cells comprise a homogeneouspopulation equivalent to a certain developmentalstage of pluripotent cells or a heterogeneouspopulation composed of cells corresponding tovarious stages of differentiation, we establishedknock-in ES cell lines in which genes forfluorescent proteins were inserted into the Rex1", "metadata": {}}
+{"_id": "24541180", "title": "", "text": "Isolation of intact nuclei of high purity frommouse liver.Current methods of nuclear isolationfrom liver disrupt the plasmalemmae viahomogenization and separation of the nuclei byhigh centrifugal force (HCF) through gradients ofsucrose or other substances for up to 80 min.The use of HCF for such a long time increasesthe potential for nuclear damage anddegradation by endogenous proteases. Wecompared four combinations of alterations toclassical nuclear isolation methods as follows.Mouse liver was gently crushed through a finemesh with and without in vivo perfusion withcollagenase. The cell suspension was centrifugedat 600 g to remove gross debris and then atmoderate centrifugal force (MCF, 16,000 g) orhigh centrifugal force (HCF, 70,000 g) throughsucrose gradients for 30 min. The purity of theisolated nuclei was assessed biologically andmorphologically, including analyses ofrepresentative marker proteins for nuclei andcytoplasm. The results indicate that MCF and no", "metadata": {}}
+{"_id": "24550453", "title": "", "text": "Two structurally independent domains of E. coliNusG create regulatory plasticity via distinctinteractions with RNA polymerase andregulators.NusG is a conserved regulatoryprotein that interacts with elongation complexes(ECs) of RNA polymerase, DNA, and RNA tomodulate transcription in multiple andsometimes opposite ways. In Escherichia coli,NusG suppresses pausing and increaseselongation rate, enhances termination by E. colirho and phage HK022 Nun protein, and promotesantitermination by lambdaN and in ribosomalRNA operons. We report NMR studies thatsuggest that E. coli NusG consists of two largelyindependent N- and C-terminal structuraldomains, NTD and CTD, respectively. Based ontests of the functions of the NTD and CTD andvariants of NusG in vivo and in vitro, we find thatNTD alone is sufficient to suppress pausing andenhance transcript elongation in vitro. However,neither domain alone can enhancerho-dependent termination or support", "metadata": {}}
+{"_id": "24552097", "title": "", "text": "Cytochemistry and C-values: theless-well-known world of nuclear DNAamounts.BACKGROUND In the plant sciencesthere are two widely applied technologies formeasuring nuclear DNA content: Feulgenabsorbance cytophotometry and flow cytometry(FCM). While FCM is, with good reasons,increasingly popular among plant scientists,absorbance-cytophotometric techniques loseground. This results in a narrowing of themethodological repertoire, which is neitherdesirable nor beneficial. Both approaches havetheir advantages, but static cytophotometryseems to pose more instrumental difficulties andmaterial-based problems than FCM, so thatFeulgen-based data in the literature are oftenless reliable than one would expect. SCOPE Thepurpose of this article is to present a selectiveoverview of the field of nuclear DNA contentmeasurement, and C-values in particular, with afocus on the technical difficulties imposed by thecharacteristics of the biological material and with", "metadata": {}}
+{"_id": "24554740", "title": "", "text": "Integrins and cell proliferation: regulation ofcyclin-dependent kinases via cytoplasmicsignaling pathways.Cell cycle progression inmammalian cells is strictly regulated by bothintegrin-mediated adhesion to the extracellularmatrix and by binding of growth factors to theirreceptors. This regulation is mediated by G1phase cyclin-dependent kinases (CDKs), whichare downstream of signaling pathways under theintegrated control of both integrins and growthfactor receptors. Recent advances demonstrate asurprisingly diverse array of integrin-dependentsignals that are channeled into the regulation ofthe G1 phase CDKs. Regulation of cyclin D1 bythe ERK pathway may provide a paradigm forunderstanding how cell adhesion can determinecell cycle progression.", "metadata": {}}
+{"_id": "24555417", "title": "", "text": "Interplay between microtubule bundling andsorting factors ensures acentriolar spindlestability during C. elegans oocyte meiosisInmany species, oocyte meiosis is carried out inthe absence of centrioles. As a result,microtubule organization, spindle assembly, andchromosome segregation proceed by uniquemechanisms. Here, we report insights into theprinciples underlying this specialized form of celldivision, through studies of C. elegans KLP-15and KLP-16, two highly homologous members ofthe kinesin-14 family of minus-end-directedkinesins. These proteins localize to theacentriolar oocyte spindle and promotemicrotubule bundling during spindle assembly;following KLP-15/16 depletion, microtubulebundles form but then collapse into adisorganized array. Surprisingly, despite thisdefect we found that during anaphase,microtubules are able to reorganize into abundled array that facilitates chromosomesegregation. This phenotype therefore enabled", "metadata": {}}
+{"_id": "24555878", "title": "", "text": "Development of a questionnaire to measureheart disease risk knowledge in people withdiabetes: the Heart Disease FactQuestionnaire.This paper describes a paper andpencil questionnaire that measures heart diseaserisk knowledge in people with diabetes. TheHeart Disease Fact Questionnaire (HDFQ) is a25-item questionnaire that was developed to tapinto respondents' knowledge of major risk factorsfor the development of CHD. Approximately halfof these items specifically addressdiabetes-related CHD risk factors. Based onextensive pilot data, the current study analyzedresponses from 524 people with diabetes toassess the psychometric properties. The HDFQ isreadable to an average 13-year old and imposeslittle burden. It shows good content and facevalidity. It demonstrates adequate internalconsistency, with Kuder-Richardson-20 formula= 0.77 and good item-total correlations. Itemanalysis showed a desirable range in P-values. Indiscriminant function analyses, HDFQ scores", "metadata": {}}
+{"_id": "24557631", "title": "", "text": "Prevalence of Multiple Sclerosis in Isfahan,IranBackground: The prevalence of multiplesclerosis (MS) shows considerable variability allover the world. According to Kurtzke, Iran isconsidered to have a low prevalence. Objective:To estimate the period prevalence and riskfactors of MS in Isfahan, central part of Iran.Methods: A cross-sectional case register studyconducted between 2004 and 2005. In theprovince of Isfahan, Iran, all patients known tohave definite MS during 2004 and 2005, beingalive and resident within Isfahan as well as beinga member of the Isfahan MS Association wereincluded in the study. Demographic andcase-related information was recorded. 1,391definite MS patients (308 men and 1,083women) from the Isfahan MS Association, Iran,have been identified. The disease was confirmedusing clinical information and MRI findings by aneurologist and radiologist. The patients wereevaluated by interview and a questionnaire.Population data were obtained from the year", "metadata": {}}
+{"_id": "24558930", "title": "", "text": "A kinetochore-independent mechanism drivesanaphase chromosome separation duringacentrosomal meiosisAlthough assembly ofacentrosomal meiotic spindles has beenextensively studied, little is known about thesegregation of chromosomes on these spindles.Here, we show in Caenorhabditis elegans oocytesthat the kinetochore protein, KNL-1, directsassembly of meiotic kinetochores that orientchromosomes. However, in contrast to mitosis,chromosome separation during meiotic anaphaseis kinetochore-independent. Before anaphase,meiotic kinetochores and spindle polesdisassemble along with the microtubules on thepoleward side of chromosomes. Duringanaphase, microtubules then form between theseparating chromosomes. Functional analysisimplicated a set of proteins that localize to aring-shaped domain between kinetochoresduring pre-anaphase spindle assembly andanaphase separation. These proteins arelocalized by the chromosomal passenger", "metadata": {}}
+{"_id": "24575065", "title": "", "text": "Association between the Medicare ModernizationAct of 2003 and patient wait times and traveldistance for chemotherapy.CONTEXT TheMedicare Prescription Drug, Improvement, andModernization Act of 2003 (MMA) alteredreimbursements for outpatient chemotherapydrugs and drug administration services.Anecdotal reports suggest that theseadjustments may have negatively affectedaccess to chemotherapy for Medicarebeneficiaries. OBJECTIVE To compare patientwait times and travel distances for chemotherapybefore and after the enactment of the MMA.DESIGN, SETTING, AND PATIENTS Analysis of anationally representative 5% sample of claimsfrom the Centers for Medicare & MedicaidServices for the period 2003 through 2006.Patients were Medicare beneficiaries withincident breast cancer, colorectal cancer,leukemia, lung cancer, or lymphoma whoreceived chemotherapy in inpatient hospital,institutional outpatient, or physician office", "metadata": {}}
+{"_id": "24581365", "title": "", "text": "20-year outcomes following conservativemanagement of clinically localized prostatecancer.CONTEXT The appropriate therapy formen with clinically localized prostate cancer isuncertain. A recent study suggested anincreasing prostate cancer mortality rate for menwho are alive more than 15 years followingdiagnosis. OBJECTIVE To estimate 20-yearsurvival based on a competing risk analysis ofmen who were diagnosed with clinically localizedprostate cancer and treated with observation orandrogen withdrawal therapy alone, stratified byage at diagnosis and histological findings.DESIGN, SETTING, AND PATIENTS Aretrospective population-based cohort studyusing Connecticut Tumor Registry datasupplemented by hospital record and histologyreview of 767 men aged 55 to 74 years withclinically localized prostate cancer diagnosedbetween January 1, 1971, and December 31,1984. Patients were treated with eitherobservation or immediate or delayed androgen", "metadata": {}}
+{"_id": "24586989", "title": "", "text": "Role of beta adrenergic receptor polymorphismsin heart failure: systematic review andmeta-analysis.Heart Failure (HF) is a commondisorder associated with substantial morbidityand mortality. beta adrenergic receptors(betaAR) are the primary pathway through whichcardiac function is influenced. Chronic beta(1)ARactivation is implicated in the pathogenesis of HFand betaAR blockade improves survival in leftventricular systolic dysfunction. Commonfunctional polymorphisms in beta adrenergicreceptor genes (ADRB) have been associatedwith HF phenotypes, and with pharmacogeneticinteraction with beta adrenergic receptorblockers (beta blockers). However, theseassociations have not been consistentlyreplicated. The evidence for ADRB variantinvolvement in pathogenesis, progression andresponse to beta blockers in HF is reviewed. Inaddition, a meta-analysis of three studiesanalysing the effect of ADRB1 Arg389Glypolymorphism on left ventricular remodelling", "metadata": {}}
+{"_id": "24594624", "title": "", "text": "New development of the yolk sac theory indiabetic embryopathy: molecular mechanism andlink to structural birth defects.Maternal diabetesmellitus is a significant risk factor for structuralbirth defects, including congenital heart defectsand neural tube defects. With the risingprevalence of type 2 diabetes mellitus andobesity in women of childbearing age, diabetesmellitus-induced birth defects have become anincreasingly significant public health problem.Maternal diabetes mellitus in vivo and highglucose in vitro induce yolk sac injuries bydamaging the morphologic condition of cells andaltering the dynamics of organelles. The yolk sacvascular system is the first system to developduring embryogenesis; therefore, it is the mostsensitive to hyperglycemia. The consequences ofyolk sac injuries include impairment of nutrienttransportation because of vasculopathy.Although the functional relationship between yolksac vasculopathy and structural birth defects hasnot yet been established, a recent study reveals", "metadata": {}}
+{"_id": "24596228", "title": "", "text": "Hepatitis B and C in HIV-infected patients.Prevalence and prognosticvalue.BACKGROUND/AIMS There is only limitedinformation on the prevalence and influence ofcoinfection with either hepatitis B or C on theclinical course in patients infected with thehuman immunodeficiency virus (HIV). METHODSFollow-up was available in 232 HIV-infectedpatients (age 37+/-8 years, CD4 count167+/-167 microl; 46% had AIDS). Sampleswere investigated for markers of HBV and HCVinfection (HBsAg, HBeAg, HBV-DNA, Anti-HBs,anti-HBc, anti-HCV, HCV-RNA). RESULTS 60/232patients (23%) were anti-HCV positive. 78% ofthese sera were positive for HCV-RNA. 22/232patients (9%) suffered from chronic HBVinfection (HBsAg positive), 18/22 (82%) of thesesera had detectable HBeAg and 19/22 (86%)HBV-DNA. Presence of HCV-RNA, HBeAg andamount of HBV-DNA were related to the degreeof immunodeficiency. In contrast to the controlgroup without HBV or HCV infection, patients", "metadata": {}}
+{"_id": "24612804", "title": "", "text": "Requirement of endogenous stem cell factor andgranulocyte-colony-stimulating factor forIL-17-mediated granulopoiesis.IL-17 is a novel,CD4+ T cell-restricted cytokine. In vivo, itstimulates hematopoiesis and causesneutrophilia consisting of mature granulocytes.In this study, we show that IL-17-mediatedgranulopoiesis requires G-CSF release and thepresence or induction of the transmembraneform of stem cell factor (SCF) for optimalgranulopoiesis. However, IL-17 also protectsmice from G-CSF neutralization-inducedneutropenia. G-CSF neutralization completelyreversed IL-17-induced BM progenitorexpansion, whereas splenic CFU-GM/CFU-granulocyte-erythrocyte-megakaryocyte-monocyte wasonly reduced by 50% in both Sl/Sld andlittermate control mice. Thus, there remained asignificant SCF/G-CSF-independent effect ofIL-17 on splenic granulopoiesis, resulting in apreservation of mature circulating granulocytes.IL-17 is a cytokine that potentially interconnects", "metadata": {}}
+{"_id": "24624992", "title": "", "text": "The expression of immediate early gene X-1(IEX-1) is differentially induced by retinoic acidsin NB4 and KG1 cells: possible implication in thedistinct phenotype of retinoic acid-responsiveand -resistant leukemic cellsIn a cell-type- andstimulus-dependent fashion, the early responsegene immediate early gene X-1 (IEX-1) isinvolved in growth control and modulation ofapoptosis. The present study demonstrates that,in the two acute promyelocytic leukemia (APL)cell lines NB4 and KG1, exhibiting distinctresponsiveness to retinoic acids (RAs), IEX-1expression is rapidly (30–60 min) induced byall-trans- or cis-RA and independently of othersignal transduction mediators, such as TNFα,NF-κB or MAP kinases. In NB4 cells (expressingPML–RARα), this increase is transient andcompletely reversible, along with a cell cyclearrest, ongoing differentiation and lowersensitivity to anti-cancer-drug-inducedapoptosis. In contrast, the RA-induced IEX-1expression in KG1 cells (expressing PLZF–RARα)", "metadata": {}}
+{"_id": "24625323", "title": "", "text": "Comorbidity between ADHD and obesity:exploring shared mechanisms and clinicalimplications.Recent studies suggest anassociation betweenattention-deficit/hyperactivity disorder (ADHD)and obesity. In this article, we systematicallyreview and critically discuss evidence on theprevalence of ADHD in obese patients as well asthe weight status of individuals with ADHD.Relevant articles were searched in PubMed,PsychInfo, and ISI Web of Science (January1980 to June 2010). We found that currentevidence indicates a high prevalence of ADHD inclinical samples of patients seeking treatment fortheir obesity. Moreover, available studies showthat individuals with ADHD havehigher-than-average body mass index z scoresand/or a significantly higher prevalence ofobesity compared with subjects without ADHD.Three mechanisms underlying the associationbetween ADHD and obesity have been proposed:1) it is possible that obesity and/or factors", "metadata": {}}
+{"_id": "24632480", "title": "", "text": "Rapamycin treatment augments motor neurondegeneration in SOD1(G93A) mouse model ofamyotrophic lateral sclerosis.Aberrant proteinmisfolding may contribute to the pathogenesis ofamyotrophic lateral sclerosis (ALS) but thedetailed mechanisms are largely unknown. Ourprevious study has shown that autophagy isaltered in the mouse model of ALS. In thepresent study, we systematically investigated thecorrelation of the autophagic alteration with themotor neurons (MNs) degeneration in the ALSmice. We have demonstrated that the autophagicprotein marker LC3-II is markedly andspecifically increased in the spinal cord MNs ofthe ALS mice. Electron microscopy andimmunochemistry studies have shown thatautophagic vacuoles are significantlyaccumulated in the dystrophic axons of spinalcord MNs of the ALS mice. All these changes inthe ALS mice appear at the age of 90 d when theALS mice display modest clinical symptoms; andthey become prominent at the age of 120 d. The", "metadata": {}}
+{"_id": "24634621", "title": "", "text": "Improvements in survival and clinical benefitwith gemcitabine as first-line therapy for patientswith advanced pancreas cancer: a randomizedtrial.PURPOSE Most patients with advancedpancreas cancer experience pain and must limittheir daily activities because of tumor-relatedsymptoms. To date, no treatment has had asignificant impact on the disease. In early studieswith gemcitabine, patients with pancreas cancerexperienced an improvement in disease-relatedsymptoms. Based on those findings, a definitivetrial was performed to assess the effectiveness ofgemcitabine in patients with newly diagnosedadvanced pancreas cancer. PATIENTS ANDMETHODS One hundred twenty-six patients withadvanced symptomatic pancreas cancercompleted a lead-in period to characterize andstabilize pain and were randomized to receiveeither gemcitabine 1,000 mg/m2 weekly x 7followed by 1 week of rest, then weekly x 3every 4 weeks thereafter (63 patients), or tofluorouracil (5-FU) 600 mg/m2 once weekly (63", "metadata": {}}
+{"_id": "24640046", "title": "", "text": "Endothelial-myofibroblast transition contributesto the early development of diabetic renalinterstitial fibrosis in streptozotocin-induceddiabetic mice.Diabetic nephropathy is the leadingcause of chronic renal failure. Myofibroblasts playa major role in the synthesis and secretion ofextracellular matrix in diabetic renal fibrosis.Increasing evidence suggests that endothelialcells may undergo endothelial-myofibroblasttransition under physiological andpathophysiological circumstances. Therefore, thisstudy investigates whetherendothelial-myofibroblast transition occurs andcontributes to the development of diabetic renalinterstitial fibrosis. Diabetes was induced byadministration of streptozotocin toTie2-Cre;LoxP-EGFP mice, an endotheliallineage-traceable mouse line generated bycrossbreeding B6.Cg-Tg(Tek-cre)12F1v/J micewith B6.Cg-Tg(ACTB-Bgeo/GFP)21Lbe/J mice.The endothelial-myofibroblast transition was alsostudied in MMECs (a mouse pancreatic", "metadata": {}}
+{"_id": "24645237", "title": "", "text": "Effect of phosducin silencing on the photokineticmotile response of Blepharisma japonicum.Thecoloured ciliate Blepharisma japonicum changesswimming velocity (positive photokinesis) andelongates its body in response to a prolongedillumination. We have recently proposed thatalterations in the phosphorylation level of theciliate phosducin (Pdc) may be involved inlight-induced cell elongation, which in turnaffects the interaction of βγ-dimer of G-proteins(Gβγ) with β-tubulin and subsequent cytoskeletalremodelling. The cellular mechanism thatgoverns the photokinetic effect in this ciliate hasnot been elucidated. In the present study, weutilise real-time PCR to demonstrate that thelevels of ciliate Pdc mRNA are significantlyreduced in Pdc-RNAi-treated cells compared tocells fed with bacteria carrying the empty vector(control cells). Using western immunoblotting,we confirmed that these cells treated withPdc-RNAi expressed a substantially lower level ofthe Pdc protein. The assay also revealed that in", "metadata": {}}
+{"_id": "24652030", "title": "", "text": "Alzheimer’s disease and NGFsignalingAge-related degeneration of basalforebrain cholinergic neurons (BFCNs) occursearly and contributes significantly to cognitivedecline in Alzheimer’s disease (AD). Properfunction and morphology of BFCNs depends onthe supply of nerve growth factor (NGF) from thecortex and the hippocampus. A large number ofexperiments have shown that decreased supplyof NGF at the level of BFCN cell bodies leads toloss of neuronal markers and shrinkage,mimicking what is observed in AD. The deliveryof sufficient amounts of NGF signal to BFCN cellbodies depends on the effective participation ofseveral factors including sufficient synthesis andrelease of NGF, adequate synthesis andexpression of NGF receptors by BFCNs, normalsignaling and retrograde transport ofNGF-receptor complex, and finally effectiveinduction of gene expression by NGF. In the pastfew years it has become clear that decreasedamounts of NGF at the level of BFCN cell bodies", "metadata": {}}
+{"_id": "24660385", "title": "", "text": "Echocardiographic assessment of left ventricularhypertrophy: comparison to necropsy findings.Todetermine the accuracy of echocardiographic leftventricular (LV) dimension and massmeasurements for detection and quantification ofLV hypertrophy, results of blindly readantemortem echocardiograms were comparedwith LV mass measurements made at necropsyin 55 patients. LV mass was calculated usingM-mode LV measurements by Penn andAmerican Society of Echocardiography (ASE)conventions and cube function and volumecorrection formulas in 52 patients. Penn-cube LVmass correlated closely with necropsy LV mass (r= 0.92, p less than 0.001) and overestimated itby only 6%; sensitivity in 18 patients with LVhypertrophy (necropsy LV mass more than 215g) was 100% (18 of 18 patients) and specificitywas 86% (29 of 34 patients). ASE-cube LV masscorrelated similarly to necropsy LV mass (r =0.90, p less than 0.001), but systematicallyoverestimated it (by a mean of 25%); the", "metadata": {}}
+{"_id": "24670522", "title": "", "text": "R93W mutation in Orai1 causes impaired calciuminflux in platelets.The intracellular Ca(2+)concentration of many nonexcitable cells isregulated by calcium store release andstore-operated calcium entry (SOCE). Inplatelets, STIM1 was recently identified as themain calcium sensor expressed in theendoplasmic reticulum. To evaluate the role ofthe SOC channel moiety, Orai1, in platelet SOCE,we generated mice expressing a mutated,inactive form of Orai1 in blood cells only(Orai1(R93W)). Platelets expressingOrai1(R93W) were characterized by markedlyreduced SOCE and impaired agonist-inducedincreases in [Ca(2+)](i). Orai1(R93W) plateletsshowed reduced integrin activation and impaireddegranulation when stimulated with low agonistconcentrations under static conditions. Thisdefect, however, did not significantly affect theability of Orai1(R93W) platelets to aggregate orto adhere to collagen under arterial flowconditions ex vivo. In contrast, these adherent", "metadata": {}}
+{"_id": "24697979", "title": "", "text": "[Efficacy on post-stroke depression treated withacupuncture at the acupoints based onziwuliuzhu and prozac].OBJECTIVE To observethe effects on post-stroke depression treatedwith acupuncture at the acu points based onziwuliuzhu (the midnight-noon ebb-flow theory).METHODS Ninety-three patients wererandomized into a comprehensive group, aziwuliuzhu group and a prozac group, 31 cases ineach group. In the ziwuliuzhu group,acupuncture was applied to the acupoints basedon ziwuliuzhu, once a day, 5 times in a week. Inthe prozac group, fluoxertine hydrochloride(prozac) was prescribed for oral administration,once a day, 20 mg each time. In thecomprehensive group, acupuncture based onziwuliuzhu combined with the oral administrationof prozac were adopted and the treatmentfrequency was the same as the ziwuliuzhu groupand the prozac group. The 4-week treatment wastaken as one session in the three groups and 6sessions were required totally. The clinical", "metadata": {}}
+{"_id": "24700152", "title": "", "text": "Linkage with methadone treatment upon releasefrom incarceration: a promisingopportunity.Injection drug users (IDUs) are atincreased risk for HIV, viral hepatitis, andtuberculosis, and making up more than a quarterof the incarcerated population in the UnitedStates. Methadone maintenance treatment ofopiate addiction is highly effective at reducingdrug use, drug-related criminal activity, and riskof HIV transmission. Recently released inmatesare at particularly high risk for overdose anddisease transmission. Linkage to methadonetreatment immediately upon release fromincarceration is a promising opportunity tocombat disease transmission, facilitate reentryinto the community, and reduce recidivism.", "metadata": {}}
+{"_id": "24704139", "title": "", "text": "The Diabetes Prevention Program: baselinecharacteristics of the randomized cohort. TheDiabetes Prevention Program ResearchGroup.OBJECTIVE The Diabetes PreventionProgram (DPP) is a 27-center randomized clinicaltrial designed to evaluate the safety and efficacyof interventions that may delay or preventdevelopment of diabetes in people at increasedrisk for type 2 diabetes. RESEARCH DESIGN ANDMETHODS Eligibility requirements were age > or= 25 years, BMI > or = 24 kg/m2 (> or = 22kg/m2 for Asian-Americans), and impairedglucose tolerance plus a fasting plasma glucoseof 5.3-6.9 mmol/l (or < or = 6.9 mmol forAmerican Indians). Randomization of participantsinto the DPP over 2.7 years ended in June 1999.Baseline data for the three treatmentgroups--intensive lifestyle modification, standardcare plus metformin, and standard care plusplacebo--are presented for the 3,234 participantswho have been randomized. RESULTS Of allparticipants , 55% were Caucasian, 20% were", "metadata": {}}
+{"_id": "24705390", "title": "", "text": "Chronic Helicobacter pylori infections inducegastric mutations in mice.BACKGROUND & AIMSHelicobacter pylori is an important etiologicfactor in the development of gastric cancer. Theaim of this study was to analyze the role of H.pylori infections in the induction of mutagenicevents in gastric epithelial cells. The effect of ahigh-salt diet as a genotoxic risk factor was alsoinvestigated. METHODS Big Blue transgenic malemice (C57Bl/6) were inoculated with H. pylori(strain SS1) or Helicobacter felis (strain CS1) for6 and 12 months. The frequency and spectrum ofmutations at the stomach level were assessed.Inflammatory host response and inducible nitricoxide synthase (iNOS) expression byreverse-transcription polymerase chain reactionand immunohistochemistry analysis were alsoperformed. RESULTS After 6 months, the gastricmutant frequency was 4-fold and 1.7-fold higherin mice infected with H. pylori and H. felis,respectively, than in uninfected mice. It wasassociated with a high frequency of transversions", "metadata": {}}
+{"_id": "24706198", "title": "", "text": "A minimal Tat system from a gram-positiveorganism: a bifunctional TatA subunitparticipates in discrete TatAC and TatAcomplexes.The Tat system transports foldedproteins across bacterial and thylakoidmembranes. In Gram-negative organisms, aTatABC substrate-binding complex and separateTatA complex are believed to coalesce to form anactive translocon, with all three subunitsessential for translocation. Most Gram-positiveorganisms lack a tatB gene, indicating majordifferences in organization and possibledifferences in mode of action. Here, we havestudied Tat complexes encoded by the tatAdCdgenes of Bacillus subtilis. Expression of tatAdCdin an Escherichia coli tat null mutant results inefficient export of a large, cofactor-containing E.coli Tat substrate, TorA. We show that the tatAdgene complements E. coli mutants lacking eithertatAE or tatB, indicating a bifunctional role forthis subunit in B. subtilis. Second, we haveidentified and characterized two distinct Tat", "metadata": {}}
+{"_id": "24707550", "title": "", "text": "A systemic granulomatous response toSchistosoma mansoni eggs alters responsivenessof bone-marrow-derived macrophages toToll-like receptor agonists.Macrophages play apivotal role in innate and acquired immuneresponses to Schistosoma mansoni. Classical(M1) or alternative (M2) activation states ofthese cells further delineate their roles in tissuedamage through innate immunity or fibroticremodeling, respectively. In the present study,we addressed the following question: Doessystemic Th2-type cytokine polarization evokedby S. mansoni affect macrophage differentiationand activation? To this end, we analyzed bonemarrow-derived macrophages from mice with S.mansoni egg-induced pulmonary granulomas andunchallenged (or naïve) mice to determine theiractivation state and their response to specificTLR agonists, including S. mansoni egg antigens.Unlike naïve macrophages, macrophages fromTh2-polarized mice constitutively expressedsignificantly higher \"found in inflammatory", "metadata": {}}
+{"_id": "24712186", "title": "", "text": "Orai1 and STIM reconstitute store-operatedcalcium channel function.The two membraneproteins, STIM1 and Orai1, have each beenshown to be essential for the activation ofstore-operated channels (SOC). Yet, how theseproteins functionally interact is not known. Here,we reveal that STIM1 and Orai1 expressedtogether reconstitute functional SOCs. Expressedalone, Orai1 strongly reduces store-operatedCa(2+) entry (SOCE) in human embryonickidney 293 cells and the Ca(2+)release-activated Ca(2+) current (I(CRAC)) inrat basophilic leukemia cells. However,expressed along with the store-sensing STIM1protein, Orai1 causes a massive increase inSOCE, enhancing the rate of Ca(2+)entry by upto 103-fold. This entry is entirelystore-dependent since the same coexpressioncauses no measurable store-independent Ca(2+)entry. The entry is completely blocked by theSOC blocker, 2-aminoethoxydiphenylborate.Orai1 and STIM1 coexpression also caused a", "metadata": {}}
+{"_id": "24713020", "title": "", "text": "Tet and TDG mediate DNA demethylationessential for mesenchymal-to-epithelialtransition in somatic cellreprogramming.Tet-mediated DNA oxidation is arecently identified mammalian epigeneticmodification, and its functional role in cell-fatetransitions remains poorly understood. Here, wederive mouse embryonic fibroblasts (MEFs)deleted in all three Tet genes and examine theircapacity for reprogramming into inducedpluripotent stem cells (iPSCs). We show thatTet-deficient MEFs cannot be reprogrammedbecause of a block in themesenchymal-to-epithelial transition (MET) step.Reprogramming of MEFs deficient in TDG issimilarly impaired. The block in reprogrammingis caused at least in part by defective activationof key miRNAs, which depends on oxidativedemethylation promoted by Tet and TDG.Reintroduction of either the affected miRNAs orcatalytically active Tet and TDG restoresreprogramming in the knockout MEFs. Thus,", "metadata": {}}
+{"_id": "24721347", "title": "", "text": "The last and the next hundred years ofmalariology.The founding fathers of malariologycombined scientific originality, perseverance inresearch, strong characters, breadth of interestand social concern. A hundred years laterresearch and understanding has made immenseprogress but the world still bears a huge burdenof malaria. For the next century researchrequires both more specialism and a holisticrange if it is to be used in control, requiringmultidisciplinary team work. Environmentalchanges and interventions produce a dynamicand changing pattern of malaria, not the staticone of the past. From the original parasite lifecycle, research has analysed a series of othercycles at electron microscope, biochemical andgenome levels on decreasing size scales andquantitative epidemiological cycles for control.Recent additions to these concepts have beenstage-specific antigens, cycles of disease ratherthan parasites alone, considering populations ofparasites rather than just cases, and also genetic", "metadata": {}}
+{"_id": "24721866", "title": "", "text": "Activation of AMP-activated protein kinasesuppresses oxidized low-densitylipoprotein-induced macrophageproliferation.Macrophage-derived foam cells playimportant roles in the progression ofatherosclerosis. We reported previously thatERK1/2-dependent granulocyte/macrophagecolony-stimulating factor (GM-CSF) expression,leading to p38 MAPK/ Akt signaling, is importantfor oxidized low density lipoprotein(Ox-LDL)-induced macrophage proliferation.Here, we investigated whether activation ofAMP-activated protein kinase (AMPK) couldsuppress macrophage proliferation.Ox-LDL-induced proliferation of mouse peritonealmacrophages was assessed by [(3)H]thymidineincorporation and cell counting assays. Theproliferation was significantly inhibited by theAMPK activator 5-aminoimidazole-4-carboxamideribonucleoside (AICAR) and restored bydominant-negative AMPKalpha1, suggesting thatAMPK activation suppressed macrophage", "metadata": {}}
+{"_id": "24724242", "title": "", "text": "Evaluation of cortical bone by peripheralquantitative computed tomography in renaltransplant recipients.BACKGROUND The absoluterisk of fractures in renal transplant patients is 3times that of matched controls. Most of thesymptomatic fractures are peripheral, suggestinga greater compromise of cortical bone. Peripheralquantitative computed tomography (pQCT) is anew imaging technique that allows separatenoninvasive evaluations of cortical and trabecularbones. We investigated cortical bone by pQCT in12 renal transplant patients (seven men and fivewomen) for comparison with 27 normal controls.METHODS pQCT (XCT 960, Stratec, Pforheim,Germany) was performed upon the distal radiusof the nondominant forearm (15% the length ofthe ulna, proximal from the radius end plate).We evaluated total and cortical bone mineraldensity (TBMD, cBMD), total (cross-sectional)and cortical area (TA, cA), cortical thickness(cThk), endosteal and periosteal circumferences,and the buckling ratio (r/cThK). RESULTS", "metadata": {}}
+{"_id": "24725136", "title": "", "text": "Ataxia, dementia, and hypogonadotropismcaused by disorderedubiquitination.BACKGROUND The combination ofataxia and hypogonadism was first describedmore than a century ago, but its genetic basishas remained elusive. METHODS We performedwhole-exome sequencing in a patient with ataxiaand hypogonadotropic hypogonadism, followedby targeted sequencing of candidate genes insimilarly affected patients. Neurologic andreproductive endocrine phenotypes werecharacterized in detail. The effects of sequencevariants and the presence of an epistaticinteraction were tested in a zebrafish model.RESULTS Digenic homozygous mutations inRNF216 and OTUD4, which encode a ubiquitin E3ligase and a deubiquitinase, respectively, werefound in three affected siblings in aconsanguineous family. Additional screeningidentified compound heterozygous truncatingmutations in RNF216 in an unrelated patient andsingle heterozygous deleterious mutations in four", "metadata": {}}
+{"_id": "24726600", "title": "", "text": "Combination cancer immunotherapies tailored tothe tumour microenvironmentEvidence suggeststhat cancer immunotherapy will be a major partof the combination treatment plan for manypatients with many cancer types in the nearfuture. There are many types of immuneprocesses involving different antitumour andtumour-promoting leucocytes, and tumour cellsuse many strategies to evade the immuneresponse. The tumour microenvironment canhelp determine which immune suppressivepathways become activated to restrainantitumour immunity. This includes immunecheckpoint receptors on effector T-cells andmyeloid cells, and release of inhibitory cytokinesand metabolites. Therapeutic approaches thattarget these pathways, particularlyimmune-checkpoint receptors, can inducedurable antitumour responses in patients withadvanced-stage cancers, including melanoma.Nevertheless, many patients do not have a goodresponse to monotherapy approaches and", "metadata": {}}
+{"_id": "24730100", "title": "", "text": "Cyclic AMP-dependent phosphorylation ofthromboxane A(2) receptor-associatedGalpha(13).Although it is well established thatcAMP inhibits platelet activation induced by allagonists, the thromboxane A(2) signaltransduction pathway was found to beparticularly sensitive to such inhibition.Therefore, we examined whethercAMP-dependent kinase mediatesphosphorylation of the thromboxane A(2)receptor-G-protein complex. It was found thatcAMP induces protein kinase A-dependent[gamma-(32)P]ATP labeling of solubilizedmembrane proteins in the region of Galphasubunits, i.e. 38-45 kDa. Moreover, ligandaffinity chromatography purification ofthromboxane A(2) receptor-G-protein complexesfrom these membranes revealed that 38-45-kDaphosphoproteins co-purify with thromboxaneA(2) receptors. Immunoprecipitation of theaffinity column eluate with a Galpha(13)antibody demonstrated that 8-Br-cAMP increased", "metadata": {}}
+{"_id": "24731248", "title": "", "text": "Tet proteins can convert 5-methylcytosine to5-formylcytosine and5-carboxylcytosine.5-methylcytosine (5mC) inDNA plays an important role in gene expression,genomic imprinting, and suppression oftransposable elements. 5mC can be converted to5-hydroxymethylcytosine (5hmC) by the Tet (teneleven translocation) proteins. Here, we showthat, in addition to 5hmC, the Tet proteins cangenerate 5-formylcytosine (5fC) and5-carboxylcytosine (5caC) from 5mC in anenzymatic activity-dependent manner.Furthermore, we reveal the presence of 5fC and5caC in genomic DNA of mouse embryonic stemcells and mouse organs. The genomic content of5hmC, 5fC, and 5caC can be increased orreduced through overexpression or depletion ofTet proteins. Thus, we identify two previouslyunknown cytosine derivatives in genomic DNA asthe products of Tet proteins. Our study raises thepossibility that DNA demethylation may occurthrough Tet-catalyzed oxidation followed by", "metadata": {}}
+{"_id": "24735908", "title": "", "text": "Long-term use of aspirin and age-relatedmacular degeneration.CONTEXT Aspirin is widelyused for relief of pain and for cardioprotectiveeffects. Its use is of concern to ophthalmologistswhen ocular surgery is being considered and alsoin the presence of age-related maculardegeneration (AMD). OBJECTIVE To examine theassociation of regular aspirin use with incidenceof AMD. DESIGN, SETTING, AND PARTICIPANTSThe Beaver Dam Eye Study, a longitudinalpopulation-based study of age-related eyediseases conducted in Wisconsin. Examinationswere performed every 5 years over a 20-yearperiod (1988-1990 through 2008-2010). Studyparticipants (N = 4926) were aged 43 to 86years at the baseline examination. At subsequentexaminations, participants were asked if theyhad regularly used aspirin at least twice a weekfor more than 3 months. MAIN OUTCOMEMEASURE Incidence of early AMD, late AMD, and2 subtypes of late AMD (neovascular AMD andpure geographic atrophy), assessed in retinal", "metadata": {}}
+{"_id": "24737389", "title": "", "text": "Growth control and ribosomopathies.Ribosomebiogenesis and protein synthesis are two of themost energy consuming processes in a growingcell. Moreover, defects in their molecularcomponents can alter the pattern of geneexpression. Thus it is understandable that cellshave developed a surveillance system to monitorthe status of the translational machinery. Recentdiscoveries of causative mutations and deletionsin genes linked to ribosome biogenesis havedefined a group of similar pathologies termedribosomopathies. Over the past decade, muchhas been learned regarding the relationshipbetween growth control and ribosomebiogenesis. The discovery of extra-ribosomalfunctions of several ribosome proteins and theirregulation of p53 levels has provided a link fromribosome impairment to cell cycle regulation.Yet, evidence suggesting p53 and/or Hdm2independent pathways also exists. In this review,we summarize recent advances in understandingthe mechanisms underlying the pathologies of", "metadata": {}}
+{"_id": "24742375", "title": "", "text": "Tunable signal processing through modularcontrol of transcription factortranslocation.Signaling pathways can inducedifferent dynamics of transcription factor (TF)activation. We explored how TFs processsignaling inputs to generate diverse dynamicresponses. The budding yeast generalstress-responsive TF Msn2 acted as a tunablesignal processor that could track, filter, orintegrate signals in an input-dependent manner.This tunable signal processing appears tooriginate from dual regulation of both nuclearimport and export by phosphorylation, asmutants with one form of regulation sustainedonly one signal-processing function. Versatilesignal processing by Msn2 is crucial forgenerating distinct dynamic responses todifferent natural stresses. Our findings revealhow complex signal-processing functions areintegrated into a single molecule and provide aguide for the design of TFs with \"programmable\"signal-processing functions.", "metadata": {}}
+{"_id": "24746892", "title": "", "text": "Killing by bactericidal antibiotics does not dependon reactive oxygen species.Bactericidalantibiotics kill by modulating their respectivetargets. This traditional view has beenchallenged by studies that propose analternative, unified mechanism of killing,whereby toxic reactive oxygen species (ROS) areproduced in the presence of antibiotics. Wefound no correlation between an individual cell'sprobability of survival in the presence ofantibiotic and its level of ROS. An ROS quencher,thiourea, protected cells from antibiotics presentat low concentrations, but the effect wasobserved under anaerobic conditions as well.There was essentially no difference in survival ofbacteria treated with various antibiotics underaerobic or anaerobic conditions. This suggeststhat ROS do not play a role in killing of bacterialpathogens by antibiotics.", "metadata": {}}
+{"_id": "24760136", "title": "", "text": "A naturally occurring mouse model of X-linkedcongenital stationary night blindness.PURPOSETo describe a naturally occurring X-linkedrecessive mutation, no b-wave (nob), thatcompromises visual transmission betweenphotoreceptors and second-order neurons inmice. METHODS Affected mice were identified byrecording the light-evoked response of theretina, the electroretinogram (ERG). To evaluatevisual transmission, cortical potentials wererecorded with a scalp electrode. The inheritancepattern for nob was defined by breeding nobanimals with normal mice. Retinal histologicanalysis was performed by light microscopy.RESULTS Although the photoreceptor-mediatedERG component (a-wave) was normal in nobmice, the major response component reflectingpostreceptoral neuronal activity (b-wave) wasmissing. Visually-driven cortical activity was alsoabnormal in nob animals. At the light microscopiclevel, the nob retina appeared to have a normalcytoarchitecture. CONCLUSIONS These findings", "metadata": {}}
+{"_id": "24766509", "title": "", "text": "Differentiation of mesenchymal stem cells andembryonic stem cells into steroidogenic cellsusing steroidogenic factor-1 and liver receptorhomolog-1.Previously, we have demonstratedthat mesenchymal stem cells could bedifferentiated into steroidogenic cells throughsteroidogenic factor-1 and 8bromo-cAMPtreatment. Use of liver receptor homolog-1,another of the nuclear receptor 5A family nuclearreceptors, with 8bromo-cAMP also resulted in thedifferentiation of human mesenchymal stem cellsinto steroid hormone-producing cells. The sameapproaches could not be applied to otherundifferentiated cells such as embryonic stemcells or embryonal carcinoma cells, because theover-expression of the nuclear receptor 5Afamily is cytotoxic to these cells. We establishedembryonic stem cells carryingtetracycline-regulated steroidogenic factor-1gene at the ROSA26 locus. The embryonic stemcells were first differentiated into a mesenchymalcell lineage by culturing on collagen IV-coated", "metadata": {}}
+{"_id": "24770122", "title": "", "text": "Chronic daily headache. A clinical andpsychological profile before and aftertreatment.To assess the clinical and personalitycharacteristics of patients with chronic dailyheadache before and after treatment, 20patients were examined and the MinnesotaMultiphasic Personality Inventory (MMPI [Italian356-item abbreviated version]) and the Straitand Trait Anxiety Index 1,2 (STAI) administered.There were two groups: group 1 (n = 6), with a\"conversion V\" configuration (with elevation ofhypochondria and hysteria scales, the depressionscale being somewhat lower); and group 2 (n =13) with elevation of depression and of otherMMPI scales. One patient had no scale elevation.STAI 1,2 scores were high in both groups.Several psychosomatic symptoms and somemigraine features were present in almost allpatients. Occurrence, severity, and duration ofheadache were recorded regularly and the MMPIand the STAI administered again aftertreatment. Improvement of headaches and a", "metadata": {}}
+{"_id": "24770913", "title": "", "text": "Potassium channel structure and function asreported by a single glycosylationsequon.Inwardly rectifying K+ channels (IRKs)are highly K(+)-selective, integral membraneproteins that help maintain resting themembrane potential and cell volume. Integralmembrane proteins as a class are frequentlyN-glycosylated with the attached carbohydratebeing extracellular and perhaps modulatingfunction. However, dynamic effects ofglycosylation have yet to be demonstrated at themolecular level. ROMK1, a member of the IRKfamily is particularly suited to the study ofglycosylation because it has a singleN-glycosylation consensus sequence (Ho, K.,Nichols, C. G., Lederer, W. J., Lytton, J.,Vassilev, P. M., Kanazirska, M. V., and Herbert,S. C. (1993) Nature 362, 31-38). We show thatROMK1 is expressed in a functional state in theplasmalemma of an insect cell line (Spodopterafrugiperda, Sf9) and has two structures,glycosylated and unglycosylated. To test", "metadata": {}}
+{"_id": "24783597", "title": "", "text": "Role of the novel Th17 cytokine IL-17F ininflammatory bowel disease (IBD): upregulatedcolonic IL-17F expression in active Crohn'sdisease and analysis of the IL17F p.His161Argpolymorphism in IBD.BACKGROUND Interleukin(IL)-17F, produced in IL-23R-expressing Th17cells, is a novel member of the IL-17 cytokinefamily. Given the association of IL23R withinflammatory bowel disease (IBD), wecharacterized the role of IL-17F in IBD includingits intestinal gene expression and the effect ofthe IL17F p. His161Arg polymorphism on diseasesusceptibility and phenotype of Crohn's disease(CD) and ulcerative colitis (UC). In addition, weanalyzed the IL17F p. His161Arg polymorphismfor potential epistasis with IL23R andNOD2/CARD15 variants. METHODS IntestinalIL-17F mRNA expression was measured byquantitative polymerase chain reaction (PCR).Genomic DNA from 1682 individuals (CD: n =499; UC: n = 216; controls: n = 967) wasanalyzed for the presence of the IL17F p.", "metadata": {}}
+{"_id": "24790460", "title": "", "text": "Targeting brain cancer: advances in themolecular pathology of malignant glioma andmedulloblastomaMalignant brain tumourscontinue to be the cause of a disproportionatelevel of morbidity and mortality across a widerange of individuals. The most common variantsin the adult and paediatric populations —malignant glioma and medulloblastoma,respectively — have been the subject ofincreasingly intensive research over the past twodecades that has led to considerable advances inthe understanding of their basic biology andpathogenesis. This Review summarizes thesedevelopments in the context of the evolvingnotion of molecular pathology and discusses theimplications that this work has on the design ofnew treatment regimens.", "metadata": {}}
+{"_id": "24795767", "title": "", "text": "Rapid helper T-cell recovery above 200 × 106/lat 3 months correlates to successful transplantoutcomes after allogeneic stem celltransplantationThe current study evaluates therole of quantitative measurement of peripherallymphocyte subsets, especially CD4+ helperT-cell recovery, in predicting transplantoutcomes including overall survival (OS) andnon-relapse mortality (NRM) after allogeneicstem cell transplantation. A total of 69 allogeneicrecipients were included with followingdiagnoses: acute myeloid leukemia 42, acutelymphoblastic leukemia 5, chronic myeloidleukemia 15, non-Hodgkin's lymphoma 5 andhigh-risk myelodysplastic syndrome 2. Theperipheral lymphocyte subset counts (CD3+ Tcells, CD3+4+ helper T cells, CD3+8+ cytotoxicT cells, CD19+ B cells, and CD56+ natural killercells) were measured at 3, 6 and 12 months. TheCD4+ helper T-cell reconstitution at 3 monthswas strongly correlated with OS (P<0.0001),NRM (P=0.0007), and opportunistic infections", "metadata": {}}
+{"_id": "24825841", "title": "", "text": "Generating an iPSC bank for HLA-matched tissuetransplantation based on known donor andrecipient HLA types.The likelihood forimmunological rejection of Human LeukocyteAntigens (HLA)-mismatched induced pluripotentstem cells (iPSCs) limits their therapeuticpotential. Here we show how a tissue bank from150 selected homozygous HLA-typed volunteerscould match 93% of the UK population with aminimal requirement for immunosuppression.Our model provides a practical approach forusing existing HLA-typed samples to generate aniPSC stem cell bank that circumvents prospectivetyping of a large number of individuals.", "metadata": {}}
+{"_id": "24828165", "title": "", "text": "Promiscuous gene expression and thedevelopmental dynamics of medullary thymicepithelial cells.Thymic epithelial cells (TEC) formthe structural and functional microenvironmentnecessary for the establishment and qualitycontrol of the T cell repertoire. In addition, theyprovide an ectopic source of numeroustissue-restricted antigens (TRA), a feature calledpromiscuous gene expression (pGE). How theregulation of pGE is related to the cell biology ofTEC subset(s), e.g. their turnover anddevelopmental interrelationship is still poorlyunderstood. The observation that pGE isforemost a property of phenotypically andfunctionally mature medullary TEC (mTEC)implies that the full implementation of pGE iscontingent on mTEC differentiation. Here, weshow that the emergence of TEC subsets andpGE is tightly correlated during ontogeny and weprovide evidence that mature CD80pos mTECdevelop from an immature CD80neg subset. Thisdifferentiation step proceeds continuously in the", "metadata": {}}
+{"_id": "24834968", "title": "", "text": "Evaluation of HER-2/neu amplification and otherbiological markers as predictors of response toneoadjuvant anthracycline-based chemotherapyin primary breast cancer: the role ofanthracycline dose intensity.OBJECTIVES Thevalue of HER-2/neu status as a predictor ofresponse to anthracycline-based chemotherapyis still a matter of debate. We evaluated thecontribution of HER-2/neu gene amplification andother biologic markers in predicting response todifferent doses of neoadjuvantanthracycline-based chemotherapy. METHODSClinical and pathologic records of 115 primarybreast cancer patients were reviewed.Forty-eight and 67 patients received high(doxorubicin > or =20 mg/m2/wk; epirubicin >or =30 mg/m2/wk) and moderate-lowanthracycline dose intensity regimens,respectively. Pathologic diagnosis, hormonalreceptor status (HR), Ki67, and HER-2/neustatus were assessed on tumor samples beforeneoadjuvant chemotherapy. HER-2/neu was", "metadata": {}}
+{"_id": "24863571", "title": "", "text": "Radioactive labeling of mitochondrial translationproducts in cultured cells.The mammalianmitochondrial genome contains 37 genes, 13 ofwhich encode polypeptide subunits in theenzyme complexes of the oxidativephosphorylation system. The other genes encodethe rRNAs and tRNAs necessary for theirtranslation. The mitochondrial translationmachinery is located in the mitochondrial matrix,and is exclusively dedicated to the synthesis ofthese 13 enzyme subunits. Mitochondrial diseasein humans is often associated with defects inmitochondrial translation. This can manifest as aglobal decrease in the rate of mitochondrialprotein synthesis, a decrease in the synthesis ofspecific polypeptides, the synthesis of abnormalpolypeptides, or in altered stability of specifictranslation products. All of these changes in thenormal pattern of mitochondrial translation canbe assessed by a straightforward technique thattakes advantage of the insensitivity of themitochondrial translation machinery to", "metadata": {}}
+{"_id": "24864273", "title": "", "text": "Caenorhabditis elegans cyclin A- and B-typegenes: a cyclin A multigene family, an ancestralcyclin B3 and differential germline expression.Wehave cloned cDNAs for Caenorhabditis eleganscyclins A1, B and B3. While cyclins A1 and B aremost closely related to either A- or B-type cyclinsof other species, cyclin B3 is less related to thesecyclins. However, this cyclin is most similar tothe recently identified chicken cyclin B3. Ouridentification of a Caenorhabditis homologdemonstrates that cyclin B3 has been conservedin evolution. Cyclin A1 is a member of an A-typemultigene family; however the cyclin A1 cDNAonly recognizes a single band on northern blots.A single-sized RNA is also observed for the cyclinB3 cDNA. In contrast, three different transcriptsare observed for the cyclin B cDNA. Based on ouranalyses using RNAs from germline-defectivemutants and from populations enriched formales, one cyclin B transcript is specific to thepaternal germline. The two other cyclin Btranscripts, as well as the cyclin A1 and cyclin B3", "metadata": {}}
+{"_id": "24865781", "title": "", "text": "A comparison of pharmacological (amitriptylineHCL) and nonpharmacological(cognitive-behavioral) therapies for chronictension headaches.Forty-one recurrent tensionheadache sufferers were randomly assigned toeither cognitive-behavioral therapy(administered in a primarily home-basedtreatment protocol) or to amitriptyline therapy(with dosage individualized at 25, 50, or 75mg/day). Cognitive-behavioral therapy andamitriptyline each yielded clinically significantimprovements in headache activity, both whenimprovement was assessed with patient dailyrecordings (56% and 27% reduction in headacheindex, respectively), and when improvement wasassessed with neurologist ratings of clinicalimprovement (94% and 69% of patients rated atleast moderately improved, respectively). Ininstances where differences in treatmenteffectiveness were observed (headache index,somatic complaints, perceptions of control ofheadache activity), cognitive-behavioral therapy", "metadata": {}}
+{"_id": "24872571", "title": "", "text": "Homeostasis model assessment: insulinresistance and β-cell function from fastingplasma glucose and insulin concentrations inmanThe steady-state basal plasma glucose andinsulin concentrations are determined by theirinteraction in a feedback loop. Acomputer-solved model has been used to predictthe homeostatic concentrations which arise fromvarying degrees of β-cell deficiency and insulinresistance. Comparison of a patient's fastingvalues with the model's predictions allows aquantitative assessment of the contributions ofinsulin resistance and deficient β-cell function tothe fasting hyperglycaemia (homeostasis modelassessment, HOMA). The accuracy and precisionof the estimate have been determined bycomparison with independent measures of insulinresistance and β-cell function usinghyperglycaemic and euglycaemic clamps and anintravenous glucose tolerance test. The estimateof insulin resistance obtained by homeostasismodel assessment correlated with estimates", "metadata": {}}
+{"_id": "24873253", "title": "", "text": "Clinical benefits and considerations ofbisphosphonate treatment in metastatic bonedisease.Patients with metastatic bone diseaseare at risk for developing skeletal-related eventsthat can negatively influence quality of life,contributing to loss of autonomy and functionalcapabilities. Bisphosphonates have become animportant component in the treatment ofpatients with bone metastases as they delay theonset and reduce the risk of skeletal-relatedevents and also palliate or control bone pain inmultiple cancer types, thus preserving quality oflife. Zoledronic acid has proven efficacy andsafety in patients with bone lesions from breastcancer, prostate cancer, lung cancer, and othersolid tumors, as well as in patients with multiplemyeloma. Current data suggest that earlytreatment with zoledronic acid (before the onsetof bone pain) may provide additional clinicalbenefits and also positive effects on survival insubsets of patients who have elevated levels ofN-telopeptide of type I collagen (NTX), a", "metadata": {}}
+{"_id": "24879055", "title": "", "text": "Distinct memory CD4+ T cells with commitmentto T follicular helper- and T helper 1-cell lineagesare generated after acute viral infection.CD4(+)T follicular helper (Tfh) cells provide the requiredsignals to B cells for germinal center reactionsthat are necessary for long-lived antibodyresponses. However, it remains unclear whetherthere are CD4(+) memory T cells committed tothe Tfh cell lineage after antigen clearance. Byusing adoptive transfer of antigen-specificmemory CD4(+) T cell subpopulations in thelymphocytic choriomeningitis virus infectionmodel, we found that there are distinct memoryCD4(+) T cell populations with commitment toeither Tfh- or Th1-cell lineages. Our conclusionsare based on gene expression profiles, epigeneticstudies, and phenotypic and functional analyses.Our findings indicate that CD4(+) memory T cells\"remember\" their previous effector lineage afterantigen clearance, being poised to reacquiretheir lineage-specific effector functions uponantigen reencounter. These findings have", "metadata": {}}
+{"_id": "24881307", "title": "", "text": "Control of synapse development and plasticity byRho GTPase regulatory proteinsSynapses arespecialized cell-cell contacts that mediatecommunication between neurons. Mostexcitatory synapses in the brain are housed ondendritic spines, small actin-rich protrusionsextending from dendrites. During developmentand in response to environmental stimuli, spinesundergo marked changes in shape and numberthought to underlie processes like learning andmemory. Improper spine development, incontrast, likely impedes information processingin the brain, since spine abnormalities areassociated with numerous brain disorders.Elucidating the mechanisms that regulate theformation and plasticity of spines and theirresident synapses is therefore crucial to ourunderstanding of cognition and disease.Rho-family GTPases, key regulators of the actincytoskeleton, play essential roles in orchestratingthe development and remodeling of spines andsynapses. Precise spatio-temporal regulation of", "metadata": {}}
+{"_id": "24896957", "title": "", "text": "Rate and molecular spectrum of spontaneousmutations in the bacterium Escherichia coli asdetermined by whole-genomesequencing.Knowledge of the rate and nature ofspontaneous mutation is fundamental tounderstanding evolutionary and molecularprocesses. In this report, we analyzespontaneous mutations accumulated overthousands of generations by wild-typeEscherichia coli and a derivative defective inmismatch repair (MMR), the primary pathway forcorrecting replication errors. The majorconclusions are (i) the mutation rate of awild-type E. coli strain is ~1 × 10(-3) pergenome per generation; (ii) mutations in thewild-type strain have the expected mutationalbias for G:C > A:T mutations, but the biaschanges to A:T > G:C mutations in the absenceof MMR; (iii) during replication, A:T > G:Ctransitions preferentially occur with A templatingthe lagging strand and T templating the leadingstrand, whereas G:C > A:T transitions", "metadata": {}}
+{"_id": "24906548", "title": "", "text": "Apolipoprotein E4 as a predictor of outcomes inpediatric mild traumatic brain injury.The epsilon4allele of the apolipoprotein E (APOE) gene hasbeen linked to negative outcomes among adultswith traumatic brain injury (TBI) across thespectrum of severity, with preliminary evidencesuggesting a similar pattern among children. Thisstudy investigated the relationship of the APOEepsilon4 allele to outcomes in children with mildTBI. Participants in this prospective, longitudinalstudy included 99 children with mild TBI betweenthe ages of 8 and 15 recruited from consecutiveadmissions to Emergency Departments at twolarge children's hospitals. Outcomes wereassessed acutely in the Emergency Departmentand at follow-ups at 2 weeks, 3 months, and 12months post-injury. Among the 99 participants,28 had at least one epsilon4 allele. Children withand without an epsilon4 allele did not differdemographically. Children with an epsilon4 allelewere significantly more likely than those withoutan epsilon4 allele to have a Glasgow Coma Scale", "metadata": {}}
+{"_id": "24916604", "title": "", "text": "Do physicians follow systemic treatment andfunding policy guidelines?BACKGROUND The useof bisphosphonates for the prevention of skeletalrelated events in women with bone metastasesfrom breast cancer is well established. Weundertook an evaluation of bisphosphonate usein clinical practice in three Canadian cancercentres. In addition we assessed whether or notphysicians at these centres are following theirlocal treatment guidelines and funding policies.METHODS Charts and electronic files of patientswho had received either clodronate orpamidronate at any time between January 2000and December 2001 at three Canadian cancercentres were retrospectively reviewed. RESULTSThere has been a marked improvement in thetime between the diagnosis of bone metastasesand the commencement of bisphosphonates froma median of 155 days in 1998 to 24 days in2001. However, despite a local funding policyrequiring that oral clodronate be the firstbisphosphonate used, this was the case in only", "metadata": {}}
+{"_id": "24917562", "title": "", "text": "Increased resting energy expenditure and weightloss are related to a systemic inflammatoryresponse in lung cancer patients.PURPOSE Todetermine whether an increased resting energyexpenditure (REE) and weight loss in lung cancerpatients are related to a systemic inflammatoryresponse. MATERIALS AND METHODS REE wasmeasured by indirect calorimetry using aventilated hood system. Soluble tumor necrosisfactor receptor 55 (sTNF-R55) and sTNF-R75,soluble intercellular adhesion molecule(sICAM)-1, soluble E (sE)-selectin,lipopolysaccharide (LPS)-binding protein (LBP),interleukin (IL)-6, and TNF-alpha were measuredusing sandwich enzyme-linked immunosorbentassay (ELISA), and C-reactive protein (CRP) wasmeasured by turbidimetry. A cross-sectionalstudy was performed to compare inflammatorymediators between hypermetabolic (REE/HarrisBenedict [HB] equation > or = 110%) versusnormometabolic (REE/HB < 110%) patients andbetween patients who lost weight (more than", "metadata": {}}
+{"_id": "24918110", "title": "", "text": "Exercise capacity and body mass as predictors ofmortality among male veterans with type 2diabetes.OBJECTIVE To demonstrate the relationof exercise capacity and BMI to mortality in apopulation of male veterans with type 2diabetes. RESEARCH DESIGN AND METHODSAfter excluding two underweight patients (BMI<18.5 kg/m2), the study population comprised831 consecutive patients with type 2 diabetes(mean age 61 +/- 9 years) referred for exercisetesting for clinical reasons between 1995 and2006. Exercise capacity was determined from amaximal exercise test and measured inmetabolic equivalents (METs). Patients wereclassified both according to BMI category(18.5-24.9, 25.0-29.9, and > or =30 kg/m2)and by exercise capacity (<5.0 or > or =5.0maximal METs). The association among exercisecapacity, BMI, other clinical variables, andall-cause mortality was assessed by Coxproportional hazards. Study participants werefollowed for mortality up to 30 June 2006.", "metadata": {}}
+{"_id": "24921368", "title": "", "text": "Impaired awareness of hypoglycaemia: areview.Impaired awareness of hypoglycaemia(IAH) is an acquired complication of insulintherapy, which affects people with type 1 andinsulin-treated type 2 diabetes mellitus, wherebythe ability to perceive the onset ofhypoglycaemia becomes diminished or absent.Deficiencies of the counter-regulatory hormonalresponses to hypoglycaemia usually co-exist.The development of IAH and counter-regulatoryfailure greatly increases the risk of severehypoglycaemia. Scoring systems have beendeveloped that can be used in the clinical settingand assist with identification of this group ofindividuals at risk of severe hypoglycaemia. Themainstay of treatment of IAH is the scrupulousavoidance of hypoglycaemia.", "metadata": {}}
+{"_id": "24922825", "title": "", "text": "A chikungunya fever vaccine utilizing aninsect-specific virus platformTraditionally,vaccine development involves tradeoffs betweenimmunogenicity and safety. Live-attenuatedvaccines typically offer rapid and durableimmunity but have reduced safety whencompared to inactivated vaccines. In contrast,the inability of inactivated vaccines to replicateenhances safety at the expense ofimmunogenicity, often necessitating multipledoses and boosters. To overcome thesetradeoffs, we developed the insect-specificalphavirus, Eilat virus (EILV), as a vaccineplatform. To address the chikungunya fever(CHIKF) pandemic, we used an EILV cDNA cloneto design a chimeric virus containing thechikungunya virus (CHIKV) structural proteins.The recombinant EILV/CHIKV was structurallyidentical at 10 Å to wild-type CHIKV, asdetermined by single-particle cryo-electronmicroscopy, and it mimicked the early stages ofCHIKV replication in vertebrate cells from", "metadata": {}}
+{"_id": "24923605", "title": "", "text": "Molecular elements of low-oxygen signaling inplants.Oxygen and its limitation are emerging asa crucial factor in plant fitness, growth anddevelopment. Recent studies revealed themechanisms by which oxygen is perceived byplant cells. This sensory system partly relies onan oxygen-mediated branch of the N-end rulepathway for protein degradation acting on aspecific clade of ethylene responsivetranscription factors (ERF-VII). A complementaryregulative step is provided by aerobicsequestration of an ERF-VII protein at theplasma membrane and its timely release whenhypoxia occurs. Complete absence of oxygentriggers the transient accumulation of reactivehydrogen peroxide and induces an additional setof reactive oxygen species-related genesinvolved in both signaling and attenuation ofoxidative stress. Moreover, temporary hypoxicenvironments that are built up as consequence ofdense cell packing have been demonstrated totrigger cell-fate determination in maize anthers.", "metadata": {}}
+{"_id": "24928817", "title": "", "text": "Purification, characterization, and sequenceanalysis of a potential virulence factor fromPorphyromonas gingivalis, peptidylargininedeiminase.The initiation and progression ofadult-onset periodontitis has been associatedwith infection of the gingival sulcus byPorphyromonas gingivalis. This organism utilizesa multitude of virulence factors to evade hostdefenses as it establishes itself as one of thepredominant pathogens in periodontal pockets. Afeature common to many other oral pathogens isthe production of ammonia due to its protectiveeffect during acidic cleansing cycles in themouth. Additionally, ammonia production by P.gingivalis has been proposed as a virulencefactor due to its negative effects on neutrophilfunction. In this study, we describe the firstpurification of a peptidylarginine deiminase(PAD) from a prokaryote. PAD exhibitsbiochemical characteristics and properties thatsuggest that it may be a virulence agent. PADdeiminates the guanidino group of", "metadata": {}}
+{"_id": "24942840", "title": "", "text": "Traumatic encephalopathy: review andprovisional research diagnosticcriteria.OBJECTIVES To determine the frequencyof neurobehavioral signs and symptoms reportedin every published case of traumaticencephalopathy with a view toward thedevelopment of clinical diagnostic criteria withpredictive validity. INTRODUCTION Cases ofpersistent or progressive neurological orneurobehavioral change following exposure toone or more head injuries have been reportedsince 1928. This condition is often referred to astraumatic encephalopathy (TE). To date,however, no diagnostic criteria have beenadvanced or accepted for the clinical diagnosis ofTE. Provisional research diagnostic criteria arerequired not only for meaningful diagnosis butalso to facilitate research to determine theepidemiology, etiology, course, prognosis,imaging and biomarkers, neuropathologicalfeatures and potentially effective treatments ofTE. METHODS All 436 published cases of TE in all", "metadata": {}}
+{"_id": "24943534", "title": "", "text": "Hepatitis C and human immunodeficiency virusinfection.In the United States, an estimated200,000 persons are infected with both hepatitisC virus (HCV) and human immunodeficiencyvirus (HIV). As the lives of HIV-infected personshave been prolonged by use of highly activeantiretroviral therapy, liver disease has emergedas an important, and in some settings, theleading cause of morbidity and mortality. Humanimmunodeficiency virus infection appears toadversely affect all stages of hepatitis Cinfection, leading to increased viral persistenceand accelerated progression of HCV-related liverdisease. In turn, hepatitis C may affect themanagement of HIV infection, increasing theincidence of liver toxicity caused by antiretroviralmedications. The medical management ofhepatitis C in HIV-infected persons remainscontroversial, in part because of the complexityof both infections and potential drug interactions,but chiefly because there is so little publishedinformation. Nonetheless, the burden of liver", "metadata": {}}
+{"_id": "24974080", "title": "", "text": "Role of the vascular endothelial growth factorpathway in tumor growth and angiogenesis.Newblood vessel formation (angiogenesis) is afundamental event in the process of tumorgrowth and metastatic dissemination. Hence, themolecular basis of tumor angiogenesis has beenof keen interest in the field of cancer research.The vascular endothelial growth factor (VEGF)pathway is well established as one of the keyregulators of this process. TheVEGF/VEGF-receptor axis is composed ofmultiple ligands and receptors with overlappingand distinct ligand-receptor binding specificities,cell-type expression, and function. Activation ofthe VEGF-receptor pathway triggers a network ofsignaling processes that promote endothelial cellgrowth, migration, and survival from pre-existingvasculature. In addition, VEGF mediates vesselpermeability, and has been associated withmalignant effusions. More recently, an importantrole for VEGF has emerged in mobilization ofendothelial progenitor cells from the bone", "metadata": {}}
+{"_id": "24979644", "title": "", "text": "Frozen robust multiarray analysis (fRMA).Robustmultiarray analysis (RMA) is the most widelyused preprocessing algorithm for Affymetrix andNimblegen gene expression microarrays. RMAperforms background correction, normalization,and summarization in a modular way. The last 2steps require multiple arrays to be analyzedsimultaneously. The ability to borrow informationacross samples provides RMA variousadvantages. For example, the summarizationstep fits a parametric model that accounts forprobe effects, assumed to be fixed across arrays,and improves outlier detection. Residuals,obtained from the fitted model, permit thecreation of useful quality metrics. However, thedependence on multiple arrays has 2 drawbacks:(1) RMA cannot be used in clinical settings wheresamples must be processed individually or insmall batches and (2) data sets preprocessedseparately are not comparable. We propose apreprocessing algorithm, frozen RMA (fRMA),which allows one to analyze microarrays", "metadata": {}}
+{"_id": "24980622", "title": "", "text": "Hypoxia in relation to vasculature andproliferation in liver metastases in patients withcolorectal cancer.PURPOSE To investigatehypoxia measured by pimonidazole binding,glucose transporter 1 (GLUT1) and carbonicanhydrase IX (CA-IX) expression, proliferation,and vascularity in liver metastases of colorectalcancer and to compare GLUT1 and CA-IXexpression in corresponding primary tumors.METHODS AND MATERIALS Twenty-five patientswith liver metastases of colorectal cancer,planned for metastasectomy, were included. Thehypoxia marker pimonidazole and proliferationmarker iododeoxyuridine were administeredbefore surgery. After immunofluorescent stainingof the frozen metastases, pimonidazole binding,vascularity, and proliferation were analyzedquantitatively. Thirteen paraffin-embeddedprimary tumors were stainedimmunohistochemically for GLUT1 and CA-IXexpression, which was analyzedsemiquantitatively in primary tumors and", "metadata": {}}
+{"_id": "24988745", "title": "", "text": "Unmet needs mediate the relationship betweensymptoms and quality of life in breast cancersurvivorsThis study aimed to compare thesymptoms, unmet needs, and QoL reported bywomen at 6 months to <2 years and 2 to 5 yearsfollowing surgery and adjuvant treatment forbreast cancer. It also evaluated the relationshipsamong symptoms, unmet needs, and QoL usingstructural equation modeling. In this study, 113and 137 survivors following breast cancertreatment 6 months to <2 years and 2 to 5years, respectively, completed the MemorialSymptom Assessment Scale, the SupportiveCare Needs Survey-34, and the MedicalOutcomes Study 12-item Short Form HealthSurvey version 2.0 during their medicalfollow-up. The mean numbers of symptoms andunmet needs were 5.43 and 3.0, respectively, forsurvivors at <2 years, and 5.24 and 2.42,respectively, for survivors at 2 to 5 yearsfollowing treatment. The most common reportedsymptoms were related primarily to physical", "metadata": {}}
+{"_id": "24989194", "title": "", "text": "Phagocytosis and deposition of vascularbeta-amyloid in rat brains injected withAlzheimer beta-amyloid.The presence ofextracellular deposits of beta-amyloid protein inthe brain is a hallmark of Alzheimer's disease(AD). In an effort to determine the effect ofamyloid in an animal model, the authors injectedamyloid cores isolated from AD brains into thecortex and hippocampus of rats. Lipofuscin, amajor contaminant of the plaque corepreparation, was injected on the contralateralside and used as a control to induce ananalogous phagocytic cell response. Rats weresacrificed 2 days, 7 days, and 1 month afterinjection and amyloid located by fourhistochemical techniques. Amyloid and lipofuscinmove from the site of injection into otherwiseundamaged neuropil, persist for at least 1 monthand are both associated with increases in glialfibrillary acidic protein and microglia (OX-42)staining. By 1 week, many of the amyloid coresare ingested by phagocytes. Some of the", "metadata": {}}
+{"_id": "24995939", "title": "", "text": "Specific sites in the C terminus of CTCF interactwith the SA2 subunit of the cohesin complex andare required for cohesin-dependent insulationactivity.Recent studies have shown that theprotein CTCF, which plays an important role ininsulation and in large-scale organization ofchromatin within the eukaryotic nucleus,depends for both activities on recruitment of thecohesin complex. We show here that theinteraction of CTCF with the cohesin complexinvolves direct contacts between the cohesinsubunit SA2 and specific regions of theC-terminal tail of CTCF. All other cohesincomponents are recruited through theirinteraction with SA2. Expression in vivo of CTCFmutants lacking the C-terminal domain, or withmutations at sites within it required for SA2binding, disrupts the normal expression profile ofthe imprinted genes IGF2-H19 and also results ina loss of insulation activity. Taken together, ourresults demonstrate that specific sites on the Cterminus of CTCF are essential for cohesin", "metadata": {}}
+{"_id": "24998637", "title": "", "text": "Interleukin 6 plays a key role in the developmentof antigen-induced arthritis.To investigate thedirect role of interleukin (IL) 6 in thedevelopment of rheumatoid arthritis,IL-6-deficient (IL-6 -/-) mice were backcrossedfor eight generations into C57BL/6 mice, a strainof mice with a genetic background ofsusceptibility for antigen-induced arthritis (AIA).Both histological and immunological comparisonswere made between IL-6-deficient (IL-6 -/-)mice and wild-type (IL-6 +/+) littermates afterthe induction of AIA. Although all IL-6 +/+ micedeveloped severe arthritis, only mild arthritiswas observed in IL-6 -/- mice. Safranin Ostaining demonstrated that articular cartilagewas well preserved in IL-6 -/- mice, whereas itwas destroyed completely in IL-6 +/+ mice. Inaddition, comparable mRNA expression for bothIL-1beta and tumor necrosis factor alpha, but notfor IL-6, was detected in the inflamed joints ofIL-6 -/- mice, suggesting that IL-6 may play amore crucial role in cartilage destruction than", "metadata": {}}
+{"_id": "24998764", "title": "", "text": "Relation between renal function within thenormal range and central and peripheral arterialstiffness in hypertension.Chronic kidney diseaseis accompanied by increased large-arterystiffness, but the relation between glomerularfiltration rate within the reference range andcentral or peripheral arterial stiffness has beenunderstudied. The link between renal functionand arterial stiffness was assessed in 305patients with never-treated essentialhypertension (men: 58%; age: 48+/-11 years,blood pressure: 151/95+/-20/11 mm Hg), freefrom overt cardiovascular disease and withserum creatinine values <1.4 mg/dL (men) and<1.2 mg/dL (women), who underwentnoninvasive aortic and upper-limb pulse wavevelocity (PWV) determination. Aortic PWV wasstrongly related to age (r=0.55; P<0.001),whereas upper-limb PWV had a weaker nonlinearrelation with age (beta=1.392; P<0.001 for age;beta=-1.312; P<0.001 for age squared) and aweak relation with aortic PWV (r=0.22;", "metadata": {}}
+{"_id": "25001628", "title": "", "text": "Comparative gene expression profiling of in vitrodifferentiated megakaryocytes and erythroblastsidentifies novel activatory and inhibitory plateletmembrane proteins.To identify previouslyunknown platelet receptors we compared thetranscriptomes of in vitro differentiatedmegakaryocytes (MKs) and erythroblasts (EBs).RNA was obtained from purified, biologicallypaired MK and EB cultures and compared usingcDNA microarrays. Bioinformatical analysis ofMK-up-regulated genes identified 151 transcriptsencoding transmembrane domain-containingproteins. Although many of these were knownplatelet genes, a number of previouslyunidentified or poorly characterized transcriptswere also detected. Many of these transcripts,including G6b, G6f, LRRC32, LAT2, and the Gprotein-coupled receptor SUCNR1, encodeproteins with structural features or functions thatsuggest they may be involved in the modulationof platelet function. Immunoblotting on plateletsconfirmed the presence of the encoded proteins,", "metadata": {}}
+{"_id": "25007443", "title": "", "text": "Topographic mapping of VMH \u0000 arcuate nucleusmicrocircuits and their reorganization byfastingIn the hypothalamic arcuate nucleus(ARC), pro-opiomelanocortin (POMC) neuronsinhibit feeding and neuropeptide-Y (NPY)neurons stimulate feeding. We tested whetherneurons in the ventromedial hypothalamicnucleus (VMH), a known satiety center, activateanorexigenic neuronal pathways in the ARC byprojecting either excitatory synaptic inputs toPOMC neurons and/or inhibitory inputs to NPYneurons. Using laser scanning photostimulationin brain slices from transgenic mice, we foundthat POMC and NPY neurons, which areinterspersed in the ARC, are neverthelessregulated by anatomically distinct synapticinputs. POMC neurons received strong excitatoryinput from the medial VMH (mVMH), whereasNPY neurons did not and, instead, received weakinhibitory input only from within the ARC. Thestrength of the excitatory input from the mVMHto POMC neurons was diminished by fasting.", "metadata": {}}
+{"_id": "25014337", "title": "", "text": "The human immunodeficiency virus type 1nonnucleoside reverse transcriptase inhibitorresistance mutation I132M confershypersensitivity to nucleoside analogs.Wepreviously identified a rare mutation in humanimmunodeficiency virus type 1 (HIV-1) reversetranscriptase (RT), I132M, which confershigh-level resistance to the nonnucleoside RTinhibitors (NNRTIs) nevirapine and delavirdine.In this study, we have further characterized therole of this mutation in viral replication capacityand in resistance to other RT inhibitors.Surprisingly, our data show that I132M confersmarked hypersusceptibility to the nucleosideanalogs lamivudine (3TC) and tenofovir at boththe virus and enzyme levels. Subunit-selectivemutagenesis studies revealed that the mutationin the p51 subunit of RT was responsible for theincreased sensitivity to the drugs, and transientkinetic analyses showed that thishypersusceptibility was due to I132M decreasingthe enzyme's affinity for the natural dCTP", "metadata": {}}
+{"_id": "25022826", "title": "", "text": "AFF1 and AFF4 differentially regulate theosteogenic differentiation of human MSCsAFF1and AFF4 belong to the AFF (AF4/FMR2) family ofproteins, which function as scaffolding proteinslinking two different transcription elongationfactors, positive elongation factor b (P-TEFb) andELL1/2, in super elongation complexes (SECs).Both AFF1 and AFF4 regulate gene transcriptionthrough elongation and chromatin remodeling.However, their function in the osteogenicdifferentiation of mesenchymal stem cells(MSCs) is unknown. In this study, we show thatsmall interfering RNA (siRNA)-mediateddepletion of AFF1 in human MSCs leads toincreased alkaline phosphatase (ALP) activity,enhanced mineralization and upregulatedexpression of osteogenic-related genes. On thecontrary, depletion of AFF4 significantly inhibitsthe osteogenic potential of MSCs. In addition, weconfirm that overexpression of AFF1 and AFF4differentially affects osteogenic differentiation invitro and MSC-mediated bone formation in vivo.", "metadata": {}}
+{"_id": "25028913", "title": "", "text": "Markers of myocardial damage and inflammationin relation to long-term mortality in unstablecoronary artery disease. FRISC Study Group.Fragmin during Instability in Coronary ArteryDisease.BACKGROUND In patients with unstablecoronary artery disease, there is a relationbetween the short-term risk of death and bloodlevels of troponin T (a marker of myocardialdamage) and C-reactive protein and fibrinogen(markers of inflammation). Using informationobtained during an extension of the follow-upperiod in the Fragmin during Instability inCoronary Artery Disease trial, we evaluated theusefulness of troponin T, C-reactive protein, andfibrinogen levels and other indicators of risk aspredictors of the long-term risk of death fromcardiac causes. METHODS Levels of C-reactiveprotein and fibrinogen at enrollment and themaximal level of troponin T during the first 24hours after enrollment were analyzed in 917patients included in a clinical trial oflow-molecular-weight heparin in unstable", "metadata": {}}
+{"_id": "25036988", "title": "", "text": "Loss of lamin B1 results in prolongation of Sphase and decondensation of chromosometerritories.Nuclear lamin B1 (LMNB1) constitutesone of the major structural proteins in the laminamesh. We silenced the expression of LMNB1 byRNA interference in the colon cancer cell lineDLD-1 and showed a dramatic redistribution ofH3K27me3 from the periphery to a morehomogeneous nuclear dispersion. In addition, weobserved telomere attrition and an increasedfrequency of micronuclei and nuclear blebs. By3D-FISH analyses, we demonstrated that thevolume and surface of chromosome territorieswere significantly larger in LMNB1-depleted cells,suggesting that LMNB1 is required to maintainchromatin condensation in interphase nuclei.These changes led to a prolonged S phase due toactivation of Chk1. Finally, silencing of LMNB1resulted in extensive changes in alternativesplicing of multiple genes and in a higher numberof enlarged nuclear speckles. Taken together,our results suggest a mechanistic role of the", "metadata": {}}
+{"_id": "25041967", "title": "", "text": "Human artificial chromosomes with alphasatellite-based de novo centromeres showincreased frequency of nondisjunction andanaphase lag.Human artificial chromosomeshave been used to model requirements forhuman chromosome segregation and to explorethe nature of sequences competent forcentromere function. Normal humancentromeres require specialized chromatin thatconsists of alpha satellite DNA complexed withepigenetically modified histones andcentromere-specific proteins. While several typesof alpha satellite DNA have been used toassemble de novo centromeres in artificialchromosome assays, the extent to which theyfully recapitulate normal centromere function hasnot been explored. Here, we have used two kindsof alpha satellite DNA, DXZ1 (from the Xchromosome) and D17Z1 (from chromosome17), to generate human artificial chromosomes.Although artificial chromosomes are mitoticallystable over many months in culture, when we", "metadata": {}}
+{"_id": "25045244", "title": "", "text": "Identification of a human HLA-E-restricted CD8+T cell subset in volunteers immunized withSalmonella enterica serovar Typhi strain Ty21atyphoid vaccine.Our previous studies involunteers immunized with Salmonella entericaserovar Typhi (S. Typhi) have suggested animportant role for CD8+ T cells in host defense.In this study we describe a novel subset ofnonclassical human HLA-E-restricted S.Typhi-specific CD8+ T cells derived from PBMC ofTy21a typhoid vaccinees. CD3+CD8+CD4-CD56-T cells effectively killed S. Typhi-infected targetsregardless of whether they share classical HLAclass I molecules with them, by aFAS-independent, granule-dependentmechanism, as evidenced by induction ofgranzyme B release and the blocking effects ofconcanamycin and strontium ions. Theexpression of HLA-E Ags, but not CD1-a, -b, or-c, on the membrane of S. Typhi-infected targetsrendered them susceptible to lysis. Moreover,anti-HLA-E Abs partially blocked these", "metadata": {}}
+{"_id": "25049067", "title": "", "text": "Costs and cost-effectiveness of alternativetuberculosis management strategies in SouthAfrica--implications for policy.OBJECTIVE Toconduct an economic analysis of the Hlabisacommunity-based directly observed therapymanagement strategy for tuberculosis and toproject costs of three alternative strategies.SETTING Hlabisa health district, KwaZulu-Natal,South Africa. METHODS An economic analysiscomparing the current tuberculosis managementstrategy in Hlabisa with three alternativestrategies (the Hlabisa strategy prior to 1991based on hospitalisation, the national strategyand sanatorium care) in terms of costs to bothhealth service and patient and ofcost-effectiveness. RESULTS The current Hlabisastrategy was the most cost-effective (R3799 perpatient cured), compared with R98307 for thestrategy used prior to 1991, R9940 for thenational strategy, and R11145 for sanatoriumcare. Between 71% and 88% of treatment costslie with the health service, and hospitalisation", "metadata": {}}
+{"_id": "25050364", "title": "", "text": "Interleukin-18 null mutation increases weightand food intake and reduces energy expenditureand lipid substrate utilization in high-fat diet fedmiceOBJECTIVE The proinflammatory cytokineinterleukin-18 (IL-18) putatively modulates foodintake and energy metabolism, but the effects ofIL-18 in high-fat diet fed animals are unknown.Whether IL-18 alters basal metabolic rate ormetabolic processes of living is unknown. Here,we tested the hypothesis that IL-18 modulatesweight gain, energy intake, whole-body energyexpenditure, and utilization of lipid as a fuelsubstrate in high-fat diet fed mice. METHODSFood intake, whole-body metabolism, and motoractivity of IL-18 knockout mice were comparedto those of wildtype littermates; anorectic effectsof intracerebroventricular IL-18 administrationwere compared between IL-18 receptorknockout, IL-18/IL-18R knockout and wildtypemice. RESULTS Chow-reared IL-18 knockoutmice were overweight at 6 months of age andthen gained excess weight on both low-fat and", "metadata": {}}
+{"_id": "25050969", "title": "", "text": "Notch activation promotes cell proliferation andthe formation of neural stem cell-like colonies inhuman glioma cellsSince Notch signaling plays acritical role in stem cells and oncogenesis, wehypothesized that Notch signaling might playroles in cancer stem cells and cancer cells with astem cell phenotype. In this study, we accessedpotential functions of the Notch pathway in theformation of cancer stem cells using humanglioma. Using RT-PCR, we found that mosthuman astrogliomas of different gradesexpressed moderate to high level of Notchreceptors and ligands. mRNA of Hes5 but notHes1, both of which are major downstreammolecules of the Notch pathway, was alsodetected. In human glioma cell lines BT325,U251, SHG-44, and U87, mRNA encodingdifferent types of Notch receptors were detected,but active form of Notch1 (NIC) was onlydetected in SHG-44 and U87 by Western blot.Interestingly, proliferation of these two gliomacell lines appeared faster than that of the other", "metadata": {}}
+{"_id": "25052749", "title": "", "text": "Rodent models in bone-related research: therelevance of calvarial defects in the assessmentof bone regeneration strategies.In vivo researchwith animal models has been a preferredexperimental system in bone-related biomedicalresearch since, by approximation, it allowsrelevant data gathering regarding physiologicaland pathological conditions that could be of useto establish more effective clinical interventions.Animal models, and more specifically rodentmodels, have been extensively used and havecontributed greatly to the development andestablishment of a wide range of translationalapproaches aiming to regenerate the bonetissue. In this regard, the calvarial defect modelhas found great application in basic and appliedresearch, nonetheless the controversialrationalization for the use of critical size defects -defects that are unable to report spontaneoushealing - or subcritical size defects in theproposed applications. Accordingly, this workaims to review the advantages and limitations of", "metadata": {}}
+{"_id": "25062868", "title": "", "text": "The transcriptional responses of Mycobacteriumtuberculosis to inhibitors of metabolism: novelinsights into drug mechanisms of action.Thedifferential transcriptional response ofMycobacterium tuberculosis to drugs andgrowth-inhibitory conditions was monitored togenerate a data set of 430 microarray profiles.Unbiased grouping of these profilesindependently clustered agents of knownmechanism of action accurately and wassuccessful at predicting the mechanism of actionof several unknown agents. These predictionswere validated biochemically for two agents ofpreviously uncategorized mechanism,pyridoacridones and phenothiazines. Analysis ofthis data set further revealed 150 underlyingclusters of coordinately regulated genes offeringthe first glimpse at the full metabolic potential ofthis organism. A signature subset of these geneclusters was sufficient to classify all knownagents as to mechanism of action.Transcriptional profiling of both crude and", "metadata": {}}
+{"_id": "25068298", "title": "", "text": "Electron microscopic studies of macrophages inearly human yolk sacs.Distribution and finestructure of macrophages were studied in 10human embryos in the 6th and 7th week ofgestation, 5.5 to 12 mm in crown-rump length.The yolk sac macrophages were found in theextravascular mesenchymal tissues andintravascular spaces long before the firstappearance of bone marrow and lymphatictissues in the embryos. In addition to themacrophages, the fibroblastic cells and the cellsof erythropoietic series were also present in theextravascular space. The macrophages showed avariety of cellular structures suggestingtransition from immature cell type with noheterophagolysosomes to mature cell type inphagocytosis. The mature macrophages avidlyphagocytized the primitive erythroblasts andoccasionally platelets. They were positivelystained for lysosomal enzymes and werecharacterized by numerous pleomorphicheterophagolysosomes which exhibited various", "metadata": {}}
+{"_id": "25069745", "title": "", "text": "Urban malaria and anaemia in children: across-sectional survey in two cities ofGhana.OBJECTIVE To describe the epidemiologyof urban malaria, an emerging problem insub-Saharan Africa. METHOD Cross-sectionalsurveys of communities in Accra and Kumasi,Ghana, determining risk factors for malariainfection and anaemia in children aged 6-60months. RESULTS Malaria prevalence ratesranged from 2% to 33% between urbancommunities. 47.1% of children were anaemic(Hb<11.0 g/dl). Factors associated with malariaprevalence were low socio-economic status, ageand anaemia. The attributable risks of anaemiaand severe anaemia (Hb<8.0 g/dl) caused bymalaria were 5% and 23% respectively.CONCLUSIONS Malaria in urban areas displayeda heterogeneity and complexity that differedfrom the rural environment, which has importantimplications for malaria control. Marked intra-cityvariation indicates the importance of targetingspecific areas or districts. The most vulnerable", "metadata": {}}
+{"_id": "25079962", "title": "", "text": "Nitrite infusions to prevent delayed cerebralvasospasm in a primate model of subarachnoidhemorrhage.CONTEXT Delayed cerebralvasospasm causes permanent neurologicaldeficits or death in at least 15% of patientsfollowing otherwise successful treatment forruptured intracranial aneurysm. Decreasedbioavailability of nitric oxide has been associatedwith the development of cerebral vasospasm.OBJECTIVE To determine whether infusions ofnitrite will prevent delayed cerebral vasospasm.DESIGN, SETTING, AND SUBJECTS A total of 14anesthetized cynomolgus monkeys had anautologous blood clot placed around the rightmiddle cerebral artery. Cerebral arteriographywas performed before clot placement and ondays 7 and 14 to assess vasospasm. The studywas conducted from August 2003 to February2004. INTERVENTIONS A 90-mg sodium nitriteintravenous solution infused over 24 hours plus a45-mg sodium nitrite bolus daily (n = 3); a180-mg sodium nitrite intravenous solution", "metadata": {}}
+{"_id": "25085979", "title": "", "text": "Developmental gene networks: a triathlon on thecourse to T cell identityCells acquire theirultimate identities by activating combinations oftranscription factors that initiate and sustainexpression of the appropriate cell type-specificgenes. T cell development depends on theprogression of progenitor cells through threemajor phases, each of which is associated withdistinct transcription factor ensembles thatcontrol the recruitment of these cells to thethymus, their proliferation, lineage commitmentand responsiveness to T cell receptor signals, allbefore the allocation of cells to particular effectorprogrammes. All three phases are essential forproper T cell development, as are themechanisms that determine the boundariesbetween each phase. Cells that fail to shut offone set of regulators before the next genenetwork phase is activated are predisposed toleukaemic transformation.", "metadata": {}}
+{"_id": "25089501", "title": "", "text": "A tumor necrosis factor-α–mediated pathwaypromoting autosomal dominant polycystic kidneydiseaseAutosomal dominant polycystic kidneydisease (ADPKD) is caused by heterozygousmutations in either PKD1 or PKD2, genes thatencode polycystin-1 and polycystin-2,respectively. We show here that tumor necrosisfactor-α (TNF-α), an inflammatory cytokinepresent in the cystic fluid of humans withADPKD, disrupts the localization of polycystin-2to the plasma membrane and primary ciliathrough a scaffold protein, FIP2, which is inducedby TNF-α. Treatment of mouse embryonic kidneyorgan cultures with TNF-α resulted in formationof cysts, and this effect was exacerbated in thePkd2+/− kidneys. TNF-α also stimulated cystformation in vivo in Pkd2+/− mice. In contrast,treatment of Pkd2+/− mice with the TNF-αinhibitor etanercept prevented cyst formation.These data reveal a pathway connecting TNF-αsignaling, polycystins and cystogenesis, theactivation of which may reduce functional", "metadata": {}}
+{"_id": "25098790", "title": "", "text": "Inappropriate inhaler use: assessment of useand patient preference of seven inhalationdevices. EDICI.Inefficient inhaler technique is acommon problem resulting in poor drug delivery,decreased disease control and increased inhaleruse. The aim of this study was to assess patients'use of different inhaler devices and to ascertainwhether patient preference is indicative of easeof use and whether current inhaler use has anyinfluence on either technique or preference. Wealso wished to define the most appropriatemethod of selecting an inhaler for a patient,taking into account observed technique anddevice cost. One hundred patients receivedinstruction, in randomized order, in the use ofseven different inhaler devices. After instructionthey were graded (using predetermined criteria)in their inhaler technique. After assessmentpatients were asked which three inhalers theymost preferred and which, if any, they currentlyused. Technique was best using thebreath-actuated inhalers; the Easi-Breathe and", "metadata": {}}
+{"_id": "25104843", "title": "", "text": "Hemoperfusion-hemodialysis ineffective forparaquat removal in life-threateningpoisoning?We report on a patient treated withhemoperfusion-hemodialysis (HP-HD) for severeparaquat poisoning. This procedure was adoptedsince the combination of adsorption and dialysismay improve overall drug removal. On admissionblood paraquat was 15.8 micrograms/ml. Hereceived conventional treatment and combinedHP-HD which started within 3 hours afteringestion of the chemical and lasted 5 hours.Blood samples were obtained during and afterHP-HD. The samples during HP-HD were takenbefore the charcoal column, between thecharcoal column and the artificial kidney andafter the artificial kidney. Blood clearances ofparaquat were 116 +/- 32 ml/min (n=6) for thecharcoal column (HP), 90 +/- 54 ml/min (n=6)for the artificial kidney (HD) and 151 +/- 37ml/min (n=6) for the combined systems(HP-HD). After HP-HD a limited rebound of bloodparaquat level was seen. One day after", "metadata": {}}
+{"_id": "25121903", "title": "", "text": "Cancer treatment and survivorship statistics,2014.The number of cancer survivors continuesto increase due to the aging and growth of thepopulation and improvements in early detectionand treatment. In order for the public healthcommunity to better serve these survivors, theAmerican Cancer Society and the NationalCancer Institute collaborated to estimate thenumber of current and future cancer survivorsusing data from the Surveillance, Epidemiology,and End Results (SEER) program registries. Inaddition, current treatment patterns for the mostcommon cancer types are described based oninformation in the National Cancer Data Base andthe SEER and SEER-Medicare linked databases;treatment-related side effects are also brieflydescribed. Nearly 14.5 million Americans with ahistory of cancer were alive on January 1, 2014;by January 1, 2024, that number will increase tonearly 19 million. The 3 most common prevalentcancers among males are prostate cancer(43%), colorectal cancer (9%), and melanoma", "metadata": {}}
+{"_id": "25124117", "title": "", "text": "Massive activation of archaeal defense genesduring viral infection.Archaeal viruses displayunusually high genetic and morphologicaldiversity. Studies of these viruses proved to beinstrumental for the expansion of knowledge onviral diversity and evolution. The Sulfolobusislandicus rod-shaped virus 2 (SIRV2) is a modelto study virus-host interactions in Archaea. It isa lytic virus that exploits a unique egressmechanism based on the formation ofremarkable pyramidal structures on the host cellenvelope. Using whole-transcriptomesequencing, we present here a global mapdefining host and viral gene expression duringthe infection cycle of SIRV2 in itshyperthermophilic host S. islandicus LAL14/1.This information was used, in combination with ayeast two-hybrid analysis of SIRV2 proteininteractions, to advance current understanding ofviral gene functions. As a consequence of SIRV2infection, transcription of more than one-third ofS. islandicus genes was differentially regulated.", "metadata": {}}
+{"_id": "25134146", "title": "", "text": "Impact of human immunodeficiency virusinfection on the histological features of chronichepatitis C: a case-control study. The MULTIVIRCgroup.Hepatitis C virus (HCV) is frequentlyencountered in human immunodeficiency virus(HIV)-infected patients because of commonroutes of transmission. Previous studiessuggested that HIV infection impaired the naturalcourse of chronic hepatitis C, with a more rapidprogression to cirrhosis. However, these studiesdid not assess the HIV infection impact onchronic hepatitis C by taking into account the riskfactors for liver fibrosis progression: alcohol, sex,age at the contamination, and duration of HCVinfection. We studied liver biopsy specimens of 2groups of 58 patients that were infected by bothHCV and HIV or by HCV alone. The 2 groupswere matched according those risk factors, andliver biopsy responses were evaluated with theMETAVIR items. The METAVIR activity was higherin HIV-positive than HIV-negative patients.Cirrhosis was more frequent: (1) in HIV-positive", "metadata": {}}
+{"_id": "25135304", "title": "", "text": "Relation of plasma leptin concentrations to sex,body fat, dietary intake, and peak oxygen uptakein young adult women and men.The purpose ofthis study was to examine the relation of leptinto metabolic and dietary factors in college-ageadults. Young adult women and men (n = 32)were recruited and underwent testing formeasurement of body mass index, bodycomposition, peak oxygen consumption(VO2peak), dietary intake, and plasma levels ofleptin and insulin. Ln leptin was significantlygreater for women than for men (2.1 versus 1.2ng/mL, respectively). This difference remainedsignificant even after adjusting ln leptin for fatmass and fat-free mass as covariates in separateanalyses. VO2peak was higher for men than forwomen and this remained significant afteradjustment for differences in fat-free mass andtotal body mass. Significant correlations werefound between ln leptin and indicators of fatmass in women and men, with highercorrelations for similar variables observed in men", "metadata": {}}
+{"_id": "25141908", "title": "", "text": "Expression of a human cytomegaloviruslatency-associated homolog of interleukin-10during the productive phase of infection.Thehuman cytomegalovirus UL111A region is activeduring both productive and latent phases ofinfection. During productive infection, the virusexpresses ORF79, a protein with oncogenicproperties, and cmvIL-10, a functional homologof human IL-10. During latent infection ofmyeloid progenitor cells, an alternately splicedvariant of cmvIL-10, termed latency-associated(LA) cmvIL-10 has previously been identified. Todetermine whether LAcmvIL-10 transcriptionoccurs during productive infection, we performed5' and 3' RACE to map UL111A-region transcriptsin productively infected human foreskinfibroblasts (HFFs). This analysis revealed thepresence of a singly spliced UL111A-regiontranscript predicted to encode LAcmvIL-10. Thistranscript was expressed in HFFs with early(beta) kinetics, a temporal class that differs fromthat of ORF79 (alpha kinetics) and cmvIL-10", "metadata": {}}
+{"_id": "25148216", "title": "", "text": "Kruppel-like factor 4 is essential forinflammatory monocyte differentiation invivo.Several members of the Kruppel-like factor(KLF) family of transcription factors playimportant roles in differentiation, survival, andtrafficking of blood and immune cell types. Wedemonstrate in this study that hematopoieticcells from KLF4(-/-) fetal livers (FL) containednormal numbers of functional hematopoieticprogenitor cells, were radioprotective, andperformed as well as KLF4(+/+) cells incompetitive repopulation assays. However,hematopoietic \"KLF4(-/-) chimeras\" generatedby transplantation of KLF4(-/-) fetal livers cellsinto lethally irradiated wild-type mice completelylacked circulating inflammatory(CD115(+)Gr1(+)) monocytes, and had reducednumbers of resident (CD115(+)Gr1(-))monocytes. Although the numbers and functionof peritoneal macrophages were normal inKLF4(-/-) chimeras, bone marrow monocyticcells from KLF4(-/-) chimeras expressed lower", "metadata": {}}
+{"_id": "25157790", "title": "", "text": "A population-based, case–control study of greentea consumption and leukemia risk insouthwestern TaiwanThis study investigated theassociation between green tea consumption andleukemia. A total of 252 cases (90.3% response)and 637 controls (53.4% response) wereenrolled. Controls were matched for cases on ageand gender. Information was collected onparticipants’ living habits, including teaconsumption. Green tea was used as a standardto estimate the total amount of individualcatechin consumption. We stratified individualconsumption of catechins into four levels.Conditional logistic regression models were fit tosubjects aged 0–15 and 16–29 years to evaluateseparate associations between leukemia andcatechin consumption. A significant inverseassociation between green tea consumption andleukemia risk was found in individuals aged16–29 years, whereas no significant associationwas found in the younger age groups. For theolder group with higher amounts of tea", "metadata": {}}
+{"_id": "25175223", "title": "", "text": "Specific HDV RNA-templated transcription by polII in vitro.RNA polymerase II is implicated in theRNA-templated RNA synthesis during replicationof viroids and Hepatitis Delta Virus (HDV);however, neither the RNA template nor proteinfactor requirements for this process are welldefined. We have developed an in vitrotranscription system based on HeLa cell nuclearextract (NE), in which a segment of antigenomicRNA corresponding to the left-hand tip region ofthe HDV rod-like structure serves as a templatefor efficient and highly specific RNA synthesis.Accumulation of the unique RNA product is highlysensitive to alpha-amanitin in HeLa NE and onlypartially sensitive to this drug in NE from PMGcells that contain an allele of thealpha-amanitin-resistant subunit of pol II,strongly suggesting pol II involvement in thisreaction. Detailed analysis of the RNA productrevealed that it represents a chimeric moleculecomposed of a newly synthesized transcriptcovalently attached to the 5' half of the RNA", "metadata": {}}
+{"_id": "25175997", "title": "", "text": "Pulmonary vascular lesions in end-stageidiopathic pulmonary fibrosis: Histopathologicstudy on lung explant specimens and correlationswith pulmonary hemodynamics.In patientspresenting with idiopathic pulmonary fibrosis(IPF), modifications of pulmonary vessels arewell defined in fibrotic areas but have not beenaccurately assessed in the intervening patches ofpreserved lung. Moreover, the relation betweenpulmonary vessel lesions and pulmonaryhemodynamics is not well known. We thereforedesigned a retrospective study on lung explantspecimens from 26 patients with a firm diagnosisof IPF who had undergone lung transplantation.Our aim was to (1) describe the vascular lesions,especially in preserved lung areas, and (2)correlate them with pulmonary hemodynamics.In dense fibrotic zones, thickening of the arterialand venous wall with severe luminal narrowingwas present in each patient. In architecturallypreserved lung zones, occlusion of venules andsmall pulmonary veins was observed in 65% of", "metadata": {}}
+{"_id": "25182647", "title": "", "text": "Maternal and perinatal outcome in severepregnancy-related liver disease.Acute fatty liverof pregnancy (AFLP) and the syndrome ofhemolysis, elevated liver enzyme levels, and lowplatelet count (HELLP) are rare but majordisorders of the third trimester of pregnancy.Over a 10-year period, 46 women (median age,30 years; range, 17-41 years) developed hepaticdysfunction severe enough to require transfer toour Liver Failure Unit. Three quarters of thewomen were nulliparous, and 5 had twinpregnancies; the median gestational age was 35weeks (range, 24-40 weeks). At admission, 32patients (70%) were preeclamptic and 21 (46%)were encephalopathic and/or ventilated.Thirty-two patients (70%) had clinical featuresand laboratory values consistent with AFLP, and7 (15%) had HELLP syndrome. One patient hadpreeclamptic liver rupture requiring livertransplantation. In 6 other patients, causes ofsevere liver dysfunction unrelated to pregnancywere found. Infectious complications occurred in", "metadata": {}}
+{"_id": "25183830", "title": "", "text": "Circadian rhythms and the regulation ofmetabolic tissue function and energyhomeostasis.Circadian oscillators play anindispensable role in the coordination ofphysiological processes with the cyclic changes inthe physical environment. A significant numberof recent clinical and molecular studies suggestthat circadian biology may play an important rolein the regulation of adipose and other metabolictissue functions. In this discussion, we presentthe hypothesis that circadian dysfunction may beinvolved in the pathogenesis of obesity, type 2diabetes, and the metabolic syndrome.", "metadata": {}}
+{"_id": "25186412", "title": "", "text": "Large-scale gene function analysis with thePANTHER classification systemThe PANTHER(protein annotation through evolutionaryrelationship) classification system(http://www.pantherdb.org/) is a comprehensivesystem that combines gene function, ontology,pathways and statistical analysis tools thatenable biologists to analyze large-scale,genome-wide data from sequencing, proteomicsor gene expression experiments. The system isbuilt with 82 complete genomes organized intogene families and subfamilies, and theirevolutionary relationships are captured inphylogenetic trees, multiple sequence alignmentsand statistical models (hidden Markov models orHMMs). Genes are classified according to theirfunction in several different ways: families andsubfamilies are annotated with ontology terms(Gene Ontology (GO) and PANTHER proteinclass), and sequences are assigned to PANTHERpathways. The PANTHER website includes a suiteof tools that enable users to browse and query", "metadata": {}}
+{"_id": "25191216", "title": "", "text": "Periostin, a novel marker of intramembranousossification, is expressed in fibrous dysplasia andin c-Fos-overexpressing bone lesions.Fibrousdysplasia is a benign bone disease caused by amutation in the gene for the stimulatory guaninenucleotide-binding protein Gs alpha, leading tohigh cyclic adenosine monophosphate levels.Histologically, fibrous dysplasia is characterizedby the production of fibrous tissue accompaniedby the deposition of ectopic type I collagen andother bone-associated extracellular matrixproteins, as well as by irregular wovenintramembranous bone onto which type Icollagen-containing Sharpey fibers are oftenattached. Fibrous dysplasia is also characterizedby high expression of c-Fos/c-Jun, known targetsfor cyclic adenosine monophosphate signaling. Inthis study, we examined the expression of thebone-related extracellular matrix protein,periostin, and its known receptor, integrin alphav beta 3 (CD51/61), in normal bones as well asin fibrous dysplasia. Immunohistochemistry and", "metadata": {}}
+{"_id": "25238950", "title": "", "text": "FGF-2 enhances intestinal stem cell survival andits expression is induced after radiationinjury.Fibroblast growth factors (FGFs) havemitogenic activity toward a wide variety of cellsof mesenchymal, neuronal, and epithelial originand regulate events in normal embryonicdevelopment, angiogenesis, wound repair, andneoplasia. FGF-2 is expressed in many normaladult tissues and can regulate migration andreplication of intestinal epithelial cells in culture.However, little is known about the effects ofFGF-2 on intestinal epithelial stem cells duringeither normal epithelial renewal or regenerationof a functional epithelium after injury. In thisstudy, we investigated the expression of FGF-2in the mouse small intestine after irradiation anddetermined the effect of exogenous FGF-2 oncrypt stem cell survival after radiation injury.Expression of FGF-2 mRNA and protein began toincrease at 12 h after gamma-irradiation, andpeak levels were observed from 48 to 120 h afterirradiation. At all times after irradiation, the", "metadata": {}}
+{"_id": "25251625", "title": "", "text": "Caspase inhibitors promote alternative cell deathpathways.The use of caspase inhibitors hasrevealed the existence of alternative backup celldeath programs for apoptosis. Thebroad-spectrum caspase inhibitor zVAD-fmkmodulates the three major types of cell death.Addition of zVAD-fmk blocks apoptotic cell death,sensitizes cells to necrotic cell death, and inducesautophagic cell death. Several studies haveshown a crucial role for the kinase RIP1 and theadenosine nucleotide translocator(ANT)-cyclophilin D (CypD) complex in necroticcell death. The underlying mechanism ofzVAD-fmk-mediated sensitization to necrotic celldeath involves the inhibition ofcaspase-8-mediated proteolysis of RIP1 anddisturbance of the ANT-CypD interaction. RIP1 isalso involved in autophagic cell death. Caspaseinhibitors and knockdown studies have revealednegative roles for catalase and caspase-8 inautophagic cell death. The positive role of RIP1and the negative role of caspase-8 in both", "metadata": {}}
+{"_id": "25254425", "title": "", "text": "Nucleosome stability mediated by histonevariants H3.3 and H2A.Z.Nucleosomescontaining the histone variant H3.3 tend to beclustered in vivo in the neighborhood oftranscriptionally active genes and overregulatory elements. It has not been clear,however, whether H3.3-containing nucleosomespossess unique properties that would affecttranscription. We report here that H3.3nucleosomes isolated from vertebrates,regardless of whether they are partnered withH2A or H2A.Z, are unusually sensitive tosalt-dependent disruption, losing H2A/H2B orH2A.Z/H2B dimers. Immunoprecipitation studiesof nucleosome core particles (NCPs) show thatNCPs that contain both H3.3 and H2A.Z are evenless stable than NCPs containing H3.3 and H2A.Intriguingly, NCPs containing H3 and H2A.Z areat least as stable as H3/H2A NCPs. These resultsestablish an hierarchy of stabilities for nativenucleosomes carrying different complements ofvariants, and suggest how H2A.Z could play", "metadata": {}}
+{"_id": "25259746", "title": "", "text": "Increased growth after long-term oral1alpha,25-vitamin D3 in childhood renalosteodystrophy.We evaluated oral 1,25-vitaminD3 for as long as 26 months in six prepubescentchildren with renal osteodystrophy previouslytreated with vitamin D2. Therapy was given at14 to 41 ng per kilogram per day to correcthypocalcemia and reverse bone disease. Serumlevels of 1,25-vitamin D3 were initially reducedat 15 +/- 5 pg per milliliter (mean +/- S.E.M.)and after treatment rose to 54 +/- 13. Serumcalcium rose from 7.5 +/- 1.6 mg per deciliter(mean +/- S.D.) to 9.8 +/- 0.6 after one month(P less than 0.02). Alkaline phosphatase activityfell from 536 +/- 298 to 208 +/- 91 IU per literafter 12 months (P less than 0.05). Serumimmunoreactive parathyroid levels fell from 900+/- 562 microliter eq per milliliter 411 +/- 377.Healing of rickets and subperiosteal erosions wasfound. Remineralization of bone wasdemonstrated by the photon absorption technic.In four patients growth velocity, evaluated for 12", "metadata": {}}
+{"_id": "25261168", "title": "", "text": "Rapid progression of familial amyloidoticpolyneuropathy: a multinational natural historystudy.OBJECTIVES To assess the associationbetween severity of neuropathy and diseasestage, and estimate the rate of neuropathyprogression in a retrospective cross-sectionalanalysis of a multinational population of patientswith familial amyloidotic polyneuropathy (FAP).METHODS We characterize neuropathy severityand rate of progression in available patients withFAP in France, the United States, Portugal, andItaly. Neuropathy Impairment Scores (NIS), timefrom symptom onset to NIS measurement,polyneuropathy disability (PND) scores, FAPdisease stage, and manual grip strength datawere collected. We estimated neuropathyprogression using Loess Fit and Gompertz Fitmodels. RESULTS For the 283 patients studied(mean age, 56.4 years), intercountry genotypicvariation in the transthyretin (TTR) mutation wasobserved, with the majority of patients inPortugal (92%) having early-onset", "metadata": {}}
+{"_id": "25263810", "title": "", "text": "The BRRF1 early gene of Epstein-Barr virusencodes a transcription factor that enhancesinduction of lytic infection by BRLF1.The switchfrom the latent to the lytic form of Epstein-Barrvirus (EBV) infection is mediated by expressionof the viral immediate-early (IE) proteins, BZLF1(Z) and BRLF1 (R). An EBV early protein, BRRF1(Na), is encoded by the opposite strand of theBRLF1 intron, but the function of this nuclearprotein in the viral life cycle is unknown. Here wedemonstrate that Na enhances the R-mediatedinduction of lytic EBV infection in 293 cellslatently infected with a recombinant EBV (R-KO)defective for the expression of both R and Na. Naalso enhances R-induced lytic infections in agastric carcinoma line (AGS) carrying the R-KOvirus, although it has no effect in a Burkittlymphoma line (BL-30) stably infected with thesame mutant virus. We show that Na is atranscription factor that increases the ability of Rto activate Z expression from the R-KO viralgenome in 293 cells and that Na by itself", "metadata": {}}
+{"_id": "25263942", "title": "", "text": "Stromal p16 expression differentiatesendometrial polyp from endometrialhyperplasiaEndometrial polyps are very commonbenign endometrial lesions, but theirpathogenesis is poorly understood, except for afew studies indicating the possibility of benignstromal neoplasm. Although the histopathologicaldiagnosis of endometrial polyp on a surgicalspecimen is straightforward, it is often difficult todifferentiate endometrial polyp from endometrialhyperplasia on a biopsy or curettage specimen.Presently, there is no immunohistochemicalmarker helpful in this differential diagnosis. Inthis study, we examined p16 expression in 35endometrial polyps and 33 cases of endometrialhyperplasia that included 16 simple hyperplasias,14 complex atypical hyperplasias, and 3 complexhyperplasias without atypia. Stromal p16expression differed significantly between the twogroups; it was seen in 31 (89 %) endometrialpolyps, but in only 1 (3 %) endometrialhyperplasia. The percentage of p16-positive", "metadata": {}}
+{"_id": "25293616", "title": "", "text": "A systematic review of mortality inschizophrenia: is the differential mortality gapworsening over time?CONTEXT Despiteimprovements in mental health services in recentdecades, it is unclear whether the risk ofmortality in schizophrenia has changed overtime. OBJECTIVE To explore the distribution ofstandardized mortality ratios (SMRs) for peoplewith schizophrenia. DATA SOURCES Broadsearch terms were used in MEDLINE, PsychINFO,Web of Science, and Google Scholar to identifyall studies that investigated mortality inschizophrenia, published between January 1,1980, and January 31, 2006. References werealso identified from review articles, referencelists, and communication with authors. STUDYSELECTION Population-based studies thatreported primary data on deaths in people withschizophrenia. DATA EXTRACTIONOperationalized criteria were used to extract keystudy features and mortality data. DATASYNTHESIS We examined the distribution of", "metadata": {}}
+{"_id": "25293721", "title": "", "text": "Antioxidant Defenses in the Rat Placenta in LateGestation: Increased Labyrinthine Expression ofSuperoxide Dismutases, Glutathione Peroxidase3, and Uncoupling Protein 21Placental oxidativestress plays a key role in the pathophysiology ofplacenta-related disorders, most notablypreeclampsia (PE) and intrauterine growthrestriction (IUGR). Oxidative stress occurs whenaccumulation of reactive oxygen species (ROS)damages DNA, proteins and lipids, an outcomethat is limited by antioxidant enzymes;mitochondrial uncoupling protein 2 (UCP2) mayalso limit oxidative stress by reducing ROSproduction. Here we characterized placentalantioxidant defenses during normal gestationand following glucocorticoid-induced IUGR.Placentas were collected on Days 16 and 22 ofnormal rat pregnancy (term = Day 23) and atDay 22 after dexamethasone treatment fromDay 13. Expression of several genes encodingantioxidant enzymes (Sod1, Sod2, Sod3, Cat,Gpx3, Txn1, Txnrd1, Txnrd2, and Txnrd3) and", "metadata": {}}
+{"_id": "25298276", "title": "", "text": "Emerging role of bisphosphonates in theclinic--antitumor activity and prevention ofmetastasis to bone.Bisphosphonates arecurrently used for the treatment of bonemetastases, and emerging data suggest thatthey may also have antitumor properties.Preclinical studies have demonstrated thatzoledronic acid can inhibit angiogenesis, invasionand adhesion of tumor cells, and overall tumorprogression, and emerging evidence suggeststhat the use of these agents may impede thedevelopment of skeletal metastases. In a recentclinical study in patients with metastatic bonedisease, basal levels of vascular endothelialgrowth factor, a factor essential forangiogenesis, were significantly reduced inpatients receiving zoledronic acid, suggestingthat zoledronic acid may have clinically relevantantiangiogenic properties. Early clinical data onprevention of bone metastases by theearly-generation bisphosphonate clodronatehave yielded promising results in patients with", "metadata": {}}
+{"_id": "25300426", "title": "", "text": "LIF/STAT3 controls ES cell self-renewal andpluripotency by a Myc-dependentmechanism.Murine ES cells can be maintained asa pluripotent, self-renewing population byLIF/STAT3-dependent signaling. The downstreameffectors of this pathway have not beenpreviously defined. In this report, we identify akey target of the LIF self-renewal pathway byshowing that STAT3 directly regulates theexpression of the Myc transcription factor.Murine ES cells express elevated levels of Mycand following LIF withdrawal, Myc mRNA levelscollapse and Myc protein becomesphosphorylated on threonine 58 (T58), triggeringits GSK3beta dependent degradation. Maintainedexpression of stable Myc (T58A) rendersself-renewal and maintenance of pluripotencyindependent of LIF. By contrast, expression of adominant negative form of Myc antagonizesself-renewal and promotes differentiation.Transcriptional control by STAT3 and suppressionof T58 phosphorylation are crucial for regulation", "metadata": {}}
+{"_id": "25300664", "title": "", "text": "Chronic renal failure accelerates atherogenesis inapolipoprotein E-deficient mice.Cardiovascularmortality is 10 to 20 times increased in patientswith chronic renal failure (CRF). Risk factors foratherosclerosis are abundant in patients withCRF. However, the pathogenesis ofcardiovascular disease in CRF remains to beelucidated. The effect of CRF on the developmentof atherosclerosis in apolipoprotein E-deficientmale mice was examined. Seven-week-old miceunderwent 5/6 nephrectomy (CRF, n = 28),unilateral nephrectomy (UNX, n = 24), or nosurgery (n = 23). Twenty-two weeks later, CRFmice showed increased aortic plaque areafraction (0.266 +/- 0.033 versus 0.045 +/-0.006; P < 0.001), aortic cholesterol content(535 +/- 62 versus 100 +/- 9 nmol/cm(2)intimal surface area; P < 0.001), and aortic rootplaque area (205,296 +/- 22,098 versus143,662 +/- 13,302 micro m(2); P < 0.05) ascompared with no-surgery mice; UNX miceshowed intermediate values. The plaques from", "metadata": {}}
+{"_id": "25301182", "title": "", "text": "Left ventricular function and exercisecapacity.CONTEXT Limited information existsregarding the role of left ventricular function inpredicting exercise capacity and impact on age-and sex-related differences. OBJECTIVES Todetermine the impact of measures of cardiacfunction assessed by echocardiography onexercise capacity and to determine if theseassociations are modified by sex or advancingage. DESIGN Cross-sectional study of patientsundergoing exercise echocardiography withroutine measurements of left ventricular systolicand diastolic function by 2-dimensional andDoppler techniques. Analyses were conducted todetermine the strongest correlates of exercisecapacity and the age and sex interactions ofthese variables with exercise capacity. SETTINGLarge tertiary referral center in Rochester,Minnesota, in 2006. PARTICIPANTS Patientsundergoing exercise echocardiography using theBruce protocol (N = 2867). Patients withechocardiographic evidence of exercise-induced", "metadata": {}}
+{"_id": "25308734", "title": "", "text": "A dynamic population model to investigateeffects of climate on geographic range andseasonality of the tick Ixodes scapularis.Adynamic population model of Ixodes scapularis,the vector of a number of tick-borne zoonoses inNorth America, was developed to simulateeffects of temperature on tick survival andseasonality. Tick development rates weremodelled as temperature-dependent time delays,calculated using mean monthly normaltemperature data from specific meteorologicalstations. Temperature also influencedhost-finding success in the model. Using datafrom stations near endemic populations of I.scapularis, the model reached repeatable, stable,cyclical equilibria with seasonal activity ofdifferent instars being very close to thatobserved in the field. In simulations run usingdata from meteorological stations in central andeastern Canada, the maximum equilibriumnumbers of ticks declined the further north wasthe station location, and simulated populations", "metadata": {}}
+{"_id": "25315295", "title": "", "text": "Inflammatory cytokines in depression:neurobiological mechanisms and therapeuticimplications.Mounting evidence indicates thatinflammatory cytokines contribute to thedevelopment of depression in both medically illand medically healthy individuals. Cytokines areimportant for development and normal brainfunction, and have the ability to influenceneurocircuitry and neurotransmitter systems toproduce behavioral alterations. Acutely,inflammatory cytokine administration oractivation of the innate immune system producesadaptive behavioral responses that promoteconservation of energy to combat infection orrecovery from injury. However, chronic exposureto elevated inflammatory cytokines andpersistent alterations in neurotransmittersystems can lead to neuropsychiatric disordersand depression. Mechanisms of cytokinebehavioral effects involve activation ofinflammatory signaling pathways in the brainthat results in changes in monoamine,", "metadata": {}}
+{"_id": "25319221", "title": "", "text": "Sputum inflammation predicts exacerbationsafter cessation of inhaled corticosteroids inCOPD.INTRODUCTION The GOLD guidelinesadvocate not to institute inhaled corticosteroids(ICS) in patients with mild-to-moderate COPD.However, many patients do use ICS and in somepatients, withdrawal is associated withdeteriorating lung function and increasedexacerbation rates. Unfortunately, physicians donot know in which patients they can stop ICStreatment safely. AIM To identify predictors ofCOPD exacerbations after ICS withdrawal.METHODS During ICS treatment,post-bronchodilator spirometry, bodyplethysmography, and health status assessmentwere performed in 68 COPD patients using ICS.Additionally, sputum cell differentials,supernatant leukotriene B(4), eosinophiliccationic protein, and myeloperoxidase, serumC-reactive protein and soluble intracellularadhesion molecule, and urinary desmosine wereassessed. Sputum was also analysed for mRNA", "metadata": {}}
+{"_id": "25328476", "title": "", "text": "Peroxisome proliferator-activated receptor alphaactivation decreases metastatic potential ofmelanoma cells in vitro via down-regulation ofAkt.PURPOSE Peroxisome proliferator-activatedreceptors (PPAR) regulate lipid and glucosemetabolism but their anticancer properties havebeen recently studied as well. We previouslyreported the antimetastatic activity of thePPARalpha ligand, fenofibrate, against melanomatumors in vivo. Here we investigated possiblemolecular mechanisms of fenofibrate antimetastatic action. EXPERIMENTAL DESIGNMonolayer cultures of mouse (B16F10) andhuman (SkMell88) melanoma cell lines, soft agarassay, and cell migration assay were used in thisstudy. In addition, we analyzed PPARalphaexpression and its transcriptional activity inresponse to fenotibrate by using Western blotsand liciferase-based reporter system. RESULTSFenofibrate inhibited migration of B16F10 andSkMel188 cells in Transwell chambers and colonyformation in soft agar. These effects were", "metadata": {}}
+{"_id": "25344732", "title": "", "text": "PHC3, a component of the hPRC-H complex,associates with E2F6 during G0 and is lost inosteosarcoma tumorsPolyhomeotic-like 3 (PHC3)is a ubiquitously expressed member of thepolycomb gene family and part of the humanpolycomb complex hPRC-H. We found that innormal cells PHC3 associated with both hPRC-Hcomplex components and with the transcriptionfactor E2F6. In differentiating and confluentcells, PHC3 and E2F6 showed nuclearcolocalization in a punctate pattern thatresembled the binding of polycomb bodies toheterochromatin. This punctate pattern was notseen in proliferating cells suggesting that PHC3may be part of an E2F6-polycomb complex thathas been shown to occupy and silence targetpromoters in G0. Previous loss of heterozygosity(LoH) analyses had shown that the regioncontaining PHC3 underwent frequent LoH inprimary human osteosarcoma tumors. When weexamined normal bone and human osteosarcomatumors, we found loss of PHC3 expression in 36", "metadata": {}}
+{"_id": "25353658", "title": "", "text": "Germinal center T follicular helper cell IL-4production is dependent on signaling lymphocyticactivation molecule receptor (CD150).CD4 T cellhelp is critical for the generation andmaintenance of germinal centers (GCs), and Tfollicular helper (T(FH)) cells are the CD4 T cellsubset required for this process. Signalinglymphocytic activation molecule(SLAM)-associated protein (SAP [SH2D1A])expression in CD4 T cells is essential for GCdevelopment. However, SAP-deficient mice haveonly a moderate defect in T(FH) differentiation,as defined by common T(FH) surface markers.CXCR5(+) T(FH) cells are found within the GC,as well as along the boundary regions of T/B cellzones. In this study, we show that GC-associatedT follicular helper (GC T(FH)) cells can beidentified by their coexpression of CXCR5 and theGL7 epitope, allowing for phenotypic andfunctional analysis of T(FH) and GC T(FH)populations. GC T(FH) cells are a functionallydiscrete subset of further polarized T(FH) cells,", "metadata": {}}
+{"_id": "25355575", "title": "", "text": "High cardiovascular mortality in Russia cannot beexplained by the classical risk factors. TheArkhangelsk study 2000Since the beginning ofthe 1990s the public health situation in Russiahas been characterized by an extremely highmortality and a significant reduction in lifeexpectancy. Cardiovascular diseases remainedthe major cause of death. Only a few largepopulation studies were conducted in Russiaduring this period. A total of 1968 men and 1737women aged 18–75 years participated in ahealth survey in Arkhangelsk, Russia, over theperiod 1999–2000. Investigation includedassessment of classic cardiovascular risk factors(family history, smoking, blood pressure, andblood lipids) along with general health variables.The paper presents sex specific data on riskfactors for coronary heart disease. Though thecardiovascular mortality is high in Russia, thecalculated risk for coronary heart disease (theFramingham risk score and the Norwegian riskscore) was lower in all age groups of men and", "metadata": {}}
+{"_id": "25365522", "title": "", "text": "Wnt7a/Fzd7 Signalling Directly Activates theAkt/mTOR Anabolic Growth Pathway in SkeletalMuscleWnt7a signals through its receptor Fzd7 toactivate the planar-cell-polarity pathway anddrive the symmetric expansion of satellite stemcells resulting in enhanced repair of skeletalmuscle. In differentiated myofibres, we observedthat Wnt7a binding to Fzd7 directly activates theAkt/mTOR growth pathway, thereby inducingmyofibre hypertrophy. Notably, the Fzd7receptor complex was associated with Gα(s) andPI(3)K and these components were required forWnt7a to activate the Akt/mTOR growth pathwayin myotubes. Wnt7a-Fzd7 activation of thispathway was completely independent ofIGF-receptor activation. Together, theseexperiments demonstrate that Wnt7a-Fzd7activates distinct pathways at differentdevelopmental stages during myogenic lineageprogression, and identify a non-canonicalanabolic signalling pathway for Wnt7a and itsreceptor Fzd7 in skeletal muscle.", "metadata": {}}
+{"_id": "25373397", "title": "", "text": "Four newly located pseudouridylate residues inEscherichia coli 23S ribosomal RNA are all at thepeptidyltransferase center: analysis by theapplication of a new sequencing technique.A newtechnique has been developed for the facilelocation of pseudouridylate (psi) residues in anyRNA molecule. The method uses two knownmodification procedures which in combinationuniquely identify U residues which have beenconverted into psi. The first procedure involvesreaction of all U-like and G-like residues with N-cyclohexyl-N'-beta-(4-methylmorpholinium)ethylcarbodiimide p-tosylate (CMC), followed byalkaline removal of all CMC groups except thoselinked to the N3 of psi. This stops reversetranscription, resulting in a gel band whichidentifies the U residue. The second procedure isuridine-specific hydrazinolysis which cleaves theRNA chain at all U residues and produces a gelband upon reverse transcription. psi residues,being resistant to hydrazinolysis, are not cleavedand do not stop reverse transcription. This leads", "metadata": {}}
+{"_id": "25388309", "title": "", "text": "Pharmacological characterization of 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (JNJ-42041935), apotent and selective hypoxia-inducible factorprolyl hydroxylase inhibitor.Thehypoxia-inducible factor (HIF) prolyl hydroxylase(PHD) enzymes represent novel targets for thetreatment of anemia, ulcerative colitis, andischemic and metabolic disease inter alia. Wehave identified a novel small-molecule inhibitorof PHD, 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid(JNJ-42041935), through structure-based drugdesign methods. The pharmacology ofJNJ-42041935 was investigated in enzyme,cellular, and whole-animal systems and wascompared with other compounds described in theliterature as PHD inhibitors. JNJ-42041935, wasa potent (pK(I) = 7.3-7.9), 2-oxoglutaratecompetitive, reversible, and selective inhibitor ofPHD enzymes. In addition, JNJ-42041935 wasused to compare the effect of selective inhibition", "metadata": {}}
+{"_id": "25404036", "title": "", "text": "Three-Dimensional Modeling and QuantitativeAnalysis of Gap Junction Distributions in CardiacTissueGap junctions play a fundamental role inintercellular communication in cardiac tissue.Various types of heart disease includinghypertrophy and ischemia are associated withalterations of the spatial arrangement of gapjunctions. Previous studies appliedtwo-dimensional optical and electron-microscopyto visualize gap junction arrangements. Innormal cardiomyocytes, gap junctions wereprimarily found at cell ends, but can be foundalso in more central regions. In this study, weextended these approaches towardthree-dimensional reconstruction of gap junctiondistributions based on high-resolution scanningconfocal microscopy and image processing. Wedeveloped methods for quantitativecharacterization of gap junction distributionsbased on analysis of intensity profiles along theprincipal axes of myocytes. The analysescharacterized gap junction polarization at cell", "metadata": {}}
+{"_id": "25413327", "title": "", "text": "Clonally derived human embryonic stem cell linesmaintain pluripotency and proliferative potentialfor prolonged periods of culture.Embryonic stem(ES) cell lines derived from human blastocystshave the developmental potential to formderivatives of all three embryonic germ layerseven after prolonged culture. Here we describethe clonal derivation of two human ES cell lines,H9.1 and H9.2. At the time of the clonalderivation of the H9.1 and H9.2 ES cell lines, theparental ES cell line, H9, had already beencontinuously cultured for 6 months. After anadditional 8 months of culture, H9.1 and H9.2 EScell lines continued to: (1) actively proliferate,(2) express high levels of telomerase, and (3)retain normal karyotypes. Telomere lengths,while somewhat variable, were maintainedbetween 8 and 12 kb in high-passage H9.1 andH9.2 cells. High-passage H9.1 and H9.2 cellsboth formed teratomas in SCID-beige mice thatincluded differentiated derivatives of all threeembryonic germ layers. These results", "metadata": {}}
+{"_id": "25416944", "title": "", "text": "Autosomal dominant lateral temporal epilepsy:two families with novel mutations in the LGI1gene.PURPOSE Mutations in the leucine rich,glioma inactivated gene (LGI1) were recentlydescribed in a small number of families withautosomal dominant lateral temporal epilepsy(ADLTE). ADLTE is characterized by partialseizures with symptoms suggestive of a lateraltemporal onset, including frequent auditory aura.Here we report the results of clinical and geneticanalyses of two newly identified families withADTLE. METHODS We identified two familieswhose seizure semiology was suggestive ofADLTE. Evaluation included a detailed historyand neurologic examination, as well as collectionof DNA. The coding sequence of the LGI1 genefrom affected subjects from both families wasanalyzed for evidence of mutation. RESULTSEach patient had a history of partial seizures,often with secondary generalization earlier in thecourse. Auditory aura was reported byapproximately two thirds of affected patients in", "metadata": {}}
+{"_id": "25419778", "title": "", "text": "Identification of Senescent Cells in the BoneMicroenvironment.Cellular senescence is afundamental mechanism by which cells remainmetabolically active yet cease dividing andundergo distinct phenotypic alterations, includingupregulation of p16Ink4a , profound secretomechanges, telomere shortening, anddecondensation of pericentromeric satellite DNA.Because senescent cells accumulate in multipletissues with aging, these cells and thedysfunctional factors they secrete, termed thesenescence-associated secretory phenotype(SASP), are increasingly recognized as promisingtherapeutic targets to prevent age-relateddegenerative pathologies, including osteoporosis.However, the cell type(s) within the bonemicroenvironment that undergoes senescencewith aging in vivo has remained poorlyunderstood, largely because previous studieshave focused on senescence in cultured cells.Thus in young (age 6 months) and old (age 24months) mice, we measured senescence and", "metadata": {}}
+{"_id": "25420421", "title": "", "text": "Changes in white blood cells and platelets inchildren with falciparum malaria: relationship todisease outcome.Little is known about thechanges in white blood cells and platelets inchildren with falciparum malaria in endemicareas. We measured the white cell count (WCC)and platelets of 230 healthy children from thecommunity, 1369 children admitted to hospitalwith symptomatic malaria, and 1461 childrenwith other medical conditions. Children withmalaria had a higher WCC compared withcommunity controls, and leucocytosis wasstrongly associated with younger age, deepbreathing, severe anaemia, thrombocytopeniaand death. The WCC was not associated with apositive blood culture. In children with malaria,high lymphocyte and low monocyte counts wereindependently associated with mortality. Aplatelet count of less than 150 x 109/l was foundin 56.7% of children with malaria, and wasassociated with age, prostration and parasitedensity, but not with bleeding problems or", "metadata": {}}
+{"_id": "25435456", "title": "", "text": "Microenvironmental regulation ofbiomacromolecular therapiesThere is currentlygreat interest in molecular therapies to treatvarious diseases, and this has promptedextensive efforts to achieve target-specific andcontrolled delivery of bioactive macromolecules(for example, proteins, antibodies, DNA andsmall interfering RNA) through the design ofsmart drug carriers. By contrast, the influence ofthe microenvironment in which the target cellresides and the effect it might have on thesuccess of biomacromolecular therapies has beenunder-appreciated. The extracellular matrix(ECM) component of the cellular niche may beparticularly important, as many diseases andinjury disrupt the normal ECM architecture, thecell adhesion to ECM, and the subsequent cellularactivities. This Review will discuss theimportance of the ECM and the ECM–cellinteractions on the cell response to bioactivemacromolecules, and suggest how thisinformation could lead to new criteria for the", "metadata": {}}
+{"_id": "25439264", "title": "", "text": "Homocysteine Induces Trophoblast Cell Deathwith Apoptotic Features1AbstractHyperhomocysteinemia has been suggested as apossible risk factor in women suffering fromhabitual abortions, placental abruption orinfarcts, preeclampsia, and/or intrauterinegrowth retardation. However, little is knownabout the pathogenic mechanisms underlying theaction of homocysteine. The present studyinvestigated the in vitro ability of homocysteineto affect trophoblast gonadotropin secretion andto induce cell death. In primary humantrophoblast cells, homocysteine treatment (20μmol/L) resulted in cellular flattening andenlargement, extension of pseudopodia, andcellular vacuolization. Cellular detachment,apoptosis, and necrosis were favored. With insitu nick end labeling, we investigated DNAdegradation, and we used M30 CytoDEATH toselectively stain the cytoplasm of apoptotic cells.Cytochrome c release from mitochondria to thecytosol and DNA cleavage in agarose gel have", "metadata": {}}
+{"_id": "25440070", "title": "", "text": "Intrahippocampal administration of an androgenreceptor antagonist, flutamide, can increaseanxiety-like behavior in intact and DHT-replacedmale rats.Testosterone (T) and its5alpha-reduced metabolite, dihydrotestosterone(DHT), can decrease anxiety-like behavior;however, the mechanisms underlying theseeffects have not been established. First, wehypothesized that if T reduces anxiety-likebehavior through actions of its 5alpha-reducedmetabolite, DHT, then gonadectomy (GDX)would increase anxiety-like behavior, an effectwhich would be reversed by systemicadministration of DHT. Second, we hypothesizedthat if T and DHT reduce anxiety-like behavior inpart through actions at intracellular androgenreceptors in the hippocampus, thenadministration of an androgen receptorantagonist, flutamide, directly to thehippocampus should increase anxiety-likebehavior of intact and DHT-replaced, but notGDX, male rats. Inserts that were empty or", "metadata": {}}
+{"_id": "25451374", "title": "", "text": "Cardiovascular risk and events in 17 low-,middle-, and high-incomecountries.BACKGROUND More than 80% ofdeaths from cardiovascular disease areestimated to occur in low-income andmiddle-income countries, but the reasons areunknown. METHODS We enrolled 156,424persons from 628 urban and rural communitiesin 17 countries (3 high-income, 10middle-income, and 4 low-income countries) andassessed their cardiovascular risk using theINTERHEART Risk Score, a validated score forquantifying risk-factor burden without the use oflaboratory testing (with higher scores indicatinggreater risk-factor burden). Participants werefollowed for incident cardiovascular disease anddeath for a mean of 4.1 years. RESULTS Themean INTERHEART Risk Score was highest inhigh-income countries, intermediate inmiddle-income countries, and lowest inlow-income countries (P<0.001). However, therates of major cardiovascular events (death from", "metadata": {}}
+{"_id": "25452937", "title": "", "text": "Increased density of tumor-associatedmacrophages is associated with decreasedsurvival in advanced thyroid cancer.Thyroidcancers are infiltrated with tumor-associatedmacrophages (TAMs), yet their role in cancerprogression is not known. The objectives of thisstudy were to characterize the density of TAMs inwell-differentiated (WDTC), poorly differentiated(PDTC), and anaplastic thyroid cancers (ATC)and to correlate TAM density withclinicopathologic parameters.Immunohistochemistry was performed on tissuemicroarray sections from WDTC (n=33), PDTC(n=37), and ATC (n=20) usingmacrophage-specific markers. Electronic medicalrecords were used to gather clinical andpathologic data. Follow-up information of PDTCpatients was available for 0-12 years. In total, 9out of 33 WDTC (27%), 20 out of 37 PDTC(54%), and 19 out of 20 ATC (95%) had anincreased density of CD68(+) TAMs (> or = 10per 0.28 mm(2); WDTC versus PDTC, P=0.03;", "metadata": {}}
+{"_id": "25453683", "title": "", "text": "Blockade of Tim-1 and Tim-4 EnhancesAtherosclerosis in Low-Density LipoproteinReceptor-Deficient Mice.OBJECTIVE T cellimmunoglobulin and mucin domain (Tim)proteins are expressed by numerous immunecells, recognize phosphatidylserine on apoptoticcells, and function as costimulators orcoinhibitors. Tim-1 is expressed by activated Tcells but is also found on dendritic cells and Bcells. Tim-4, present on macrophages anddendritic cells, plays a critical role in apoptoticcell clearance, regulates the number ofphosphatidylserine-expressing activated T cells,and is genetically associated with lowlow-density lipoprotein and triglyceride levels.Because these functions of Tim-1 and Tim-4could affect atherosclerosis, their modulation haspotential therapeutic value in cardiovasculardisease. APPROACH AND RESULTS ldlr(-/-) micewere fed a high-fat diet for 4 weeks while beingtreated with control (rat immunoglobulin G1) oranti-Tim-1 (3D10) or -Tim-4 (21H12)", "metadata": {}}
+{"_id": "25462689", "title": "", "text": "Genetic and physical analysis of double-strandbreak repair and recombination inSaccharomyces cerevisiae.We have investigatedHO endonuclease-induced double-strand break(DSB) recombination and repair in a LACZduplication plasmid in yeast. A 117-bp MATafragment, embedded in one copy of LACZ,served as a site for initiation of a DSB when HOendonuclease was expressed. The DSB could berepaired using wild-type sequences located on asecond, promoterless, copy of LACZ on the sameplasmid. In contrast to normal mating-typeswitching, crossing-over associated with geneconversion occurred at least 50% of the time.The proportion of conversion eventsaccompanied by exchange was greater when thetwo copies of LACZ were in direct orientation(80%), than when inverted (50%). In addition,the fraction of plasmids lost was significantlygreater in the inverted orientation. The kineticsof appearance of intermediates and finalproducts were also monitored. The repair of the", "metadata": {}}
+{"_id": "25475802", "title": "", "text": "Nitroxergic nerves mediate vagally inducedrelaxation in the isolated stomach of the guineapig.Here we show that the relaxation induced bystimulation of the vagus nerve in the presence ofcholinergic (muscarinic) and adrenergic blockadein the isolated stomach of the guinea pig ismediated by nitric oxide (NO). This issubstantiated by inhibition of vagal relaxation byNG-monomethyl-L-arginine, an inhibitor of NOsynthesis. The effect ofNG-monomethyl-L-arginine was partiallyreversed by coincubation with L-arginine but notwith D-arginine. NO activates soluble guanylatecyclase, and relaxation of the stomach inducedby vagal stimulation was prevented by aninhibitor of soluble guanylate cyclase, methyleneblue, further supporting our conclusions. Therelaxant effect of vagal stimulation was alsoablated by hexamethonium, an inhibitor ofganglionic nicotinic receptors, thereby showingthat ganglionic transmission did not rely on NO,through its release from preganglionic neurons.", "metadata": {}}
+{"_id": "25479072", "title": "", "text": "Efficient T cell activation requires an optimaldwell-time of interaction between the TCR andthe pMHC complexCytotoxic T cell (CTL)activation by antigen requires the specificdetection of peptide–major histo-compatibilityclass I (pMHC) molecules on the target-cellsurface by the T cell receptor (TCR). Weexamined the effect of mutations in theantigen-binding site of a Kb-restricted TCR on Tcell activation, antigen binding and dissociationfrom antigen. These parameters were alsoexamined for variants derived from aKd-restricted peptide that was recognized by aCTL clone. Using these two independentsystems, we show that T cell activation can beimpaired by mutations that either decrease orincrease the binding half-life of the TCR-pMHCinteraction. Our data indicate that efficient T cellactivation occurs within an optimal dwell-timerange of TCR-pMHC interaction. This restricteddwell-time range is consistent with the exclusionof either extremely low or high affinity T cells", "metadata": {}}
+{"_id": "25483562", "title": "", "text": "Crystal structure of human insulin-regulatedaminopeptidase with specificity for cyclicpeptides.Insulin-regulated aminopeptidase (IRAPor oxytocinase) is a membrane-boundzinc-metallopeptidase that cleaves neuroactivepeptides in the brain and produces memoryenhancing effects when inhibited. We havedetermined the crystal structure of human IRAPrevealing a closed, four domain arrangementwith a large, mostly buried cavity abutting theactive site. The structure reveals that the GAMENexopeptidase loop adopts a very differentconformation from other aminopeptidases, thusexplaining IRAP's unique specificity for cyclicpeptides such as oxytocin and vasopressin.Computational docking of a series ofIRAP-specific cognitive enhancers into the crystalstructure provides a molecular basis for theirstructure-activity relationships and demonstratesthat the structure will be a powerful tool in thedevelopment of new classes of cognitiveenhancers for treating a variety of memory", "metadata": {}}
+{"_id": "25488034", "title": "", "text": "Glutathione and glutathione-dependent enzymesrepresent a co-ordinately regulated defenceagainst oxidative stress.Increases in theintracellular levels of reactive oxygen species(ROS), frequently referred to as oxidative stress,represents a potentially toxic insult which if notcounteracted will lead to membrane dysfunction,DNA damage and inactivation of proteins.Chronic oxidative stress has numerouspathological consequences including cancer,arthritis and neurodegenerative disease.Glutathione-associated metabolism is a majormechanism for cellular protection against agentswhich generate oxidative stress. It is becomingincreasingly apparent that the glutathionetripeptide is central to a complex multifaceteddetoxification system, where there is substantialinter-dependence between separate componentmembers. Glutathione participates indetoxification at several different levels, and mayscavenge free radicals, reduce peroxides or beconjugated with electrophilic compounds. Thus,", "metadata": {}}
+{"_id": "25493293", "title": "", "text": "Does socioeconomic status matter? Ameta-analysis on parent training effectivenessfor disruptive child behavior.Disadvantagedfamily socioeconomic status (SES) is oftenassumed to diminish parent training programeffectiveness. In examining effects of SES,influences of initial problem severity have beenlargely ignored. In the present meta-analysis, weexamined (a) whether there is a differentialinfluence of SES on parent training effectivenessat immediate posttreatment and at 1-yearfollow-up-controlling for levels of initial problemseverity--and (b) whether SES interacts withinitial problem severity in its effect on programeffectiveness. Seventy-five studies on parenttraining program effectiveness to reducedisruptive child behavior were included. Separateanalyses were conducted for immediateposttreatment and approximately 1-yearfollow-up assessments. Immediatelyposttreatment, disadvantaged samples benefitedless from parent training, but only when they", "metadata": {}}
+{"_id": "25499612", "title": "", "text": "Infectiousness of malaria-endemic humanpopulations to vectors.Despite its key role indetermining the stability and intensity of malariatransmission, the infectiousness of humanpopulations to mosquitoes has rarely beenestimated. Field-based analyses of malariatransmission have frequently relied on theprevalence of asexual parasites or gametocytesas proxies for infectiousness. We now summarizeempirical data on human infectiousness fromAfrica and Papua New Guinea. Over a wide rangeof transmission intensities there is littlerelationship between the infectiousness ofhuman populations to vector mosquitoes andmosquito-to-human transmission intensity. Wecompare these data with the predictions of astochastic simulation model of Plasmodiumfalciparum epidemiology. This model predictedlittle variation in the infectiousness of the humanpopulation for entomologic inoculation rates(EIRs) greater than approximately 10 infectiousbites per year, demonstrating that the lack of", "metadata": {}}
+{"_id": "25504006", "title": "", "text": "Molecular analysis of circulating tumourcells—biology and biomarkersGrowing evidencefor intratumour heterogeneity informs us thatsingle-site biopsies fall short of revealing thecomplete genomic landscape of a tumour. Withan expanding repertoire of targeted agentsentering the clinic, screening tumours forgenomic aberrations is increasingly important, asis interrogating the tumours for resistancemechanisms upon disease progression. Multiplebiopsies separated spatially and temporally areimpractical, uncomfortable for the patient andnot without risk. Here, we describe howcirculating tumour cells (CTCs), captured from aminimally invasive blood test—and readilyamenable to serial sampling—have the potentialto inform intratumour heterogeneity and tumourevolution, although it remains to be determinedhow useful this will be in the clinic. Technologiesfor detecting and isolating CTCs include thevalidated CellSearch® system, but othertechnologies are gaining prominence. We also", "metadata": {}}
+{"_id": "25510546", "title": "", "text": "Endoplasmic reticulum stress contributes to betacell apoptosis in type 2 diabetesIncreased lipidsupply causes beta cell death, which maycontribute to reduced beta cell mass in type 2diabetes. We investigated whether endoplasmicreticulum (ER) stress is necessary forlipid-induced apoptosis in beta cells and alsowhether ER stress is present in islets of ananimal model of diabetes and of humans withtype 2 diabetes. Expression of genes involved inER stress was evaluated in insulin-secretingMIN6 cells exposed to elevated lipids, in isletsisolated from db/db mice and in pancreassections of humans with type 2 diabetes.Overproduction of the ER chaperone heat shock70 kDa protein 5 (HSPA5, previously known asimmunoglobulin heavy chain binding protein[BIP]) was performed to assess whetherattenuation of ER stress affected lipid-inducedapoptosis. We demonstrated that thepro-apoptotic fatty acid palmitate triggers acomprehensive ER stress response in MIN6 cells,", "metadata": {}}
+{"_id": "25513319", "title": "", "text": "Coactivator SRC-2-dependent metabolicreprogramming mediates prostate cancersurvival and metastasis.Metabolic pathwayreprogramming is a hallmark of cancer cellgrowth and survival and supports the anabolicand energetic demands of these rapidly dividingcells. The underlying regulators of the tumormetabolic program are not completelyunderstood; however, these factors havepotential as cancer therapy targets. Here, wedetermined that upregulation of the oncogenictranscriptional coregulator steroid receptorcoactivator 2 (SRC-2), also known as NCOA2,drives glutamine-dependent de novo lipogenesis,which supports tumor cell survival and eventualmetastasis. SRC-2 was highly elevated in avariety of tumors, especially in prostate cancer,in which SRC-2 was amplified and overexpressedin 37% of the metastatic tumors evaluated. Inprostate cancer cells, SRC-2 stimulated reductivecarboxylation of α-ketoglutarate to generatecitrate via retrograde TCA cycling, promoting", "metadata": {}}
+{"_id": "25515662", "title": "", "text": "In vitro substrate specificity of protein tyrosinekinasesSynthetic peptides such as P60stcautophosphorylation site peptides andangiotensin are indiscriminately phosphorylatedby protein tyrosine kinases. The observation hasled to the general belief that protein tyrosinekinases are highly promiscuous, displayinglittlein vitro site specificity. In recent years,evidence has been accumulating to indicate thatsuch a belief requires close examination.Synthetic peptides showing high substrateactivity for specific groups of protein tyrosinekinases have been obtained. Systematicmodification of certain substrate peptidessuggests that kinase substrate determinantsreside with specific amino acid residues proximalto the target tyrosine. A number of proteinkinases have been shown to be regulated bytyrosine phosphorylation at specific sites byhighly specific protein tyrosine kinases. Theseand other selected biochemical studies thatcontribute to the evolving view ofin vitro", "metadata": {}}
+{"_id": "25515907", "title": "", "text": "Relative effectiveness of clinic and home bloodpressure monitoring compared with ambulatoryblood pressure monitoring in diagnosis ofhypertension: systematic reviewOBJECTIVE Todetermine the relative accuracy of clinicmeasurements and home blood pressuremonitoring compared with ambulatory bloodpressure monitoring as a reference standard forthe diagnosis of hypertension. DESIGNSystematic review with meta-analysis withhierarchical summary receiver operatingcharacteristic models. Methodological quality wasappraised, including evidence of validation ofblood pressure measurement equipment. DATASOURCES Medline (from 1966), Embase (from1980), Cochrane Database of SystematicReviews, DARE, Medion, ARIF, and TRIP up toMay 2010. Eligibility criteria for selecting studiesEligible studies examined diagnosis ofhypertension in adults of all ages using homeand/or clinic blood pressure measurementcompared with those made using ambulatory", "metadata": {}}
+{"_id": "25516011", "title": "", "text": "Purification and characterization of mousehematopoietic stem cells.Mouse bone marrowhematopoietic stem cells were isolated with theuse of a variety of phenotypic markers. Thesecells can proliferate and differentiate withapproximately unit efficiency intomyelomonocytic cells, B cells, or T cells. Thirty ofthese cells are sufficient to save 50 percent oflethally irradiated mice, and to reconstitute allblood cell types in the survivors.", "metadata": {}}
+{"_id": "25519138", "title": "", "text": "Regulation of arabinose and xylose metabolismin Escherichia coli.Bacteria such as Escherichiacoli will often consume one sugar at a time whenfed multiple sugars, in a process known ascarbon catabolite repression. The classic exampleinvolves glucose and lactose, where E. coli willfirst consume glucose, and only when it hasconsumed all of the glucose will it begin toconsume lactose. In addition to that of lactose,glucose also represses the consumption of manyother sugars, including arabinose and xylose. Inthis work, we characterized a second hierarchy inE. coli, that between arabinose and xylose. Weshow that, when grown in a mixture of the twopentoses, E. coli will consume arabinose before itconsumes xylose. Consistent with a mechanisminvolving catabolite repression, the expression ofthe xylose metabolic genes is repressed in thepresence of arabinose. We found that thisrepression is AraC dependent and involves amechanism where arabinose-bound AraC bindsto the xylose promoters and represses gene", "metadata": {}}
+{"_id": "25523969", "title": "", "text": "MicroRNA expression profiling of humanmetastatic cancers identifies cancer genetargets.Small non-coding microRNAs (miRNAs)contribute to cancer development andprogression, and are differentially expressed innormal tissues and cancers. However, thespecific role of miRNAs in the metastatic processis still unknown. To seek a specific miRNAexpression signature characterizing themetastatic phenotype of solid tumours, weperformed a miRNA microarray analysis on 43paired primary tumours (ten colon, ten bladder,13 breast, and ten lung cancers) and one of theirrelated metastatic lymph nodes. We identified ametastatic cancer miRNA signature comprising15 overexpressed and 17 underexpressedmiRNAs. Our results were confirmed by qRT-PCRanalysis. Among the miRNAs identified, somehave a well-characterized association with cancerprogression, eg miR-10b, miR-21, miR-30a,miR-30e, miR-125b, miR-141, miR-200b,miR-200c, and miR-205. To further support our", "metadata": {}}
+{"_id": "25536577", "title": "", "text": "Circos: an information aesthetic for comparativegenomics.We created a visualization tool calledCircos to facilitate the identification and analysisof similarities and differences arising fromcomparisons of genomes. Our tool is effective indisplaying variation in genome structure and,generally, any other kind of positionalrelationships between genomic intervals. Suchdata are routinely produced by sequencealignments, hybridization arrays, genomemapping, and genotyping studies. Circos uses acircular ideogram layout to facilitate the displayof relationships between pairs of positions by theuse of ribbons, which encode the position, size,and orientation of related genomic elements.Circos is capable of displaying data as scatter,line, and histogram plots, heat maps, tiles,connectors, and text. Bitmap or vector imagescan be created from GFF-style data inputs andhierarchical configuration files, which can beeasily generated by automated tools, makingCircos suitable for rapid deployment in data", "metadata": {}}
+{"_id": "25543207", "title": "", "text": "Pharmacokinetic, pharmacodynamic and clinicalprofile of novel antiplatelet drugs targetingvascular diseases.Platelet inhibitors are themainstay treatment for patients with vasculardiseases. The current 'gold standard' antiplateletagent clopidogrel has several pharmacologicaland clinical limitations that have prompted thesearch for more effective platelet antagonists.The candidates include various blockers of thepurinergic P2Y12 receptor such as prasugrel, anoral irreversible thienopyridine; two adenosinetriphosphate analogues that bind reversibly tothe P2Y12 receptor: ticagrelor (oral) andcangrelor (intravenous); elinogrel, adirect-acting reversible P2Y12 receptor inhibitor(the only antiplatelet compound that can beadministered both intravenously and orally); BX667, an orally active and reversiblesmall-molecule P2Y12 receptor antagonist; SCH530348, SCH 205831, SCH 602539 and E5555,highly selective and orally active antagonists onthe protease-activated receptor 1. A number of", "metadata": {}}
+{"_id": "25550665", "title": "", "text": "BLM is required for faithful chromosomesegregation and its localization defines a class ofultrafine anaphase bridges.Mutations in BLMcause Bloom's syndrome, a disorder associatedwith cancer predisposition and chromosomalinstability. We investigated whether BLM plays arole in ensuring the faithful chromosomesegregation in human cells. We show thatBLM-defective cells display a higher frequency ofanaphase bridges and lagging chromatin than doisogenic corrected derivatives that eptopicallyexpress the BLM protein. In normal cellsundergoing mitosis, BLM protein localizes toanaphase bridges, where it colocalizes with itscellular partners, topoisomerase IIIalpha andhRMI1 (BLAP75). Using BLM staining as amarker, we have identified a class of ultrafineDNA bridges in anaphase that are surprisinglyprevalent in the anaphase population of normalhuman cells. These so-called BLM-DNA bridges,which also stain for the PICH protein, frequentlylink centromeric loci, and are present at an", "metadata": {}}
+{"_id": "25562234", "title": "", "text": "Association Between High Serum Soluble Corinand Hypertension: A Cross-Sectional Study in aGeneral Population of China.BACKGROUND Corinhas been suggested to be associated withhypertension by cell- and animal-based studies.However, the association still lackspopulation-based evidence which criticallypromotes translation from basic research toclinical and preventive practice. Here, we aimedto explore the association in a general populationof China. METHODS From January to May 2010,we conducted a cross-sectional study in 2,498participants aged above 30 years, residing inGusu district of Suzhou. Serum soluble corin andblood pressure were measured. RESULTSHypertensive participants had a higher level ofserum corin than nonhypertensive participants(median (interquartile range): 1,836.83(1,497.85-2,327.87) pg/ml vs. 1,579.14(1,322.18-1,956.82) pg/ml, P < 0.001). Higherserum corin was positively associated withprevalent hypertension (odds ratio (OR) = 2.01,", "metadata": {}}
+{"_id": "25571386", "title": "", "text": "Shared and distinct genetic variants in type 1diabetes and celiac disease.BACKGROUND Twoinflammatory disorders, type 1 diabetes andceliac disease, cosegregate in populations,suggesting a common genetic origin. Since bothdiseases are associated with the HLA class IIgenes on chromosome 6p21, we tested whethernon-HLA loci are shared. METHODS Weevaluated the association between type 1diabetes and eight loci related to the risk ofceliac disease by genotyping and statisticalanalyses of DNA samples from 8064 patientswith type 1 diabetes, 9339 control subjects, and2828 families providing 3064 parent-child trios(consisting of an affected child and both biologicparents). We also investigated 18 loci associatedwith type 1 diabetes in 2560 patients with celiacdisease and 9339 control subjects. RESULTSThree celiac disease loci--RGS1 on chromosome1q31, IL18RAP on chromosome 2q12, andTAGAP on chromosome 6q25--were associatedwith type 1 diabetes (P<1.00x10(-4)). The 32-bp", "metadata": {}}
+{"_id": "25576204", "title": "", "text": "Promotion of tumorigenesis by heterozygousdisruption of the beclin 1 autophagygene.Malignant cells often display defects inautophagy, an evolutionarily conserved pathwayfor degrading long-lived proteins and cytoplasmicorganelles. However, as yet, there is no geneticevidence for a role of autophagy genes in tumorsuppression. The beclin 1 autophagy gene ismonoallelically deleted in 40-75% of cases ofhuman sporadic breast, ovarian, and prostatecancer. Therefore, we used a targeted mutantmouse model to test the hypothesis thatmonoallelic deletion of beclin 1 promotestumorigenesis. Here we show that heterozygousdisruption of beclin 1 increases the frequency ofspontaneous malignancies and accelerates thedevelopment of hepatitis B virus-inducedpremalignant lesions. Molecular analyses oftumors in beclin 1 heterozygous mice show thatthe remaining wild-type allele is neither mutatednor silenced. Furthermore, beclin 1 heterozygousdisruption results in increased cellular", "metadata": {}}
+{"_id": "25589047", "title": "", "text": "Treatment-related mortality with bevacizumab incancer patients: a meta-analysis.CONTEXT Fataladverse events (FAEs) have been reported incancer patients treated with the widely usedangiogenesis inhibitor bevacizumab incombination with chemotherapy. Currently, therole of bevacizumab in treatment-relatedmortality is not clear. OBJECTIVE To perform asystematic review and meta-analysis ofpublished randomized controlled trials (RCTs) todetermine the overall risk of FAEs associatedwith bevacizumab. DATA SOURCES PubMed,EMBASE, and Web of Science databases as wellas abstracts presented at American Society ofClinical Oncology conferences from January 1966to October 2010 were searched to identifyrelevant studies. STUDY SELECTION AND DATAEXTRACTION Eligible studies includedprospective RCTs in which bevacizumab incombination with chemotherapy or biologicaltherapy was compared with chemotherapy orbiological therapy alone. Summary incidence", "metadata": {}}
+{"_id": "25597580", "title": "", "text": "Quiescent and active hippocampal neural stemcells with distinct morphologies respondselectively to physiological and pathologicalstimuli and aging.New neurons are generated inthe adult hippocampus throughout life by neuralstem/progenitor cells (NSCs), and neurogenesisis a plastic process responsive to externalstimuli. We show that canonical Notch signalingthrough RBP-J is required for hippocampalneurogenesis. Notch signaling distinguishesmorphologically distinct Sox2(+) NSCs, andwithin these pools subpopulations can shuttlebetween mitotically active or quiescent. Radialand horizontal NSCs respond selectively toneurogenic stimuli. Physical exercise activatesthe quiescent radial population whereas epilepticseizures induce expansion of the horizontal NSCpool. Surprisingly, reduced neurogenesiscorrelates with a loss of active horizontal NSCs inaged mice rather than a total loss of stem cells,and the transition to a quiescent state isreversible to rejuvenate neurogenesis in the", "metadata": {}}
+{"_id": "25599283", "title": "", "text": "Low serum vitamin D is associated with high riskof diabetes in Korean adults.Vitamin D may playa role in glucose metabolism. A low vitamin Dlevel has been associated with increased risk ofdiabetes mellitus, but the association has notbeen confirmed in Asians. Our objective was toexamine the association of serum25-hydroxyvitamin D [25(OH)D] levels withinsulin resistance and diabetes mellitus in Koreanadults based on a large population-based survey.Cross-sectional analyses were carried out on5787 Korean adults (2453 men and 3334women) who were 20 y or older and participatedin the Fourth Korea NHANES conducted in 2008.Diabetes mellitus was defined as fasting plasmaglucose ≥7 mmol/L or current use of oralhypoglycemic agents or insulin. Insulinresistance was estimated by homeostatic modelassessment for insulin resistance (HOMA-IR) andquantitative insulin sensitivity check index(QUICKI). Compared to individuals with asufficient serum 25(OH)D concentration ≥75", "metadata": {}}
+{"_id": "25602549", "title": "", "text": "When NK cells overcome their lack ofeducation.Cells of the immune system haveevolved various molecular mechanisms to sensetheir environment and react to alterations of self.NK cells are lymphocytes with effector andregulatory functions, which are remarkablyadaptable to changes in self. In a studypublished in this issue of the JCI, Tarek andcolleagues report the clinical benefits ofmanipulating NK cell adaptation to self in aninnovative mAb-based therapy againstneuroblastoma (NB). This novel therapeuticstrategy should stimulate further research on NKcell therapies.", "metadata": {}}
+{"_id": "25606339", "title": "", "text": "Toll-like receptor-3 mediates HIV-1transactivation via NFκB and JNK pathways andhistone acetylation, but prolonged activationsuppresses Tat and HIV-1 replication.TLR3 hasbeen implicated in the pathogenesis of severalviral infections, including SIV- andHIV-1-induced inflammation and AIDS. Howeverthe molecular mechanisms of theseTLR3-mediated effects are not known, and it isnot known whether HIV interacts with cellularTLR3 to affect disease process. Here weinvestigate the effects of TLR3 ligands on HIV-1transactivation using both primary humanmacrophages and cells containing integratedcopies of the HIV-1 promoter. We demonstratethat TLR3 activation induced upregulation oftranscription factors such as c-Jun,CCAAT/enhancer-binding protein alpha (CEBPA),signal transducer and activator of transcription(STAT)-1, STAT-2, RELB, and nuclear factorkappa-B1 (NFκB1), most of which are known toregulate the HIV promoter activity. We also", "metadata": {}}
+{"_id": "25612629", "title": "", "text": "Patent ductus arteriosus: are current neonataltreatment options better or worse than notreatment at all?Although a moderate-sizedpatent ductus arteriosus (PDA) needs to beclosed by the time a child is 1-2 years old, thereis great uncertainty about whether it needs to beclosed during the neonatal period. Although 95%of neonatologists believe that a moderate-sizedPDA should be closed if it persists in infants(born before 28 weeks) who still requiremechanical ventilation, the number ofneonatologists who treat a PDA when it occurs ininfants who do not require mechanical ventilationvaries widely. Both the high likelihood ofspontaneous ductus closure and the absence ofrandomized controlled trials, specificallyaddressing the risks and benefits of neonatalductus closure, add to the current uncertainty.New information suggests that earlypharmacologic treatment has several importantshort-term benefits for the preterm newborn. Bycontrast, ductus ligation, while eliminating the", "metadata": {}}
+{"_id": "25623469", "title": "", "text": "A conserved phosphatase cascade that regulatesnuclear membrane biogenesis.A newly emergingfamily of phosphatases that are members of thehaloacid dehalogenase superfamily contains thecatalytic motif DXDX(T/V). A member of thisDXDX(T/V) phosphatase family known as Dullardwas recently shown to be a potential regulator ofneural tube development in Xenopus [Satow R,Chan TC, Asashima M (2002) Biochem BiophysRes Commun 295:85-91]. Herein, wedemonstrate that human Dullard and the yeastprotein Nem1p perform similar functions inmammalian cells and yeast cells, respectively. Inaddition to similarity in primary sequence,Dullard and Nem1p possess similar domains andshow similar substrate preferences, and bothlocalize to the nuclear envelope. Additionally, weshow that human Dullard can rescue theaberrant nuclear envelope morphology ofnem1Delta yeast cells, functionally replacingNem1p. Finally, Nem1p, has been shown todeposphorylate the yeast phosphatidic acid", "metadata": {}}
+{"_id": "25628793", "title": "", "text": "Increased expression of CYP1A1 and CYP1B1 inovarian/peritoneal endometrioticlesions.Endometriosis is an estrogen-dependentdisease affecting up to 10% of all premenopausalwomen. There is evidence that differentendometriosis sites show distinct local estrogenconcentration, which, in turn, might be due to aunique local estrogen metabolism. We aimed toinvestigate whether there was a site-specificregulation of selected enzymes responsible forthe oxidative metabolism of estrogens in biopsysamples and endometrial and endometrioticstromal cells. Cytochrome P450 (CYP) 1A1 andCYP1B1 mRNA and protein expressions indeep-infiltrating (rectal, retossigmoidal, anduterossacral) lesions, superficial (ovarian andperitoneal) lesions, and eutopic and healthy(control) endometrium were evaluated byreal-time PCR and western blot. Using across-sectional study design with 58premenopausal women who were not underhormonal treatment, we were able to identify an", "metadata": {}}
+{"_id": "25629722", "title": "", "text": "Eset partners with Oct4 to restrictextraembryonic trophoblast lineage potential inembryonic stem cells.The histone H3 Lys 9(H3K9) methyltransferase Eset is an epigeneticregulator critical for the development of the innercell mass (ICM). Although ICM-derivedembryonic stem (ES) cells are normally unable tocontribute to the trophectoderm (TE) inblastocysts, we find that depletion of Eset byshRNAs leads to differentiation with theformation of trophoblast-like cells and inductionof trophoblast-associated gene expression. Usingchromatin immmunoprecipitation (ChIP) andsequencing (ChIP-seq) analyses, we identifiedEset target genes with Eset-dependent H3K9trimethylation. We confirmed that genes that arepreferentially expressed in the TE (Tcfap2a andCdx2) are bound and repressed by Eset.Single-cell PCR analysis shows that theexpression of Cdx2 and Tcfap2a is also inducedin Eset-depleted morula cells. Importantly,Eset-depleted cells can incorporate into the TE of", "metadata": {}}
+{"_id": "25641414", "title": "", "text": "Suicides after pregnancy in Finland, 1987-94:register linkage study.OBJECTIVE To determinerates of suicide associated with pregnancy by thetype of pregnancy. DESIGN Register linkagestudy. Information on suicides in women ofreproductive age was linked with the Finnishbirth, abortion, and hospital discharge registersto find out how many women who committedsuicide had had a completed pregnancy duringher last year of life. SETTING Nationwide datafrom Finland. SUBJECTS Women who committedsuicide in 1987-94. RESULTS There were 73suicides associated with pregnancy, representing5.4% of all suicides in women in this age group.The mean annual suicide rate was 11.3 per100,000. The suicide rate associated with birthwas significantly lower (5.9) and the ratesassociated with miscarriage (18.1) and inducedabortion (34.7) were significantly higher than inthe population. The risk associated with birthwas higher among teenagers and that associatedwith abortion was increased in all age groups.", "metadata": {}}
+{"_id": "25643818", "title": "", "text": "Metformin-associated lactic acidosis: a rare orvery rare clinical entity?AIMS Lactic acidosis is awell recognized complication of biguanidetherapy which is potentially serious. Although theprevalence of metformin-associated lacticacidosis (MALA) is much lower than thatassociated with phenformin, it is still beingreported sporadically which raises concerns forthe practising clinicians. We review the currentlyavailable world-wide data of the prevalence ofMALA, the risk factors for its development andthe current practical guidelines on the use ofmetformin to minimize the risk of this potentialhazard. METHODS An extensive literature searchwas conducted from both Medline and Ovid(1965-98) using the following keywords: 'Type 2diabetes mellitus', 'oral hypoglycaemic drugs','biguanides', 'metformin-associated lacticacidosis' and 'renal impairment'. RESULTS MALAwas found to be a very rare clinical entity, being20 times less common thanphenformin-associated lactic acidosis. Amongst", "metadata": {}}
+{"_id": "25649545", "title": "", "text": "Inborn errors of human JAKs and STATs.Inbornerrors of the genes encoding two of the fourhuman JAKs (JAK3 and TYK2) and three of thesix human STATs (STAT1, STAT3, and STAT5B)have been described. We review the disordersarising from mutations in these five genes,highlighting the way in which the molecular andcellular pathogenesis of these conditions hasbeen clarified by the discovery of inborn errors ofcytokines, hormones, and their receptors,including those interacting with JAKs and STATs.The phenotypic similarities between mice andhumans lacking individual JAK-STAT componentssuggest that the functions of JAKs and STATs arelargely conserved in mammals. However, a widearray of phenotypic differences has emergedbetween mice and humans carrying biallelic nullalleles of JAK3, TYK2, STAT1, or STAT5B.Moreover, the high degree of allelicheterogeneity at the human JAK3, TYK2, STAT1,and STAT3 loci has revealed highly diverseimmunological and clinical phenotypes, which", "metadata": {}}
+{"_id": "25649714", "title": "", "text": "Mental health problems of homeless children andfamilies: longitudinal study.OBJECTIVE Toestablish the mental health needs of homelesschildren and families before and after rehousing.DESIGN Cross sectional, longitudinal study.SETTING City of Birmingham. SUBJECTS 58rehoused families with 103 children aged 2-16years and 21 comparison families of lowsocioeconomic status in stable housing, with 54children. MAIN OUTCOME MEASURES Children'smental health problems and level ofcommunication; mothers' mental healthproblems and social support one year afterrehousing. RESULTS Mental health problemsremained significantly higher in rehousedmothers and their children than in thecomparison group (mothers 26% v 5%, P =0.04; children 39% v 11%, P = 0.0003).Homeless mothers continued to havesignificantly less social support at follow up.Mothers with a history of abuse and poor socialintegration were more likely to have children", "metadata": {}}
+{"_id": "25653703", "title": "", "text": "The flip side of perception-action coupling:locomotor experience and the ontogeny ofvisual-postural coupling.The possible role ofmotor development on psychological function isonce again a topic of great theoretical andpractical importance. The revival of this issue hasstemmed from a different approach to the topic,away from Gesell's interest in the long-termprediction of psychological functions from earlymotoric assessments, toward an attempt tounderstand how the acquisition of motor skillsorchestrates psychological changes. This paperdescribes how the acquisition of one motor skill,prone locomotion, has been linked todevelopmental changes in an infant's ability toregulate posture based on information availablein patterns of optic flow. It is argued that theonset of prone locomotion presses the infant todifferentiate spatially delimited regions of opticflow to effectively and efficiently control theimportant subtasks nested within the larger taskof locomotion, namely, steering, attending to the", "metadata": {}}
+{"_id": "25657127", "title": "", "text": "Crystal structure of the first plant urease fromjack bean: 83 years of journey from its firstcrystal to molecular structure.Urease, anickel-dependent metalloenzyme, is synthesizedby plants, some bacteria, and fungi. It catalyzesthe hydrolysis of urea into ammonia and carbondioxide. Although the amino acid sequences ofplant and bacterial ureases are closely related,some biological activities differ significantly.Plant ureases but not bacterial ureases possessinsecticidal properties independent of itsureolytic activity. To date, the structuralinformation is available only for bacterial ureasesalthough the jack bean urease (Canavaliaensiformis; JBU), the best-studied plant urease,was the first enzyme to be crystallized in 1926.To better understand the biological properties ofplant ureases including the mechanism ofinsecticidal activity, we initiated the structuralstudies on some of them. Here, we report thecrystal structure of JBU, the first plant ureasestructure, at 2.05 A resolution. The active-site", "metadata": {}}
+{"_id": "25670099", "title": "", "text": "Studies of nuclear and cytoplasmic behaviourduring the five mitotic cycles that precedegastrulation in Drosophila embryogenesis.Usingdifferential interference contrast optics,combined with cinematography, we have studiedthe morphological changes that the living,syncytial embryo undergoes from stage 10through 14 of Drosophila embryogenesis, that isjust prior to and during formation of the cellularblastoderm. We have supplemented thesestudies with data collected from fixed, stained,whole embryos. The following information hasbeen obtained. The average duration of nuclearcycles 10, 11, 12 and 13 is about 9, 10, 12 and21 min, respectively (25 degrees C). In thesefour cycles, the duration of that portion of themitotic period that lacks a discrete nuclearenvelope is 3, 3, 3 and 5 min, respectively. Thelength of nuclear cycle 14 varies in aposition-specific manner throughout the embryo,the shortest cycles being of 65 min duration.During nuclear cycles 10 through 13, it is", "metadata": {}}
+{"_id": "25677651", "title": "", "text": "Activation of liver X receptors and retinoid Xreceptors prevents bacterial-inducedmacrophage apoptosis.Microbe-macrophageinteractions play a central role in thepathogenesis of many infections. The ability ofsome bacterial pathogens to induce macrophageapoptosis has been suggested to contribute totheir ability to elude innate immune responsesand successfully colonize the host. Here, weprovide evidence that activation of liver Xreceptors (LXRs) and retinoid X receptors (RXRs)inhibits apoptotic responses of macrophages tomacrophage colony-stimulating factor (M-CSF)withdrawal and several inducers of apoptosis. Inaddition, combined activation of LXR and RXRprotected macrophages from apoptosis causedby infection with Bacillus anthracis, Escherichiacoli, and Salmonella typhimurium.Expression-profiling studies demonstrated thatLXR and RXR agonists induced the expression ofantiapoptotic regulators, including AIM/CT2,Bcl-X(L), and Birc1a. Conversely, LXR and RXR", "metadata": {}}
+{"_id": "25682129", "title": "", "text": "p53 binding to nucleosomal DNA depends on therotational positioning of DNA responseelement.The sequence-specific binding to DNA iscrucial for the p53 tumor suppressor function. Toinvestigate the constraints imposed on p53-DNArecognition by nucleosomal organization, westudied binding of the p53 DNA binding domain(p53DBD) and full-length wild-type p53 proteinto a single p53 response element (p53RE) placednear the nucleosomal dyad in six rotationalsettings. We demonstrate that the strongest p53binding occurs when the p53RE in thenucleosome is bent in the same direction asobserved for the p53-DNA complexes in solutionand in co-crystals. The p53RE becomesinaccessible, however, if its orientation in thecore particle is changed by approximately 180degrees. Our observations indicate that theorientation of the binding sites on a nucleosomemay play a significant role in the initial p53-DNArecognition and subsequent cofactor recruitment.", "metadata": {}}
+{"_id": "25687558", "title": "", "text": "Diminished sympathetic nervous system activityin genetically obese (ob/ob) mouse.Thegenetically obese (ob/ob) mouse exhibitsdefective thermoregulatory responses to coldexposure. Pathophysiological explanations forthis phenomenon have focused on abnormalitiesin intracellular metabolism or insensitivity ofperipheral tissues to the thermogenic effects ofcatecholamines. Because the sympatheticnervous system (SNS) is subject to feedbackregulation, a peripheral impairment inthermogenesis should be associated with acompensatory increase in SNS activity. Toexamine SNS activity in the ob/ob mouse,norepinephrine (NE) turnover was measured inheart and interscapular brown adipose tissue(IBAT) of ob/ob and lean mice. The results fromstudies utilizing radiolabeled NE or inhibition ofNE biosynthesis with alpha-methyl-p-tyrosine tomeasure NE turnover demonstrated reductions inSNS activity of 33-56% in heart and of 45-73%in IBAT in ob/ob mice at ambient temperature", "metadata": {}}
+{"_id": "25690516", "title": "", "text": "Quality of life of young adults with idiopathicshort stature: effect of growth hormonetreatment. Dutch Growth Hormone WorkingGroup.The aim of the study was to evaluatewhether treatment with recombinant humangrowth hormone (rhGH) affects the quality of lifeof young adults who were diagnosed asidiopathic short stature (ISS) during childhood,and whether their quality of life and aspects ofthe personality are different from normal.Experiences and expectations concerning rhGHtreatment of the subjects and their parents werealso investigated. Eighty-nine subjects wereincluded into the study: 24 subjects (16M, 8F)were treated with rhGH from childhood, whereas65 subjects (40M, 25F) were never treated. Atthe time of the interview all subjects hadattained final height [mean (SD) -2.3 (0.9) SDSfor Dutch references], and the age of the treatedsubjects was 20.5 (1.0) y, and 25.7 (3.5) y ofthe control subjects (p < 0.001). The level ofeducation was similar, but the treated subjects", "metadata": {}}
+{"_id": "25690564", "title": "", "text": "Neighborhood Racial/Ethnic Concentration, SocialDisadvantage, and Homicide Risk: An EcologicalAnalysis of 10 U.S. CitiesHomicide is one of theleading causes of death among African-Americanand Hispanic men. We investigated howneighborhood characteristics associated withsocial disadvantage explain racial/ethnichomicide gaps in 10 U.S. cities. The testhypotheses were that (1) higher concentrationsof African-Americans and Hispanics would beassociated with higher homicide rates and (2)the relationship between racial/ethnicconcentration and homicide would be attenuatedafter adjusting for neighborhood characteristics(e.g., unemployment, median household income,low educational attainment, and femaleheadship). The test hypotheses were examinedusing separate Poisson regression models, whichadjusted for spatial autocorrelation. Homiciderates were greater in neighborhoods with higherconcentrations of African-Americans andHispanics than in other groups, and the", "metadata": {}}
+{"_id": "25691541", "title": "", "text": "Preterm patent ductus arteriosus: A continuingconundrum for the neonatologist?How to managethe preterm patent ductus arteriosus (PDA)remains a conundrum. On the one hand,physiology and statistical association withadverse outcomes suggest that it is pathological.On the other hand, clinical trials of treatmentstrategies have failed to show any long-termbenefit. Ultrasound studies of PDA havesuggested that the haemodynamic impact maybe much earlier after birth than previouslythought (in the first hours); however, we still donot know when to treat PDA. Studies that havetested symptomatic or pre-symptomatictreatment are mainly historical and have nottested the effect of no treatment. Prophylactictreatment is the best-studied regimen butimprovements in some short-term outcomes donot translate to any difference in longer-termoutcomes. Neonatologists have been reluctant toengage in trials that test treatment againstalmost never treating. Observations of very early", "metadata": {}}
+{"_id": "25691878", "title": "", "text": "Political and economic aspects of the transition touniversal health coverage.Countries havereached universal health coverage by differentpaths and with varying health systems.Nonetheless, the trajectory toward universalhealth coverage regularly has three commonfeatures. The first is a political process driven bya variety of social forces to create publicprogrammes or regulations that expand accessto care, improve equity, and pool financial risks.The second is a growth in incomes and aconcomitant rise in health spending, which buysmore health services for more people. The thirdis an increase in the share of health spendingthat is pooled rather than paid out-of-pocket byhouseholds. This pooled share is sometimesmobilised as taxes and channelled throughgovernments that provide or subsidise care--inother cases it is mobilised in the form ofcontributions to mandatory insurance schemes.The predominance of pooled spending is anecessary condition (but not sufficient) for", "metadata": {}}
+{"_id": "25725663", "title": "", "text": "Wedelolactone protects human bronchialepithelial cell injury against cigarette smokeextract-induced oxidant stress and inflammationresponses through Nrf2 pathway.Cigarettesmoke is the leading cause of the developmentof various lung diseases including lung cancerthrough triggering oxidant stress andinflammatory responses which contributed to thelesions of normal human bronchial epithelial(NHBE) cell. Wedelolactone (WEL), a naturalcompound from Eclipta prostrata L., has beenfound to possess the inhibitive effects on theproliferation and growth of cancers. In thepresent study, we investigated the effects of WELon NHBE cell injury induced by cigarette smokeextract (CSE) in vitro. It showed that thepretreatment WEL (2.5-20μM) resulted in asignificant protective effect on 10% CSE-inducedcell death in NHBE cells. The pretreatment withWEL dose-dependently and significantly reversedthe activities of SOD, CAT, GSH and the level ofMDA to normal level. We also found that the", "metadata": {}}
+{"_id": "25726838", "title": "", "text": "IL-17 promotes tumor development through theinduction of tumor promoting microenvironmentsat tumor sites and myeloid-derived suppressorcells.The role of immune responses in tumordevelopment is a central issue for tumor biologyand immunology. IL-17 is an important cytokinefor inflammatory and autoimmune diseases.Although IL-17-producing cells are detected incancer patients and tumor-bearing mice, the roleof IL-17 in tumor development is controversial,and mechanisms remain to be fully elucidated. Inthe current study, we found that thedevelopment of tumors was inhibited inIL-17R-deficient mice. A defect in IFN-gammaRincreased tumor growth, whereas tumor growthwas inhibited in mice that were deficient in bothIL-17R and IFN-gammaR compared withwild-type animals. Further experiments showedthat neutralization of IL-17 by Abs inhibitedtumor growth in wild-type mice, whereassystemic administration of IL-17 promoted tumorgrowth. The IL-17R deficiency increased CD8 T", "metadata": {}}
+{"_id": "25732836", "title": "", "text": "Circulating tumor cells and[18F]fluorodeoxyglucose positron emissiontomography/computed tomography for outcomeprediction in metastatic breast cancer.PURPOSECirculating tumor cells (CTCs) and[(18)F]fluorodeoxyglucose (FDG) positronemission tomography (PET)/computedtomography (CT) are two new promising tools fortherapeutic monitoring. In this study, wecompared the prognostic value of CTC andFDG-PET/CT monitoring during systemic therapyfor metastatic breast cancer (MBC). PATIENTSAND METHODS A retrospective analyses of 115MBC patients who started a new line of therapyand who had CTC counts and FDG-PET/CT scansperformed at baseline and at 9 to 12 weeksduring therapy (midtherapy) was performed.Patients were categorized according tomidtherapy CTC counts as favorable (ie, < fiveCTCs/7.5 mL blood) or unfavorable (> or = fiveCTCs/7.5 mL blood) outcomes. CTC counts andFDG-PET/CT response at midtherapy were", "metadata": {}}
+{"_id": "25737507", "title": "", "text": "Phylogenetic analysis of Portuguese FelineImmunodeficiency Virus sequences reveals highgenetic diversity.Feline Immunodeficiency Virus(FIV) is a Lentivirus responsible for animmunodeficiency like disease in domestic cats.Based on the genetic diversity of the V3-V5region of env gene FIV is divided in fivephylogenetic subtypes (A, B, C, D and E) with aworld-wide distribution. To understand thesubtype diversity of FIV in Portugal a serologicalsurvey was conducted during 1 year in theVeterinary Faculty Hospital, Lisbon, Portugal toidentify seropositive animals. Two viral genomicregions were amplified by a nested PCR,sequenced and the phylogenetic relationshipsbetween 24 new Portuguese FIV sequences andother previously published FIV isolates wereassessed. The introduction of these sequencesinduced a subclustering in subtype B includingmost of the new Portuguese sequences.Moreover, a new cluster emerged, with twohighly divergent new sequences that might", "metadata": {}}
+{"_id": "25738896", "title": "", "text": "Aire deficiency promotes TRP-1-specific immunerejection of melanoma.The thymic transcriptionfactor autoimmune regulator (Aire) preventsautoimmunity in part by promoting expression oftissue-specific self-antigens, which include manycancer antigens. For example, AIRE-deficientpatients are predisposed to vitiligo, anautoimmune disease of melanocytes that is oftentriggered by efficacious immunotherapies againstmelanoma. Therefore, we hypothesized that Airedeficiency in mice may elevate immuneresponses to cancer and provide insights intohow such responses might be triggered. In thisstudy, we show that Aire deficiency decreasesthymic expression of TRP-1 (TYRP1), which is aself-antigen in melanocytes and a cancer antigenin melanomas. Aire deficiency resulted indefective negative selection of TRP-1-specific Tcells without affecting thymic numbers ofregulatory T cells. Aire-deficient mice displayedelevated T-cell immune responses that wereassociated with suppression of melanoma", "metadata": {}}
+{"_id": "25742130", "title": "", "text": "Mass screening programmes and trends incervical cancer in Finland and theNetherlands.With respect to cervical cancermanagement, Finland and the Netherlands arecomparable in relevant characteristics, e.g.,fertility rate, age-of-mother at first birth and anational screening programme for several years.The aim of this study is to compare trends inincidence of and mortality from cervical cancer inFinland and the Netherlands in relation to theintroduction and intensity of the screeningprogrammes. Therefore, incidence and mortalityrates were calculated using the Cancer Registriesof Finland and the Netherlands. Data onscreening intensity were obtained from theFinnish Cancer Registry and the Dutch evaluationcentre at ErasmusMC-Rotterdam. Women aged30-60 have been screened every 5 years, inFinland since 1992 and in the Netherlands since1996. Screening protocols for smear taking andreferral to the gynaecologist are comparable.Incidence and mortality rates have declined", "metadata": {}}
+{"_id": "25742205", "title": "", "text": "Biochemical characterization of theRan-RanBP1-RanGAP system: are RanBPproteins and the acidic tail of RanGAP requiredfor the Ran-RanGAP GTPase reaction?RanBP typeproteins have been reported to increase thecatalytic efficiency of the RanGAP-mediatedGTPase reaction on Ran. Since the structure ofthe Ran-RanBP1-RanGAP complex showedRanBP1 to be located away from the active site,we reinvestigated the reaction using fluorescencespectroscopy under pre-steady-state conditions.We can show that RanBP1 indeed does notinfluence the rate-limiting step of the reaction,which is the cleavage of GTP and/or the releaseof product P(i). It does, however, influence thedynamics of the Ran-RanGAP interaction, itsmost dramatic effect being the 20-foldstimulation of the already very fast associationreaction such that it is under diffusion control(4.5 x 10(8) M(-1) s(-1)). Having established avaluable kinetic system for the interactionanalysis, we also found, in contrast to previous", "metadata": {}}
+{"_id": "25747721", "title": "", "text": "Concomitant induction of CD4+ and CD8+ T cellresponses in volunteers immunized withSalmonella enterica serovar typhi strain CVD908-htrA.Type 1 cell-mediated immunity mightplay an important role in protection from typhoidfever. We evaluated whether immunization withSalmonella enterica serovar Typhi (S. Typhi)strain CVD 908-htrA (a Delta aroC Delta aroDDelta htrA mutant), a leading live oral typhoidvaccine candidate, elicits specific CD4(+) andCD8(+) S. Typhi immune responses. Potent CTLresponses and IFN-gamma secretion by CD8(+)T cells were detected following immunizationwith CVD 908-htrA in high (4.5 x 10(8) CFU) andlow (5 x 10(7) CFU) dosages. S. Typhi-specificCTL were observed in six of eight vaccinees (fourhigh and two low dose) after immunization. Meanincreases in the frequency of IFN-gammaspot-forming cells (SFC) in the presence of S.Typhi-infected targets were 221 +/- 41SFC/10(6) PBMC and 233 +/- 87 SFC/10(6)PBMC, in the high and low dose groups,", "metadata": {}}
+{"_id": "25748308", "title": "", "text": "The diverse functions of GAPDH: views fromdifferent subcellular compartments.Multiple rolesfor glyceraldehyde-3-phosphate dehydrogenase(GAPDH) have been recently appreciated. Inaddition to the cytoplasm where the majority ofGAPDH is located under the basal condition,GAPDH is also found in the particulate fractions,such as the nucleus, the mitochondria, and thesmall vesicular fractions. When cells are exposedto various stressors, dynamic subcellularre-distribution of GAPDH occurs. Here we reviewthese multifunctional properties of GAPDH,especially linking them to its oligomerization,posttranslational modification, and subcellularlocalization. This includes mechanisticdescriptions of how S-nitrosylation of GAPDHunder oxidative stress may lead to celldeath/dysfunction via nuclear translocation ofGAPDH, which is counteracted by a cytosolicGOSPEL. GAPDH is also involved in variousdiseases, especially neurodegenerative disordersand cancers. Therapeutic strategies to these", "metadata": {}}
+{"_id": "25761154", "title": "", "text": "Exercise-induced asthma: a practical guide todefinitions, diagnosis, prevalence, andtreatment.Exercise-induced asthma is defined asan intermittent narrowing of the airways,demonstrated by a decrease in some measure offlow, that the patient experiences as wheezing,chest tightness, coughing, and difficultybreathing that is triggered by exercise. Exercisewill trigger asthma in most individuals who havechronic asthma, as well as in some who do nototherwise have asthma. Definitive diagnosisrequires demonstration of a drop in flow rate,typically > or = 13-15% for forced expiratoryvolume in one second (FEV1) and > or =15-20% for peak expiratory flow rate (PEFR),after exercise, associated with symptoms.Prevalence data indicate that this disorder is verycommon in those who participate in recreationalsports as well as in highly competitive athletes,with at least 12-15% of unselected athleteshaving positive exercise challenges. Treatment ofexercise induced asthma involves use of", "metadata": {}}
+{"_id": "25786167", "title": "", "text": "Effect of sample quality on the sensitivity ofendoscopic biopsy for detecting gastric andduodenal lesions in dogs and cats.BACKGROUNDThe quality of histopathology slides of endoscopicbiopsies from different laboratories varies, butthe effect of biopsy quality on outcome isunknown. HYPOTHESIS The ability todemonstrate a histologic lesion in the stomach orduodenum of a dog or cat is affected by thequality of endoscopic biopsy samples submitted.More endoscopic samples are needed to find alesion in poor-quality tissue specimens. ANIMALSTissues from 99 dogs and 51 cats were examinedas clinical cases at 8 veterinary institutions orpractices in 5 countries. METHODSHistopathology slides from sequential cases thatunderwent endoscopic biopsy were submitted byparticipating institutions. Quality of the histologicsection of tissue (inadequate, marginal,adequate), type of lesion (lymphangiectasia,crypt lesion, villus blunting, cellular infiltrate),and severity of lesion (normal, mild, moderate,", "metadata": {}}
+{"_id": "25787749", "title": "", "text": "G-quadruplexes significantly stimulate Pif1helicase-catalyzed duplex DNA unwinding.Theevolutionarily conserved G-quadruplexes (G4s)are faithfully inherited and serve a variety ofcellular functions such as telomere maintenance,gene regulation, DNA replication initiation, andepigenetic regulation. Different from theWatson-Crick base-pairing found in duplex DNA,G4s are formed via Hoogsteen base pairing andare very stable and compact DNA structures.Failure of untangling them in the cell impedesDNA-based transactions and leads to genomeinstability. Cells have evolved highly specifichelicases to resolve G4 structures. We used arecombinant nuclear form of Saccharomycescerevisiae Pif1 to characterize Pif1-mediated DNAunwinding with a substrate mimicking anongoing lagging strand synthesis stalled by G4s,which resembles a replication origin and aG4-structured flap in Okazaki fragmentmaturation. We find that the presence of G4 maygreatly stimulate the Pif1 helicase to unwind", "metadata": {}}
+{"_id": "25789730", "title": "", "text": "Diffusion tensor imaging detects anddifferentiates axon and myelin degeneration inmouse optic nerve after retinal ischemia.Bothaxon and myelin degeneration have significantimpact on the long-term disability of patientswith white matter disorder. However, the clinicalmanifestations of the neurological dysfunctioncaused by white matter disorders are notsufficient to determine the origin of neurologicaldeficits. A noninvasive biological marker capableof detecting and differentiating axon and myelindegeneration would be a significant addition tocurrently available tools. Directional diffusivitiesderived from diffusion tensor imaging (DTI) havebeen previously proposed by this group aspotential biological markers to detect anddifferentiate axon and myelin degeneration. Tofurther test the hypothesis that axial(lambdaparallel) and radial(lambdaperpendicular) diffusivities reflect axonand myelin pathologies, respectively, the opticnerve was examined serially using DTI in a", "metadata": {}}
+{"_id": "25799020", "title": "", "text": "Direct isolation and identification of promoters inthe human genome.Transcriptional regulatoryelements play essential roles in gene expressionduring animal development and cellular responseto environmental signals, but our knowledge ofthese regions in the human genome is limiteddespite the availability of the complete genomesequence. Promoters mark the start of everytranscript and are an important class ofregulatory elements. A large, complex proteinstructure known as the pre-initiation complex(PIC) is assembled on all active promoters, andthe presence of these proteins distinguishespromoters from other sequences in the genome.Using components of the PIC as tags, we isolatedpromoters directly from human cells asprotein-DNA complexes and identified theresulting DNA sequences using genomic tilingmicroarrays. Our experiments in four human celllines uncovered 252 PIC-binding sites in 44semirandomly selected human genomic regionscomprising 1% (30 megabase pairs) of the", "metadata": {}}
+{"_id": "25806385", "title": "", "text": "Attempted suicide in Europe: rates, trends andsociodemographic characteristics of suicideattempters during the period 1989-1992. Resultsof the WHO/EURO Multicentre Study onParasuicide.The World Health Organization/EUROMulticentre Project on Parasuicide is part of theaction to implement target 12 of the WHOprogramme, \"Health for All by the Year 2000', forthe European region. Sixteen centres in 13European countries are participating in themonitoring aspect of the project, in which trendsin the epidemiology of suicide attempts areassessed. The highest average maleage-standardized rate of suicide attempts wasfound for Helsinki, Finland (314/100,000), andthe lowest rate (45/100,000) was for Guipuzcoa,Spain, representing a sevenfold difference. Thehighest average female age-standardized ratewas found for Cergy-Pontoise, France(462/100,000), and the lowest (69/100,000)again for Guipuzcoa, Spain. With only oneexception (Helsinki), the person-based suicide", "metadata": {}}
+{"_id": "25811797", "title": "", "text": "Recurrent outbreaks of Salmonella Enteritidisinfections in a Texas restaurant: phage type 4arrives in the United States.In recent yearsinfection caused by Salmonella serotypeEnteritidis (SE) phage type 4 has spread throughEurope but has been uncommon in the USA. Thefirst recognized outbreak of this strain in the USAoccurred in a Chinese restaurant in EI Paso,Texas, in April 1993; no source was identified. InSeptember 1993, a second outbreak caused bySE phage type 4 was associated with the samerestaurant. To determine the cause of the secondoutbreak, we compared food exposures of the 19patients with that of two control groups. Egg rollswere the only item significantly associated withillness in both analyses (first control group: oddsratio [OR] 8.2, 95% confidence interval [CI]2.3-31.6; second control group: OR 13.1, 95%CI 2.1-97.0). Retrospective analysis of the Apriloutbreak also implicated egg rolls (OR 32.4, 95%CI 9.1-126.6). Egg roll batter was made frompooled shell eggs and was left at room", "metadata": {}}
+{"_id": "25813706", "title": "", "text": "Strand-specific mismatch correction in nuclearextracts of human and Drosophila melanogastercell lines.Nuclear extracts derived from HeLa andDrosophila melanogaster KC cell lines have beenfound to correct single base-base mispairs withinopen circular DNA heteroduplexes containing astrand-specific, site-specific incision located 808base pairs from the mismatch. Correction in bothextract systems is strand specific, being highlybiased to the incised DNA strand. Differentmispairs within a homologous set ofheteroduplexes were processed with differentefficiencies (G.T greater than G.G approximatelyequal to A.C greater than C.C), and correctionwas accompanied by mismatch-dependent DNAsynthesis localized to the region spanning themispair and the strand break, thusdemonstrating that mismatch recognition isassociated with the repair reaction. Correction ofeach of these heteroduplexes was abolished byaphidicolin but was relatively insensitive to thepresence of high concentrations of ddTTP,", "metadata": {}}
+{"_id": "25816994", "title": "", "text": "Renal outcomes with telmisartan, ramipril, orboth, in people at high vascular risk (theONTARGET study): a multicentre, randomised,double-blind, controlled trial.BACKGROUNDAngiotensin receptor blockers (ARB) andangiotensin converting enzyme (ACE) inhibitorsare known to reduce proteinuria. Theircombination might be more effective than eithertreatment alone, but long-term data forcomparative changes in renal function are notavailable. We investigated the renal effects oframipril (an ACE inhibitor), telmisartan (an ARB),and their combination in patients aged 55 yearsor older with established atherosclerotic vasculardisease or with diabetes with end-organ damage.METHODS The trial ran from 2001 to 2007. Aftera 3-week run-in period, 25 620 participants wererandomly assigned to ramipril 10 mg a day(n=8576), telmisartan 80 mg a day (n=8542), orto a combination of both drugs (n=8502; medianfollow-up was 56 months), and renal functionand proteinuria were measured. The primary", "metadata": {}}
+{"_id": "25817686", "title": "", "text": "Hypothermic preservation up-regulates calpainexpression and increases ubiquitination incultured vascular endothelial cells: influence ofdopamine pretreatment.BACKGROUND Prolongedhypothermia, as occurs during solid organtransplantation, negatively influencestransplantation outcome. Proteolysis is one ofthe deleterious events implicated in preservationinjury of organ allografts. This strongly affectsgraft quality and hence immediate organfunction. Since donor catecholamine treatmentimproves transplantation outcome after renaltransplantation, the present study wasconducted to examine the influence of dopamine(DA) pretreatment on hypothermia inducedproteolysis in endothelial cells subjected toprolonged cold storage. MATERIALS ANDMETHODS Lactate dehydrogenase (LDH) assay,two-dimensional electrophoresis, ubiquitinationanalysis, intracellular calcium measurement, andWestern blot analysis were performed on humanumbilical vein endothelial cells (HUVEC)", "metadata": {}}
+{"_id": "25821556", "title": "", "text": "The three 'C' s of chromosome conformationcapture: controls, controls, controlsTranscriptionregulation in higher eukaryotes is controlled byregulatory elements such as enhancers that arerecognized by transcription factors. In manycases regulatory elements can be located atdistances up to several megabases from theirtarget genes. Recent evidence shows thatlong-range control of gene expression can bemediated through direct physical interactionsbetween genes and these regulatory elements.Such looping interactions can be detected usingthe chromosome conformation capture (3C)methodology. Although 3C is experimentallystraightforward, to draw meaningful conclusionsone must carefully design 3C experiments andimplement the conscientious use of controls. Thegeneral guidelines presented here should helpexperimental design and minimizemisinterpretation of 3C experiments.", "metadata": {}}
+{"_id": "25822299", "title": "", "text": "Effects of exercise training of 8 weeks anddetraining on plasma levels ofendothelium-derived factors, endothelin-1 andnitric oxide, in healthy young humans.Vascularendothelial cells produce nitric oxide (NO), whichis a potent vasodilator substance and has beenproposed as having antiatherosclerotic property.Vascular endothelial cells also produceendothelin-1 (ET-1), which is a potentvasoconstrictor peptide and has potentproliferating activity on vascular smooth musclecells. Therefore, ET-1 has been implicated in theprogression of atheromatous vascular disease.Because exercise training has been reported toproduce an alteration in the function of vascularendothelial cells in animals, we hypothesizedthat exercise training influences the productionof NO and ET-1 in humans. The purpose of thepresent study was to examine whether chronicexercise could influence the plasma levels of NO(measured as the stable end product of NO, i.e.,nitrite/nitrate [NOx]) and ET-1 in humans. Eight", "metadata": {}}
+{"_id": "25827024", "title": "", "text": "Neuron-specific expression of CuZnSOD preventsthe loss of muscle mass and function that occursin homozygous CuZnSOD-knockoutmice.Deletion of copper-zinc superoxidedismutase (CuZnSOD) in Sod1(-/-) mice leads toaccelerated loss of muscle mass and force duringaging, but the losses do not occur withmuscle-specific deletion of CuZnSOD. Todetermine the role of motor neurons in themuscle decline, we generated transgenicSod1(-/-) mice in which CuZnSOD wasexpressed under control of the synapsin 1promoter (SynTgSod1(-/-) mice).SynTgSod1(-/-) mice expressed CuZnSOD inbrain, spinal cord, and peripheral nerve, but notin other tissues. Sciatic nerve CuZnSOD contentin SynTgSod1(-/-) mice was ~20% that ofcontrol mice, but no reduction in muscle mass orisometric force was observed in SynTgSod1(-/-)mice compared with control animals, whereasmuscles of age-matched Sod1(-/-) micedisplayed 30-40% reductions in mass and force.", "metadata": {}}
+{"_id": "25830701", "title": "", "text": "A developmental transition in definitiveerythropoiesis: erythropoietin expression issequentially regulated by retinoic acid receptorsand HNF4.The cytokine erythropoietin (Epo)promotes erythropoietic progenitor cellproliferation and is required for erythropoieticdifferentiation. We have found that the Epo geneis a direct transcriptional target gene of retinoicacid signaling during early erythropoiesis (priorto embryonic day E12.5) in the fetal liver. Mouseembryos lacking the retinoic acid receptor geneRXR alpha have a morphological and histologicalphenotype that is comparable with embryos inwhich the Epo gene itself has been mutated, andflow cytometric analysis indicates that RXRalpha-deficient embryos are deficient in erythroiddifferentiation. Epo mRNA levels are reducedsubstantially in the fetal livers of RXR alpha(-/-)embryos at E10.25 and E11.25, and geneticanalysis shows that the RXR alpha and Epogenes are coupled in the same pathway. Wefurthermore show that the Epo gene is retinoic", "metadata": {}}
+{"_id": "25832301", "title": "", "text": "Tetraspanin 7 (TSPAN7) expression isupregulated in multiple myeloma patients andinhibits myeloma tumour development invivo.BACKGROUND Increased expression of thetetraspanin TSPAN7 has been observed in anumber of cancers; however, it is unclear howTSPAN7 plays a role in cancer progression.METHODS We investigated the expression ofTSPAN7 in the haematological malignancymultiple myleoma (MM) and assessed theconsequences of TSPAN7 expression in theadhesion, migration and growth of MM plasmacells (PC) in vitro and in bone marrow (BM)homing and tumour growth in vivo. Finally, wecharacterised the association of TSPAN7 with cellsurface partner molecules in vitro. RESULTSTSPAN7 was found to be highly expressed at theRNA and protein level in CD138(+) MM PC fromapproximately 50% of MM patients. TSPAN7overexpression in the murine myeloma cell line5TGM1 significantly reduced tumour burden in5TGM1/KaLwRij mice 4 weeks after intravenous", "metadata": {}}
+{"_id": "25837950", "title": "", "text": "Association of body mass index with outcomes inpatients with CKD.Obesity is associated withhigher mortality in the general population, butthis association is reversed in patients ondialysis. The nature of the relationship of obesitywith adverse clinical outcomes innondialysis-dependent CKD and the putativeinteraction of the severity of disease with thisassociation are unclear. We analyzed data from anationally representative cohort of 453,946United States veterans with eGFR<60 ml/min per1.73 m(2). The associations of body mass indexcategories (<20, 20 to <25, 25 to <30, 30 to<35, 35 to <40, 40 to <45, 45 to <50, and ≥50kg/m(2)) with all-cause mortality and diseaseprogression (using multiple definitions, includingincidence of ESRD, doubling of serum creatinine,and the slopes of eGFR) were examined in Coxproportional hazards models and logisticregression models. Multivariable adjustmentswere made for age, race, comorbidities andmedications, and baseline eGFR. Body mass", "metadata": {}}
+{"_id": "25838286", "title": "", "text": "WRN, the protein deficient in Werner syndrome,plays a critical structural role in optimizing DNArepair.Werner syndrome (WS) predisposespatients to cancer and premature aging, owing tomutations in WRN. The WRN protein is aRECQ-like helicase and is thought to participatein DNA double-strand break (DSB) repair bynon-homologous end joining (NHEJ) orhomologous recombination (HR). It has beenpreviously shown that non-homologous DNAends develop extensive deletions during repair inWS cells, and that this WS phenotype wascomplemented by wild-type (wt) WRN. WRNpossesses both 3' --> 5' exonuclease and 3' -->5' helicase activities. To determine the relativecontributions of each of these distinct enzymaticactivities to DSB repair, we examined NHEJ andHR in WS cells (WRN-/-) complemented witheither wtWRN, exonuclease-defective WRN (E-),helicase-defective WRN (H-) orexonuclease/helicase-defective WRN (E-H-). Thesingle E-and H- mutants each partially", "metadata": {}}
+{"_id": "25842866", "title": "", "text": "In vitro generated antibodies specific fortelomeric guanine-quadruplex DNA react withStylonychia lemnae macronuclei.Most eukaryotictelomeres contain a repeating motif withstretches of guanine residues that form a3'-terminal overhang extending beyond thetelomeric duplex region. The telomeric repeat ofhypotrichous ciliates, d(T(4)G(4)), forms a16-nucleotide 3'-overhang. Such sequences canadopt parallel-stranded as well asantiparallel-stranded quadruplex conformationsin vitro. Although it has been proposed thatguanine-quadruplex conformations may haveimportant cellular roles including telomerefunction, recombination, and transcription,evidence for the existence of this DNA structurein vivo has been elusive to date. We havegenerated high-affinity single-chain antibodyfragment (scFv) probes for theguanine-quadruplex formed by the Stylonychiatelomeric repeat, by ribosome display from theHuman Combinatorial Antibody Library. Of the", "metadata": {}}
+{"_id": "25853741", "title": "", "text": "Incidence of skin cancer after renaltransplantation in The Netherlands.The incidenceof squamous cell carcinoma (SCC) and basal cellcarcinoma (BCC) was analyzed separately in all764 patients who received a renal allograftbetween 1966 and 1988 at the Leiden UniversityHospital. The mean follow-up period was 8.7posttransplant years (range 1-21 years). Duringthis time period 176 skin cancers were diagnosedin 47 patients. The overall risk to develop a firsttumor increased from 10% after 10 years to40% after 20 years of graft survival. The overallincidence of SCC was 250 times higher and thatof BCC 10 times higher when compared with thegeneral Dutch population. Moreover thelocalization of SCCs and BCCs differedconsiderably. Solar radiation is thought to be animportant risk factor for the development of skincancer. However, the occurrence of skin cancerin long-term graft survivors forms also a majorproblem in a country with a higher geographicallatitude and a moderate amount of", "metadata": {}}
+{"_id": "25858295", "title": "", "text": "Myogenic and morphogenetic defects in the hearttubes of murine embryos lacking the homeo boxgene Nkx2-5.The murine homeo box geneNkx2-5 is expressed in precardiac mesoderm andin the myocardium of embryonic and fetalhearts. Targeted interruption of Nkx2-5 resultedin abnormal heart morphogenesis, growthretardation and embryonic lethality atapproximately 9-10 days postcoitum (p.c.).Heart tube formation occurred normally inmutant embryos, but looping morphogenesis, acritical determinant of heart form, was notinitiated at the linear heart tube stage (8.25-8.5days p.c.). Commitment to the cardiac musclelineage, expression of most myofilament genesand myofibrillogenesis were not compromised.However, the myosin light-chain 2V gene(MLC2V) was not expressed in mutant hearts norin mutant ES cell-derived cardiocytes. MLC2Vexpression normally occurs only in ventricularcells and is the earliest known molecular markerof ventricular differentiation. The regional", "metadata": {}}
+{"_id": "25878014", "title": "", "text": "Hygiene hypothesis in inflammatory boweldisease: a critical review of the literature.Thehygiene hypothesis is thought to be a significantcontributor to the growing incidence ofinflammatory bowel disease (IBD) around theworld, although the evidence for specific factorsthat underlie the hygiene hypothesis in IBD isunclear. We aimed to systematically review theliterature to determine which hygiene-relatedfactors are associated with the development ofIBD. Publications identified from a broad basedMEDLINE and Current Contents search between1966 and 2007 on key terms relevant to the'hygiene hypothesis' and IBD including H pyloriexposure, helminths, cold chain hypothesis,measles infection and vaccination, antibiotic use,breastfeeding, family size, sibship, urbanupbringing, day care attendance and domestichygiene were reviewed. The literature suggeststhat the hygiene hypothesis and its associationwith decreased microbial exposure in childhoodprobably plays an important role in the", "metadata": {}}
+{"_id": "25886725", "title": "", "text": "Are dual eligibles admitted to poorer qualityskilled nursing facilities?BACKGROUND Dualeligibles, persons who qualify for both Medicareand Medicaid coverage, often receive poorerquality care relative to other Medicarebeneficiaries. OBJECTIVES To determine whetherdual eligibles are discharged to lower qualitypost-acute skilled nursing facilities (SNFs)compared with Medicare-only beneficiaries.RESEARCH DESIGN Following the random utilitymaximization model, we specified a dischargefunction using a conditional logit model andtested how this discharge rule varied bydual-eligibility status. SUBJECTS A total of692,875 Medicare fee-for-service patients (22%duals) who were discharged for Medicare paidSNF care between July 2004 and June 2005.MEASURES Medicare enrollment and theMedicaid Analytic Extract files were used todetermine dual eligibility. The proportion ofMedicaid patients and nursing staffcharacteristics provided measures of SNF quality.", "metadata": {}}
+{"_id": "25895285", "title": "", "text": "Quantitative phosphoproteomic analysis ofacquired cancer drug resistance to pazopaniband dasatinibAcquired drug resistance impactsthe majority of patients being treated withtyrosine kinase inhibitors (TKIs) and remains akey challenge in modern anti-cancer therapy.The lack of clinically effective therapies toovercome resistance represents an unmet need.Understanding the signalling that drives drugresistance will facilitate the development of newsalvage therapies to treat patients withsecondary TKI resistance. In this study, weutilise mass spectrometry to characterise theglobal phosphoproteomic alterations thataccompany the acquisition of resistance to twoFDA-approved TKIs, pazopanib and dasatinib, inthe A204 rhabdoid tumour cell line. Our analysisfinds that only 6% and 9.7% of the quantifiedphosphoproteome is altered upon the acquisitionof pazopanib and dasatinib resistance,respectively. Pazopanib resistant cells displayelevated phosphorylation in cytoskeletal", "metadata": {}}
+{"_id": "25897733", "title": "", "text": "Pandemic H1N12009 influenza and HIV: a reviewof natural history, management and vaccineimmunogenicity.PURPOSE OF REVIEW The 2009pandemic HIN1 influenza strain (H1N12009)produced more severe disease and increased riskfor mortality. As an at-risk population for moresevere influenza illness, particular concernregarding HIV patients triggered a focused effortto evaluate disease burden and vaccine efficacyin these populations. RECENT FINDINGS As withother immune-compromised individuals, mostHIV-infected individuals recovered without majorconsequence. Although HIV infection wasassumed to be a risk factor for more severedisease and death, the published literature doesnot indicate this to be so. Neuraminadaseinhibitors were well tolerated by this populationand there was no evidence of clinically significantpharmacokinetic interactions with antiretroviraltherapy. Immunogenicity was increased withH1N12009 vaccine compared to the historicalresults of nonpandemic vaccines and optimized", "metadata": {}}
+{"_id": "25900857", "title": "", "text": "Population genomics of the honey bee revealsstrong signatures of positive selection on workertraits.Most theories used to explain the evolutionof eusociality rest upon two key assumptions:mutations affecting the phenotype of sterileworkers evolve by positive selection if theresulting traits benefit fertile kin, and thatworker traits provide the primary mechanismallowing social insects to adapt to theirenvironment. Despite the common view thatpositive selection drives phenotypic evolution ofworkers, we know very little about theprevalence of positive selection acting on thegenomes of eusocial insects. We mapped thefootprints of positive selection in Apis melliferathrough analysis of 40 individual genomes,allowing us to identify thousands of genes andregulatory sequences with signatures of adaptiveevolution over multiple timescales. We foundApoidea- and Apis-specific genes to be enrichedfor signatures of positive selection, indicatingthat novel genes play a disproportionately large", "metadata": {}}
+{"_id": "25901598", "title": "", "text": "An acetylation switch in p53 mediates holo-TFIIDrecruitment.Posttranslational modificationsmediate important regulatory functions inbiology. The acetylation of the p53 transcriptionfactor, for example, promotes transcriptionalactivation of target genes including p21. Here weshow that the acetylation of two lysine residuesin p53 promotes recruitment of the TFIID subunitTAF1 to the p21 promoter through itsbromodomains. UV irradiation of cellsdiacetylates p53 at lysines 373 and 382, which inturn recruits TAF1 to a distal p53-binding site onthe p21 promoter prior to looping to the corepromoter. Disruption of acetyl-p53/bromodomaininteraction inhibits TAF1 recruitment to both thedistal p53-binding site and the core promoter.Further, the TFIID subunits TAF4, TAF5, and TBPare detected on the core promoter prior to TAF1,suggesting that, upon DNA damage, distinctsubunits of TFIID may be recruited separately tothe p21 promoter and that the transcriptionalactivation depends on posttranslational", "metadata": {}}
+{"_id": "25915873", "title": "", "text": "Dasatinib inhibits both osteoclast activation andprostate cancer PC-3-cell-induced osteoclastformation.PURPOSE Therapies to target prostatecancer bone metastases have only limitedeffects. New treatments are focused on theinteraction between cancer cells, bone marrowcells and the bone matrix. Osteoclasts play animportant role in the development of bonetumors caused by prostate cancer. Since Srckinase has been shown to be necessary forosteoclast function, we hypothesized thatdasatinib, a Src family kinase inhibitor, wouldreduce osteoclast activity and prostate cancer(PC-3) cell-induced osteoclast formation.RESULTS Dasatinib inhibited RANKL-inducedosteoclast differentiation of bone marrow-derivedmonocytes with an EC(50) of 7.5 nM. PC-3 cells,a human prostate cancer cell line, were able todifferentiate RAW 264.7 cells, a murinemonocytic cell line, into osteoclasts, anddasatinib inhibited this differentiation. Inaddition, conditioned medium from PC-3 cell", "metadata": {}}
+{"_id": "25928548", "title": "", "text": "BMP receptor ALK3 controls collecting systemdevelopment.The molecular signals that regulategrowth and branching of the ureteric bud duringformation of the renal collecting system arelargely undefined. Members of the bonemorphogenetic protein (BMP) family signalthrough the type I BMP receptor ALK3 to inhibitureteric bud and collecting duct cellmorphogenesis in vitro. We investigated thefunction of the BMP signaling pathway in vivo bygenerating a murine model of ALK3 deficiencyrestricted to the ureteric bud lineage(Alk3(UB-/-) mice). At the onset of branchingmorphogenesis, Alk3(UB-/-) kidneys arecharacterized by an abnormal primary (1degrees ) ureteric bud branch pattern and anincreased number of ureteric bud branches.However, during later stages of renaldevelopment, Alk3(UB-/-) kidneys have fewerureteric bud branches and collecting ducts thanwild-type kidneys. Postnatal Alk3(UB-/-) miceexhibit a dysplastic renal phenotype", "metadata": {}}
+{"_id": "25937484", "title": "", "text": "Increased release of ferritin and iron byiron-loaded alveolar macrophages in cigarettesmokers.The lower respiratory tract of cigarettesmokers contains an increased amount of ironthat is predominantly sequestered within alveolarmacrophages (AM), but is also present inalveolar epithelial fluid. Extracellularferritin-bound iron could potentially be releasedby reductants present in cigarette smoke andcatalyze generation of highly reactive hydroxylradicals capable of causing oxidant injury. Todetermine whether AM are a source of alveolarextracellular ferritin and iron, we assessed invitro release of iron, ferritin, and transferrin byAM recovered by bronchoalveolar lavage (BAL) of27 healthy subjects including nine nonsmokers(NS), nine light smokers (LS), and nine heavysmokers (HS). Release of iron in vitro over 20 hwas increased in AM recovered from LS (2.24 +/-0.21 nmol/10(6) AM/20 h, p < 0.001) and HS(3.11 +/- 0.32 nmol/10(6) AM, p < 0.001)compared with NS (1.28 +/- 0.08 nmol/10(6)", "metadata": {}}
+{"_id": "25938221", "title": "", "text": "The spectrum of retinopathy in adults withPlasmodium falciparum malariaA specificretinopathy has been described in Africanchildren with cerebral malaria, but in adults thishas not been extensively studied. Since thestructure and function of the retinal vasculaturegreatly resembles the cerebral vasculature,study of retinal changes can reveal insights intothe pathophysiology of cerebral malaria. Adetailed observational study of malarialretinopathy in Bangladeshi adults was performedusing high-definition portable retinalphotography. Retinopathy was present in 17/27adults (63%) with severe malaria and 14/20adults (70%) with cerebral malaria. Moderate orsevere retinopathy was more frequent in cerebralmalaria (11/20, 55%) than in uncomplicatedmalaria (3/15, 20%; P=0.039), bacterial sepsis(0/5, 0%; P=0.038) or healthy controls (0/18,0%; P<0.001). The spectrum of malarialretinopathy was similar to that previouslydescribed in African children, but no vessel", "metadata": {}}
+{"_id": "25938251", "title": "", "text": "Prospective randomized open blinded end-point(PROBE) study. A novel design for interventiontrials. Prospective Randomized Open BlindedEnd-Point.A novel design for intervention studiesis presented, the so called PROBE study(Prospective Randomized Open, BlindedEnd-point). This design is compared to theclassical double-blind design. Among theadvantages of the PROBE design are lower costand greater similarity to standard clinicalpractice, which should make the results moreeasily applicable in routine medical care. Sinceend-points are evaluated by a blinded end-pointcommittee it is obvious that there should be nodifference between the two types of trials in thisregard.", "metadata": {}}
+{"_id": "25942757", "title": "", "text": "PSGL-1 function in immunity and steady statehomeostasis.The substantial importance ofP-selectin glycoprotein ligand 1 (PSGL-1) inleukocyte trafficking has continued to emergebeyond its initial identification as a selectinligand. PSGL-1 seemed to be a relatively simplemolecule with an extracellular mucin domainextended as a flexible rod, teleologicallyconsistent with its primary role in tetheringleukocytes to endothelial selectins. The rollinginteraction between leukocyte and endotheliummediated by this selectin-PSGL-1 interactionrequires branched O-glycan extensions onspecific PSGL-1 amino acid residues. In somecells, such as neutrophils, theglycosyltransferases involved in formation of theO-glycans are constitutively expressed, while inother cells, such as T cells, they are expressedonly after appropriate activation. Thus, PSGL-1supports leukocyte recruitment in both innateand adaptive arms of the immune response. Acomplex array of amino acids within the selectins", "metadata": {}}
+{"_id": "25946292", "title": "", "text": "Ligand binding determines whether CD46 isinternalized by clathrin-coated pits ormacropinocytosis.CD46 is a ubiquitous humancell surface receptor for the complementcomponents C3b and C4b and for variouspathogens, including the measles virus andhuman herpes virus 6. Ligand binding to CD46affects (i) protection of autologous cells fromcomplement attack by breakdown of complementcomponents, (ii) intracellular signals that affectthe regulation of immune cell function, (iii)antigen presentation, and (iv) down-regulation ofcell surface CD46. Recent evidence indicates thatCD46 signaling can link innate and acquiredimmune function. The molecular mechanisms forthese processes and the importance ofintracellular trafficking of the receptor have notyet been elucidated. We demonstrate here that,in nonlymphoid cells, CD46 is constitutivelyinternalized via clathrin-coated pits, traffics tomultivesicular bodies, and is recycled to the cellsurface. However, cross-linking of CD46 at the", "metadata": {}}
+{"_id": "25950264", "title": "", "text": "A three-dimensional cell biology model of humanhepatocellular carcinoma in vitroWe establishedan in vitro 3-D model of metastatichepatocellular carcinoma (HCC) by culturingMHCC97H cells on molecular scaffolds within arotating wall vessel bioreactor. Morphologicaland biochemical analyses revealed that the 3-DHCC model mirrored many clinical pathologicalfeatures of HCC in vivo, including cancer cellmorphology, tissue ultrastructure, proteinproduction and secretion, glucose metabolism,tissue-specific gene expression, and apoptosis.Xenografts into livers of nude mice resulted intumorigenesis and distant metastasis. This 3-DHCC spheroid is a promising model for HCCtumor biology, anticancer drug screening, andfor the establishment of HCC animal models.", "metadata": {}}
+{"_id": "25953438", "title": "", "text": "Patterns of age-specific mortality in children inendemic areas of sub-SaharanAfrica.Understanding of the age- and season-dependence of malaria mortality is an importantprerequisite for epidemiologic models of malariaimmunity. However, most studies of malariamortality have aggregated their results intobroad age groups and across seasons, making ithard to predict the likely impact of interventionstargeted at specific age groups of children. Wepresent age-specific mortality rates for childrenaged < 15 years for the period of 2001-2005 in 7demographic surveillance sites in areas ofsub-Saharan Africa with stable endemicPlasmodium falciparum malaria. We use verbalautopsies (VAs) to estimate the proportion ofdeaths by age group due to malaria, and thuscalculate malaria-specific mortality rates for eachsite, age-group, and month of the year. In allsites a substantial proportion of deaths (rangingfrom 20.1% in a Mozambican site to 46.2% in asite in Burkina Faso) were attributed to malaria.", "metadata": {}}
+{"_id": "25969485", "title": "", "text": "Obesity due to melanocortin 4 receptor (MC4R)deficiency is associated with increased lineargrowth and final height, fastinghyperinsulinemia, and incompletely suppressedgrowth hormone secretion.CONTEXTMelanocortin receptor 4 (MC4R) deficiency ischaracterized by increased linear growth greaterthan expected for the degree of obesity.OBJECTIVE The objective of the investigationwas to study the somatotroph axis in obeseMC4R-deficient patients and equally obesecontrols. PATIENTS AND METHODS We obtainedanthropometric measurements and insulinconcentrations in 153 MC4R-deficient subjectsand 1392 controls matched for age and severityof obesity. We measured fasting IGF-I, IGF-II,IGF binding protein (IGFBP)-1, IGFBP-3, andacid-labile subunit levels in a subset of 33MC4R-deficient patients and 36 control subjects.We examined pulsatile GH secretion in six adultMC4R-deficient subjects and six obese controls.RESULTS Height sd score was significantly", "metadata": {}}
+{"_id": "25970224", "title": "", "text": "The selectivity of beta-adrenoceptor antagonistson isoprenaline-induced changes in heart rate,blood pressure, soleus muscle contractility andairways function in anaesthetized cats.Thebeta-adrenoceptor antagonist of propranolol,metoprolol, atenolol and butoxamine inanaesthetized cats has been measured andcompared with the activity of four syntheticphenylethanolamine derivatives. The effects ofisoprenaline on four parameters in theanaesthetized cat: heart rate, blood pressure,soleus muscle contractility and airway reactance,were measured and the modification of theisoprenaline dose-response relation by each ofthe antagonist drugs assessed. Parallel shifts inlog dose-response curves for isoprenaline werecaused by propranolol for all parameters, bymetoprolol and atenolol for each parameterexcept blood pressure, and butoxamine for eachexcept soleus muscle and heart rate. Selectivityof action of the antagonists between differentorgans was measured by comparing DR10", "metadata": {}}
+{"_id": "25973484", "title": "", "text": "Breast cancer and obesity: an update.Obesityhas a complicated relationship to both breastcancer risk and the clinical behavior of theestablished disease. In postmenopausal women,particularly the elderly, various measures ofobesity have been positively associated with risk.However, before menopause increased bodyweight is inversely related to breast cancer risk.In both premenopausal and postmenopausalbreast cancer, the mechanisms by which bodyweight and obesity affect risk have been relatedto estrogenic activity. Obesity has also beenrelated to advanced disease at diagnosis andwith a poor prognosis in both premenopausal andpostmenopausal breast cancer. Breast cancer inAfrican-American women, considering itsrelationship to obesity, exhibits some importantdifferences from those described in whitewomen, although the high prevalence of obesityin African-American women may contribute tothe relatively poor prognosis compared withwhite American women. Despite the emphasis on", "metadata": {}}
+{"_id": "25974070", "title": "", "text": "Dietary saturated and unsaturated fats asdeterminants of blood pressure and vascularfunction.The amount and type of dietary fat havelong been associated with the risk of CVD.Arterial stiffness and endothelial dysfunction areimportant risk factors in the aetiology of CHD. Arange of methods exists to assess vascularfunction that may be used in nutritional science,including clinic and ambulatory blood pressuremonitoring, pulse wave analysis, pulse wavevelocity, flow-mediated dilatation and venousocclusion plethysmography. The present reviewfocuses on the quantity and type of dietary fatand effects on blood pressure, arterialcompliance and endothelial function. Concerningfat quantity, the amount of dietary fat consumedhabitually appears to have little influence onvascular function independent of fatty acidcomposition, although single high-fat mealspostprandially impair endothelial functioncompared with low-fat meals. The mechanism isrelated to increased circulating lipoproteins and", "metadata": {}}
+{"_id": "25985964", "title": "", "text": "Very small embryonic-like stem cells withmaximum regenerative potential get discardedduring cord blood banking and bone marrowprocessing for autologous stem cell therapy.Verysmall embryonic-like stem cells (VSELs) arepossibly lost during cord blood banking and bonemarrow (BM) processing for autologus stem celltherapy mainly because of their small size. Thepresent study was conducted on human umbilicalcord blood (UCB, n=6) and discarded red bloodcells (RBC) fraction obtained after separation ofmononuclear cells from human BM (n=6), to testthis hypothesis. The results show that VSELs,which are pluripotent stem cells with maximumregenerative potential, settle along with theRBCs during Ficoll-Hypaque density separation.These cells are very small in size (3-5 μm), havehigh nucleo-cytoplasmic ratio, and expressnuclear Oct-4, cell surface protein SSEA-4, andother pluripotent markers such as Nanog, Sox-2,Rex-1, and Tert as indicated byimmunolocalization and quantitative polymerase", "metadata": {}}
+{"_id": "25988622", "title": "", "text": "CNS repair requires both effector and regulatoryT cells with distinct temporal and spatialprofiles.Monocyte-derived macrophages(mo-MΦs) and T cells have been shown tocontribute to spinal cord repair. Recently, theremote brain choroid plexus epithelium (CP) wasidentified as a portal for monocyte recruitment,and its activation for leukocyte trafficking wasfound to be IFN-γ-dependent. Here, weaddressed how the need for effector T cells canbe reconciled with the role ofinflammation-resolving immune cells in therepair process. Using an acute spinal cord injurymodel, we show that in mice deficient inIFN-γ-producing T cells, the CP was notactivated, and recruitment ofinflammation-resolving mo-MΦ to the spinal cordparenchyma was limited. We furtherdemonstrate that mo-MΦ locally regulatedrecruitment of thymic-derived Foxp3(+)regulatory T (Treg) cells to the injured spinalcord parenchyma at the subacute/chronic phase.", "metadata": {}}
+{"_id": "25993718", "title": "", "text": "Sperm function tests and fertility.Traditionally,the diagnosis of male infertility has dependedupon a descriptive evaluation of human semenwith emphasis on the number of spermatozoathat are present in the ejaculate, their motilityand their morphology. The fundamental tenetunderlying this approach is that male fertility canbe defined by reference to a thresholdconcentration of motile, morphologically normalspermatozoa that must be exceeded in order toachieve conception. Many independent studieshave demonstrated that this fundamentalconcept is flawed and, in reality, it is not somuch the absolute number of spermatozoa thatdetermines fertility, but their functionalcompetence. In the light of this conclusion, arange of in vitro tests have been developed tomonitor various aspects of sperm functionincluding their potential for movement, cervicalmucus penetration, capacitation, zonarecognition, the acrosome reaction andsperm-oocyte fusion. Such functional assays", "metadata": {}}
+{"_id": "25994317", "title": "", "text": "Isolation and characterization of the cDNAencoding BKLF/TEF-2, a majorCACCC-box-binding protein in erythroid cells andselected other cells.CACCC boxes are among thecritical sequences present in regulatory elementsof genes expressed in erythroid cells, as well asin selected other cell types. While an erythroidcell-specific CACCC-box-binding protein, EKLF,has been shown to be required in vivo for properexpression of the adult beta-globin gene, it isdispensable for the regulation of several otherglobin and nonglobin erythroid cell-expressedgenes. In the work described here, we searchedfor additional CACCC-box transcription factorsthat might be active in murine erythroid cells.We identified a major gel shift activity (termedBKLF), present in yolk sac and fetal livererythroid cells, that could be distinguished fromEKLF by specific antisera. Throughrelaxed-stringency hybridization, we obtainedthe cDNA encoding BKLF, a highly basic, novelzinc finger protein that is related to EKLF and", "metadata": {}}
+{"_id": "26000593", "title": "", "text": "Effect of osteoporosis treatments on risk ofnon-vertebral fractures: review andmeta-analysis of intention-to-treat studiesMostosteoporosis treatments have proven efficacy inreducing the risk of vertebral fractures, whereasevidence is less straightforward for prevention ofnon-vertebral fractures. Conclusions as to theefficacy of a treatment should be based primarilyon analyses of the intention to treat (ITT)population rather than on exploratory subgroupanalyses; however, non-vertebral anti-fractureefficacy has been largely derived by post-hocsubgroup analyses. This review andmeta-analysis was performed to assessnon-vertebral anti-fracture efficacy of severalosteoporosis therapies, including a morestringent assessment of the ITT populations.Data on non-vertebral anti-fracture efficacy, adefined endpoint of the ITT analyses andconfirmed by radiographs, were obtained fromrandomized, placebo-controlled, phase III clinicaltrials of at least 3-year duration. Meta-analyses", "metadata": {}}
+{"_id": "26008063", "title": "", "text": "Islet1 deletion causes kidney agenesis andhydroureter resembling CAKUT.Islet1 (Isl1) is atranscription factor transiently expressed in asubset of heart and limb progenitors. Duringstudies of limb development, conditional Isl1deletion produced unexpected kidneyabnormalities. Here, we studied the renalexpression of Isl1 and whether it has a role inkidney development. In situ hybridizationrevealed Isl1 expression in the mesenchymalcells surrounding the base of the ureteric bud inmice. Conditional deletion of Isl1 caused kidneyagenesis or hypoplasia and hydroureter, aphenotype resembling human congenitalanomalies of the kidney and urinary tract(CAKUT). The absence of Isl1 led to ectopicbranching of the ureteric bud out from thenephric duct or to the formation of accessorybuds, both of which could lead to obstruction ofthe ureter-bladder junction and consequenthydroureter. The abnormal elongation and poorbranching of the ureteric buds were the likely", "metadata": {}}
+{"_id": "26008462", "title": "", "text": "Tissue transglutaminase (TG2)--a woundresponse enzyme.Repair of tissue after injurydepends on a series of concerted but overlappingevents including, inflammation,re-epithelialization, neovascularization andsynthesis and stabilization of a fibrousextracellular matrix (ECM) that is remodeled toemulate normal tissue over time. Particularmembers of the transglutaminase (TG) familyare upregulated during wound healing and act asa novel class of wound-healing mediators duringthe repair process. This group of enzymes whichcrosslink proteins via epsilon(gamma-glutamyl)lysine bridges are involved in wound healingthrough their ability to stabilize proteins and alsoby regulating the behavior of a wide variety ofcell types that are recruited to the damaged areain order to carry out tissue repair. In this articlewe discuss the function of the most widelyexpressed member of the TG family \"tissuetransglutaminase\" (TG2) in wound repair. Usingboth early and recent evidence from the", "metadata": {}}
+{"_id": "26011884", "title": "", "text": "Crystal structures of the glutamate receptor ionchannel GluK3 and GluK5 amino-terminaldomains.Ionotropic glutamate receptors (iGluRs)mediate the majority of fast excitatory synapticneurotransmission in the central nervous system.The selective assembly of iGluRs into AMPA,kainate, and N-methyl-d-aspartic acid (NMDA)receptor subtypes is regulated by theirextracellular amino-terminal domains (ATDs).Kainate receptors are further classified intolow-affinity receptor families (GluK1-GluK3) andhigh-affinity receptor families (GluK4-GluK5)based on their affinity for the neurotoxin kainicacid. These two families share a 42% sequenceidentity for the intact receptor but only a 27%sequence identity at the level of ATD. We havedetermined for the first time the high-resolutioncrystal structures of GluK3 and GluK5 ATDs, bothof which crystallize as dimers but with astrikingly different dimer assembly at the R1interface. By contrast, for both GluK3 and GluK5,the R2 domain dimer assembly is similar to those", "metadata": {}}
+{"_id": "26016929", "title": "", "text": "Effectiveness of screening older people forimpaired vision in community setting: systematicreview of evidence from randomised controlledtrials.OBJECTIVE To assess whether populationscreening for impaired vision among older peoplein the community leads to improvements invision. DESIGN Systematic review of randomisedcontrolled trials of population screening in thecommunity that included any assessment ofvision or visual function with at least 6 months'follow up. SUBJECTS Adults aged 65 or over.MAIN OUTCOME MEASURE Proportions withvisual impairment in intervention and controlgroups with any method of assessing visualimpairment. RESULTS There were no trials thatprimarily assessed visual screening. Outcomedata on vision were available for 3494 people infive trials of multiphasic assessment. All thetrials used self reported measures for visionimpairment, both as screening tools and asoutcome measures. The inclusion of a visualscreening component in the assessment did not", "metadata": {}}
+{"_id": "26019505", "title": "", "text": "Protein interaction network of the mammalianHippo pathway reveals mechanisms ofkinase-phosphatase interactions.The Hippopathway regulates organ size and tissuehomeostasis in response to multiple stimuli,including cell density and mechanotransduction.Pharmacological inhibition of phosphatases canalso stimulate Hippo signaling in cell culture. Wedefined the Hippo protein-protein interactionnetwork with and without inhibition of serine andthreonine phosphatases by okadaic acid. Weidentified 749 protein interactions, including 599previously unrecognized interactions, anddemonstrated that several interactions withserine and threonine phosphatases werephosphorylation-dependent. Mutation of theT-loop of MST2 (mammalian STE20-like proteinkinase 2), which prevented autophosphorylation,disrupted its association with STRIPAK(striatin-interacting phosphatase and kinasecomplex). Deletion of the amino-terminalforkhead-associated domain of SLMAP", "metadata": {}}
+{"_id": "26025370", "title": "", "text": "Differential Effects of N-Acetylcysteine,Theophylline or Bicarbonate on Contrast-InducedRat Renal VasoconstrictionBackground:Vasoconstriction and reactive oxygen species(ROS) accumulation following contrast media(CM) injection are the key factors triggeringCM-induced nephropathy. We compared theeffects of N-acetylcysteine (NAC), theophylline orsodium bicarbonate on intrarenalvasoconstriction and ROS generation in a ratmodel of CM-induced nephropathy. Methods:Following a 3-day dehydration, Sprague-Dawleyrats received CM (Telebrix) or sham ‘CM’injection of 0.9% saline. Part of them receivedNAC, theophylline or bicarbonate prior to CM.Medullar renal blood flow was estimated by laserDoppler. The animals were sacrificed 1, 15 or 30min after the respective treatments, theirkidneys allocated and intrarenal STAT-8isoprostane, PGE2 and NO assessed. Results:Vasoconstriction was significantly attenuated byNAC. Theophylline only mildly attenuated the", "metadata": {}}
+{"_id": "26025820", "title": "", "text": "Induction of AMPK activity corrects earlypathophysiological alterations in the subtotalnephrectomy model of chronic kidneydisease.The rat kidney ablation and infarction(A/I) model of subtotal or 5/6th nephrectomy isthe most commonly studied model of nondiabeticchronic kidney disease (CKD). The A/I kidney at1 wk exhibits reductions in kidney function, asdetermined by glomerular filtration rate, anddiminished metabolic efficiency as determined byoxygen consumption per sodium transport(QO2/TNa). As renoprotective AMPK activity isaffected by metabolic changes and cellularstress, we evaluated AMPK activity in this modelsystem. We show that these earlypathophysiological changes are accompanied bya paradoxical decrease in AMPK activity. Overtime, these kidney parameters progressivelyworsen with extensive kidney structural,functional, metabolic, and fibrotic changesobserved at 4 wk after A/I. We show thatinduction of AMPK activity with either metformin", "metadata": {}}
+{"_id": "26026009", "title": "", "text": "Magnetic resonance imaging for volumeestimation of large multinodular goitres: acomparison with scintigraphy.As a result ofincreasing interest in non-surgical treatment forthe reduction of goitre size the use of magneticresonance (MR) imaging for volume estimation oflarge multinodular goitres was evaluated in 20patients (three males and 17 females; age 61+/- 21 years) with a multinodular goitre largerthan 100 ml. In addition, MR measurementswere compared with scintigraphic (SC) volumeestimations. Intraobserver coefficient of variation(CV) of MR measurements was 2.2 +/- 2.0%(Observer 1) and interobserver CV 4.1 +/- 2.2%(Observers 1 and 2). In all 20 patients signs ofmechanical complications were shown on MRimages. For SC measurements intraobserver CVwas 7.5 +/- 5.7% (Observer 3) and 5.4 +/-5.1% (Observer 4). Interobserver CV was 10.1+/- 6.1%. The correlation betweenmeasurements with both methods was notstrong (r = 0.665) and the resulting CV was 17.3", "metadata": {}}
+{"_id": "26030079", "title": "", "text": "Differential role of CbpA and PspA in modulationof in vitro CXC chemokine responses ofrespiratory epithelial cells to infection withStreptococcus pneumoniae.Respiratory epithelialcells play an active part in the host response torespiratory pathogens, such as Streptococcuspneumoniae, by releasing chemokinesresponsible for neutrophil recruitment. In orderto investigate the role of specific pneumococcalvirulence factors in eliciting CXC chemokineresponses, type II pneumocytes (A549) andnasopharyngeal cells (Detroit-562) were infectedwith S. pneumoniae D39 or mutants lackingcholine-binding protein A (CbpA), pneumococcalsurface protein A (PspA), or specific domainsthereof. In response to wild-type D39, both A549and Detroit-562 cells showed a significantincrease in CXC chemokine mRNA andinterleukin-8 protein. This response wasincreased twofold when a cbpA deletion mutant(DeltaCbpA) was used, suggesting that CbpAinhibits CXC chemokine induction. All three", "metadata": {}}
+{"_id": "26038789", "title": "", "text": "HIV-1 therapy with monoclonal antibody3BNC117 elicits host immune responses againstHIV-13BNC117 is a broad and potentneutralizing antibody to HIV-1 that targets theCD4 binding site on the viral envelope spike.When administered passively, this antibody canprevent infection in animal models and suppressviremia in HIV-1–infected individuals. Here wereport that HIV-1 immunotherapy with a singleinjection of 3BNC117 affects host antibodyresponses in viremic individuals. In comparisonto untreated controls that showed little change intheir neutralizing activity over a 6-month period,3BNC117 infusion significantly improvedneutralizing responses to heterologous tier 2viruses in nearly all study participants. Weconclude that 3BNC117-mediatedimmunotherapy enhances host humoralimmunity to HIV-1.", "metadata": {}}
+{"_id": "26045237", "title": "", "text": "Safety and efficacy of RNAi therapy fortransthyretin amyloidosis.BACKGROUNDTransthyretin amyloidosis is caused by thedeposition of hepatocyte-derived transthyretinamyloid in peripheral nerves and the heart. Atherapeutic approach mediated by RNAinterference (RNAi) could reduce the productionof transthyretin. METHODS We identified apotent antitransthyretin small interfering RNA,which was encapsulated in two distinct first- andsecond-generation formulations of lipidnanoparticles, generating ALN-TTR01 andALN-TTR02, respectively. Each formulation wasstudied in a single-dose, placebo-controlledphase 1 trial to assess safety and effect ontransthyretin levels. We first evaluatedALN-TTR01 (at doses of 0.01 to 1.0 mg perkilogram of body weight) in 32 patients withtransthyretin amyloidosis and then evaluatedALN-TTR02 (at doses of 0.01 to 0.5 mg perkilogram) in 17 healthy volunteers. RESULTSRapid, dose-dependent, and durable lowering of", "metadata": {}}
+{"_id": "26047921", "title": "", "text": "The mechanosensitive ion channel Piezo1 isinhibited by the peptide GsMTx4.Cells canrespond to mechanical stress by gatingmechanosensitive ion channels (MSCs). Thecloning of Piezo1, a eukaryotic cation selectiveMSC, defines a new system for studyingmechanical transduction at the cellular level.Because Piezo1 has electrophysiologicalproperties similar to those of endogenouscationic MSCs that are selectively inhibited bythe peptide GsMTx4, we tested whether thepeptide targets Piezo1 activity. ExtracellularGsMTx4 at micromolar concentrations reversiblyinhibited \u000080% of the mechanically inducedcurrent of outside-out patches from transfectedHEK293 cells. The inhibition was voltageinsensitive, and as seen with endogenous MSCs,the mirror image d enantiomer inhibited like thel. The rate constants for binding and unbindingbased on Piezo1 current kinetics providedassociation and dissociation rates of 7.0 × 10(5)M(-1) s(-1) and 0.11 s(-1), respectively, and a", "metadata": {}}
+{"_id": "26058927", "title": "", "text": "Thiazolidinediones improve beta-cell function intype 2 diabetic patients.Thiazolidinediones(TZDs) improve glycemic control and insulinsensitivity in patients with type 2 diabetesmellitus (T2DM). There is growing evidence fromin vivo and in vitro studies that TZDs improvepancreatic beta-cell function. The aim of thisstudy was to determine whether TZD-inducedimprovement in glycemic control is associatedwith improved beta-cell function. We studied 11normal glucose-tolerant and 53 T2DM subjects[age 53+/-2 yr; BMI 29.4+/-0.8 kg/m2; fastingplasma glucose (FPG) 10.3+/-0.4 mM; Hb A1c8.2+/-0.3%]. Diabetic patients were randomizedto receive placebo or TZD for 4 mo. Subjectsreceived 1) 2-h OGTT with determination ofplasma glucose, insulin, and C-peptideconcentrations and 2) two-step euglycemicinsulin (40 and 160 mU.m-2.min-1) clamp with[3-(3)H]glucose. T2DM patients were thenrandomized to receive 4 mo of treatment withpioglitazone (45 mg/day), rosiglitazone (8", "metadata": {}}
+{"_id": "26059876", "title": "", "text": "A novel Ku70 function in colorectal homeostasisseparate from nonhomologous end joiningKu70,a known nonhomologous end-joining (NHEJ)factor, also functions in tumor suppression,although this molecular mechanism remainsuncharacterized. Previously, we showed thatmice deficient for DNA ligase IV (Lig4), anotherkey NHEJ factor, succumbed to aggressivelymphoma in the absence of tumor suppressorp53. However, the tumor phenotype is abrogatedby the introduction of a hypomorphic mutantp53R172P, which impaired p53-mediatedapoptosis but not cell-cycle arrest. However,Lig4−/−p53R172P mice succumbed to severediabetes. To further elucidate the role of NHEJand p53-mediated apoptosis in vivo, we bredKu70−/− p53R172P mice. Unexpectedly, thesemice were free of diabetes, although 80% of themutant mice had abnormally enlarged colonswith pronounced inflammation. Remarkably,most of these mutant mice progressed todysplasia, adenoma and adenocarcinoma; this is", "metadata": {}}
+{"_id": "26064662", "title": "", "text": "Association of Sickle Cell Trait With HemoglobinA1c in African AmericansImportance HemoglobinA1c (HbA1c) reflects past glucoseconcentrations, but this relationship may differbetween those with sickle cell trait (SCT) andthose without it. Objective To evaluate theassociation between SCT and HbA1c for givenlevels of fasting or 2-hour glucose levels amongAfrican Americans. Design, Setting, andParticipants Retrospective cohort study usingdata collected from 7938 participants in 2community-based cohorts, the Coronary ArteryRisk Development in Young Adults (CARDIA)study and the Jackson Heart Study (JHS). Fromthe CARDIA study, 2637 patients contributed amaximum of 2 visits (2005-2011); from the JHS,5301 participants contributed a maximum of 3visits (2000-2013). All visits were scheduled atapproximately 5-year intervals. Participantswithout SCT data, those without any concurrentHbA1c and glucose measurements, and thosewith hemoglobin variants HbSS, HbCC, or HbAC", "metadata": {}}
+{"_id": "26064942", "title": "", "text": "PGAP2 mutations, affecting theGPI-anchor-synthesis pathway, causehyperphosphatasia with mental retardationsyndrome.Recently, mutations in genes involvedin the biosynthesis of theglycosylphosphatidylinositol (GPI) anchor havebeen identified in a new subclass of congenitaldisorders of glycosylation (CDGs) with a distinctspectrum of clinical features. To date, mutationshave been identified in six genes (PIGA, PIGL,PIGM, PIGN, PIGO, and PIGV) encoding proteinsin the GPI-anchor-synthesis pathway inindividuals with severe neurological features,including seizures, muscular hypotonia, andintellectual disability. We developed a diagnosticgene panel for targeting all known genesencoding proteins in the GPI-anchor-synthesispathway to screen individuals matching thesefeatures, and we detected three missensemutations in PGAP2, c.46C>T, c.380T>C, andc.479C>T, in two unrelated individuals withhyperphosphatasia with mental retardation", "metadata": {}}
+{"_id": "26067999", "title": "", "text": "Screening for Lung Cancer: U.S. PreventiveServices Task Force RecommendationStatementThe U.S. Preventive Services TaskForce (USPSTF) makes recommendations aboutthe effectiveness of specific preventive careservices for patients without related signs orsymptoms. It bases its recommendations on theevidence of both the benefits and harms of theservice and an assessment of the balance. TheUSPSTF does not consider the costs of providinga service in this assessment. The USPSTFrecognizes that clinical decisions involve moreconsiderations than evidence alone. Cliniciansshould understand the evidence but individualizedecision making to the specific patient orsituation. Similarly, the USPSTF notes that policyand coverage decisions involve considerations inaddition to the evidence of clinical benefits andharms. Summary of Recommendation andEvidence The USPSTF recommends annualscreening for lung cancer with low-dosecomputed tomography (LDCT) in adults aged 55", "metadata": {}}
+{"_id": "26068103", "title": "", "text": "Dual role of interleukin-10 in the regulation ofrespiratory syncitial virus (RSV)-induced lunginflammation.RSV lower respiratory tractinfections (LRTI) are among the most commondiseases necessitating hospital admission inchildren. In addition to causing acute respiratoryfailure, RSV infections are associated withsequelae such as secondary bacterial infectionsand reactive airway disease. One characteristichost response observed in severe RSV-inducedLRTI and/or subsequent development of asthmais increased expression of interleukin (IL)-10.However, contradictory results have beenreported regarding whether IL-10 inhibitsasthmatic responses or intensifies the disease.We aimed to reconcile these discordantobservations by elucidating the role of IL-10 inregulating the host response to RSV LRTI. In thisstudy, we used a lung-specific, inducible IL-10over-expression (OE) transgenic mouse model toaddress this question. Our results showed thatthe presence of IL-10 at the time of RSV", "metadata": {}}
+{"_id": "26071782", "title": "", "text": "Latent membrane protein 1 of Epstein–Barr viruscoordinately regulates proliferation with controlof apoptosisLatent membrane protein 1 (LMP1),an oncoprotein encoded by Epstein–Barr virus(EBV), is an integral membrane protein, whichacts like a constitutively active receptor. LMP1 iscritical for some facet of EBV's induction andmaintenance of proliferation of infected B cells.It, in part, mimics signaling by the CD40receptor and has been implicated in regulatingproliferation, survival, or both properties ofEBV-infected cells. We established a conditionalLMP1 allele in the context of the intact EBVgenome to define the immediate-early cellulartarget genes regulated by LMP1 in order toassess its contributions to infected human Bcells. The functional analysis of this conditionalsystem indicated that LMP1 specifically inducesmitogenic B-cell activation through c-myc andJun/AP1 family members and confirms its directrole in upregulating expression of multiple geneswith opposing activities involved in cell survival.", "metadata": {}}
+{"_id": "26079071", "title": "", "text": "Crizotinib in ROS1-rearranged non-small-celllung cancer.BACKGROUND Chromosomalrearrangements of the gene encoding ROS1proto-oncogene receptor tyrosine kinase (ROS1)define a distinct molecular subgroup ofnon-small-cell lung cancers (NSCLCs) that maybe susceptible to therapeutic ROS1 kinaseinhibition. Crizotinib is a small-molecule tyrosinekinase inhibitor of anaplastic lymphoma kinase(ALK), ROS1, and another proto-oncogenereceptor tyrosine kinase, MET. METHODS Weenrolled 50 patients with advanced NSCLC whotested positive for ROS1 rearrangement in anexpansion cohort of the phase 1 study ofcrizotinib. Patients were treated with crizotinib atthe standard oral dose of 250 mg twice daily andassessed for safety, pharmacokinetics, andresponse to therapy. ROS1 fusion partners wereidentified with the use of next-generationsequencing orreverse-transcriptase-polymerase-chain-reactionassays. RESULTS The objective response rate", "metadata": {}}
+{"_id": "26083387", "title": "", "text": "The S. cerevisiae Rrm3p DNA helicase moveswith the replication fork and affects replication ofall yeast chromosomes.The Saccharomycescerevisiae DNA helicase Rrm3p is needed fornormal fork progression through >1000 discretesites scattered throughout the genome. Here weshow that replication of all yeast chromosomeswas markedly delayed in rrm3 cells. Delayedreplication was seen even in a region that lacksany predicted Rrm3p-dependent sites. Based onthe pattern of replication intermediates intwo-dimensional gels, the rate of fork movementin rrm3 cells appeared similar to wild-typeexcept at known Rrm3p-dependent sites. Thesedata suggest that although Rrm3p has a globalrole in DNA replication, its activity is needed onlyor primarily at specific, difficult-to-replicate sites.By the criterion of chromatinimmunoprecipitation, Rrm3p was associated withboth Rrm3p-dependent and -independent sites,and moved with the replication fork throughboth. In addition, Rrm3p interacted with Pol2p,", "metadata": {}}
+{"_id": "26089649", "title": "", "text": "The pathophysiology of protein-overloadproteinuria.Alterations in glomerular function andstructure were studied in protein-overloadnephrosis in the rat induced by intraperitonealadministration of bovine serum albumin (BSA).Fractional clearance (C/GFR) studies using inulinand tracer proteins of different molecular sizeand charge revealed in proteinuric rats 1)unchanged glomerular filtration rate and renalplasma flow; 2) a 34-fold increase in C/GFR ofrat serum albumin, reaching values similar toBSA; 3) a 2-fold increase in C/GFR for anionichorse radish peroxidase (HRP), but normalvalues for neutral and cationic HRP, and 4) an11- and 3-fold increase for heterologous IgG andIgM, respectively. Glomerular epithelial cellsshowed degenerative changes, but thedistribution of anionic sites in the glomerularbasement membrane was found to be unaltered,as determined by polyethyleneimine bindingstudies. In summary, an elevation of serumalbumin concentration resulted in an increased", "metadata": {}}
+{"_id": "26099680", "title": "", "text": "Effects of aging on central and peripheralmammalian clocks.Circadian organizationchanges with age, but we do not know the extentto which age-related changes are the result ofalterations in the central pacemakers, theperipheral oscillators, or the couplingmechanisms that hold the system together. Byusing transgenic rats with a luciferase (luc)reporter, we assessed the effects of aging on therhythm of expression of the Period 1 (Per1) genein the suprachiasmatic nucleus (SCN) and inperipheral tissues. Young (2 months) and aged(24-26 months) Per1-luc transgenic rats,entrained to light-dark cycles, were killed, andtissues were removed and cultured. Per1-lucexpression was measured from 10 tissues. In theSCN, the central mammalian pacemaker,Per1-luc expression was robustly rhythmic formore than 7 weeks in culture. The onlydifference between SCN rhythmicity in youngand old rats was a small but significantage-related shortening of the free-running", "metadata": {}}
+{"_id": "26104554", "title": "", "text": "CtBP3/BARS drives membrane fission indynamin-independent transportpathwaysMembrane fission is a fundamental stepin membrane transport. So far, the only fissionprotein machinery that has been implicated in invivo transport involves dynamin, and functions inseveral, but not all, transport pathways. Thus,other fission machineries may exist. Here, wereport that carboxy-terminal binding protein3/brefeldin A-ribosylated substrate(CtBP3/BARS) controls fission in basolateraltransport from the Golgi to the plasmamembrane and in fluid-phase endocytosis,whereas dynamin is not involved in these steps.Conversely, CtBP3/BARS protein is inactive inapical transport to the plasma membrane and inreceptor-mediated endocytosis, both steps beingcontrolled by dynamin. This indicates thatCtBP3/BARS controls membrane fission inendocytic and exocytic transport pathways,distinct from those that require dynamin.", "metadata": {}}
+{"_id": "26105746", "title": "", "text": "Influenza A myocarditis developing in an adultliver transplant recipient despite vaccination: acase report and review of the literature.Solidorgan transplant recipients receiving chronicimmunosuppressive agents are at increased riskto acquire influenza virus despite vaccination.Myocarditis is a known but rare complication ofinfluenza infection. We present the first adultliver transplant recipient who receivedprophylactic vaccination but developed influenzaA myocarditis. This may occur in solid organtransplant recipients, because they have reducedresponse to protein vaccines, which may leavethem vulnerable to infections. Studies areneeded to evaluate if antiviral chemoprophylaxisin solid organ transplant recipients duringinfluenza season would be an effectivepreventive therapy against influenza in thishigh-risk population.", "metadata": {}}
+{"_id": "26107000", "title": "", "text": "Extrapulmonary effects of chronic obstructivepulmonary disease on physical activity: across-sectional study.RATIONALE Physicalactivity is reduced in patients with chronicobstructive pulmonary disease (COPD). COPDhas a systemic component that includessignificant extrapulmonary effects that maycontribute to its severity in individual patients.OBJECTIVES To investigate the association ofextrapulmonary effects of the disease and itscomorbidities with reduced physical activity inpatients with COPD. METHODS In across-sectional study, 170 outpatients with COPD(GOLD [Global Initiative for Chronic ObstructiveLung Disease] stages I-IV; BODE [body massindex, airway obstruction, dyspnea, and exercisecapacity] score 0-10) underwent a series oftests. Physical activity was assessed over 5 to 6consecutive days by using a multisensoraccelerometer armband that records steps perday and the physical activity level (total dailyenergy expenditure divided by whole-night", "metadata": {}}
+{"_id": "26108767", "title": "", "text": "Cleavage efficient 2A peptides for high levelmonoclonal antibody expression in CHOcells.Linking the heavy chain (HC) and light chain(LC) genes required for monoclonal antibodies(mAb) production on a single cassette using 2Apeptides allows control of LC and HC ratio andreduces non-expressing cells. Four 2A peptidesderived from the foot-and-mouth disease virus(F2A), equine rhinitis A virus (E2A), porcineteschovirus-1 (P2A) and Thosea asigna virus(T2A), respectively, were compared forexpression of 3 biosimilar IgG1 mAbs in Chinesehamster ovary (CHO) cell lines. HC and LC werelinked by different 2A peptides both in theabsence and presence of GSG linkers. Insertionof a furin recognition site upstream of 2A allowedremoval of 2A residues that would otherwise beattached to the HC. Different 2A peptidesexhibited different cleavage efficiencies thatcorrelated to the mAb expression level. Therelative cleavage efficiency of each 2A peptideremains similar for expression of different IgG1", "metadata": {}}
+{"_id": "26112624", "title": "", "text": "The complexity of human ribosome biogenesisrevealed by systematic nucleolar screening ofPre-rRNA processing factors.Mature ribosomalRNAs (rRNAs) are produced from polycistronicprecursors following complex processing.Precursor (pre)-rRNA processing has beenextensively characterized in yeast and wasassumed to be conserved in humans. Wefunctionally characterized 625 nucleolar proteinsin HeLa cells and identified 286 required forprocessing, including 74 without a yeasthomolog. For selected candidates, wedemonstrated that pre-rRNA processing defectsare conserved in different cell types (includingprimary cells), defects are not due to activationof a p53-dependent nucleolar tumor surveillancepathway, and they precede cell-cycle arrest andapoptosis. We also investigated the exosome'srole in processing internal transcribed spacers(ITSs) and report that 3' end maturation of 18SrRNA involves EXOSC10/Rrp6, a yeast ITS2processing factor. We conclude that human cells", "metadata": {}}
+{"_id": "26112696", "title": "", "text": "Maximal aerobic capacity in African-Americanand Caucasian prepubertal children.The purposeof this study was to examine differences inresting, submaximal, and maximal (VO2max)oxygen consumption (VO2) in African-American(n = 44) and Caucasian (n = 31) prepubertalchildren aged 5-10 yr. Resting VO2 wasmeasured via indirect calorimetry in the fastedstate. Submaximal VO2 and VO2max weredetermined during an all out, progressivetreadmill exercise test appropriate for children.Dual-energy X-ray absorptiometry was used todetermine total fat mass (FM), soft lean tissuemass (LTM), and leg soft LTM. Doubly labeledwater was used to determine total energyexpenditure (TEE) and activity energyexpenditure (AEE). A significant effect ofethnicity (P < 0.01) was found for VO2max butnot resting or submaximal VO2, withAfrican-American children having absoluteVO2max approximately 15% lower thanCaucasian children (1.21 +/- 0.032 vs. 1.43 +/-", "metadata": {}}
+{"_id": "26117607", "title": "", "text": "Penaeus monodon Dscam (PmDscam) has ahighly diverse cytoplasmic tail and is the firstmembrane-bound shrimp Dscam to bereported.Down syndrome cell adhesion molecule(Dscam) seems likely to play a key role in the\"alternative adaptive immunity\" that has beenreported in invertebrates. Dscam consists of acytoplasmic tail that is involved in signaltransduction and a hypervariable extracellularregion that might use a pathogen recognitionmechanism similar to that used by the vertebrateantibodies. In our previous paper, we isolated aunique tail-less form of Dscam from Litopenaeusvannamei. In this study, we report the firstmembrane-bound form of shrimp Dscam:PmDscam was isolated from Penaeus monodon,and it occurred in both membrane-bound andtail-less forms. Phylogenetic analysis showedthat while the crustacean Dscams from shrimpand water flea did not share a single subclade,they were distinct from the invertebrateDscam-like molecules and from the insecta", "metadata": {}}
+{"_id": "26118532", "title": "", "text": "The different biological effects of telomestatinand TMPyP4 can be attributed to their selectivityfor interaction with intramolecular orintermolecular G-quadruplexstructures.Demonstration of the existence ofG-quadruplex structures in telomeres ofStylonychia macronuclei and in the promoter ofc-myc in human cells has validated thesesecondary DNA structures as potential targets fordrug design. The next important issue is theselectivity of G-quadruplex-interactive agents forthe different types of G-quadruplex structures.In this study, we have taken an important step inassociating specific biological effects of thesedrugs with selective interaction with eitherintermolecular or intramolecular G-quadruplexstructures formed in telomeres. Telomestatin is anatural product isolated from Streptomycesanulatus 3533-SV4 and has been shown to be avery potent telomerase inhibitor through itsG-quadruplex interaction. We havedemonstrated that telomestatin interacts", "metadata": {}}
+{"_id": "26121646", "title": "", "text": "Targeting oxidative stress to treatendometriosis.INTRODUCTION Endometriosisaffects 10% of women of reproductive age. It isdefined as the presence of implanted activeendometrial tissue outside the uterine cavity.The exact pathophysiology of endometriosis isstill uncertain, although several optionaletiological theories have been suggested. Beingso common, a novel treatment for endometriosisis widely quested. Recent studies addressing thepathological characteristics of endometriosishave revealed a vicious cycle in which oxidativestress (OS) is generated, which in turn facilitatesthe implantation of the ectopic endometrium. Atthe same time, the generation of high amountsof reactive oxygen species further triggers astate of OS. AREAS COVERED The authorexamined the evidence associating OS andendometriosis. After establishing an association,a search for antioxidant agents that wereinvestigated specifically on endometriosispatients are described including Vitamins C and", "metadata": {}}
+{"_id": "26124606", "title": "", "text": "Interferon alpha for the treatment of chronichepatitis C in patients infected with humanimmunodeficiency virus. Hepatitis-HIV SpanishStudy Group.Liver disease secondary to hepatitisC virus (HCV) infection is a rising cause ofmorbidity and mortality among individuals whohave been infected parenterally with humanimmunodeficiency virus (HIV) such as injectiondrug users, hemophiliacs, and transfusedpatients. We analyzed both the efficacy ofinterferon (IFN) alpha therapy in these patientsand the predictors of response to this agent. Atotal of 119 patients with chronic hepatitis C (90of whom were infected with HIV and 29 of whomwere not) were included in a multicenter,prospective, open, nonrandomized observationalstudy. IFN-alpha was given subcutaneously in adosage of 5 million units three times a weekduring a 3-month period; those patients whoresponded received a dose of 3 million unitsgiven subcutaneously three times a week for anadditional 9 months. One hundred seven patients", "metadata": {}}
+{"_id": "26132041", "title": "", "text": "Vanishing cerebellar infarcts in a migrainepatient.Recent population-based studies havesuggested that migraine is a risk factor for thedevelopment of infarct-like lesions in theterritory of the posterior circulation. Theselesions are thought to be true vascular infarctsbased on their size, location and magneticresonance imaging (MRI) characteristics.However, as there are no postmortem studiesidentifying the pathology of these MRI findings,their true aetiology is unknown. A case patientwith migraine is presented, who developed whatappeared to be cerebellar infarcts on MRI, butthese lesions vanished on repeat imaging 16days later, questioning their aetiology asvascular ischaemic based infarcts.", "metadata": {}}
+{"_id": "26133404", "title": "", "text": "A novel viral transcript with homology to humaninterleukin-10 is expressed during latent humancytomegalovirus infection.Humancytomegalovirus (CMV) establishes latentinfections in hematopoietic cells such asgranulocyte-macrophage progenitors (GM-Ps).During latency the virus is sequestered in anonreplicating state, although limitedtranscriptional activity has been previouslyreported. In this study we sought to furtherexamine viral gene expression during the latentphase of infection. Using an experimental modelof latency, primary human GM-Ps were latentlyinfected with CMV strain Toledo and extractedRNA subjected to reverse transcription-PCR byusing CMV gene-specific primers. Using thisapproach, we detected transcription from theUL111.5A region of the viral genome. Thistranscription was also detected in GM-Ps latentlyinfected with AD169 and Towne strains,indicating that expression was CMV strainindependent. Significantly, we detected", "metadata": {}}
+{"_id": "26150367", "title": "", "text": "Treatments for somnambulism in adults:assessing the evidence.Somnambulism, orsleepwalking, is a parasomnia of non-rapid eyemovement (NREM) sleep where movementbehaviours usually confined to wakefulness aredisplayed during sleep. Generally, if sleepwalkingis causing distress or danger in spite of safetymeasures, medical or psychological treatment isindicated. Clinicians will need to assess theevidence for treatment options. MEDLINE,EMBASE, PsycINFO and the Ovid Evidence-BasedMedicine Reviews (EBM) multifile databases weresearched. No properly powered rigorouscontrolled trials were found for treatment ofsleepwalking in adults. Seven reports describedsmall trials with some kind of control arm, orretrospective case series which included 30 ormore patients. With no high quality evidence tounderpin recommendations for treatments ofsomnambulism, full discussion with patients isadvised. Adequately powered, well-designedclinical trials are now needed, and multi-centre", "metadata": {}}
+{"_id": "26182390", "title": "", "text": "Premature chromosome condensation: evidencefor in vivo cell fusion in human malignanttumours.Premature chromosome condensation(PCC) was studied in direct preparations oftissues from patients with haematologicaldiseases and carcinomas of various histologicaltypes. PCC was found in 6 out of 166malignancies (128 haematological cases, 35carcinomas and 3 malignant effusions) analysedwith the GTG-technique. Chromosome analysisrevealed S-phase and G1-phase PCC in eachcase; the frequency of PCC varied between 1, 4and 8.6% of the metaphases analysed. It issuggested that PCC chromosomes, whichrepresent cell fusion in vivo, are not very rare innaturally-occurring human malignancies, andthat cell fusion may affect the malignantphenotype. In conjunction with other factorsthey may also explain the heterogeneity oftumour cell populations.", "metadata": {}}
+{"_id": "26199970", "title": "", "text": "Blockade of the angiotensin system improvesmental health domain of quality of life: Ameta-analysis of randomized clinicaltrialsObjective: It is unclear whether blockade ofthe angiotensin system has effects on mentalhealth. Our objective was to determine theimpact of angiotensin converting enzymeinhibitors and angiotensin II type 1 receptor(AT1R) blockers on mental health domain ofquality of life. Study design: Meta-analysis ofpublished literature. Data sources: PubMed andclinicaltrials.gov databases. The last search wasconducted in January 2017. Study selection:Randomized controlled trials comparing anyangiotensin converting enzyme inhibitor or AT1Rblocker versus placebo or non-angiotensinconverting enzyme inhibitor or non-AT1R blockerwere selected. Study participants were adultswithout any major physical symptoms. Weadhered to meta-analysis reporting methods asper PRISMA and the Cochrane Collaboration.Data synthesis: Eleven studies were included in", "metadata": {}}
+{"_id": "26230669", "title": "", "text": "The role of epigenetics in aging andautoimmunity.The decline in immunocompetencewith age is accompanied by the increase in theincidence of autoimmune diseases. Aging of theimmune system, or immunosenescence, ischaracterized by a decline of both T and B cellfunction, and paradoxically the presence oflow-grade chronic inflammation. There isgrowing evidence that epigenetics, the study ofinherited changes in gene expression that arenot encoded by the DNA sequence itself, changeswith aging. Interestingly, emerging evidencesuggests a key role for epigenetics in humanpathologies, including inflammatory andneoplastic disorders. Here, we will review thepotential mechanisms that contribute to theincrease in autoimmune responses in aging. Inparticular, we will discuss how epigeneticalterations, especially DNA methylation andhistone acetylation, are accumulated duringaging and how these events contribute toautoimmunity risk.", "metadata": {}}
+{"_id": "26231129", "title": "", "text": "A framework for understanding and targetingresidual disease in oncogene-driven solidcancersMolecular targeted therapy has thepotential to dramatically improve survival inpatients with cancer. However, complete anddurable responses to targeted therapy are rare inindividuals with advanced-stage solid cancers.Even the most effective targeted therapiesgenerally do not induce a complete tumorresponse, resulting in residual disease and tumorprogression that limits patient survival. Wediscuss the emerging need to more fullyunderstand the molecular basis of residualdisease as a prelude to designing therapeuticstrategies to minimize or eliminate residualdisease so that we can move from temporary tochronic control of disease, or a cure, for patientswith advanced-stage solid cancers. Ultimately,we propose a shift from the current reactiveparadigm of analyzing and treating acquired drugresistance to a pre-emptive paradigm of definingthe mechanisms that result in residual disease,", "metadata": {}}
+{"_id": "26244918", "title": "", "text": "Long-term inhibition of dipeptidyl peptidase-4 inAlzheimer's prone mice.We tested here theimpact of a long-term inhibition of dipeptidylpeptidase-4 (DPP-4) with sitagliptin on thedeposition of amyloid-beta within the brain anddeficits in memory-related behavioral paradigmsin a model of Alzheimer's disease (AD): doubletransgenic miceB6*Cg-Tg(APPswe,PSEN1dE9)85Dbo/J. Micebegan to receive sitagliptin at 7 months of age.Three different dose of sitagliptin (5, 10 and 20mg/kg), were administered daily for 12 weeks bygastric gavage. The treatments counteracted: (i)the memory impairment in the contextual fearconditioning test; (ii) increased the brain levelsof GLP-1; (iii) produced significant reductions ofnitrosative stress and inflammation hallmarkswithin the brain, as well as (iv) a significantdiminution in the ultimate number and total areaof betaAPP and Abeta deposits. All these effectsmuch more evident for the dose of 20 mg/kgsitagliptin. The long-term inhibition of the", "metadata": {}}
+{"_id": "26283293", "title": "", "text": "Structural and mechanistic insights intophospholipid transfer by Ups1–Mdm35 inmitochondriaEukaryotic cells arecompartmentalized into membrane-boundedorganelles whose functions rely on lipidtrafficking to achieve membrane-specificcompositions of lipids. Here we focused on theUps1-Mdm35 system, which mediatesphosphatidic acid (PA) transfer between theouter and inner mitochondrial membranes, anddetermined the X-ray structures of Mdm35 andUps1-Mdm35 with and without PA. TheUps1-Mdm35 complex constitutes a singledomain that has a deep pocket and flexibleΩ-loop lid. Structure-based mutational analysesrevealed that a basic residue at the pocketbottom and the Ω-loop lid are important for PAextraction from the membrane following Ups1binding. Ups1 binding to the membrane isenhanced by the dissociation of Mdm35. We alsoshow that basic residues around the pocketentrance are important for Ups1 binding to the", "metadata": {}}
+{"_id": "26297042", "title": "", "text": "Redox regulation of cell migration andadhesion.Reactive oxygen species (ROS),particularly hydrogen peroxide, and the proteinsthat regulate them play important roles in themigration and adhesion of cells. Stimulation ofcell surface receptors with growth factors andchemoattractants generates ROS, which relaysignals from the cell surface to key signalingproteins inside the cell. ROS act within cells topromote migration and also in nonmigrating cellsto influence the behavior of migrating cells.Hydrogen peroxide has also been suggested toact as a chemoattractant in its own right,drawing immune cells to wounds. We discussrecent progress made towards understandinghow organisms use ROS, and to what degreethey depend on them, during the relatedprocesses of cell migration and adhesion.", "metadata": {}}
+{"_id": "26314743", "title": "", "text": "Systemic Inflammatory Response Syndrome,Quick Sequential Organ Function Assessment,and Organ Dysfunction: Insights From aProspective Database of ED Patients WithInfectionBACKGROUND: A proposed revision ofsepsis definitions has abandoned the systemicinflammatory response syndrome (SIRS),defined organ dysfunction as an increase in totalSequential Organ Function Assessment (SOFA)score of ≥ 2, and conceived “qSOFA” (quickSOFA) as a bedside indicator of organdysfunction. We aimed to (1) determine theprognostic impact of SIRS, (2) compare thediagnostic accuracy of SIRS and qSOFA for organdysfunction, and (3) compare standard(Sepsis\u00002) and revised (Sepsis\u00003) definitionsfor organ dysfunction in ED patients withinfection. METHODS: Consecutive ED patientsadmitted with presumed infection wereprospectively enrolled over 3 years. Sufficientobservational data were collected to calculateSIRS, qSOFA, SOFA, comorbidity, and mortality.", "metadata": {}}
+{"_id": "26330861", "title": "", "text": "Requirement of NAD and SIR2 for life-spanextension by calorie restriction in Saccharomycescerevisiae.Calorie restriction extends life-span ina wide variety of organisms. Although it hasbeen suggested that calorie restriction may workby reducing the levels of reactive oxygen speciesproduced during respiration, the mechanism bywhich this regimen slows aging is uncertain.Here, we mimicked calorie restriction in yeast byphysiological or genetic means and showed asubstantial extension in life-span. This extensionwas not observed in strains mutant for SIR2(which encodes the silencing protein Sir2p) orNPT1 (a gene in a pathway in the synthesis ofNAD, the oxidized form of nicotinamide adeninedinucleotide). These findings suggest that theincreased longevity induced by calorie restrictionrequires the activation of Sir2p by NAD.", "metadata": {}}
+{"_id": "26336593", "title": "", "text": "Pathways disrupted in human ALS motor neuronsidentified through genetic correction of mutantSOD1.Although many distinct mutations in avariety of genes are known to cause AmyotrophicLateral Sclerosis (ALS), it remains poorlyunderstood how they selectively impact motorneuron biology and whether they converge oncommon pathways to cause neuronaldegeneration. Here, we have combinedreprogramming and stem cell differentiationapproaches with genome engineering and RNAsequencing to define the transcriptional andfunctional changes that are induced in humanmotor neurons by mutant SOD1. Mutant SOD1protein induced a transcriptional signatureindicative of increased oxidative stress, reducedmitochondrial function, altered subcellulartransport, and activation of the ER stress andunfolded protein response pathways. Functionalstudies demonstrated that these pathways wereperturbed in a manner dependent on the SOD1mutation. Finally, interrogation of", "metadata": {}}
+{"_id": "26341063", "title": "", "text": "Effect of enalapril on 12-year survival and lifeexpectancy in patients with left ventricularsystolic dysfunction: a follow-upstudy.BACKGROUND In the studies of leftventricular dysfunction (SOLVD), enalaprilreduced mortality in patients with symptomaticbut not asymptomatic left ventricular systolicdysfunction during the trial. We did a 12-yearfollow-up of SOLVD to establish if the mortalityreduction with enalapril among patients withheart failure was sustained, and whether asubsequent reduction in mortality would emergeamong those with asymptomatic ventriculardysfunction. METHODS Of the 6797 patientspreviously enrolled in the SOLVD prevention andtreatment trials, we ascertained the subsequentvital status of 5165 individuals who were alivewhen the trials had been completed. Follow-upwas done through direct contacts in Belgium andlinkages with national death registries andfederal beneficiary or historic tax summary filesin the USA and Canada. FINDINGS Follow-up", "metadata": {}}
+{"_id": "26374799", "title": "", "text": "TGFbeta/activin/nodal signaling is necessary forthe maintenance of pluripotency in humanembryonic stem cells.Human embryonic stemcells (hESCs) self-renew indefinitely and give riseto derivatives of all three primary germ layers,yet little is known about the signaling cascadesthat govern their pluripotent character. Becauseit plays a prominent role in the early cell fatedecisions of embryonic development, we haveexamined the role of TGFbeta superfamilysignaling in hESCs. We found that, inundifferentiated cells, the TGFbeta/activin/nodalbranch is activated (through the signaltransducer SMAD2/3) while the BMP/GDF branch(SMAD1/5) is only active in isolated mitotic cells.Upon early differentiation, SMAD2/3 signaling isdecreased while SMAD1/5 signaling is activated.We next tested the functional role ofTGFbeta/activin/nodal signaling in hESCs andfound that it is required for the maintenance ofmarkers of the undifferentiated state. We extendthese findings to show that SMAD2/3 activation", "metadata": {}}
+{"_id": "26378103", "title": "", "text": "The structure and expression of a novel geneactivated in early mouse embryogenesis.Wereport the cloning and sequence determination ofthe mouse H19 gene. This gene is under thegenetic control of two trans-acting loci in themouse, termed raf and Rif. These loci determinethe adult basal and inducible levels, respectively,of H19 mRNA, as well as the mRNA foralpha-fetoprotein. By elucidating the sequenceand structure of the H19 gene we show that it isunrelated to the alpha-fetoprotein gene, andtherefore must have acquired its regulation byraf and Rif independently. The sequence alsoindicates that the H19 gene has a very unusualstructure. It is composed of five exons, 1307,135, 119, 127 and 560 bp in size, along with fourvery small introns whose combined lengths are270 bases. The largest open reading frame of thegene, sufficient to encode a protein ofapproximately 14 kd, is contained entirely withinthe first large exon, 680 bases downstream ofthe cap site of the mRNA. Preceding the", "metadata": {}}
+{"_id": "26409363", "title": "", "text": "Diminished linear growth during intermittentcalcitriol therapy in children undergoingCCPD.Daily calcitriol therapy has been reportedto improve linear growth in children with renalbone disease, and 1,25-dihydroxyvitamin D is akey regultor of chondrocyte proliferation anddifferentiation. Whereas large intermittent dosesof calcitriol can lower serum parathyroidhormone (PTH) levels and reverse the skeletalchanges of secondary hyperparathyroidism, theimpact of intermittent calcitriol therapy on lineargrowth in children is not known. Thus, westudied 16 pre-pubertal patients with bonebiopsy-proven secondary hyperparathyroidismwho completed a 12-month prospective clinicaltrial of intermittent calcitriol therapy.Biochemical results and growth data obtainedduring intermittent calcitriol therapy werecompared to values determined during thepreceding 12 months of daily calcitriol therapy ineach study subject; changes in bone histologywere assessed after one year of intermittent", "metadata": {}}
+{"_id": "26445118", "title": "", "text": "Comparison of pain syndromes associated withnervous or somatic lesions and development of anew neuropathic pain diagnostic questionnaire(DN4)Few studies have directly compared theclinical features of neuropathic andnon-neuropathic pains. For this purpose, theFrench Neuropathic Pain Group developed aclinician-administered questionnaire named DN4consisting of both sensory descriptors and signsrelated to bedside sensory examination. Thisquestionnaire was used in a prospective study of160 patients presenting with pain associatedwith a definite neurological or somatic lesion.The most common aetiologies of nervous lesions(n=89) were traumatic nerve injury, postherpetic neuralgia and post stroke pain.Non-neurological lesions (n=71) wererepresented by osteoarthritis, inflammatoryarthropathies and mechanical low back pain.Each patient was seen independently by twoexperts in order to confirm the diagnosis ofneuropathic or non-neuropathic pain. The", "metadata": {}}
+{"_id": "26456326", "title": "", "text": "Changing the density of alcohol outlets to reducealcohol-related problems.Increasingly, it seems,legal and political debates regarding the grantingof new liquor licences are turning to the issue ofwhether the number and density of alcoholoutlets makes a difference in rates of alcoholconsumption and alcohol-related harm. But whatis the state of the evidence on this question? Inthis Harm Reduction Digest Livingston, Chikritzhsand Room review the research literature on theeffects of density of alcohol sales outlets onalcohol consumption and alcohol-relatedproblems; suggest a new way of conceptualisingthe relationships; and discuss the implicationsfor reducing alcohol-related harm.", "metadata": {}}
+{"_id": "26461066", "title": "", "text": "[Pharmacokinetics and biotransformation of theantimycotic drug ciclopiroxolamine in animalsand man after topical and systemicadministration].1. Following the dermalapplication of the carbon-14 labelled broadspectrum antimycotic 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone, 2-aminoethanol salt(ciclopiroxolamine, Hoe 296, Batrafen) in theform of a 1% aqueous cream to healthy humandorsal skin (penetration time: 6 h; occlusivedressing for 5 h), percutaneous absorptionaccounted on average for 1.3% of the doseapplied. Excretion occurred via the kidney, withbiological half-lives of 1.7 h. As can be seen frompenetration studies of cadaverous skin, thehorny layer contained the highestconcentrations, with values of 2300-4500microgram/cm3. The levels determined in thecorium were still above the minimum inhibitoryconcentrations. These concentrations werealready obtained at the first test stage (1.5 hafter application) and did not change virtually at", "metadata": {}}
+{"_id": "26462632", "title": "", "text": "Maximizing the diagnostic utility of endoscopicbiopsy in dogs and cats with gastrointestinaldisease.Flexible endoscopy has become avaluable tool for the diagnosis of many smallanimal gastrointestinal (GI) diseases, but thetechniques must be performed carefully so thatthe results are meaningful. This article reviewsthe current diagnostic utility of flexibleendoscopy, including practical/technicalconsiderations for endoscopic biopsy, optimalinstrumentation for mucosal specimen collection,the correlation of endoscopic indices to clinicalactivity and to histopathologic findings, and newdevelopments in the endoscopic diagnosis of GIdisease. Recent studies have defined endoscopicbiopsy guidelines for the optimal number andquality of diagnostic specimens from differentregions of the gut. They also have shown thevalue of ileal biopsy in the diagnosis of canineand feline chronic enteropathies, and havedemonstrated the utility of endoscopic biopsyspecimens beyond routine hematoxylin and eosin", "metadata": {}}
+{"_id": "26474812", "title": "", "text": "Age-structured red blood cell susceptibility andthe dynamics of malaria infections.Malariaparasites and immune responses in an infectedhuman interact on a dynamic landscape, in whicha population of replicating parasites depletes apopulation of replenishing red blood cells (RBCs).These underlying dynamics receive relativelylittle attention, but they offer unique insights intothe processes that control most malariainfections. Here, we focus on the observationthat three of the four malaria-parasite speciesthat infect humans are restricted to particularage classes of RBC. We explicitly incorporate thisobservation in models of infection dynamics todistinguish common from species-specificpressures on host immune responses, and wefind that age structuring has profound effects onthe course of infection. For all four speciesconditions exist under which the parasites maypersist at low densities, or may clear, even in theabsence of an immune response. Catastrophicanemia can occur even with the two species that", "metadata": {}}
+{"_id": "26488879", "title": "", "text": "Helicobacter pylori AlpA and AlpB bind hostlaminin and influence gastric inflammation ingerbils.Helicobacter pylori persistently colonizeshumans, causing gastritis, ulcers, and gastriccancer. Adherence to the gastric epithelium hasbeen shown to enhance inflammation, yet only afew H. pylori adhesins have been paired withtargets in host tissue. The alpAB locus has beenreported to encode adhesins involved inadherence to human gastric tissue. We reportthat abrogation of H. pylori AlpA and AlpBreduces binding of H. pylori to laminin whileexpression of plasmid-borne alpA or alpB conferslaminin-binding ability to Escherichia coli. An H.pylori strain lacking only AlpB is also deficient inlaminin binding. Thus, we conclude that bothAlpA and AlpB contribute to H. pylori lamininbinding. Contrary to expectations, the H. pyloriSS1 mutant deficient in AlpA and AlpB causesmore severe inflammation than the isogenicwild-type strain in gerbils. Identification oflaminin as the target of AlpA and AlpB will", "metadata": {}}
+{"_id": "26491450", "title": "", "text": "A quantitative analysis of kinase inhibitorselectivityKinase inhibitors are a new class oftherapeutics with a propensity to inhibit multipletargets. The biological consequences ofmulti-kinase activity are poorly defined, and animportant step toward understanding therelationship between selectivity, efficacy andsafety is the exploration of how inhibitorsinteract with the human kinome. We presentinteraction maps for 38 kinase inhibitors across apanel of 317 kinases representing >50% of thepredicted human protein kinome. The dataconstitute the most comprehensive study ofkinase inhibitor selectivity to date and reveal awide diversity of interaction patterns. To enablea global analysis of the results, we introduce theconcept of a selectivity score as a general tool toquantify and differentiate the observedinteraction patterns. We further investigate theimpact of panel size and find that small assaypanels do not provide a robust measure ofselectivity.", "metadata": {}}
+{"_id": "26495128", "title": "", "text": "Ribosomal protein S9 is a novelB23/NPM-binding protein required for normal cellproliferation.B23 (NPM/nucleophosmin) is amultifunctional nucleolar protein and a memberof the nucleoplasmin superfamily of acidichistone chaperones. B23 is essential for normalembryonic development and plays an importantrole in genomic stability, ribosome biogenesis,and anti-apoptotic signaling. Altered proteinexpression or genomic mutation of B23 isencountered in many different forms of cancer.Although described as multifunctional, a genuinemolecular function of B23 is not fully understood.Here we show that B23 is associated with aprotein complex consisting of ribosomal proteinsand ribosome-associated RNA helicases. A novel,RNA-independent interaction between ribosomalprotein S9 (RPS9) and B23 was furtherinvestigated. We found that S9 binding requiresan intact B23 oligomerization domain. Depletionof S9 by small interfering RNA resulted indecreased protein synthesis and G(1) cell cycle", "metadata": {}}
+{"_id": "26501027", "title": "", "text": "Vasculature-associated cells expressing nestin indeveloping bones encompass early cells in theosteoblast and endotheliallineage.Nestin-positive (Nes(+)) cells areimportant hematopoiesis-supporting constituentsin adult bone marrow. However, how these cellsoriginate during endochondral bone developmentis unknown. Studies using mice expressing GFPunder the direction of nestin promoter/enhancer(Nes-GFP) revealed distinct endothelial andnonendothelial Nes(+) cells in the embryonicperichondrium; the latter were early cells of theosteoblast lineage immediately descended fromtheir progenitors upon Indian hedgehog actionand Runx2 expression. During vascular invasionand formation of ossification centers, theseNes(+) cells were closely associated with eachother and increased in number progressively.Interestingly, cells targeted bytamoxifen-inducible cre recombinase driven bynestin enhancer (Nes-creER) in developing bonemarrow were predominantly endothelial cells.", "metadata": {}}
+{"_id": "26532518", "title": "", "text": "Public health, academic medicine, and thealcohol industry's corporate social responsibilityactivities.We explored the emerging relationshipsamong the alcohol industry, academic medicine,and the public health community in the contextof public health theory dealing with corporatesocial responsibility. We reviewed sponsorship ofscientific research, efforts to influence publicperceptions of research, dissemination ofscientific information, and industry-funded policyinitiatives. To the extent that the scientificevidence supports the reduction of alcoholconsumption through regulatory and legalmeasures, the academic community has comeinto increasing conflict with the views of thealcohol industry. We concluded that the alcoholindustry has intensified its scientific andpolicy-related activities under the generalframework of corporate social responsibilityinitiatives, most of which can be described asinstrumental to the industry's economicinterests.", "metadata": {}}
+{"_id": "26561572", "title": "", "text": "RET, ROS1 and ALK fusions in lungcancerThrough an integrated molecular- andhistopathology-based screening system, weperformed a screening for fusions of anaplasticlymphoma kinase (ALK) and c-ros oncogene 1,receptor tyrosine kinase (ROS1) in 1,529 lungcancers and identified 44 ALK-fusion–positiveand 13 ROS1-fusion–positive adenocarcinomas,including for unidentified fusion partners forROS1. In addition, we discovered previouslyunidentified kinase fusions that may bepromising for molecular-targeted therapy,kinesin family member 5B (KIF5B)-retproto-oncogene (RET) and coiled-coil domaincontaining 6 (CCDC6)-RET, in 14adenocarcinomas. A multivariate analysis of1,116 adenocarcinomas containing these 71kinase-fusion–positive adenocarcinomasidentified four independent factors that areindicators of poor prognosis: age ≥50 years,male sex, high pathological stage and negativekinase-fusion status.", "metadata": {}}
+{"_id": "26596106", "title": "", "text": "Genetic and biochemical interactions amongYar1, Ltv1 and Rps3 define novel links betweenenvironmental stress and ribosome biogenesis inSaccharomyces cerevisiae.In the yeast S.cerevisiae, ribosome assembly is linked toenvironmental conditions by the coordinatetranscriptional regulation of genes required forribosome biogenesis. In this study we show thattwo nonessential stress-responsive genes, YAR1and LTV1, function in 40S subunit production.We provide genetic and biochemical evidencethat Yar1, a small ankyrin-repeat protein,physically interacts with RpS3, a component ofthe 40S subunit, and with Ltv1, a proteinrecently identified as a substoichiometriccomponent of a 43S preribosomal particle. Wedemonstrate that cells lacking YAR1 or LTV1 arehypersensitive to particular protein synthesisinhibitors and exhibit aberrant polysome profiles,with a reduced absolute number of 40S subunitsand an excess of free 60S subunits. Surprisingly,both mutants are also hypersensitive to a variety", "metadata": {}}
+{"_id": "26607366", "title": "", "text": "Rational design of acridine-based ligands withselectivity for human telomericquadruplexes.Structure-based modeling methodshave been used to design a series ofdisubstituted triazole-linked acridine compoundswith selectivity for human telomeric quadruplexDNAs. A focused library of these compounds wasprepared using click chemistry and the selectivityconcept was validated against two promoterquadruplexes from the c-kit gene with knownmolecular structures, as well as with duplex DNAusing a FRET-based melting method. Leadcompounds were found to have reduced effectson the thermal stability of the c-kit quadruplexesand duplex DNA structures. These effects werefurther explored with a series of competitionexperiments, which confirmed that binding toduplex DNA is very low even at highduplex:telomeric quadruplex ratios. Selectivity tothe c-kit quadruplexes is more complex, withsome evidence of their stabilization at increasingexcess over human telomeric quadruplex DNA.", "metadata": {}}
+{"_id": "26611094", "title": "", "text": "Hospital volume and the outcomes of mechanicalventilation.BACKGROUND An increased volumeof patients is associated with improved survivalin numerous high-risk medical and surgicalconditions. The relationship between the numberof patients admitted (hospital volume) andoutcome among patients with critical illnesses isunknown. METHODS We analyzed data from20,241 nonsurgical patients receiving mechanicalventilation at 37 acute care hospitals in theAcute Physiology and Chronic Health Evaluationclinical information system from 2002 through2003. Multivariate analyses were performed toadjust for the severity of illness and otherdifferences in the case mix. RESULTS An increasein hospital volume was associated with improvedsurvival among patients receiving mechanicalventilation in the intensive care unit (ICU) and inthe hospital. Admission to a hospital in thehighest quartile according to volume (i.e., >400patients receiving mechanical ventilation peryear) was associated with a 37 percent reduction", "metadata": {}}
+{"_id": "26611834", "title": "", "text": "A meta-analysis of depression during pregnancyand the risk of preterm birth, low birth weight,and intrauterine growth restriction.CONTEXTMaternal depressive symptoms during pregnancyhave been reported in some, but not all, studiesto be associated with an increased risk ofpreterm birth (PTB), low birth weight (LBW), andintrauterine growth restriction (IUGR).OBJECTIVE To estimate the risk of PTB, LBW,and IUGR associated with antenatal depression.DATA SOURCES AND STUDY SELECTION Wesearched for English-language andnon-English-language articles via the MEDLINE,PsycINFO, CINAHL, Social Work Abstracts, SocialServices Abstracts, and Dissertation AbstractsInternational databases (January 1980 throughDecember 2009). We aimed to includeprospective studies reporting data on antenataldepression and at least 1 adverse birth outcome:PTB (<37 weeks' gestation), LBW (<2500 g), orIUGR (<10th percentile for gestational age). Of862 reviewed studies, 29 US-published and", "metadata": {}}
+{"_id": "26612216", "title": "", "text": "ES cell pluripotency and germ-layer formationrequire the SWI/SNF chromatin remodelingcomponent BAF250a.ATP-dependent chromatinremodeling complexes are a notable group ofepigenetic modifiers that use the energy of ATPhydrolysis to change the structure of chromatin,thereby altering its accessibility to nuclearfactors. BAF250a (ARID1a) is a unique anddefining subunit of the BAF chromatinremodeling complex with the potential tofacilitate chromosome alterations critical duringdevelopment. Our studies show that ablation ofBAF250a in early mouse embryos results indevelopmental arrest (about embryonic day 6.5)and absence of the mesodermal layer, indicatingits critical role in early germ-layer formation.Moreover, BAF250a deficiency compromises EScell pluripotency, severely inhibits self-renewal,and promotes differentiation into primitiveendoderm-like cells under normal feeder-freeculture conditions. Interestingly, this phenotypecan be partially rescued by the presence of", "metadata": {}}
+{"_id": "26625002", "title": "", "text": "Metabolic shutdown in Escherichia coli cellslacking the outer membrane channel TolC.Theouter membrane channel TolC is a keycomponent of multidrug efflux and type Isecretion transporters in Escherichia coli.Mutational inactivation of TolC renders cellshighly susceptible to antibiotics and leads todefects in secretion of protein toxins. Despiteimpairment of various transport functions, nogrowth defects were reported in cells lackingTolC. Unexpectedly, we found that the loss ofTolC notably impairs cell division and growth inminimal glucose medium. The TolC-dependentphenotype was further exacerbated by the lossof ygiB and ygiC genes expressed in the sameoperon as tolC and their homologues yjfM andyjfC located elsewhere on the chromosome. Ourresults show that this growth deficiency iscaused by depletion of the critical metaboliteNAD(+) and high NADH/NAD(+) ratios. Theincreased amounts of PspA and decreased ratesof NADH oxidation in Delta tolC membranes", "metadata": {}}
+{"_id": "26652147", "title": "", "text": "Acyl and total ghrelin are suppressed strongly byingested proteins, weakly by lipids, andbiphasically by carbohydrates.CONTEXT Ghrelinis an orexigenic hormone that can increase bodyweight. Its circulating levels increase beforemeals and are suppressed after food ingestion.Understanding the effects of specific types ofingested macronutrients on ghrelin regulationcould facilitate the design of weight-reducingdiets. OBJECTIVE We sought to understand howingestion of carbohydrates, proteins, or lipidsaffect acyl (bioactive) and total ghrelin levelsamong human subjects, hypothesizing that lipidsmight suppress ghrelin levels less effectivelythan do either carbohydrates or proteins.DESIGN This was a randomized, within-subjectscross-over study. SETTING The study wasconducted at a University Clinical ResearchCenter. PARTICIPANTS There were 16 healthyhuman subjects included in the study.INTERVENTIONS Isocaloric, isovolemicbeverages composed primarily of carbohydrates,", "metadata": {}}
+{"_id": "26658659", "title": "", "text": "Hydrogen sulfide increases nitric oxideproduction with calcium-dependent activation ofendothelial nitric oxide synthase in endothelialcells.Hydrogen sulfide (H(2)S) was recentlydiscovered to be synthesized in mammaliantissues by several different enzymes. Numerousstudies have shown that H(2)S has vasodilatorand antihypertensive effects in thecardiovascular system. However, intracellularmechanisms of the H(2)S-induced vasodilationand its interactions with otherendothelium-derived relaxing factors, such asnitric oxide (NO), remain unclear. Weinvestigated whether H(2)S directly regulatesendothelial NO synthase (eNOS) activity and NOproduction in endothelial cells. NaHS, a H(2)Sdonor, dose-dependently increased NOproduction in cultured endothelial cells. Thiseffect was abolished by a calcium chelator(BAPTA-AM), but not by the absence ofextracellular calcium. The NaHS-induced NOproduction was partially blocked by inhibitors of", "metadata": {}}
+{"_id": "26668245", "title": "", "text": "Fear of falling and visual field loss fromglaucoma.OBJECTIVE To determine if visual field(VF) loss resulting from glaucoma is associatedwith greater fear of falling. DESIGN Prospective,observational study. PARTICIPANTS Fear offalling was compared between 83 glaucomasubjects with bilateral VF loss and 60 controlsubjects with good visual acuity and withoutsignificant VF loss recruited from patientsfollowed up for suspicion of glaucoma. METHODSParticipants completed the University of Illinoisat Chicago Fear of Falling Questionnaire. Theextent of fear of falling was assessed usingRasch analysis. MAIN OUTCOME MEASURESSubject ability to perform tasks without fear offalling was expressed in logits, with lower scoresimplying less ability and greater fear of falling.RESULTS Glaucoma subjects had greater VF lossthan control subjects (median better-eye meandeviation [MD] of -8.0 decibels [dB] vs. +0.2 dB;P<0.001), but did not differ with regard to age,race, gender, employment status, the presence", "metadata": {}}
+{"_id": "26672703", "title": "", "text": "Repeat instability: mechanisms of dynamicmutationsDisease-causing repeat instability is animportant and unique form of mutation that islinked to more than 40 neurological,neurodegenerative and neuromuscular disorders.DNA repeat expansion mutations are dynamicand ongoing within tissues and acrossgenerations. The patterns of inherited andtissue-specific instability are determined by bothgene-specific cis-elements and trans-acting DNAmetabolic proteins. Repeat instability probablyinvolves the formation of unusual DNA structuresduring DNA replication, repair andrecombination. Experimental advances towardsexplaining the mechanisms of repeat instabilityhave broadened our understanding of thismutational process. They have revealedsurprising ways in which metabolic pathways candrive or protect from repeat instability.", "metadata": {}}
+{"_id": "26673492", "title": "", "text": "Demographic Risk Factors for Alcohol-RelatedAggression In and Around Licensed Venues.AIMSFew studies have examined the role of genderand both area-level and individualsocio-economic status (SES) as independentpredictors of alcohol-related aggression (ARA) inand around licensed venues. METHODS The aimof the present study was to investigate therelationship between gender, area-level SES andindividual SES (operationalised as occupationalcategory) and ARA in and around licensedvenues. The sample comprised 697 men and 649women aged 16-47, who completed a patronintercept survey as part of a larger studyassessing trends in harm and stakeholders' viewssurrounding local community level interventionsin dealing with alcohol-related problems in thenight-time economy. RESULTS Binary logisticregression analyses showed that age, gender,occupational category, area-level SES and levelof intoxication at time of interview were allsignificant predictors of involvement in ARA.", "metadata": {}}
+{"_id": "26688294", "title": "", "text": "Schizophrenia susceptibility pathway neuregulin1–ErbB4 suppresses Src upregulation of NMDAreceptorsHypofunction of the N-methylD-aspartate subtype of glutamate receptor(NMDAR) is hypothesized to be a mechanismunderlying cognitive dysfunction in individualswith schizophrenia. For the schizophrenia-linkedgenes NRG1 and ERBB4, NMDAR hypofunction isthus considered a key detrimental consequenceof the excessive NRG1-ErbB4 signaling found inpeople with schizophrenia. However, we showhere that neuregulin 1β–ErbB4 (NRG1β-ErbB4)signaling does not cause general hypofunction ofNMDARs. Rather, we find that, in thehippocampus and prefrontal cortex,NRG1β-ErbB4 signaling suppresses theenhancement of synaptic NMDAR currents by thenonreceptor tyrosine kinase Src. NRG1β-ErbB4signaling prevented induction of long-termpotentiation at hippocampal Schaffercollateral–CA1 synapses and suppressedSrc-dependent enhancement of NMDAR", "metadata": {}}
+{"_id": "26702468", "title": "", "text": "Intestinal bacteria and the regulation of immunecell homeostasis.The human intestine iscolonized by an estimated 100 trillion bacteria.Some of these bacteria are essential for normalphysiology, whereas others have been implicatedin the pathogenesis of multiple inflammatorydiseases including IBD and asthma. This reviewexamines the influence of signals from intestinalbacteria on the homeostasis of the mammalianimmune system in the context of health anddisease. We review the bacterial composition ofthe mammalian intestine, knownbacterial-derived immunoregulatory molecules,and the mammalian innate immune receptorsthat recognize them. We discuss the influence ofbacterial-derived signals on immune cell functionand the mechanisms by which these signalsmodulate the development and progression ofinflammatory disease. We conclude with anexamination of successes and future challengesin using bacterial communities or their productsin the prevention or treatment of human disease.", "metadata": {}}
+{"_id": "26710772", "title": "", "text": "Sympathetic activation during early pregnancy inhumans.Sympathetic activity has been reportedto increase in normotensive pregnant women,and to be even greater in women withgestational hypertension and preeclampsia atterm. Whether sympathetic overactivity developsearly during pregnancy, remaining highthroughout gestation, or whether it only occursat term providing the substrate for hypertensivedisorders is unknown. We tested the hypothesisthat sympathetic activation occurs early duringpregnancy in humans. Eleven healthy women(29 ± 3 (SD) years) without prior hypertensivepregnancies were tested during the mid-lutealphase (PRE) and early pregnancy (EARLY; 6.2 ±1.2 weeks of gestation). Muscle sympatheticnerve activity (MSNA) and haemodynamics weremeasured supine, at 30 deg and 60 deg uprighttilt for 5 min each. Blood samples were drawn forcatecholamines, direct renin, and aldosterone.MSNA was significantly greater during EARLYthan PRE (supine: 25 ± 8 vs. 14 ± 8 bursts", "metadata": {}}
+{"_id": "26720366", "title": "", "text": "Psychological adaptation in children withidiopathic short stature treated with growthhormone or placebo.The influence of shortstature on psychological adaptation in childhoodand adolescence is controversial. GH is currentlyused to treat children with idiopathic shortstature (ISS, also known as non-GH-deficientshort stature). This study represents the firstdouble-blind, placebo-controlled trial of theeffects of GH on the psychological adaptation ofchildren and adolescents with ISS, treated withGH until adult height was attained. Sixty-eightchildren (53 males, 15 females), 9-16 yr old,with marked ISS (measured height or predictedadult height -2.5 sd or less) received either GH0.074 mg/kg or placebo sc three times per weekuntil height velocity decreased to less than 1.5cm/yr. Parents completed the Child BehaviorChecklist (CBCL) and children the Self-PerceptionProfile (SPP) and Silhouette ApperceptionTechnique at baseline and annually thereafter.Baseline behavioral/emotional adjustment", "metadata": {}}
+{"_id": "26731863", "title": "", "text": "Distinct and essential roles of transcriptionfactors IRF-3 and IRF-7 in response to virusesfor IFN-alpha/beta gene induction.Induction ofthe interferon (IFN)-alpha/beta genetranscription in virus-infected cells is an eventcentral to innate immunity. Mice lacking thetranscription factor IRF-3 are more vulnerable tovirus infection. In embryonic fibroblasts,virus-induced IFN-alpha/beta gene expressionlevels are reduced and the spectrum of theIFN-alpha mRNA subspecies altered.Furthermore, cells additionally defective in IRF-7expression totally fail to induce these genes inresponse to infections by any of the virus typestested. In these cells, a normal profile ofIFN-alpha/beta mRNA induction can be achievedby coexpressing both IRF-3 and IRF-7. Theseresults demonstrate the essential and distinctroles of thetwo factors, which together ensurethe transcriptional efficiency and diversity ofIFN-alpha/beta genes for the antiviral response.", "metadata": {}}
+{"_id": "26735018", "title": "", "text": "Interleukin-2- and interferon-gamma-secreting Tcells in normal and diseased human intestinalmucosa.A sensitive reverse haemolytic plaqueassay to detect lymphokine-secreting T cells, andNorthern blot analysis to detect expression oflymphokine messenger RNA (mRNA) were usedto study interferon-gamma (IFN-gamma) andinterleukin-2 (IL-2) production in the mucosa ofchildren with Crohn's disease or ulcerative colitis(UC), and in histologically normal mucosa frompatients without inflammatory bowel disease. Inthe mucosa of most patients with UC and controlpatients, IL-2- and IFN-gamma-secreting cellswere absent or were present at only low levels.In contrast, in mucosa from patients withCrohn's disease, lymphokine-secreting cells werereadily detectable (3-18%). IFN-gamma mRNAwas detected by Northern blot analysis in 5/6Crohn's tissues, but only in 1/5 UC samples andnone of nine samples of control mucosa. Thesestudies reveal an ongoing cell-mediated immuneresponse in the mucosa in Crohn's disease.", "metadata": {}}
+{"_id": "26735905", "title": "", "text": "Metabolic reprogramming of stromal fibroblaststhrough p62-mTORC1 signaling promotesinflammation and tumorigenesis.The tumormicroenvironment plays a critical role in cancerprogression, but the precise mechanisms bywhich stromal cells influence the epithelium arepoorly understood. Here we show that p62 levelswere reduced in the stroma of several tumorsand that its loss in the tumor microenvironmentor stromal fibroblasts resulted in increasedtumorigenesis of epithelial prostate cancer cells.The mechanism involves the regulation ofcellular redox through an mTORC1/c-Mycpathway of stromal glucose and amino acidmetabolism, resulting in increased stromal IL-6production, which is required for tumorpromotion in the epithelial compartment. Thus,p62 is an anti-inflammatory tumor suppressorthat acts through the modulation of metabolismin the tumor stroma.", "metadata": {}}
+{"_id": "26751583", "title": "", "text": "Drosophila RNAi screen reveals CD36 familymember required for mycobacterialinfection.Certain pathogens, such asMycobacterium tuberculosis, survive within thehostile intracellular environment of amacrophage. To identify host factors required formycobacterial entry and survival withinmacrophages, we performed a genomewide RNAinterference screen in Drosophilamacrophage-like cells, using Mycobacteriumfortuitum. We identified factors required forgeneral phagocytosis, as well as those neededspecifically for mycobacterial infection. Onespecific factor, Peste (Pes), is a CD36 familymember required for uptake of mycobacteria,but not Escherichia coli or Staphylococcusaureus. Moreover, mammalian class B scavengerreceptors (SRs) conferred uptake of bacteria intononphagocytic cells, with SR-BI and SR-BIIuniquely mediating uptake of M. fortuitum, whichsuggests a conserved role for class B SRs inpattern recognition and innate immunity.", "metadata": {}}
+{"_id": "26798867", "title": "", "text": "Knowledge, attitudes, and practice on secondprimary cancer screening among cancersurvivors: a qualitative study.OBJECTIVE Thegoal of this study was to examine the knowledge,attitude, and practice on second cancerscreening among cancer survivors. METHODSThree focus group interviews were conductedwith thirteen disease-free stomach, colorectal,breast and thyroid cancer survivors. Recurrentissues were identified and then placed intothematic categories. RESULTS None of the studyparticipants had heard SPC, and they could notdifferentiate SPC from 'recurrence' or'metastasis.' Survivors believed that they hadbeen cured, and they were not aware of theirincreased risk of SPC. Although they had highawareness of cancer screening, they could notmake a distinction between 'cancer screening'and 'routine surveillance test' after cancertreatment. Survivors said that they would havehad the screening for SPC if they had knownabout it. They preferred physicians as the most", "metadata": {}}
+{"_id": "26848994", "title": "", "text": "LncRNA HANR Promotes Tumorigenesis andIncrease of Chemoresistance in HepatocellularCarcinomaBackground/Aims: Hepatocellularcarcinoma (HCC) is the fifth most commoncancer in the world and the third leading cause ofcancer-related death. Critical roles for longnon-coding RNAs (lncRNAs) have recently beendemonstrated for a variety of cancers, includinghepatocellular carcinoma. However, the effectand mechanism of lncRNAs in HCC tumorigenesisand chemoresistance have not been extensivelycharacterized. Methods: In the current study, wehave identified a HCC-expressed lncRNA termedas HANR (HCC associated long non-coding RNA).We identified HANR by microarray analysis andvalidated its up-regulated expression byquantitative PCR. RNA pull-down and pathwayanalyses were conducted to evaluate physicaland functional interactions with HANR. In vivoexperiments were performed to assesstumorigenesis and increase of chemoresistance.In addition, the HANR expression in HCC", "metadata": {}}
+{"_id": "26851674", "title": "", "text": "Dissection of signaling cascades through gp130in vivo: reciprocal roles for STAT3- andSHP2-mediated signals in immune responses.Wegenerated a series of knockin mouse lines, inwhich the cytokine receptor gp130-dependentSTAT3 and/or SHP2 signals were disrupted, byreplacing the mouse gp130 gene with humangp130 mutant cDNAs. The SHP2 signal-deficientmice (gp130F759/F759 were born normal butdisplayed splenomegaly and lymphadenopathyand an enhanced acute phase reaction. Incontrast, the STAT3 signal-deficient mice(gp130FXQ/FXXQ) died perinatally, like thegp130-deficient mice (gp130D/D). Thegp130F759/F759 mice showed prolongedgp130-induced STAT3 activation, indicating anegative regulatory role for SHP2. Th1-typecytokine production and IgG2a and IgG2bproduction were increased in thegp130F759/F759 mice, while they weredecreased in the gp130FXXQ/FXXQ immunesystem. These results indicate that the balance", "metadata": {}}
+{"_id": "26873988", "title": "", "text": "Viral interleukin-10 expressed by humancytomegalovirus during the latent phase ofinfection modulates latently infected myeloid celldifferentiation.The human cytomegalovirusUL111A gene is expressed during latent andproductive infections, and it codes for homologsof interleukin-10 (IL-10). We examined whetherviral IL-10 expressed during latency altereddifferentiation of latently infected myeloidprogenitors. In comparison to infection withparental virus or mock infection, latent infectionwith a virus in which the gene encoding viralIL-10 has been deleted upregulated cytokinesassociated with dendritic cell (DC) formation andincreased the proportion of myeloid DCs. Thesedata demonstrate that viral IL-10 restricts theability of latently infected myeloid progenitors todifferentiate into DCs and identifies animmunomodulatory role for viral IL-10 whichmay limit the host's ability to clear latent virus.", "metadata": {}}
+{"_id": "26886351", "title": "", "text": "Bortezomib enhances dendritic cell(DC)-mediated induction of immunity to humanmyeloma via exposure of cell surface heat shockprotein 90 on dying tumor cells: therapeuticimplications.Most anticancer chemotherapies areimmunosuppressive and induce nonimmunogenictumor cell death. Bortezomib, a specific inhibitorof 26S proteasome, has shown clinical activity inseveral human tumors, including myeloma. Herewe show that the uptake of human myelomacells by dendritic cells (DCs) after tumor celldeath by bortezomib, but not gamma irradiationor steroids, leads to the induction of antitumorimmunity, including against primary tumor cells,without the need for any additional adjuvants.The delivery of activating signal frombortezomib-killed tumor cells to DCs depends oncell-cell contact between DCs and dying tumorcells and is mediated by bortezomib-inducedexposure of heat shock protein 90 (hsp90) onthe surface of dying cells. The combination ofbortezomib and geldanamycin (an hsp90", "metadata": {}}
+{"_id": "26887439", "title": "", "text": "Survivin depletion preferentially reduces thesurvival of activated K-Ras-transformed cells.Toidentify cancer-specific targets, we haveconducted a synthetic lethal screen using a smallinterfering RNA (siRNA) library targetingapproximately 4,000 individual genes forenhanced killing in the DLD-1 colon carcinomacell line that expresses an activated copy of theK-Ras oncogene. We found that siRNAs targetingbaculoviral inhibitor of apoptosisrepeat-containing 5 (survivin) significantlyreduced the survival of activatedK-Ras-transformed cells compared with itsnormal isogenic counterpart in which the mutantK-Ras gene had been disrupted (DKS-8). Inaddition, survivin siRNA induced a transientG(2)-M arrest and marked polyploidy that wasassociated with increased caspase-3 activation inthe activated K-Ras cells. These results indicatethat tumors expressing the activated K-Rasoncogene may be particularly sensitive toinhibitors of the survivin protein.", "metadata": {}}
+{"_id": "26899920", "title": "", "text": "Small molecules enable cardiac reprogrammingof mouse fibroblasts with a single factor, Oct4.Itwas recently shown that mouse fibroblasts couldbe reprogrammed into cells of a cardiac fate byforced expression of multiple transcriptionfactors and microRNAs. For ultimate applicationof such a reprogramming strategy for cell-basedtherapy or in vivo cardiac regeneration, reducingor eliminating the genetic manipulations by smallmolecules would be highly desirable. Here, wereport the identification of a definedsmall-molecule cocktail that enables the highlyefficient conversion of mouse fibroblasts intocardiac cells with only one transcription factor,Oct4, without any evidence of entrance into thepluripotent state. Small-molecule-inducedcardiomyocytes spontaneously contract andexhibit a ventricular phenotype. Furthermore,these induced cardiomyocytes pass through acardiac progenitor stage. This study lays thefoundation for future pharmacologicalreprogramming approaches and provides a", "metadata": {}}
+{"_id": "26902591", "title": "", "text": "A switch from white to brown fat increasesenergy expenditure in cancer-associatedcachexia.Cancer-associated cachexia (CAC) is awasting syndrome characterized by systemicinflammation, body weight loss, atrophy of whiteadipose tissue (WAT) and skeletal muscle.Limited therapeutic options are available and theunderlying mechanisms are poorly defined. Herewe show that a phenotypic switch from WAT tobrown fat, a phenomenon termed WAT browning,takes place in the initial stages of CAC, beforeskeletal muscle atrophy. WAT browning isassociated with increased expression ofuncoupling protein 1 (UCP1), which uncouplesmitochondrial respiration toward thermogenesisinstead of ATP synthesis, leading to increasedlipid mobilization and energy expenditure incachectic mice. Chronic inflammation and thecytokine interleukin-6 increase UCP1 expressionin WAT, and treatments that reduceinflammation or β-adrenergic blockade reduceWAT browning and ameliorate the severity of", "metadata": {}}
+{"_id": "26907074", "title": "", "text": "Potential Mechanisms of Action of Lithium inBipolar DisorderLithium has been used for overhalf a century for the treatment of bipolardisorder as the archetypal mood stabilizer, andhas a wealth of empirical evidence supporting itsefficacy in this role. Despite this, the specificmechanisms by which lithium exerts itsmood-stabilizing effects are not well understood.Given the inherently complex nature of thepathophysiology of bipolar disorder, this paperaims to capture what is known about the actionsof lithium ranging from macroscopic changes inmood, cognition and brain structure, to itseffects at the microscopic level onneurotransmission and intracellular andmolecular pathways. A comprehensive literaturesearch of databases including MEDLINE, EMBASEand PsycINFO was conducted using relevantkeywords and the findings from the literaturewere then reviewed and synthesized. Numerousstudies report that lithium is effective in thetreatment of acute mania and for the long-term", "metadata": {}}
+{"_id": "26952804", "title": "", "text": "The role of autophagy in cancer developmentand response to therapyAutophagy is a processin which subcellular membranes undergodynamic morphological changes that lead to thedegradation of cellular proteins and cytoplasmicorganelles. This process is an important cellularresponse to stress or starvation. Many studieshave shed light on the importance of autophagyin cancer, but it is still unclear whetherautophagy suppresses tumorigenesis or providescancer cells with a rescue mechanism underunfavourable conditions. What is the presentstate of our knowledge about the role ofautophagy in cancer development, and inresponse to therapy? And how can theautophagic process be manipulated to improveanticancer therapeutics?", "metadata": {}}
+{"_id": "26973393", "title": "", "text": "The quest to overcome resistance toEGFR-targeted therapies in cancerAll patientswith metastatic lung, colorectal, pancreatic orhead and neck cancers who initially benefit fromepidermal growth factor receptor(EGFR)-targeted therapies eventually developresistance. An increasing understanding of thenumber and complexity of resistancemechanisms highlights the Herculean challengeof killing tumors that are resistant to EGFRinhibitors. Our growing knowledge of resistancepathways provides an opportunity to developnew mechanism-based inhibitors andcombination therapies to prevent or overcometherapeutic resistance in tumors. We present acomprehensive review of resistance pathways toEGFR-targeted therapies in lung, colorectal andhead and neck cancers and discuss therapeuticstrategies that are designed to circumventresistance.", "metadata": {}}
+{"_id": "26990001", "title": "", "text": "An organ culture model for the study ofmetanephric development.A murine whole organmetanephric culture system was designed tostudy the developmental aspects of mammaliannephrogenesis. Metanephros and ureteric budwere removed from CFI albino mouse embryosat 13.5 +/- 0.4 days gestation, and grown inDulbecco's modified Eagle's Minimal EssentialMedium supplemented with 20 per cent donorbovine serum at 37C in a mixed air--5 per centCO2 environment. Under the experimentalconditions employed, the metanephric explantsshowed organotypic tubular and glomerularepithelial development. A well-developedproximal tubule with microvilli, and characteristicintracellular organelles and intercellular junctionsdeveloped by 72 hours of culture. By 120 hoursof culture, unique devascularized glomeruliconsisting of parietal and visceral epitheliallayers formed. The glomerular visceral epithelialcells formed foot processes and slit porediaphragms, and produced islands of basement", "metadata": {}}
+{"_id": "26993601", "title": "", "text": "Molecular layers underlying cytoskeletalremodelling during cortical developmentDuringneural development, the cytoskeleton ofnewborn neurons undergoes extensive anddynamic remodelling to facilitate the sequentialsteps of neurogenesis, cell migration andterminal differentiation. It is clear from studyingthe mechanisms that precipitate these functionsthat different configurations of the cytoskeletonprefigure the correct execution of each step anddefine cohorts of proteins the functions of whichare indispensable for the control of neuronalmigration but not terminal differentiation. Thesecombinatorial protein functions are alsopredetermined by regulated gene expression andthe precise subcellular localisation of theirprotein products. Here, we expand on this viewin the context of recent data on how thecytoskeleton is regulated during the maturationof cortical neurons within the developing brain.", "metadata": {}}
+{"_id": "26996935", "title": "", "text": "Strong bias in the bacterial CRISPR elementsthat confer immunity to phage.Clusteredregularly interspaced short palindromic repeats(CRISPR)-Cas systems provide adaptiveimmunity against phage via spacer-encodedCRISPR RNAs that are complementary toinvasive nucleic acids. Here, we challengeStreptococcus thermophilus with abacteriophage, and used PCR-basedmetagenomics to monitor phage-derived spacersdaily for 15 days in two experiments. Spacersthat target the host chromosome are infrequentand strongly selected against, suggestingautoimmunity is lethal. In experiments thatrecover over half a million spacers, we observeearly dominance by a few spacer sub-populationsand rapid oscillations in sub-populationabundances. In two CRISPR systems and inreplicate experiments, a few spacers account forthe majority of spacer sequences. Nearly allphage locations targeted by the acquired spacershave a proto-spacer adjacent motif (PAM),", "metadata": {}}
+{"_id": "27022864", "title": "", "text": "Chronic hypoxia induces modification of theN-methyl-D-aspartate receptor in rat brain.Thisstudy examined [3H]MK-801 binding to theN-methyl-D-aspartate (NMDA) receptor inmembranes prepared from cerebral cortex,hippocampus and corpus striatum of 3 week oldrats exposed to 10 weeks of intermittenthypobaric hypoxia (4300 m; 450 Torr) andcompared results with those of normoxiccontrols. The cortex, hippocampus and striatumof hypoxic animals had a 36, 35 and 31%reduction in binding sites (Bmax) and a 29, 32and 17% decrease (reflecting increased affinity)in the dissociation constant (Kd) when comparedto controls. In the cerebral cortex, bothglutamate (100 microM) and glycine (10 microM)enhanced 3[H]MK-801 binding by two to 3-fold.Coagonist glutamate, however, had a higherEC50 (0.44 microM) in the hypoxic corticalmembranes when compared to controls (0.28microM). No significant differences were found inthe EC50 of glycine. The results show that the", "metadata": {}}
+{"_id": "27024392", "title": "", "text": "Cannabinoids in Clinical PracticeCannabis has apotential for clinical use often obscured byunreliable and purely anecdotal reports. Themost important natural cannabinoid is thepsychoactive tetrahydrocannabinol (Δ9-THC);others include cannabidiol (CBD) andcannabigerol (CBG). Not all the observed effectscan be ascribed to THC, and the otherconstituents may also modulate its action; forexample CBD reduces anxiety induced by THC. Astandardised extract of the herb may betherefore be more beneficial in practice andclinical trial protocols have been drawn up toassess this. The mechanism of action is still notfully understood, although cannabinoid receptorshave been cloned and natural ligands identified.Cannabis is frequently used by patients withmultiple sclerosis (MS) for muscle spasm andpain, and in an experimental model of MS lowdoses of cannabinoids alleviated tremor. Most ofthe controlled studies have been carried out withTHC rather than cannabis herb and so do not", "metadata": {}}
+{"_id": "27049238", "title": "", "text": "Large deformation of red blood cell ghosts in asimple shear flow.Red blood cells are known tochange shape in response to local flowconditions. Deformability affects red blood cellphysiological function and the hydrodynamicproperties of blood. The immersed boundarymethod is used to simulate three-dimensionalmembrane-fluid flow interactions for cells withthe same internal and external fluid viscosities.The method has been validated for smalldeformations of an initially spherical capsule insimple shear flow for both neo-Hookean and theEvans-Skalak membrane models. Initially oblatespheroidal capsules are simulated and it is shownthat the red blood cell membrane exhibitsasymptotic behavior as the ratio of the dilationmodulus to the extensional modulus is increasedand a good approximation of local areaconservation is obtained. Tank treading behavioris observed and its period calculated.", "metadata": {}}
+{"_id": "27054878", "title": "", "text": "Preoperative C-reactive protein predictslong-term mortality and hospital length of stayafter primary, nonemergent coronary arterybypass grafting.BACKGROUND PreoperativeC-reactive protein (CRP) levels more than 10mg/l have been shown to be associated withincreased morbidity and mortality after cardiacsurgery. We examine the value of preoperativeCRP levels less than 10 mg/l for predictinglong-term, all-cause mortality and hospitallength of stay in surgical patients undergoingprimary, nonemergent coronary artery bypassgraft-only surgery. METHODS We examined theassociation between preoperative CRP levelsstratified into four categories (< 1, 1-3, 3-10,and > 10 mg/l), and 7-yr all-cause mortality andhospital length of stay in 914 prospectivelyenrolled primary, nonemergent coronary arterybypass graft-only surgical patients using aproportional hazards regression model. RESULTSEighty-seven patients (9.5%) died during amean follow-up period of 4.8 +/- 1.5 yr. After", "metadata": {}}
+{"_id": "27061085", "title": "", "text": "Transcript assembly and quantification byRNA-Seq reveals unannotated transcripts andisoform switching during celldifferentiation.High-throughput mRNAsequencing (RNA-Seq) promises simultaneoustranscript discovery and abundance estimation.However, this would require algorithms that arenot restricted by prior gene annotations and thataccount for alternative transcription and splicing.Here we introduce such algorithms in anopen-source software program called Cufflinks.To test Cufflinks, we sequenced and analyzed>430 million paired 75-bp RNA-Seq reads from amouse myoblast cell line over a differentiationtime series. We detected 13,692 knowntranscripts and 3,724 previously unannotatedones, 62% of which are supported byindependent expression data or by homologousgenes in other species. Over the time series, 330genes showed complete switches in thedominant transcription start site (TSS) or spliceisoform, and we observed more subtle shifts in", "metadata": {}}
+{"_id": "27063470", "title": "", "text": "Sporadic Creutzfeldt-Jakob disease in the UnitedKingdom: analysis of epidemiological surveillancedata for 1970-96.OBJECTIVE To identify changesin the occurrence of Creutzfeldt-Jakob diseasethat might be related to the epidemic of bovinespongiform encephalopathy. DESIGNEpidemiological surveillance of the UnitedKingdom population for Creutzfeldt-Jakobdisease based on (a) referral of suspected casesby neurologists, neuropathologists, andneurophysiologists and (b) death certificates.SETTING England and Wales during 1970-84,and whole of the United Kingdom during1985-96. SUBJECTS All 662 patients identified assporadic cases of Creutzfeldt-Jakob disease.MAIN OUTCOME MEASURES Age distribution ofpatients, age specific time trends of disease,occupational exposure to cattle, potentialexposure to causative agent of bovinespongiform encephalopathy. RESULTS During1970-96 there was an increase in the number ofsporadic cases of Creutzfeldt-Jakob disease", "metadata": {}}
+{"_id": "27076725", "title": "", "text": "Documented head injury in early adulthood andrisk of Alzheimer's disease and otherdementias.BACKGROUND The associationbetween antecedent head injury and AD isinconsistent. OBJECTIVE To examine theassociation between early adult head injury, asdocumented by military hospital records, anddementia in late life; and to evaluate theinteraction between head injury and APOEepsilon4 as risk factors for dementia. METHODSThe study had a population-based prospectivehistorical cohort design. It included men whowere World War II Navy and Marine veterans,and were hospitalized during their militaryservice with a diagnosis of either anonpenetrating head injury or another unrelatedcondition. In 1996 to 1997, military medicalrecords were abstracted to document theoccurrence and details of closed head injury. Theentire sample was then evaluated for dementiaand AD using a multistage procedure. Therewere 548 veterans with head injury and 1228", "metadata": {}}
+{"_id": "27077180", "title": "", "text": "Transient receptor potential channels as drugtargets: from the science of basic research to theart of medicine.The large Trp gene familyencodes transient receptor potential (TRP)proteins that form novel cation-selective ionchannels. In mammals, 28 Trp channel geneshave been identified. TRP proteins exhibit diversepermeation and gating properties and areinvolved in a plethora of physiologic functionswith a strong impact on cellular sensing andsignaling pathways. Indeed, mutations in humangenes encoding TRP channels, the so-called \"TRPchannelopathies,\" are responsible for a numberof hereditary diseases that affect themusculoskeletal, cardiovascular, genitourinary,and nervous systems. This review gives anoverview of the functional properties ofmammalian TRP channels, describes their rolesin acquired and hereditary diseases, anddiscusses their potential as drug targets fortherapeutic intervention.", "metadata": {}}
+{"_id": "27078065", "title": "", "text": "Identification of genes associated with theastrocyte-specific gene Gfap during astrocytedifferentiation.Chromosomes and genes arenon-randomly arranged within the mammaliancell nucleus, and gene clustering is of greatsignificance in transcriptional regulation.However, the relevance of gene clustering andtheir expression during the differentiation ofneural precursor cells (NPCs) into astrocytesremains unclear. We performed a genome-wideenhanced circular chromosomal conformationcapture (e4C) to screen for genes associatedwith the astrocyte-specific gene glial fibrillaryacidic protein (Gfap) during astrocytedifferentiation. We identified 18 genes that werespecifically associated with Gfap and expressedin NPC-derived astrocytes. Our results provideadditional evidence for the functional significanceof gene clustering in transcriptional regulationduring NPC differentiation.", "metadata": {}}
+{"_id": "27093166", "title": "", "text": "Ketamine reduces LPS-induced HMGB1 viaactivation of the Nrf2/HO-1 pathway and NF-κBsuppression.BACKGROUND Ketamine, as ananesthetic agent, has an anti-inflammatoryeffect. In the present study, we investigatedwhether ketamine inhibits release of highmobility group box 1 (HMGB1), a late-phasecytokine of sepsis, in lipopolysaccharide(LPS)-stimulated macrophages through hemeoxygenase-1 (HO-1) induction. METHODSMacrophages were preincubated with variousconcentrations of ketamine and then treated withLPS (1 μg/mL). The cell culture supernatantswere collected to measure inflammatorymediators (HMGB1, nitric oxide, tumor necrosisfactor-α, and interleukin 1β) by enzyme-linkedimmunosorbent assay. Moreover, HO-1 proteinexpression, the phosphorylation and degradationof IκB-α, and the nuclear translocation of nuclearfactor E2-related factor 2 and nuclear factor κB(NF-κB) p65 were tested by Western blotanalysis. In addition, to further identify the role", "metadata": {}}
+{"_id": "27099731", "title": "", "text": "Association Between Early Screening for PatentDuctus Arteriosus and In-Hospital MortalityAmong Extremely Preterm Infants.IMPORTANCEThere is currently no consensus for the screeningand treatment of patent ductus arteriosus (PDA)in extremely preterm infants. Lesspharmacological closure and more supportivemanagement have been observed withoutevidence to support these changes. OBJECTIVETo evaluate the association between earlyscreening echocardiography for PDA andin-hospital mortality. DESIGN, SETTING, ANDPARTICIPANTS Comparison of screened and notscreened preterm infants enrolled in the EPIPAGE2 national prospective population-based cohortstudy that included all preterm infants born atless than 29 weeks of gestation and hospitalizedin 68 neonatal intensive care units in Francefrom April through December 2011. Two mainanalyses were performed to adjust for potentialselection bias, one using propensity scorematching and one using neonatal unit preference", "metadata": {}}
+{"_id": "27123743", "title": "", "text": "Role of birthweight in the etiology of breastcancer.Breast cancer may originate in utero. Wereviewed the available evidence on theassociation between birthweight and the risk ofbreast cancer. To date, 26 research papersaddressing this issue have been published. Themajority of studies identified a positive linkbetween birthweight and premenopausal, but notpostmenopausal, breast cancer. The relative riskestimate for breast cancer comparing womenwith high birthweight to women with lowbirthweight combining all studies including bothpre- and postmenopausal breast cancer was 1.23(95% confidence interval 1.13-1.34). Themechanisms underlying this association likelyinclude elevated levels of growth factors thatmay increase the number of susceptible stemcells in the mammary gland or initiate tumorsthrough DNA mutations. Loss of imprinting (LOI)of growth hormone genes relevant forintrauterine growth, such as insulin-like growthfactor 2 (IGF2), leads to abnormally high levels", "metadata": {}}
+{"_id": "27127885", "title": "", "text": "An activator of the cAMP/PKA/CREB pathwaypromotes osteogenesis from humanmesenchymal stem cells.Mesenchymal stem cells(MSCs) are multipotent adult stem cells capableof differentiating along the osteoblast, adipocyte,and chondrocyte lineages. Regulation of MSCsdifferentiation may be a useful tool forregenerative medicine and cell-based therapy.The discovery of small molecule that activatesthe osteogenic differentiation of MSCs could aidin the development of a new anabolic drug forosteoporosis treatment. We identified CW008, aderivative of pyrazole-pyridine, that stimulatesosteoblast differentiation of human MSCs andincreases bone formation in ovariectomizedmice. CW008 promotes osteogenesis byactivating cAMP/PKA/CREB signaling pathwayand inhibiting leptin secretion. These resultssuggest that CW008 is an agonist ofcAMP/PKA/CREB pathway in osteogenicdifferentiation and that application of CW008may be useful for the treatment of bone-related", "metadata": {}}
+{"_id": "27129115", "title": "", "text": "Magnesium sulphate for women at risk ofpreterm birth for neuroprotection of thefetus.BACKGROUND Epidemiological and basicscience evidence suggests that magnesiumsulphate before birth may be neuroprotective forthe fetus. OBJECTIVES To assess the effects ofmagnesium sulphate as a neuroprotective agentwhen given to women considered at risk ofpreterm birth. SEARCH STRATEGY We searchedthe Cochrane Pregnancy and Childbirth Group'sTrials Register (31 August 2008). SELECTIONCRITERIA Randomised controlled trials ofantenatal magnesium sulphate therapy inwomen threatening or likely to give birth at lessthan 37 weeks' gestational age. For onesubgroup analysis, studies were broadlycategorised by the primary intent of the studyinto \"neuroprotective intent\", or \"other intent(maternal neuroprotective - pre-eclampsia)\", or\"other intent (tocolytic)\". DATA COLLECTIONAND ANALYSIS At least two authors assessedtrial eligibility and quality, and extracted data.", "metadata": {}}
+{"_id": "27134527", "title": "", "text": "The growing landscape of lysine acetylation linksmetabolism and cell signallingLysine acetylationis a conserved protein post-translationalmodification that links acetyl-coenzyme Ametabolism and cellular signalling. Recentadvances in the identification and quantificationof lysine acetylation by mass spectrometry haveincreased our understanding of lysineacetylation, implicating it in many biologicalprocesses through the regulation of proteininteractions, activity and localization. In addition,proteins are frequently modified by other typesof acylations, such as formylation, butyrylation,propionylation, succinylation, malonylation,myristoylation, glutarylation and crotonylation.The intricate link between lysine acylation andcellular metabolism has been clarified by theoccurrence of several such metabolite-sensitiveacylations and their selective removal by sirtuindeacylases. These emerging findings point tonew functions for different lysine acylations anddeacylating enzymes and also highlight the", "metadata": {}}
+{"_id": "27134931", "title": "", "text": "COMPASS, a histone H3 (Lysine 4)methyltransferase required for telomericsilencing of gene expression.The trithorax (Trx)family of proteins is required for maintaining aspecific pattern of gene expression in someorganisms. Recently we reported the isolationand characterization of COMPASS, a multiproteincomplex that includes the Trx-related proteinSet1 of the yeast Saccharomyces cerevisiae.Here we report that COMPASS catalyzesmethylation of the fourth lysine of histone H3 invitro. Set1 and several other components ofCOMPASS are also required for histone H3methylation in vivo and for transcriptionalsilencing of a gene located near a chromosometelomere.", "metadata": {}}
+{"_id": "27138601", "title": "", "text": "Free water elimination diffusion tractography: Acomparison with conventional andfluid-attenuated inversion recovery, diffusiontensor imaging acquisitions.PURPOSE Whitematter tractography reconstructions usingconventional diffusion tensor imaging (DTI) nearcerebrospinal fluid (CSF) spaces are oftenadversely affected by CSF partial volume effects(PVEs). This study evaluates the ability of freewater elimination (FWE) DTI methods tominimize the PVE of CSF for deterministictractography applications. MATERIALS ANDMETHODS Ten healthy individuals were scannedwith \"traditional,\" FLAIR (fluid-attenuatedinversion recovery), and FWE DTI scans. Thefornix, corpus callosum, and cingulum bundleswere reconstructed using deterministictractography. The FWE DTI scan was performedtwice to separately match total acquisition time(long FWE) and number of measurements(encoding directions, short FWE) to the FLAIRand \"traditional\" DTI scans. PVE resolution was", "metadata": {}}
+{"_id": "27150276", "title": "", "text": "A systematic review of randomized controlledtrials of acupuncture in the treatment ofdepression.BACKGROUND Acupuncture hasbecome a popular complementary andalternative treatment approach. This reviewexamined the randomized controlled trials(RCTs) examining the effects of acupuncturetreatment of depression. METHODS RCTs of thetreatment of depression with acupuncture werelocated using MEDLINE, Allied andComplementary Medicine and the CochraneCentral Register of Controlled Trials. Themethodology of RCTs was assessed using theJadad criteria, and elements of research design,i.e., randomization, blinding, assessment ofattrition rates, were quantified for systematiccomparisons among studies. RESULTS Amongthe 9 RCTs examined, five were deemed to be oflow quality based upon Jadad criteria. The oddsratios derived from comparing acupuncture withcontrol conditions within the RCTs suggests someevidence for the utility of acupuncture in", "metadata": {}}
+{"_id": "27158570", "title": "", "text": "Genome-Wide Gene-Sodium Interaction Analyseson Blood Pressure: The Genetic EpidemiologyNetwork of Salt-Sensitivity Study.We performedgenome-wide analyses to identify genomic locithat interact with sodium to influence bloodpressure (BP) using single-marker-based (1 and2 df joint tests) and gene-based tests among1876 Chinese participants of the GeneticEpidemiology Network of Salt-Sensitivity(GenSalt) study. Among GenSalt participants,the average of 3 urine samples was used toestimate sodium excretion. Nine BPmeasurements were taken using a random zerosphygmomanometer. A total of 2.05 millionsingle-nucleotide polymorphisms were imputedusing Affymetrix 6.0 genotype data and theChinese Han of Beijing and Japanese of TokyoHapMap reference panel. Promising findings(P<1.00×10(-4)) from GenSalt were evaluatedfor replication among 775 Chinese participants ofthe Multi-Ethnic Study of Atherosclerosis (MESA).Single-nucleotide polymorphism and gene-based", "metadata": {}}
+{"_id": "27162821", "title": "", "text": "Percentile curves for hemoglobin and red cellvolume in infancy and childhood.Percentilecurves were calculated for hemoglobin and meancorpuscular volume in children between 0.5 and16 years of age. The curves were derived fromseveral populations of non-indigent whitechildren who lived near sea level. Subjects wereexcluded from the reference population if theyhad laboratory evidence of iron deficiency,thalassemia minor, and/or hemoglobinopathy.The final reference populations included 9,946children for the derivation of the hemoglobincurves and 2,314 for the MCV curves. Thepercentile curves should be particularlyapplicable to the diagnosis and screening of irondeficiency and thalassemia minor.", "metadata": {}}
+{"_id": "27166444", "title": "", "text": "Preservation of pancreatic beta-cell function andprevention of type 2 diabetes by pharmacologicaltreatment of insulin resistance in high-riskhispanic women.Type 2 diabetes frequentlyresults from progressive failure of pancreaticbeta-cell function in the presence of chronicinsulin resistance. We tested whether chronicamelioration of insulin resistance would preservepancreatic beta-cell function and delay orprevent the onset of type 2 diabetes in high-riskHispanic women. Women with previousgestational diabetes were randomized to placebo(n = 133) or the insulin-sensitizing drugtroglitazone (400 mg/day; n = 133)administered in double-blind fashion. Fastingplasma glucose was measured every 3 months,and oral glucose tolerance tests (OGTTs) wereperformed annually to detect diabetes.Intravenous glucose tolerance tests (IVGTTs)were performed at baseline and 3 months laterto identify early metabolic changes associatedwith any protection from diabetes. Women who", "metadata": {}}
+{"_id": "27167110", "title": "", "text": "Androgen regulation of micro-RNAs in prostatecancer.BACKGROUND Androgens play a criticalrole in the growth of both androgen dependentand castration-resistant prostate cancer (CRPC).Only a few micro-RNAs (miRNAs) have beensuggested to be androgen regulated. We aim toidentify androgen regulated miRNAs. METHODSWe utilized LNCaP derived model, we haveestablished, and which overexpresses theandrogen receptor (AR), the VCaP cell line, and13 intact-castrated prostate cancer (PC)xenograft pairs, as well as clinical specimens ofuntreated (PC) and CRPC. The expression ofmiRNAs was analyzed by microarrays andquantitative RT-PCR (Q-RT-PCR). Transfection ofpre-miR-141 and anti-miR-141 was also used.RESULTS Seventeen miRNAs were > 1.5-fold up-or downregulated upon dihydrotestosterone(DHT) treatment in the cell lines, and 42 aftercastration in the AR-positive xenografts. Onlyfour miRNAs (miR-10a, miR-141, miR-150*, andmiR-1225-5p) showed similar androgen", "metadata": {}}
+{"_id": "27188320", "title": "", "text": "Relationship between drug treatment services,retention, and outcomes.OBJECTIVE Thislongitudinal study conducted path analyses toexamine the relationships between treatmentprocesses and outcomes among patients incommunity-based drug treatment programs.METHODS A total of 1,939 patients from 36outpatient drug-free and residential treatmentprograms in 13 California counties were assessedat intake, discharge, three months afteradmission, and nine months after admission.Path analyses were conducted to relate thequantity and quality of services that werereceived in the first three months of treatment totreatment retention and outcomes at thenine-month follow-up. Patients were determinedto have a favorable outcome if for at least 30days before the follow-up assessment they didnot use drugs, were not involved in criminalactivity, and lived in the community. The pathanalyses controlled for patients' baselinecharacteristics. RESULTS Greater service", "metadata": {}}
+{"_id": "27240667", "title": "", "text": "Breast cancer mortality trends in the UnitedStates according to estrogen receptor status andage at diagnosis.PURPOSE Since 1990, overallbreast cancer mortality rates in the United Statesdecreased 24%. This decline has been attributedto mammography screening and adjuvantsystemic therapy. However, the efficacy of thesemodalities may depend on estrogen receptor(ER) expression and age. We therefore examinedbreast cancer mortality trends in the UnitedStates according to ER status and age. METHODSUsing the Surveillance, Epidemiology, and EndResults (SEER) program (1990-2003), wecalculated trends in incidence-based mortality(IBM), annual hazard rates for breast cancerdeaths after diagnosis, and relative hazard ratesfor women with ER-positive and ER-negativetumors. Relative hazard rates were assessedwith Cox proportional hazards models, adjustedfor stage and grade, and stratified by age atdiagnosis. RESULTS During the study period, IBMand annual hazard rates for breast cancer deaths", "metadata": {}}
+{"_id": "27240699", "title": "", "text": "An adenovirus mutant that replicates selectivelyin p53-deficient human tumor cells.The humanadenovirus E1B gene encodes a 55-kilodaltonprotein that inactivates the cellular tumorsuppressor protein p53. Here it is shown that amutant adenovirus that does not express thisviral protein can replicate in and lysep53-deficient human tumor cells but not cellswith functional p53. Ectopic expression of the55-kilodalton EIB protein in the latter cellsrendered them sensitive to infection with themutant virus. Injection of the mutant virus intop53-deficient human cervical carcinomas grownin nude mice caused a significant reduction intumor size and caused complete regression of 60percent of the tumors. These data raise thepossibility that mutant adenoviruses can be usedto treat certain human tumors.", "metadata": {}}
+{"_id": "27243019", "title": "", "text": "Immune reconstitution after cord bloodtransplantation: peculiarities, clinical implicationsand management strategies.Umbilical cord blood(UCB) is now widely used as an alternativehematopoietic stem cell source for patientslacking closely matched related or unrelatedadult donors. UCB transplantation hastraditionally been associated with delayedengraftment, poor immune reconstitution andconsequent increased risk of infection. Morerecent clinical studies, however, suggest thatconditioning regimens and in particular theomission of in vivo T-cell depletion may play acrucial role in post-transplant T-cell expansion,facilitating a uniquely rapid immune recoveryafter UCB transplantation. The peculiarcharacteristics of UCB cells, the importance ofthymic function and the role of conditioningregimens and graft-versus-host diseaseinfluencing immune reconstitution are described.The last part of the review reports available dataon UCB, as well as third-party peripheral blood", "metadata": {}}
+{"_id": "27247460", "title": "", "text": "OVEREXPRESSION OF BOTH CLOCK AND BMAL1INHIBITS ENTRY TO S PHASE IN HUMAN COLONCANCER CELLS.Many physiological, biochemicaland behavioral processes operate under thecircadian rhythm, which is generated by aninternal time-keeping mechanism commonlyreferred to as the biological clock, in almost allorganisms from bacteria to mammals. The corecircadian oscillator is composed of anautoregulatory transcription-translation feedbackloop, in which CLOCK and BMAL1 are positiveregulators. A cell has two mechanisms, \"cellcycle\" and \"cell rhythm\", the relationshipbetween which remains controversial. Therefore,the aim of this study was to explore the effect ofClock and Bmal1 on cell cycle, especially on theG1 phase, using vectors with the tetracyclineoperator-repressor system. The present studyrevealed that simultaneous induction of Bmal1and Clock had an influential effect on the cellcycle in SW480/T-REx/Clock/Bmal1 cells, inwhich both Clock and Bmal1 could be induced by", "metadata": {}}
+{"_id": "27260630", "title": "", "text": "Composition of gall bladder stones associatedwith octreotide: response to oral ursodeoxycholicacid.Octreotide, an effective treatment foracromegaly, induces gall bladder stones in13-60% of patients. Because knowledge of stonecomposition is essential for studies of theirpathogenesis, treatment, and prevention, thiswas investigated by direct and indirect methodsin 14 octreotide treated acromegalic patientswith gall stones. Chemical analysis of gall stonesretrieved at cholecystectomy from two patients,showed that they contained 71% and 87%cholesterol by weight. In the remaining 12patients, localised computed tomography of thegall bladder showed that eight had stones withmaximum attenuation scores of < 100Hounsfield units (values of < 100 HU predictcholesterol rich, dissolvable stones). Gall bladderbile was obtained by ultrasound guided, fineneedle puncture from six patients. All sixpatients had supersaturated bile (mean (SEM)cholesterol saturation index of 1.19 (0.08)", "metadata": {}}
+{"_id": "27264454", "title": "", "text": "Imiquimod 5% cream for the treatment ofsuperficial basal cell carcinoma: results from arandomized vehicle-controlled phase III study inEurope.BACKGROUND Imiquimod is an immuneresponse modifier that acts through toll-likereceptor 7 to induce cytokine production and asubsequent innate and adaptive cell-mediatedimmune response. Clinical studies havedemonstrated clinical and histological clearanceof superficial basal cell carcinoma (sBCC) aftertreatment with imiquimod 5% cream.OBJECTIVES To evaluate the safety and clinicalefficacy of imiquimod (Aldaratrade mark; 3MPharmaceuticals, St Paul, MN, U.S.A.) 5% creamfor the treatment of sBCC in a multicentre,randomized, parallel, vehicle-controlled,double-blind, phase III clinical study conductedat 26 centres in Europe. METHODS Subjects whohad at least one histologically confirmed sBCCtumour were randomized to apply imiquimod orvehicle cream to the target tumour once daily,seven times per week (7 x/week) for 6 weeks.", "metadata": {}}
+{"_id": "27270151", "title": "", "text": "Changing the course of pancreatic cancer--Focuson recent translational advances.In the pastdecade, insightful preclinical research has led toimportant breakthroughs in our understanding ofpancreatic cancer. Even though the vast majorityof pancreatic cancers are KRAS mutated, not allpancreatic cancer tumors are \"KRAS equal\";there seems to be varying dependencies on theKRAS pathway. While KRAS-targeting therapieshave been disappointing in the clinic, 'syntheticlethal' approaches hold promise in this setting.The pancreatic cancer stromal microenvironmentappears to have contradictory roles. While thereis evidence to suggest that stromal barrierprevents drug delivery, in other circumstances,stroma can play a protective role and itsdisruption enhances tumor dissemination.Clinical trials aimed at manipulating the variousstromal components are in progress. BRCAmutation-related pancreatic tumors illustrate aunique subtype with enhanced susceptibility toDNA damaging agents and PARP-inhibition. DNA", "metadata": {}}
+{"_id": "27274441", "title": "", "text": "Swc2 is a widely conserved H2AZ-bindingmodule essential for ATP-dependent histoneexchangeThe histone variant H2AZ isincorporated preferentially at specific locations inchromatin to modulate chromosome functions. InSaccharomyces cerevisiae, deposition of histoneH2AZ is mediated by the multiprotein SWR1complex, which catalyzes ATP-dependentexchange of nucleosomal histone H2A for H2AZ.Here, we define interactions between SWR1components and H2AZ, revealing a link betweenthe ATPase domain of Swr1 and three subunitsrequired for the binding of H2AZ. We discoveredthat Swc2 binds directly to and is essential fortransfer of H2AZ. Swc6 and Arp6 are necessaryfor the association of Swc2 and for nucleosomebinding, whereas other subunits, Swc5 and Yaf9,are required for H2AZ transfer but neither H2AZnor nucleosome binding. Finally, the C-terminalα-helix of H2AZ is crucial for its recognition bySWR1. These findings provide insight on theinitial events of histone exchange.", "metadata": {}}
+{"_id": "27279525", "title": "", "text": "Detection, characterization, and spontaneousdifferentiation in vitro of very smallembryonic-like putative stem cells in adultmammalian ovary.The present study wasundertaken to detect, characterize, and studydifferentiation potential of stem cells in adultrabbit, sheep, monkey, and menopausal humanovarian surface epithelium (OSE). Two distinctpopulations of putative stem cells (PSCs) ofvariable size were detected in scraped OSE, onebeing smaller and other similar in size to thesurrounding red blood cells in the scraped OSE.The smaller 1-3 μm very small embryonic-likePSCs were pluripotent in nature with nuclearOct-4 and cell surface SSEA-4, whereas thebigger 4-7 μm cells with cytoplasmic localizationof Oct-4 and minimal expression of SSEA-4 werepossibly the tissue committed progenitor stemcells. Pluripotent gene transcripts of Oct-4,Oct-4A, Nanog, Sox-2, TERT, and Stat-3 inhuman and sheep OSE were detected by reversetranscriptase-polymerase chain reaction. The", "metadata": {}}
+{"_id": "27306942", "title": "", "text": "Rearrangement of CRLF2 is associated withmutation of JAK kinases, alteration of IKZF1,Hispanic/Latino ethnicity, and a poor outcome inpediatric B-progenitor acute lymphoblasticleukemia.Gene expression profiling of 207uniformly treated children with high-riskB-progenitor acute lymphoblastic leukemiarevealed 29 of 207 cases (14%) with markedlyelevated expression of CRLF2 (cytokinereceptor-like factor 2). Each of the 29 casesharbored a genomic rearrangement of CRLF2: 18of 29 (62%) had a translocation of theimmunoglobulin heavy chain gene IGH@ on14q32 to CRLF2 in the pseudoautosomal region 1of Xp22.3/Yp11.3, whereas 10 (34%) cases hada 320-kb interstitial deletion centromeric ofCRLF2, resulting in a P2RY8-CRLF2 fusion. Onecase had both IGH@-CRLF2 and P2RY8-CRLF2,and another had a novel CRLF2 rearrangement.Only 2 of 29 cases were Down syndrome. CRLF2rearrangements were significantly associatedwith activating mutations of JAK1 or JAK2,", "metadata": {}}
+{"_id": "27373088", "title": "", "text": "Substrate requirements for ErmC'methyltransferase activity.ErmC' is amethyltransferase that confers resistance to themacrolide-lincosamide-streptogramin B group ofantibiotics by catalyzing the methylation of 23SrRNA at a specific adenine residue (A-2085 inBacillus subtilis; A-2058 in Escherichia coli). Thegene for ErmC' was cloned and expressed to ahigh level in E. coli, and the protein was purifiedto virtual homogeneity. Studies of substraterequirements of ErmC' have shown that a262-nucleotide RNA fragment within domain V ofB. subtilis 23S rRNA can be utilized efficiently asa substrate for methylation at A-2085. Kineticstudies of the monomethylation reaction showedthat the apparent Km of this 262-nucleotide RNAoligonucleotide was 26-fold greater than thevalue determined for full-size and domain V 23SrRNA. In addition, the Vmax for this fragmentalso rose sevenfold. A model of RNA-ErmC'interaction involving multiple binding sites isproposed from the kinetic data presented.", "metadata": {}}
+{"_id": "27391365", "title": "", "text": "Validity of the World Health Organization AdultADHD Self-Report Scale (ASRS) Screener in arepresentative sample of health planmembers.The validity of the six-question WorldHealth Organization Adult ADHD Self-ReportScale (ASRS) Screener was assessed in a sampleof subscribers to a large health plan in the US. Aconvenience subsample of 668 subscribers wasadministered the ASRS Screener twice to assesstest-retest reliability and then a third time inconjunction with a clinical interviewer for DSM-IVadult ADHD. The data were weighted to adjustfor discrepancies between the sample and thepopulation on socio-demographics and pastmedical claims. Internal consistency reliability ofthe continuous ASRS Screener was in the range0.63-0.72 and test-retest reliability (Pearsoncorrelations) in the range 0.58-0.77. Afour-category version The ASRS Screener hadstrong concordance with clinician diagnoses, withan area under the receiver operatingcharacteristic curve (AUC) of 0.90. The brevity", "metadata": {}}
+{"_id": "27393799", "title": "", "text": "The body-mass index of twins who have beenreared apart.To assess the relative importance ofgenetic and environmental effects on thebody-mass index (weight in kilograms divided bythe square of the height in meters), we studiedsamples of identical and fraternal twins, rearedapart or reared together. The samples consistedof 93 pairs of identical twins reared apart, 154pairs of identical twins reared together, 218 pairsof fraternal twins reared apart, and 208 pairs offraternal twins reared together. The intrapaircorrelation coefficients of the values forbody-mass index of identical twins reared apartwere 0.70 for men and 0.66 for women. Theseare the most direct estimates of the relativeimportance of genetic influences (heritability) onthe body-mass index, and they were only slightlylower than those for twins reared together in thisand earlier studies. Similar estimates werederived from maximum-likelihood model-fittinganalyses--0.74 for men and 0.69 for women.Nonadditive genetic variance made a significant", "metadata": {}}
+{"_id": "27396415", "title": "", "text": "A study of high cell density cultivation process ofrecombinant Helicobacter pylori multi-epitopevaccine engineering bacteria.OBJECTIVE Toestablish high cell density cultivation process ofrecombinant Helicobacter pylori multi-epitopevaccine engineering bacteria BIB. METHODSBased on the results of shake flask fermentation,the process was magnified into volume of a 50 Lfermenter to optimize and verify the factorsaffecting the yield of the target protein, such asthe fermentation medium, working seedinoculation amount, inducer concentration,induction starting time, induction duration,inducer adding mode and feeding strategy.RESULTS After activated in modified TB mediumat 37°C for 8 h, the BIB working seed wasinoculated at 5% (v/v) and was induced forexpression for another 11 h by the finalconcentration of 5 mmol/L lactose. In growthphase, glucose at rate of 80 ml/h was used ascarbon source, and in induction phase, glycerolat rate of 40 ml/h was used as carbon source;", "metadata": {}}
+{"_id": "27403802", "title": "", "text": "Phorbol esters and cytokines regulate theexpression of the NEMO-related protein, amolecule involved in a NF-kappa B-independentpathway.The NF-kappaB signaling pathway playsa crucial role in the immune, inflammatory, andapoptotic responses. Recently, we identified theNF-kappaB Essential Modulator (NEMO) as anessential component of this pathway. NEMO is astructural and regulatory subunit of the highmolecular kinase complex (IKK) responsible forthe phosphorylation of NF-kappaB inhibitors.Data base searching led to the isolation of acDNA encoding a protein we called NRP(NEMO-related protein), which shows a stronghomology to NEMO. Here we show that NRP ispresent in a novel high molecular weightcomplex, that contains none of the knownmembers of the IKK complex. Consistently, wecould not observe any effect of NRP onNF-kappaB signaling. Nonetheless, we coulddemonstrate that treatment with phorbol estersinduces NRP phosphorylation and decreases its", "metadata": {}}
+{"_id": "27408104", "title": "", "text": "Tailoring Nutritional Advice for Mexicans Basedon Prevalence Profiles of Diet-Related AdaptiveGene PolymorphismsDiet-related adaptive gene(DRAG) polymorphisms identified in specificpopulations are associated with chronic disordersin carriers of the adaptive alleles due to changesin dietary and lifestyle patterns in recent times.Mexico's population is comprised of Amerindians(AM) and Mestizos who have variable AM,European (EUR) and African genetic ancestry andan increased risk of nutrition-related chronicdiseases. Nutritional advice based on theMexican genome and the traditional food cultureis needed to develop preventive and therapeuticstrategies. Therefore, we aimed to provide aprevalence profile of several DRAGpolymorphisms in the Mexican population,including Central West (CW) Mexicosubpopulations. Geographic heat maps were builtusing ArcGIS10 (Esri, Redlands, CA, USA)software, based on the published data of theMTHFR C677T (rs1801133), ABCA1 Arg230Cys", "metadata": {}}
+{"_id": "27428509", "title": "", "text": "Prevention of Type 2 Diabetes Mellitus ThroughInhibition of the Renin-Angiotensin SystemType2 diabetes mellitus is becoming a major healthproblem associated with excess morbidity andmortality. As the prevalence of type 2 diabetes israpidly increasing, prevention of the diseaseshould be considered as a key objective in thenear future. Besides lifestyle changes, variouspharmacological treatments have proven theirefficacy in placebo-controlled clinical trials,including antidiabetic drugs such as metformin,acarbose and troglitazone, or antiobesity agentssuch as orlistat. Arterial hypertension, a clinicalentity in which insulin resistance is common, isstrongly associated with type 2 diabetes and mayprecede the disease by several years. Whileantihypertensive agents such as diuretics orβ-adrenoceptor antagonists may worsen insulinresistance and impair glucose tolerance, newerantihypertensive agents exert neutral or evenslightly positive metabolic effects. Numerousclinical trials have investigated the effects of ACE", "metadata": {}}
+{"_id": "27437459", "title": "", "text": "Randomized dose-finding clinical trial of oncolyticimmunotherapeutic vaccinia JX-594 in livercancerOncolytic viruses and activeimmunotherapeutics have complementarymechanisms of action (MOA) that are both selfamplifying in tumors, yet the impact of dose onsubject outcome is unclear. JX-594 (Pexa-Vec) isan oncolytic and immunotherapeutic vacciniavirus. To determine the optimal JX-594 dose insubjects with advanced hepatocellular carcinoma(HCC), we conducted a randomized phase 2dose-finding trial (n = 30). Radiologists infusedlow- or high-dose JX-594 into liver tumors (days1, 15 and 29); infusions resulted in acutedetectable intravascular JX-594 genomes.Objective intrahepatic Modified ResponseEvaluation Criteria in Solid Tumors (mRECIST)(15%) and Choi (62%) response rates andintrahepatic disease control (50%) wereequivalent in injected and distant noninjectedtumors at both doses. JX-594 replication andgranulocyte-macrophage colony-stimulating", "metadata": {}}
+{"_id": "27438378", "title": "", "text": "Misread protein creates membrane channels: anessential step in the bactericidal action ofaminoglycosides.Among the pleiotropic effects ofaminoglycosides, their irreversible uptake andtheir blockade of initiating ribosomes haveappeared to explain their bactericidal action,while the contributions of translationalmisreading and membrane damage and themechanism of that damage have remaineduncertain. We now present evidence thatincorporation of misread proteins into themembrane can account for the membranedamage. The bactericidal action thus appears toresult from the following sequence, in which eachstep is essential: slight initial entry of theantibiotic; interaction with chain-elongatingribosomes, resulting in misreading; incorporationof misread protein into the membrane, creatingabnormal channels; increased (and irreversible)entry through these channels, and henceincreased misreading and formation of channels;and, finally, blockade of initiating ribosomes.", "metadata": {}}
+{"_id": "27446873", "title": "", "text": "Rate of cervical cancer, severe intraepithelialneoplasia, and adenocarcinoma in situ in primaryHPV DNA screening with cytology triage:randomised study within organised screeningprogramme.OBJECTIVE To assess theperformance and impact of primary humanpapillomavirus (HPV) DNA screening withcytology triage compared with conventionalcytology on cervical cancer and severepre-cancerous lesions. DESIGN Randomised trial.SETTING Population based screening programmefor cervical cancer in southern Finland in 2003-5.PARTICIPANTS 58 076 women, aged 30-60,invited to the routine population based screeningprogramme for cervical cancer. INTERVENTIONSPrimary HPV DNA test (hybrid capture II) withcytology triage if the result was positive orconventional cytological screening (reference).MAIN OUTCOME MEASURES Rate of cervicalcancer, cervical intraepithelial neoplasia (CIN)grade III, and adenocarcinoma in situ (as acomposite outcome referred to as CIN III+)", "metadata": {}}
+{"_id": "27449472", "title": "", "text": "Metabolic syndrome as a risk factor fordiabetes.The metabolic syndrome was initiallydescribed as an insulin-resistance syndromecharacterized by the clustering of metabolictraits such as high triglycerides, low high-densitylipoprotein cholesterol, high blood pressure,abdominal obesity and different degrees ofimpaired glucose regulation. Although differentdefinitions have been developed by variousconsensus groups, epidemiological studiesdemonstrate that they all associate the metabolicsyndrome with a similar cardiometabolic risk,which is high for diabetes (ranging betweenthree- and 20-fold), depending on the number ofcomponents and the inclusion of impaired fastingglucose, impaired glucose tolerance or both. Thelatter appear to indicate the failure of the betacell to produce enough insulin to compensate forthe increased demand due to insulin resistance.There is a hyperbolic relationship between insulinproduction and insulin sensitivity, which can becalculated by the disposition index. When this is", "metadata": {}}
+{"_id": "27453479", "title": "", "text": "The fallacy of the ecological fallacy: the potentialmisuse of a concept and theconsequences.Ecological studies have beenevaluated in epidemiological contexts in terms ofthe \"ecological fallacy. \" Although the empiricalevidence for a lack of comparability betweencorrelations derived from ecological- andindividual-level analyses is compelling, theconceptual meaning of the ecological fallacyremains problematic. This paper argues thatissues in cross-level inference can be usefullyconceptualized as validity problems, problemsnot peculiar to ecological-level analyses. Such anapproach increases the recognition of bothpotential inference problems in individual-levelstudies and the unique contributions of ecologicalvariables. This, in turn, expands the terrain forthe location of causes for disease andinterventions to improve the public's health.", "metadata": {}}
+{"_id": "27460509", "title": "", "text": "Blocking caspase-activated apoptosis improvescontractility in failing myocardium.Cardiacmyocyte apoptosis has been demonstrated inend-stage failing human hearts. The therapeuticutility of blocking apoptosis in congestive heartfailure (CHF) has not been elucidated. This studyinvestigated the role of caspase activation incardiac contractility and sarcomere organizationin the development of CHF. In a rabbit model ofheart failure obtained by rapid ventricularpacing, we demonstrate, using in vivotranscoronary adenovirus-mediated genedelivery of the potent caspase inhibitor p35, thatcaspase activation is associated with a reductionin contractile force of failing myocytes bydestroying sarcomeric structure. In this animalmodel gene transfer of p35 prevented the rise incaspase 3 activity and DNA-histone formation.Genetically manipulated hearts expressing p35had a significant improvement in left ventricularpressure rise (+dp/dt), decreased end-diastolicchamber pressure (LVEDP), and the development", "metadata": {}}
+{"_id": "27466734", "title": "", "text": "Development and validation of QRISK3 riskprediction algorithms to estimate future risk ofcardiovascular disease: prospective cohortstudyObjectives To develop and validate updatedQRISK3 prediction algorithms to estimate the 10year risk of cardiovascular disease in women andmen accounting for potential new risk factors.Design Prospective open cohort study. SettingGeneral practices in England providing data forthe QResearch database. Participants 1309QResearch general practices in England: 981practices were used to develop the scores and aseparate set of 328 practices were used tovalidate the scores. 7.89 million patients aged25-84 years were in the derivation cohort and2.67 million patients in the validation cohort.Patients were free of cardiovascular disease andnot prescribed statins at baseline. Methods Coxproportional hazards models in the derivationcohort to derive separate risk equations in menand women for evaluation at 10 years. Riskfactors considered included those already in", "metadata": {}}
+{"_id": "27527854", "title": "", "text": "The importance of engaging policy-makers at theoutset to guide research on and introduction ofvaccines: the use of policy-makersurveys.Face-to-face surveys of policy-makersand other influential leaders are a useful tool toidentify, at an early stage, (a) major issuesregarding the introduction of a new vaccine, (b)persons and groups in a country who play amajor decision-making or influential role in theintroduction of vaccines, (c) potential obstaclesto the introduction of vaccines, and (d)data-needs of policy-makers to overcome theseobstacles. By surveying the opinions and beliefsof those who will make or influence decisions onwhether to introduce a new vaccine, thesestudies can help ensure that research activitiesrespond to the needs of policy-makers incountries endemic for the target diseases. Thesesurveys can also inform vaccine-introductionstrategies by identifying financially and politicallyfeasible means of distributing, targeting, andfinancing the vaccines. This paper describes the", "metadata": {}}
+{"_id": "27545868", "title": "", "text": "Histone acetyltransferase PCAF regulatesinflammatory molecules in the development ofrenal injury.Kidney diseases, including chronickidney disease (CKD) and acute kidney injury(AKI), are associated with inflammation. Themechanism that regulates inflammation in theserenal injuries remains unclear. Here, wedemonstrated that p300/CBP-associated factor(PCAF), a histone acetyltransferase, wasoverexpressed in the kidneys of db/db mice andlipopolysaccharide (LPS)-injected mice.Moreover, elevated histone acetylation, such asH3K18ac, and up-regulation of someinflammatory genes, such as ICAM-1, VCAM-1,and MCP-1, were found upon these renalinjuries. Furthermore, increased H3K18ac wasrecruited to the promoters of ICAM-1, VCAM-1,and MCP-1 in the kidneys of LPS-injected mice.In vitro studies demonstrated that PCAFknockdown in human renal proximal tubuleepithelial cells (HK-2) led to downregulation ofinflammatory molecules, including VCAM-1,", "metadata": {}}
+{"_id": "27550580", "title": "", "text": "T1 mapping for myocardial extracellular volumemeasurement by CMR: bolus only versus primedinfusion technique.OBJECTIVES The aim of thisstudy was to determine the accuracy of thecontrast \"bolus only\" T1 mapping cardiacmagnetic resonance (CMR) technique formeasuring myocardial extracellular volumefraction (ECV). BACKGROUND Myocardial ECVcan be measured with T1 mapping before andafter contrast agent if the contrast agentdistribution between blood/myocardium is atequilibrium. Equilibrium distribution can beachieved with a primed contrast infusion(equilibrium contrast-CMR [EQ-CMR]) or mightbe approximated by the dynamic equilibrationachieved by delayed post-bolus measurement.This bolus only approach is highly attractive, butcurrently limited data support its use. Wecompared the bolus only technique with 2independent standards: collagen volume fraction(CVF) from myocardial biopsy in aortic stenosis(AS); and the infusion technique in 5", "metadata": {}}
+{"_id": "27555165", "title": "", "text": "Cytomegalovirus US2 destroys two componentsof the MHC class II pathway, preventingrecognition by CD4+ T cellsHumancytomegalovirus (HCMV) is a ubiquitousherpesvirus that causes life-threatening diseasein patients who are immunosuppressed for bonemarrow or tissue transplantation or who haveAIDS (ref. 1). HCMV establishes lifelong latentinfections and, after periodic reactivation fromlatency, uses a panel of immune evasion proteinsto survive and replicate in the face of robust,fully primed host immunity.Monocyte/macrophages are important host cellsfor HCMV, serving as a latent reservoir and as ameans of dissemination throughout the body.Macrophages and other HCMV-permissive cells,such as endothelial and glial cells, can expressMHC class II proteins and present antigens toCD4+ T lymphocytes. Here, we show that theHCMV protein US2 causes degradation of twoessential proteins in the MHC class II antigenpresentation pathway: HLA-DR-α and DM-α. This", "metadata": {}}
+{"_id": "27567994", "title": "", "text": "CD169-positive macrophages dominateantitumor immunity by crosspresenting deadcell-associated antigens.The generation oftumor-directed cytotoxic T lymphocytes isconsidered crucial for the induction of antitumorimmunity. To activate these CD8(+) T cells,antigen-presenting cells (APCs) must initiallyacquire tumor cell-associated antigens. Themajor source of tumor antigens is dead tumorcells, but little is known about how APCs indraining lymph nodes acquire and crosspresentthese antigens. Here we show that CD169(+)macrophages phagocytose dead tumor cellstransported via lymphatic flow and subsequentlycrosspresent tumor antigens to CD8(+) T cells.Subcutaneous immunization with irradiatedtumor cells protects mice from syngenic tumor.However, tumor antigen-specific CD8(+) T cellactivation and subsequent antitumor immunityare severely impaired in mice depleted withCD169(+) macrophages. Neither migratorydendritic cells (DCs) nor lymph node-resident", "metadata": {}}
+{"_id": "27569370", "title": "", "text": "Emerging mechanisms in morphogen-mediatedaxon guidance.Early in animal development,gradients of secreted morphogenic molecules,such as Sonic hedgehog (Shh), Wnt andTGFbeta/Bmp family members, regulate cellproliferation and determine the fate andphenotype of the target cells by activatingwell-characterized signalling pathways, whichultimately control gene transcription. Shh, Wntand TGFbeta/Bmp signalling also play animportant and evolutionary conserved role inneural circuit assembly. They regulate neuronalpolarization, axon and dendrite development andsynaptogenesis, processes that require rapid andlocal changes in cytoskeletal organization andplasma membrane components. A key questionthen is whether morphogen signalling at thegrowth cone uses similar mechanisms andintracellular pathway components to thosedescribed for morphogen-mediated cellspecification. This review discusses recentadvances towards the understanding of this", "metadata": {}}
+{"_id": "27580223", "title": "", "text": "Lessons learnt from malaria epidemics in theIslamic Republic of Iran.The Islamic Republic ofIran is in the pre-elimination phase of malariacontrol, but malaria epidemics are still a concernin the south of the country. This retrospectivestudy presents the epidemiologicalcharacteristics and predisposing factors of 60 ofthe malaria epidemics reported in Sistan vaBaluchestan province during 2005-09. Azero-truncated negative binomial model wasused to investigate the relation betweenpredictor variables and the total number ofmalaria cases. Malaria epidemics occurred mainlyin the southern part of the province, mostlybetween July and October, peaking in August.Most malaria epidemics were small-scale (68.3%were < 100 cases) and short (51.7% lasted < 1month). Plasmodium falciparum was present in46.7% of the epidemics. An increase in therainfall rate as well as population movementswere the most significant predisposing factors.The results may help inform an epidemic", "metadata": {}}
+{"_id": "27587267", "title": "", "text": "Autoradiography of chromosomal DNA fibersfrom Chinese hamster cells.Ignorance of the truelength of the DNA molecules in the chromosomesof higher organisms has always been a majorobstacle to understanding chromosomestructure. Consequently, attempts have beenmade, usually with the aid of electronmicroscopy, to estimate the size of DNA in higherorganisms. Solari (1) has reported the longestsuch DNA measured before now-a DNA fiberfrom a sea urchin sperm at least 93 μ, long.", "metadata": {}}
+{"_id": "27588420", "title": "", "text": "Epigenetic memory and preferentiallineage-specific differentiation in inducedpluripotent stem cells derived from humanpancreatic islet beta cells.Human inducedpluripotent stem cells (HiPSCs) appear to behighly similar to human embryonic stem cells(HESCs). Using two genetic lineage-tracingsystems, we demonstrate the generation of iPSClines from human pancreatic islet beta cells.These reprogrammed cells acquired markers ofpluripotent cells and differentiated into the threeembryonic germ layers. However, the betacell-derived iPSCs (BiPSCs) maintained openchromatin structure at key beta-cell genes,together with a unique DNA methylationsignature that distinguishes them from otherPSCs. BiPSCs also demonstrated an increasedability to differentiate into insulin-producing cellsboth in vitro and in vivo, compared with ESCsand isogenic non-beta iPSCs. Our results suggestthat the epigenetic memory may predisposeBiPSCs to differentiate more readily into insulin", "metadata": {}}
+{"_id": "27602752", "title": "", "text": "CCL2/monocyte chemoattractant protein-1mediates enhanced transmigration of humanimmunodeficiency virus (HIV)-infectedleukocytes across the blood-brain barrier: apotential mechanism of HIV-CNS invasion andNeuroAIDS.Encephalitis and dementia associatedwith acquired immunodeficiency syndrome(AIDS) are characterized by leukocyte infiltrationinto the CNS, microglia activation, aberrantchemokine expression, blood-brain barrier (BBB)disruption, and eventual loss of neurons. Little isknown about whether human immunodeficiencyvirus 1 (HIV-1) infection of leukocytes affectstheir ability to transmigrate in response tochemokines and to alter BBB integrity. We nowdemonstrate that HIV infection of humanleukocytes results in their increasedtransmigration across our tissue culture model ofthe human BBB in response to the chemokineCCL2, as well as in disruption of the BBB, asevidenced by enhanced permeability, reductionof tight junction proteins, and expression of", "metadata": {}}
+{"_id": "27615329", "title": "", "text": "Prostaglandin E2 as an inhibitory modulator offibrogenesis in human lung allografts.RATIONALEDonor mesenchymal stromal/stem cell (MSC)expansion and fibrotic differentiation isassociated with development of bronchiolitisobliterans syndrome (BOS) in human lungallografts. However, the regulators of fibroticdifferentiation of these resident mesenchymalcells are not well understood. OBJECTIVES Thisstudy examines the role of endogenous andexogenous prostaglandin (PG)E2 as a modulatorof fibrotic differentiation of human lungallograft-derived MSCs. METHODS Effect of PGE2on proliferation, collagen secretion, andα-smooth muscle actin (α-SMA) expression wasassessed in lung-resident MSCs (LR-MSCs)derived from patients with and without BOS. Theresponse pathway involved was elucidated byuse of specific agonists and antagonists.MEASUREMENT AND MAIN RESULTS PGE2treatment of LR-MSCs derived from normal lungallografts significantly inhibited their", "metadata": {}}
+{"_id": "27635177", "title": "", "text": "Association of DNA polymerase mu (pol mu) withKu and ligase IV: role for pol mu in end-joiningdouble-strand break repair.Mammalian DNApolymerase mu (pol mu) is related to terminaldeoxynucleotidyl transferase, but its biologicalrole is not yet clear. We show here that afterexposure of cells to ionizing radiation (IR), levelsof pol mu protein increase. pol mu also formsdiscrete nuclear foci after IR, and these foci arelargely coincident with IR-induced foci ofgammaH2AX, a previously characterized markerof sites of DNA double-strand breaks. pol mu isthus part of the cellular response to DNAdouble-strand breaks. pol mu also associates incell extracts with the nonhomologous end-joiningrepair factor Ku and requires both Ku andanother end-joining factor, XRCC4-ligase IV, toform a stable complex on DNA in vitro. pol mu inturn facilitates both stable recruitment ofXRCC4-ligase IV to Ku-bound DNA and ligaseIV-dependent end joining. In contrast, therelated mammalian DNA polymerase beta does", "metadata": {}}
+{"_id": "27647593", "title": "", "text": "Stromal-epithelial metabolic coupling in cancer:integrating autophagy and metabolism in thetumor microenvironment.Cancer cells do notexist as pure homogeneous populations in vivo.Instead they are embedded in \"cancer cell nests\"that are surrounded by stromal cells, especiallycancer associated fibroblasts. Thus, it is notunreasonable to suspect that stromal fibroblastscould influence the metabolism of adjacentcancer cells, and visa versa. In accordance withthis idea, we have recently proposed that theWarburg effect in cancer cells may be due toculturing cancer cells by themselves, out of theirnormal stromal context or tumormicroenvironment. In fact, when cancer cells areco-cultured with fibroblasts, then cancer cellsincrease their mitochondrial mass, whilefibroblasts lose their mitochondria. An in depthanalysis of this phenomenon reveals thataggressive cancer cells are \"parasites\" that useoxidative stress as a \"weapon\" to extractnutrients from surrounding stromal cells.", "metadata": {}}
+{"_id": "27665523", "title": "", "text": "Oxidative stress in renal dysfunction:mechanisms, clinical sequelae and therapeuticoptionsOxidative stress has been increasinglylinked to the high incidence of cardiovascularevents in patients with chronic kidney disease(CKD), especially as traditional cardiovascularrisk factors seem to not be able to account forthe huge cardiovascular morbidity and mortalityin this population group. Oxidative stress isincreased in patients with renal impairment as aresult of increased oxidant activity and reducedantioxidant capacity, and this is increased in agraded manner with increasing renaldysfunction. Inflammation, which is also presentin CKD, further amplifies the oxidant generationprocess. The two clinical sequelae of oxidativestress are endothelial dysfunction and leftventricular hypertrophy, which have adversecardiovascular consequences. With our newunderstanding of oxidative stress, it is nowimportant to assess treatment options thatreduce it in the hope that they reverse", "metadata": {}}
+{"_id": "27686445", "title": "", "text": "Effect of age, sex, and sites on the cellularity ofthe adipose tissue in mice and rats renderedobese by a high-fat diet.Cell size and number ofparametrial fat pads were determined in Swissmice made obese by means of a high-fat diet(40% lard w/w) given ad lib. This diet and acontrol were introduced to two groups ofmothers during gestation and lactation, andsucklings were given the same diets as theirmothers at weaning and throughout life.2-wk oldmice suckled by mothers fed a high-fat diet havefatter parametrial pads. This difference is duesolely to an increase in fat cell size. Afterweaning, until the 18th wk, the two groupsdiffered with a striking fat cell enlargement seenin the obese group. Later on, whereas cellnumbers did not change in the control group, aconstant and uninterrupted increase in number isshown in those of obese mice until the 52nd wk.Hyperplasia was observed only in adults. Whenthe high-fat diet was introduced to adult rats italso triggered an increase in fat cell number.", "metadata": {}}
+{"_id": "27693891", "title": "", "text": "Transcriptional integration of mitochondrialbiogenesis.Gene regulatory factors encoded bythe nuclear genome are essential formitochondrial biogenesis and function. Some ofthese factors act exclusively within themitochondria to regulate the control ofmitochondrial transcription, translation, andother functions. Others govern the expression ofnuclear genes required for mitochondrialmetabolism and organelle biogenesis. Theperoxisome proliferator-activated receptor γcoactivator-1 (PGC-1) family of transcriptionalcoactivators play a major role in transducing andintegrating physiological signals governingmetabolism, differentiation, and cell growth tothe transcriptional machinery controllingmitochondrial functional capacity. Thus, thePGC-1 coactivators serve as a central componentof the transcriptional regulatory circuitry thatcoordinately controls the energy-generatingfunctions of mitochondria in accordance with themetabolic demands imposed by changing", "metadata": {}}
+{"_id": "27709445", "title": "", "text": "RFID system evaluation against radiatedtransient noiseIn this paper a radiofrequencyidentification system according to standardISO/IEC 14443 type-B is evaluated in  presenceof transient noise. This real time communicationsystem working at 13.56 MHz is interfered in acontrolled environment by different transientbursts varying their level, frequency andduration. The transient burst interference isapplied in an AC main wire close to the systemand the effect over the digital communicationsystem is evaluated using two different methods.The first one is observing directly an RFIDequipment in presence of transient signals, andthe second one is capturing the  interference intime domain an evaluating its effect by means ofsimulation. The RFID system is affected by thesetransient noises  causing different types oferrors. It is shown that it is essential to measureand evaluate in time domain the transientphenomena to ensure that the RFID system donot have susceptibility problems.", "metadata": {}}
+{"_id": "27711043", "title": "", "text": "Musculoskeletal pain in Europe: its impact and acomparison of population and medicalperceptions of treatment in eight Europeancountries.OBJECTIVES To describe the impact ofmusculoskeletal pain (MP); to comparemanagement of MP by the population and byprimary care physicians; and to identifymisconceptions about treatment. METHODS 5803people with MP and 1483 primary carephysicians, randomly selected, in eight Europeancountries were interviewed by telephone. Astructured questionnaire was used to ask aboutusual management of MP and perceived benefitsand risks of treatment. Current health status(SF-12) was also assessed. RESULTS Fromprimary care physicians' perceptions, MP appearsto be well managed. All presenting patients areoffered some form of treatment, 90% or moredoctors are trying to improve patients' quality oflife, and most are aware and concerned aboutthe risks of treatment with NSAIDs. From apopulation perspective, up to 27% of people with", "metadata": {}}
+{"_id": "27712433", "title": "", "text": "[Palliative care in Germany].The delivery ofpalliative care in Germany is still characterizedby a wide-spread undersupply both for inpatientsand outpatients. Nevertheless over the last 15years progress has also been made in Germany,which is pleasing and which has directedprofessional and public attention increasingly tothe situation of the incurably ill and dying. In thecourse of this development the first structuresfor specialized palliative care have beenestablished. In particular the situation forinpatients in hospitals and hospices is pleasing,even if a satisfaction for total coverage is not yetreached. More seriously however is the demandfor the outpatients. Financial means, which aresteered so far only rudimentarily for palliativecare, must be made sufficiently available, inorder to be able to meet the demand with thehelp of appropriate structural offers. It isimportant to realize the needs of the incurably illand dying and of their relatives and friends. Oursociety has to call attention to this subject and it", "metadata": {}}
+{"_id": "27731651", "title": "", "text": "A view to a kill: the bacterial type VI secretionsystem.The bacterial type VI secretion system(T6SS) is an organelle that is structurally andmechanistically analogous to an intracellularmembrane-attached contractile phage tail.Recent studies determined that a rapidconformational change in the structure of asheath protein complex propels T6SS spike andtube components along with antibacterial andantieukaryotic effectors out of predatoryT6SS(+) cells and into prey cells. The contractedorganelle is then recycled in an ATP-dependentprocess. T6SS is regulated at transcriptional andposttranslational levels, the latter involvingdetection of membrane perturbation in somespecies. In addition to directly targetingeukaryotic cells, the T6SS can also target otherbacteria coinfecting a mammalian host,highlighting the importance of the T6SS not onlyfor bacterial survival in environmentalecosystems, but also in the context of infectionand disease. This review highlights these and", "metadata": {}}
+{"_id": "27768226", "title": "", "text": "Open Access Increases Citation RatePLoS Biologypublishes today a research article by GuntherEysenbach that is not about biology. It is aboutcitations. It provides robust evidence thatopen-access articles (OA articles) are moreimmediately recognized and cited than non-OAarticles. As such, it adds objective support to thebelief we have always held that open-accesspublication speeds up scientific dialog betweenresearchers and, consequently, should beextended to the whole scientific literature asquickly as possible. It is therefore fitting that wepublish such a paper. We have long argued thatpapers freely available in a journal will be moreoften read and cited than those behind asubscription barrier. However, solid evidence tosupport or refute such a claim has beensurprisingly hard to find. Since most open-accessjournals are new, comparisons of the effects ofopen access with established subscription-basedjournals are easily confounded by age andreputation. In the current study, Eysenbach", "metadata": {}}
+{"_id": "27772649", "title": "", "text": "Serum immunoglobulin A from patients withceliac disease inhibits human T84 intestinal cryptepithelial cell differentiation.BACKGROUND &AIMS Celiac disease is characterized by disturbedjejunal crypt-villus axis biology withimmunoglobulin (Ig) A deposits underlining theepithelium. The aim of this study was to testwhether celiac disease serum IgA(reticulin/endomysial autoantibodies) interfereswith the mesenchymal-epithelial cell cross-talk.METHODS Differentiation of T84 epithelial cellswas induced with IMR-90 fibroblasts ortransforming growth factor beta inthree-dimensional collagen gel cultures. Theeffects of purified celiac IgA and monoclonaltissue transglutaminase antibodies (CUB7402)were studied by adding the antibodies to thecocultures. RESULTS Active celiac disease IgA,reactive for tissue transglutaminase, significantlyinhibited T84 epithelial cell differentiation (P <0.001) and increased epithelial cell proliferation(P = 0.024). Similar effects were obtained with", "metadata": {}}
+{"_id": "27789588", "title": "", "text": "Pathogenesis of diseases associated withantineutrophil cytoplasm autoantibodies.Little isknown about the etiologies of diseasesassociated with circulating antineutrophilcytoplasm autoantibodies (ANCA), such asprimary vasculitides and inflammatory boweldiseases. However, the understanding ofimmune mechanisms supposedly involved in thepathogenesis of these diseases is still growing. Inthe present review, we first focus on themechanisms triggering the development ofANCA, including the potential role of microbialsuperantigens and the possible defect(s) in theprogression of apoptosis or in the removal ofapoptotic cells. We next concentrate on thecontribution of ANCA to the clinical symptomsand on the pathogenic role of ANCA, includingthe accessibility of ANCA antigens as targets forcirculating antibodies and the mode of action ofANCA. Mechanisms of neutrophil activation byANCA include the engagement of Fcgammareceptors, the possible mechanisms of", "metadata": {}}
+{"_id": "27815697", "title": "", "text": "The common marmoset as a novel animal modelsystem for biomedical and neuroscience researchapplications.The common marmoset (Callithrixjacchus), a small New World primate, has beenattracting much attention in the research field ofbiomedical science and neuroscience, based onits (i) cross-reactivity with human cytokines orhormones, (ii) comparative ease in handling dueto its small size, (iii) high reproductive efficiency,(iv) establishment of basic research tools, and(v) advantages of its unique behavioral andcognitive characters. Various neurologicaldisease models have been developed in thecommon marmoset, including Parkinson'sdisease, Huntington's disease, Alzheimer'sdisease, stroke, multiple sclerosis and spinal cordinjury. We recently developed transgeniccommon marmoset with germline transmission,which is expected to provide a new animal modelfor the study of human diseases. In this review,we summarize the recent progress of biomedicalresearch and neuroscience using common", "metadata": {}}
+{"_id": "27822315", "title": "", "text": "Liver receptor homolog-1 regulates thetranscription of steroidogenic enzymes andinduces the differentiation of mesenchymal stemcells into steroidogenic cells.Steroidogenicfactor-1 (SF-1, also known as Ad4BP) has beendemonstrated to be a primary transcriptionalregulator of steroidogenic-related genes.However, mRNA for liver receptor homolog-1(LRH-1), which together with SF-1, belongs tothe NR5A nuclear receptor family, is expressedat much higher levels than SF-1 mRNA in thehuman gonad. In our previous studies, wedemonstrated that SF-1 induced thedifferentiation of bone marrow-derivedmesenchymal stem cells (MSCs) intosteroidogenic cells such as Leydig oradrenocortical cells. The introduction of LRH-1into human MSCs (hMSCs) with the aid of cAMPalso induced the expression of steroidogenicenzymes, including CYP17, and theirdifferentiation into steroid hormone-producingcells. Promoter analysis, EMSA, and chromatin", "metadata": {}}
+{"_id": "27840664", "title": "", "text": "Checkpoint responses to replication forkbarriers.The fidelity of DNA replication is ofparamount importance to the maintenance ofgenome integrity. When an active replication forkis perturbed, multiple cellular pathways arerecruited to stabilize the replication apparatusand to help to bypass or correct the causativeproblem. However, if the problem is notcorrected, the fork may collapse, exposing freeDNA ends to potentially inappropriateprocessing. In prokaryotes, replication forkcollapse promotes the activity of recombinationproteins to restore a replication fork. Recentwork has demonstrated that recombination isalso intimately linked to replication in eukaryoticcells, and that recombination proteins arerecruited to collapsed, but not stalled, replicationforks. In this review we discuss the differenttypes of potential replication fork barriers (RFB)and how these distinct RFBs can result indifferent DNA structures at the stalled replicationfork. The DNA structure checkpoints which act", "metadata": {}}
+{"_id": "27841037", "title": "", "text": "Ecology, economics and political will: thevicissitudes of malaria strategies in Asia.Thedocumented history of malaria in parts of Asiagoes back more than 2,000 years, during whichthe disease has been a major player on thesocioeconomic stage in many nation states asthey waxed and waned in power and prosperity.On a much shorter time scale, the last halfcentury has seen in microcosm a history of largefluctuations in endemicity and impact of malariaacross the spectrum of rice fields and rainforests, mountains and plains that reflect thevast ecological diversity inhabited by thismajority aggregation of mankind. That periodhas seen some of the most dramatic changes insocial and economic structure, in population size,density and mobility, and in political structure inhistory: all have played a part in the changingface of malaria in this extensive region of theworld. While the majority of global malaria casescurrently reside in Africa, greater numbersinhabited Asia earlier this century before malaria", "metadata": {}}
+{"_id": "27866735", "title": "", "text": "Global and regional risk of disabling sequelaefrom bacterial meningitis: a systematic reviewand meta-analysis.Few data sources areavailable to assess the global and regional risk ofsequelae from bacterial meningitis. We aimed toestimate the risks of major and minor sequelaecaused by bacterial meningitis, estimate thedistribution of the different types of sequelae,and compare risk by region and income. Wesystematically reviewed published papers from1980 to 2008. Standard global burden of diseasecategories (cognitive deficit, bilateral hearingloss, motor deficit, seizures, visual impairment,hydrocephalus) were labelled as major sequelae.Less severe, minor sequelae (behaviouralproblems, learning difficulties, unilateral hearingloss, hypotonia, diplopia), and multipleimpairments were also included. 132 paperswere selected for inclusion. The median (IQR)risk of at least one major or minor sequela afterhospital discharge was 19.9% (12.3-35.3%).The risk of at least one major sequela was", "metadata": {}}
+{"_id": "27873158", "title": "", "text": "Efficacy of human papillomavirus testing for thedetection of invasive cervical cancers andcervical intraepithelial neoplasia: a randomisedcontrolled trial.BACKGROUND Humanpapillomavirus (HPV) testing is known to bemore sensitive, but less specific than cytology fordetecting cervical intraepithelial neoplasia (CIN).We assessed the efficacy of cervical-cancerscreening policies that are based on HPV testing.METHODS Between March, 2004, and December,2004, in two separate recruitment phases,women aged 25-60 years were randomlyassigned to conventional cytology or to HPVtesting in combination with liquid-based cytology(first phase) or alone (second phase).Randomisation was done by computer in twoscreening centres and by sequential opening ofnumbered sealed envelopes in the remainingseven centres. During phase one, women whowere HPV-positive and aged 35-60 years werereferred to colposcopy, whereas women aged25-34 years were referred to colposcopy only if", "metadata": {}}
+{"_id": "27889071", "title": "", "text": "Microcytosis, iron deficiency and thalassaemia ina multi-ethnic community: a pilot study.The highprevalence of microcytosis (defined here asmean cell haemoglobin<27 pg) with no otherabnormality is a principal cause of confusion inscreening for haemoglobin disorders. Here wereport the results of a small pilot study aiming toresolve this confusion by routinely proceeding toplasma ferritin and HPLC assay, using theoriginal sequestrene blood sample, whenmicrocytosis is detected. Participants compriseda random sample of 1,302 people referred for afull blood count by their General Practitioner (GP)to the laboratory of a North London districtgeneral hospital serving a multi-ethnic inner-citypopulation. Ethnicity was established byquestionnaire. In North Europeans, microcytosiswas present in 3% of males (half wereiron-deficient) and 11% of females (most wereiron-deficient). Among ethnic minorities,microcytosis was present in 35% of males (onetenth were iron-deficient), and 45% of females", "metadata": {}}
+{"_id": "27900414", "title": "", "text": "Crystal structure of the human AAA+ proteinRuvBL1.RuvBL1 is an evolutionarily highlyconserved eukaryotic protein belonging to theAAA(+)-family of ATPases (ATPase associatedwith diverse cellular activities). It playsimportant roles in essential signaling pathwayssuch as the c-Myc and Wnt pathways inchromatin remodeling, transcriptional anddevelopmental regulation, and DNA repair andapoptosis. Herein we present thethree-dimensional structure of theselenomethionine variant of human RuvBL1refined using diffraction data to 2.2A ofresolution. The crystal structure of the hexameris formed of ADP-bound RuvBL1 monomers. Themonomers contain three domains, of which thefirst and the third are involved in ATP bindingand hydrolysis. Although it has been shown thatATPase activity of RuvBL1 is needed for severalin vivo functions, we could only detect a marginalactivity with the purified protein. Structuralhomology and DNA binding studies demonstrate", "metadata": {}}
+{"_id": "27907205", "title": "", "text": "Characteristics of a monoclonal antibody(RM124) against acute myelocytic leukemiacells.A monoclonal antibody was raised againstcells from an experimental rat myelocyticleukemia (BNML). The major characteristics ofthe rat leukemia model resemble those of humanacute myelocytic leukemia. The monoclonalantibody (MCA) RM124 was characterized withrespect to its labeling pattern of BNML leukemiacells, normal rat bone marrow cells, and thehemopoietic stem cell (HSC), by flow cytometricmethods and complement-dependentcytotoxicity assays. Flow cytometry revealed amuch higher labeling of the leukemic cells by theMCA-RM124 compared with normal bone marrowcells, including CFU-S and CFU-C. Only asubpopulation of the normal granulocytesshowed cross reactivity, however, at a lowerlabeling density. On using the cytotoxicityassays, it was evident that there was a selectivekilling of leukemic cells as compared with theactivity towards the normal hemopoietic stem", "metadata": {}}
+{"_id": "27910499", "title": "", "text": "Quantitative assessment of T-cell repertoirerecovery after hematopoietic stem celltransplantationDelayed T cell recovery andrestricted T cell receptor (TCR) diversity afterallogeneic hematopoietic stem celltransplantation (allo-HSCT) are associated withincreased risks of infection and cancer relapse.Technical challenges have limited faithfulmeasurement of TCR diversity after allo-HSCT.Here we combined 5' rapid amplification ofcomplementary DNA ends PCR with deepsequencing to quantify TCR diversity in 28recipients of allo-HSCT using a singleoligonucleotide pair. Analysis of duplicate bloodsamples confirmed that we accuratelydetermined the frequency of individual TCRs.After 6 months, cord blood-graft recipientsapproximated the TCR diversity of healthyindividuals, whereas recipients of T cell-depletedperipheral-blood stem cell grafts had 28-fold and14-fold lower CD4(+) and CD8(+) T celldiversities, respectively. After 12 months, these", "metadata": {}}
+{"_id": "27944135", "title": "", "text": "Silver sulfadiazine for the treatment ofpartial-thickness burns and venous stasisulcers.BACKGROUND For decadessilver-containing antibiotics such as silversulfadiazine (SSD) have been applied asstandard topical therapy for patients withpartial-thickness burns and venous stasis ulcers.This evidence-based review intends to answerthe following research question: in ambulatorypatients with partial-thickness burns or stasisdermatitis ulcers, does the use of topical SSDcompared with nonantibiotic dressings improvemortality, wound healing, re-epithelialization, orinfection rates? METHODS MEDLINE, EMBASE,Cochrane Library, and other databases weresearched. We considered trials that enrolledpatients of any age with partial-thickness burnsor venous stasis ulcers and randomized them toeither topical SSD or placebo, saline-soakedgauze, paraffin gauze, sterile dry dressing, ornonantibiotic moist dressing. Outcomes includedmortality, wound healing, speed of", "metadata": {}}
+{"_id": "27949347", "title": "", "text": "Putting p53 in ContextTP53 is the mostfrequently mutated gene in human cancer.Functionally, p53 is activated by a host of stressstimuli and, in turn, governs an exquisitelycomplex anti-proliferative transcriptionalprogram that touches upon a bewildering arrayof biological responses. Despite the manyunveiled facets of the p53 network, a clearappreciation of how and in what contexts p53exerts its diverse effects remains unclear. Howcan we interpret p53's disparate activities andthe consequences of its dysfunction tounderstand how cell type, mutation profile, andepigenetic cell state dictate outcomes, and howmight we restore its tumor-suppressive activitiesin cancer?", "metadata": {}}
+{"_id": "27995781", "title": "", "text": "Modeling the evolution of culture-adapted humanembryonic stem cells.The long-term culture ofhuman embryonic stem (ES) cells is inevitablysubject to evolution, since any mutant thatarises with a growth advantage will be selectivelyamplified. However, the evolutionary influencesof population size, mutation rate, and selectionpressure are frequently overlooked. We haveconstructed a Monte Carlo simulation model topredict how changes in these factors caninfluence the appearance and spread of mutantES cells, and verified its applicability bycomparison with in vitro data. This simulationprovides an estimate for the expected rate ofgeneration of culture-adapted ES cells underdifferent assumptions for the key parameters. Inparticular, it highlights the effect of populationsize, suggesting that the maintenance of cells insmall populations reduces the likelihood thatabnormal cultures will develop.", "metadata": {}}
+{"_id": "28006126", "title": "", "text": "CD28 delivers a unique signal leading to theselective recruitment of RelA and p52 NF-kappaBsubunits on IL-8 and Bcl-xL genepromoters.CD28 is one of the most importantcostimulatory receptors necessary for full Tlymphocyte activation. The CD28 receptor canenhance T cell antigen receptor (TCR) signals, aswell as deliver independent signals. Indeed,CD28 engagement by B7 can generateTCR-independent signals leading to IkappaBkinase and NF-kappaB activation. Here wedemonstrate that the TCR-independent CD28signal leads to the selective transcription ofsurvival (Bcl-xL) and inflammatory (IL-8 and Bcell activation factor, but not proliferative (IL-2),genes, in a NF-kappaB-dependent manner.CD28-stimulated T cells actively secrete IL-8,and Bcl-xL up-regulation protects T cells fromradiation-induced apoptosis. The transcription ofCD28-induced genes is mediated by the specificrecruitment of RelA and p52 NF-kappaB subunitsto target promoters. In contrast, p50 and c-Rel,", "metadata": {}}
+{"_id": "28015516", "title": "", "text": "Netting neutrophils are major inducers of type IIFN production in pediatric systemic lupuserythematosus.Systemic lupus erythematosus(SLE) is a systemic autoimmune diseasecharacterized by a breakdown of tolerance tonuclear antigens and the development ofimmune complexes. Genomic approaches haveshown that human SLE leukocyteshomogeneously express type I interferon(IFN)-induced and neutrophil-related transcripts.Increased production and/or bioavailability ofIFN-α and associated alterations in dendritic cell(DC) homeostasis have been linked to lupuspathogenesis. Although neutrophils have longbeen shown to be associated with lupus, theirpotential role in disease pathogenesis remainselusive. Here, we show that mature SLEneutrophils are primed in vivo by type I IFN anddie upon exposure to SLE-derivedanti-ribonucleoprotein antibodies, releasingneutrophil extracellular traps (NETs). SLE NETscontain DNA as well as large amounts of LL37", "metadata": {}}
+{"_id": "28017005", "title": "", "text": "Assessment for selection for the health careprofessions and specialty training: consensusstatement and recommendations from theOttawa 2010 Conference.Assessment forselection in medicine and the health professionsshould follow the same quality assuranceprocesses as in-course assessment. Theliterature on selection is limited and is notstrongly theoretical or conceptual. For writtentesting, there is evidence of the predictivevalidity of Medical College Admission Test(MCAT) for medical school and licensingexamination performance. There is also evidencefor the predictive validity of grade point average,particularly in combination with MCAT forgraduate entry but little evidence about thepredictive validity of school leaver scores.Interviews have not been shown to be robustselection measures. Studies of multiplemini-interviews have indicated good predictivevalidity and reliability. Of other measures used inselection, only the growing interest in personality", "metadata": {}}
+{"_id": "28025754", "title": "", "text": "THE GLYOXAL BIS(2-HYDROXYANIL) METHODMODIFIED FOR LOCALIZING INSOLUBLECALCIUM SALTS.TO enable staining of insolublecalcium salts with glyoxal bis(2-hydroxyanil)(GBHA), the original solution containing 2 ml of0.4% GBHA in absolute ethanol, and 0.3 ml ofaqueous 5% NaOH, and limited to staining onlysoluble calcium salts, was modified as follows: 1,2 ml of 0.4% GBHA in absolute ethanol in 0.6 mlof 10% aqueous NaOH; 11, 0.1 gm GBHA in 2 mlof 3.4% NaOH in 75% ethanol. To preventdiffusion and loss of calcium, the tissues wereprocessed by the freeze-substitution orfreeze-dry method and sections stained withoutremoving the paraffin. Modification I is effectiveonly when 1 or 2 drops placed on the section areevaporated gradually to dryness, concentratingthe GBHA and NaOH on the insoluble calciumsalts. Modification II is effective when dried orpoured on the the section and allowed to stainfor 5 min. The stained slides are immersed for 15min in 90% ethanol saturated with KCN and", "metadata": {}}
+{"_id": "28069701", "title": "", "text": "Detecting selective sweeps: a new approachbased on hidden markov models.Detecting andlocalizing selective sweeps on the basis of SNPdata has recently received considerableattention. Here we introduce the use of hiddenMarkov models (HMMs) for the detection ofselective sweeps in DNA sequences. Likepreviously published methods, our HMMs use thesite frequency spectrum, and the spatial patternof diversity along the sequence, to identifyselection. In contrast to earlier approaches, ourHMMs explicitly model the correlation structurebetween linked sites. The detection power of ourmethods, and their accuracy for estimating theselected site location, is similar to that ofcompeting methods for constant sizepopulations. In the case of populationbottlenecks, however, our methods frequentlyshowed fewer false positives.", "metadata": {}}
+{"_id": "28071965", "title": "", "text": "A Balance between Secreted Inhibitors and EdgeSensing Controls GastruloidSelf-Organization.The earliest aspects of humanembryogenesis remain mysterious. To modelpatterning events in the human embryo, we usedcolonies of human embryonic stem cells (hESCs)grown on micropatterned substrate anddifferentiated with BMP4. These gastruloidsrecapitulate the embryonic arrangement of themammalian germ layers and provide an assay toassess the structural and signaling mechanismspatterning the human gastrula. Structurally,high-density hESCs localize their receptors totransforming growth factor β at their lateral sidein the center of the colony while maintainingapical localization of receptors at the edge. Thisrelocalization insulates cells at the center fromapically applied ligands while maintainingresponse to basally presented ones. In addition,BMP4 directly induces the expression of its owninhibitor, NOGGIN, generating areaction-diffusion mechanism that underlies", "metadata": {}}
+{"_id": "28086354", "title": "", "text": "Tenectin is a novel alphaPS2betaPS integrinligand required for wing morphogenesis andmale genital looping inDrosophila.Morphogenesis of the adult structuresof holometabolous insects is regulated byecdysteroids and juvenile hormones and involvescell-cell interactions mediated in part by the cellsurface integrin receptors and their extracellularmatrix (ECM) ligands. These adhesion moleculesand their regulation by hormones are not wellcharacterized. We describe the gene structure ofa newly described ECM molecule, tenectin, anddemonstrate that it is a hormonally regulatedECM protein required for proper morphogenesisof the adult wing and male genitalia. Tenectin'sfunction as a new ligand of the PS2 integrins isdemonstrated by both genetic interactions in thefly and by cell spreading and cell adhesionassays in cultured cells. Its interaction with thePS2 integrins is dependent on RGD and RGD-likemotifs. Tenectin's function in loopingmorphogenesis in the development of the male", "metadata": {}}
+{"_id": "28107602", "title": "", "text": "Schedule-dependent interaction betweenanticancer treatmentsThe oncogene MDMX isoverexpressed in many cancers, leading tosuppression of the tumor suppressor p53.Inhibitors of the oncogene product MDMXtherefore might help reactivate p53 and enhancethe efficacy of DNA-damaging drugs. However,we currently lack a quantitative understanding ofhow MDMX inhibition affects the p53 signalingpathway and cell sensitivity to DNA damage. Livecell imaging showed that MDMX depletiontriggered two distinct phases of p53accumulation in single cells: an initial postmitoticpulse, followed by low-amplitude oscillations.The response to DNA damage was sharplydifferent in these two phases; in the first phase,MDMX depletion was synergistic with DNAdamage in causing cell death, whereas in thesecond phase, depletion of MDMX inhibited celldeath. Thus a quantitative understanding ofsignal dynamics and cellular states is importantfor designing an optimal schedule of dual-drug", "metadata": {}}
+{"_id": "28138927", "title": "", "text": "Potent, Selective, and Orally BioavailableInhibitors of VPS34 Provide Chemical Tools toModulate Autophagy in Vivo.Autophagy is adynamic process that regulateslysosomal-dependent degradation of cellularcomponents. Until recently the study ofautophagy has been hampered by the lack ofreliable pharmacological tools, but selectiveinhibitors are now available to modulate the PI3-kinase VPS34, which is required for autophagy.Here we describe the discovery of potent andselective VPS34 inhibitors, their pharmacokinetic(PK) properties, and ability to inhibit autophagyin cellular and mouse models.", "metadata": {}}
+{"_id": "28149602", "title": "", "text": "The role of neutrophils in the pathogenesis ofsystemic lupus erythematosus.PURPOSE OFREVIEW Recent discoveries implicate neutrophilsas important regulators of innate and adaptiveimmunity and in the development of organdamage in systemic autoimmune diseases,including systemic lupus erythematosus (SLE).RECENT FINDINGS Various putative SLEbiomarkers are neutrophil-related, includingneutrophil granular proteins and histonesundergoing post-translational modificationsduring neutrophil extracellular trap (NET)formation. In the bone marrow, lupus neutrophilscan drive B and T cell abnormalities, at least inpart, by their enhanced production of type-Iinterferons, tumor necrosis factor-alpha (TNFα)and the B-cell stimulating factors B-cellactivating factor (BAFF) and aproliferation-inducing ligand (APRIL). Lupusneutrophils and, in particular, lupus low-densitygranulocytes (a distinct pathogenic subset)display epigenetic modifications and genomic", "metadata": {}}
+{"_id": "28164534", "title": "", "text": "Enhancement of proteasome function by PA28αoverexpression protects against oxidativestress.The principal function of the proteasome istargeted degradation of intracellular proteins.Proteasome dysfunction has been observed inexperimental cardiomyopathies and implicated inhuman congestive heart failure. Measures toenhance proteasome proteolytic function arecurrently lacking but would be beneficial intesting the pathogenic role of proteasomedysfunction and could have significanttherapeutic potential. The association ofproteasome activator 28 (PA28) with the 20Sproteasome may play a role in antigenprocessing. It is unclear, however, whether thePA28 plays any important role outside of antigenpresentation, although up-regulation of PA28 hasbeen observed in certain types ofcardiomyopathy. Here, we show that PA28αoverexpression (PA28αOE) stabilized PA28β,increased 11S proteasomes, and enhanced thedegradation of a previously validated", "metadata": {}}
+{"_id": "28193026", "title": "", "text": "A unified concept of species and itsconsequences for the future oftaxonomyContemporary species concepts arediverse. Nonetheless, all share the fundamentalidea that species are segments of lineages at thepopulation level of biological organization. Theydiffer in the secondary properties (e.g., intrinsicreproductive isolation, monophyly,diagnosability) that are treated as necessary forconsidering lineages to be species. A unifiedspecies concept can be achieved by interpretingthe common fundamental idea of being aseparately evolving lineage segment as the onlynecessary property of species and viewing thevarious secondary properties either as lines ofevidence relevant to assessing lineageseparation or as properties that define differentsubcategories of the species category (e.g.,reproductively isolated species, monophyleticspecies, diagnosable species). This unifiedspecies concept has a number of consequencesfor taxonomy, including the need to acknowledge", "metadata": {}}
+{"_id": "28195565", "title": "", "text": "Regulation of the small GTP-binding protein Rhoby cell adhesion and the cytoskeleton.Solublefactors from serum such as lysophosphatidic acid(LPA) are thought to activate the smallGTP-binding protein Rho based on their ability toinduce actin stress fibers and focal adhesions in aRho-dependent manner. Cell adhesion toextracellular matrices (ECM) has also beenproposed to activate Rho, but this point has beencontroversial due to the difficulty ofdistinguishing changes in Rho activity from thestructural contributions of ECM to the formationof focal adhesions. To address these questions,we established an assay for GTP-bound cellularRho. Plating Swiss 3T3 cells onfibronectin-coated dishes elicited a transientinhibition of Rho, followed by a phase of Rhoactivation. The activation phase was greatlyenhanced by serum. In serum-starved adherentcells, LPA induced transient Rho activation,whereas in suspended cells Rho activation wassustained. Furthermore, suspended cells showed", "metadata": {}}
+{"_id": "28206748", "title": "", "text": "Core binding factors are necessary for naturalkiller cell development and cooperate with Notchsignaling during T-cell specification.CBFbeta isthe non-DNA binding subunit of the core bindingfactors (CBFs). Mice with reduced CBFbeta levelsdisplay profound, early defects in T-cell but notB-cell development. Here we show that CBFbetais also required at very early stages of naturalkiller (NK)-cell development. We alsodemonstrate that T-cell development abortsduring specification, as the expression of Gata3and Tcf7, which encode key regulators of Tlineage specification, is substantially reduced, asare functional thymic progenitors. Constitutivelyactive Notch or IL-7 signaling cannot restoreT-cell expansion or differentiation of CBFbetainsufficient cells, nor can overexpression ofRunx1 or CBFbeta overcome a lack of Notchsignaling. Therefore, the ability of the prethymiccell to respond appropriately to Notch isdependent on CBFbeta, and both signalsconverge to activate the T-cell developmental", "metadata": {}}
+{"_id": "28207326", "title": "", "text": "VEGF and podocytes in diabeticnephropathy.Vascular endothelial growthfactor-A (VEGF-A) is a protein secreted bypodocytes that is necessary for survival ofendothelial cells, podocytes, and mesangial cells.VEGF-A regulates slit-diaphragm signaling andpodocyte shape via VEGF-receptor2-nephrin-nck-actin interactions. Chronichyperglycemia-induced excess podocyte VEGF-Aand low endothelial nitric oxide drive thedevelopment and the progression of diabeticnephropathy. The abnormal cross-talk betweenVEGF-A and nitric oxide pathways is fueled bythe diabetic milieu, resulting in increasedoxidative stress. Recent findings on thesepathogenic molecular mechanisms provide newpotential targets for therapy for diabetic renaldisease.", "metadata": {}}
+{"_id": "28230867", "title": "", "text": "Detection and distribution patterns of telomeraseactivity in insects.Telomeres of most insectsconsist of pentanucleotide (TTAGG)n repeats,although the repeats are absent in Diptera andsome other insect species, where the telomereregions are perhaps maintained withouttelomerase. To understand various and unusualtelomere formation in insects, we have studiedthe characteristic features of a putative insecttelomerase that has not been previouslydescribed. Using a modified telomeric repeatamplification protocol (TRAP), we first detectedthe telomerase activity in crickets, cockroachesand two Lepidopteran insects. The telomerasefrom crickets and cockroaches required dATP,dGTP and dTTP but not dCTP as a substrate andsequence analyses of the products of TRAPrevealed that the (TTAGG)n repeats aresynthesized by telomerase. The cockroachtelomerase was detected both in somatic (fatbody, muscle and neural tissues) and germ line(testis) cells, suggesting that expression of this", "metadata": {}}
+{"_id": "28243325", "title": "", "text": "Conversion of the lac repressor into anallosterically regulated transcriptional activatorfor mammalian cells.A novel mammalianregulatory system was created by using theEscherichia coli lac repressor. The lac repressorwas converted into a mammalian transcriptionalactivator by modifying the lac repressor codingregion to include a nuclear localization signalfrom the simian virus 40 (SV40) large tumorantigen and the transcription activation domainfrom the herpes simplex virus type 1 virionprotein 16. The lac activator protein (LAP)fusions were potent activators of severalpromoters containing lac operator sequencespositioned either upstream or downstream of thetranscription unit. A single lac operator allowedfor transactivation, whereas multiple operatorsacted synergistically when separated by a smalldistance. Promoters containing 14 or 21 operatorsequences were induced at least 1,000-fold inresponse to LAP, reaching levels of activity 20 to30 times greater than that of the SV40 early", "metadata": {}}
+{"_id": "28247027", "title": "", "text": "Antigen availability determines CD8\u0000 Tcell-dendritic cell interaction kinetics andmemory fate decisions.T cells are activated byantigen (Ag)-bearing dendritic cells (DCs) inlymph nodes in three phases. The duration of theinitial phase of transient, serial DC-T cellinteractions is inversely correlated with Ag dose.The second phase, characterized by stable DC-Tcell contacts, is believed to be necessary forfull-fledged T cell activation. Here we haveshown that this is not the case. CD8\u0000 T cellsinteracting with DCs presenting low-dose,short-lived Ag did not transition to phase 2,whereas higher Ag dose yielded phase 2transition. Both antigenic constellationspromoted T cell proliferation and effectordifferentiation but yielded different transcriptomesignatures at 12 hr and 24 hr. T cells thatexperienced phase 2 developed long-livedmemory, whereas conditions without stablecontacts yielded immunological amnesia. Thus, Tcells make fate decisions within hours after Ag", "metadata": {}}
+{"_id": "28249680", "title": "", "text": "BAX/BAK-independent mitoptosis during celldeath induced by proteasomeinhibition?Proteasome inhibitors induce rapiddeath of cancer cells. We show that in epithelialcancer cells, such death is associated withdramatic and simultaneous up-regulation ofseveral BH3-only proteins, including BIK, BIM,MCL-1S, NOXA, and PUMA, as well as p53.Elevated levels of these proteins seem to be theresult of direct inhibition of their proteasomaldegradation, induction of transcription, andactive translation. Subsequent cell death isindependent of BAX, and probably BAK, andproceeds through the intrinsic mitochondrialapoptosis pathway. We identify the cascade ofmolecular events responsible for cell deathinduced by a prototypical proteasome inhibitor,MG132, starting with rapid accumulation ofBH3-only proteins in the mitochondria,proceeding through mitochondrial membranepermeabilization and subsequent loss ofDeltaPsi(m), and leading to irreversible changes", "metadata": {}}
+{"_id": "28264919", "title": "", "text": "Site of action of a ribosomal RNA methylaseresponsible for resistance to erythromycin andother antibiotics.The enzyme which confersresistance to erythromycin in the producingorganism Streptomyces erythraeus dimethylatesa single adenine residue in Bacillusstearothermophilus 23 S rRNA. This correspondsto residue Ade 2058 in Escherichia coli 23 S RNA.The methylase responsible for resistance tomacrolides, lincomycin, and streptograminB-related antibiotics in Staphylococcus aureusalso acts at this site.", "metadata": {}}
+{"_id": "28271439", "title": "", "text": "53BP1 nuclear bodies form around DNA lesionsgenerated by mitotic transmission ofchromosomes under replication stressCompletionof genome duplication is challenged by structuraland topological barriers that impede progressionof replication forks. Although this can seriouslyundermine genome integrity, the fate of DNAwith unresolved replication intermediates is notknown. Here, we show that mild replicationstress increases the frequency of chromosomallesions that are transmitted to daughter cells.Throughout G1, these lesions are sequestered innuclear compartments marked by p53-bindingprotein 1 (53BP1) and otherchromatin-associated genome caretakers. Weshow that the number of such 53BP1 nuclearbodies increases after genetic ablation of BLM, aDNA helicase associated with dissolution ofentangled DNA. Conversely, 53BP1 nuclearbodies are partially suppressed by knockingdown SMC2, a condensin subunit required formechanical stability of mitotic chromosomes.", "metadata": {}}
+{"_id": "28334217", "title": "", "text": "Targeted inhibition of tumor-specific glutaminasediminishes cell-autonomoustumorigenesis.Glutaminase (GLS), whichconverts glutamine to glutamate, plays a keyrole in cancer cell metabolism, growth, andproliferation. GLS is being explored as a cancertherapeutic target, but whether GLS inhibitorsaffect cancer cell-autonomous growth or the hostmicroenvironment or have off-target effects isunknown. Here, we report that loss of one copyof Gls blunted tumor progression in animmune-competent MYC-mediated mouse modelof hepatocellular carcinoma. Compared withresults in untreated animals with MYC-inducedhepatocellular carcinoma, administration of theGLS-specific inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES)prolonged survival without any apparenttoxicities. BPTES also inhibited growth of aMYC-dependent human B cell lymphoma cell line(P493) by blocking DNA replication, leading tocell death and fragmentation. In mice harboring", "metadata": {}}
+{"_id": "28338268", "title": "", "text": "Dominant optic atrophy, deafness, ptosis,ophthalmoplegia, dystaxia, and myopathy. Anew syndrome.Twenty-three members of a96-member family exhibited an autosomaldominant disorder which has not previously beendescribed. This disorder involves progressiveoptic atrophy, abnormal electroretinographywithout retinal pigment changes, andprogressive sensorineural hearing loss usuallyevident in the first or second decade of life. Inmidlife, ptosis, ophthalmoplegia, dystaxia, and anonspecific myopathy occur.", "metadata": {}}
+{"_id": "28369117", "title": "", "text": "Dynein is required for polarized dendritictransport and uniform microtubule orientation inaxonsAxons and dendrites differ in bothmicrotubule organization and in the organellesand proteins they contain. Here we show that themicrotubule motor dynein has a crucial role inpolarized transport and in controlling theorientation of axonal microtubules in Drosophilamelanogaster dendritic arborization (da)neurons. Changes in organelle distribution withinthe dendritic arbors of dynein mutant neuronscorrelate with a proximal shift in dendritic branchposition. Dynein is also necessary for thedendrite-specific localization of Golgi outpostsand the ion channel Pickpocket. Axonalmicrotubules are normally oriented uniformlyplus-end-distal; however, without dynein, axonscontain both plus- and minus-end distalmicrotubules. These data suggest that dynein isrequired for the distinguishing properties of theaxon and dendrites: without dynein, dendriticorganelles and proteins enter the axon and the", "metadata": {}}
+{"_id": "28386343", "title": "", "text": "Small molecule screening in human inducedpluripotent stem cell-derived terminal celltypes.A need for better clinical outcomes hasheightened interest in the use of physiologicallyrelevant human cells in the drug discoveryprocess. Patient-specific human inducedpluripotent stem cells may offer a relevant,robust, scalable, and cost-effective model ofhuman disease physiology. Small molecule highthroughput screening in human inducedpluripotent stem cell-derived cells with the intentof identifying novel therapeutic compounds isstarting to influence the drug discovery process;however, the use of these cells presents manyhigh throughput screening developmentchallenges. This technology has the potential totransform the way drug discovery is performed.", "metadata": {}}
+{"_id": "28390999", "title": "", "text": "Gene expression during gonadogenesis in thechicken embryo.Genes implicated in vertebratesex determination and differentiation werestudied in embryonic chicken gonads usingreverse transcription and the polymerase chainreaction (RT-PCR). Expression profiles wereobtained during gonadal sex differentiation forAMH, SOX9, SOX3, the Wilm's Tumour gene,WT1, and the orphan nuclear receptor genes,SF1 and DAX1. Some of these genes showedsexually dimorphic expression profiles duringgonadal development, whereas others wereexpressed at similar levels in both sexes. Thegene encoding Anti-Müllerian hormone (AMH)was expressed in both sexes prior to and duringsexual differentiation of the gonads, with levelsof expression consistently higher in males than infemales. SOX9 expression was male-specific, andwas up-regulated after the detection of AMHtranscripts. SOX3 expression was observed priorto clear SOX9 expression and was up-regulatedin both sexes at the onset of gonadal sex", "metadata": {}}
+{"_id": "28392393", "title": "", "text": "Organ-resident, nonlymphoid cells suppressproliferation of autoimmune T-helperlymphocytes.Local presentation of autoantigenby organ-resident cells inappropriatelyexpressing Ia determinants has been implicatedin organ-specific autoimmunity. Experimentalautoimmune uveoretinitis, induced in rats byimmunization with retinal soluble antigen, isused as a model of organ-specific autoimmunity.In an in vitro system derived from this model,uveitogenic rat T-helper lymphocytes specific tothe retinal soluble antigen, or control T-helperlymphocytes reactive to the purified proteinderivative of tuberculin, were cocultured withIa-expressing syngeneic retinal glial cells (Müllercells) in the presence of specific antigen. Antigenpresentation was not apparent under ordinaryculture conditions, and the Müller cellsprofoundly suppressed the proliferative responseof primed T-helper lymphocytes to antigenpresented on conventional antigen-presentingcells, as well as their subsequent interleukin-2", "metadata": {}}
+{"_id": "28419824", "title": "", "text": "Drug induced refractory headache--clinicalfeatures and management.Two hundred patientswho were taking daily symptomatic or immediaterelief medications, often in excessive quantities,yet suffering from daily or near daily severeheadaches were studied. One hundred andsixteen (58%) of them were also takingconcomitant prophylactic medications and theywere ineffective. Low tyramine, low caffeinedietary instructions and biofeedback trainingwere given to all patients. The effect ofcontinuing symptomatic medications,discontinuing symptomatic medications, andadding or changing prophylactic medicationswere studied in the various treatment groups. Itis concluded that; 1.) Daily use of symptomaticor immediate relief medications result in chronicdaily headache. 2.) Discontinuing dailysymptomatic medications itself result inimprovement of headache. 3.) Concomitant useof symptomatic medications nullifies the effect ofprophylactic medications. 4.) Discontinuing daily", "metadata": {}}
+{"_id": "28436879", "title": "", "text": "Neuromodulation of neurons andsynapses.Neuromodulation underlies theflexibility of neural circuit operation andbehavior. Individual neuromodulators can havedivergent actions in a neuron by targetingmultiple physiological mechanisms. Conversely,multiple neuromodulators may have convergentactions through overlapping targets. Thedivergent and convergent neuromodulatoractions can be unambiguously synergistic orantagonistic, but neuromodulation often entailsbalanced adjustment of nonlinear membrane andsynaptic properties by targeting ion channel andsynaptic dynamics rather than just excitability orsynaptic strength. In addition, neuromodulatorscan exert effects at multiple timescales, fromshort-term adjustments of neuron and synapsefunction to persistent long-term regulation. Thisshort review summarizes some highlights of thediverse actions of neuromodulators on ionchannel and synaptic properties.", "metadata": {}}
+{"_id": "28441310", "title": "", "text": "Mutation frequency and specificity with age inliver, bladder and brain of lacI transgenicmice.Mutation frequency and specificity weredetermined as a function of age in nuclear DNAfrom liver, bladder, and brain of Big Blue lacItransgenic mice aged 1.5-25 months. Mutationsaccumulated with age in liver and accumulatedmore rapidly in bladder. In the brain a smallinitial increase in mutation frequency wasobserved in young animals; however, no furtherincrease was observed in adult mice. Toinvestigate the origin of mutations, themutational spectra for each tissue and age weredetermined. DNA sequence analysis of mutantlacI transgenes revealed no significant changesin mutational specificity in any tissue at any age.The spectra of mutations found in aging animalswere identical to those in younger animals,suggesting that they originated from a commonset of DNA lesions manifested during DNAreplication. The data also indicated that therewere no significant age-related mutational", "metadata": {}}
+{"_id": "28468276", "title": "", "text": "Breaching the basement membrane: who, whenand how?The basement membrane (BM), aspecialized network of extracellular matrixmacromolecules, surrounds epithelial,endothelial, muscle, fat and nerve cells. Duringdevelopment, immune surveillance and diseasestates ranging from cancer to fibrosis, host cellspenetrate the BM by engaging tissue-invasiveprograms, the identity of which remain largelyundefined. Although it is commonly assumedthat all cells employ similar mechanisms to crossBM barriers, accumulating evidence indicatesthat cells might selectively mobilizeprotease-dependent or -independent invasionprograms. New data indicate thatprotease-dependent transmigration is largelyreliant on a group of membrane-anchoredmetalloenzymes, termed the membrane-typematrix metalloproteinases, which irreversiblyremodel BM structure. By contrast, mechanismsthat enable protease-independent transmigrationremain undefined and potentially involve the", "metadata": {}}
+{"_id": "28517384", "title": "", "text": "Soluble MD-2 is an acute-phase protein and anopsonin for Gram-negative bacteria.Myeloiddifferentiation factor-2 (MD-2) is alipopolysaccharide (LPS)-binding protein usuallycoexpressed with and binding to Toll-likereceptor 4 (TLR4), conferring LPS responsivenessof immune cells. MD-2 is also found as a solubleprotein. Soluble MD-2 (sMD-2) levels aremarkedly elevated in plasma from patients withsevere infections, and in other fluids frominflamed tissues. We show that sMD-2 is a typeII acute-phase protein. Soluble MD-2 mRNA andprotein levels are up-regulated in mouse liverafter the induction of an acute-phase response.It is secreted by human hepatocytic cells andup-regulated by interleukin-6. Soluble MD-2binds to Gram-negative but not Gram-positivebacteria, and sMD-2 secreted by hepatocyticcells is an essential cofactor for the activation ofTLR4-expressing cells by Gram-negativebacteria. Soluble MD-2 opsonization ofGram-negative bacteria accelerates and", "metadata": {}}
+{"_id": "28530299", "title": "", "text": "Division-coupled astrocytic differentiation andage-related depletion of neural stem cells in theadult hippocampus.Production of new neurons inthe adult hippocampus decreases with age; thisdecline may underlie age-related cognitiveimpairment. Here we show that continuousdepletion of the neural stem cell pool, as aconsequence of their division, may contribute tothe age-related decrease in hippocampalneurogenesis. Our results indicate that adulthippocampal stem cells, upon exiting theirquiescent state, rapidly undergo a series ofasymmetric divisions to produce dividingprogeny destined to become neurons andsubsequently convert into mature astrocytes.Thus, the decrease in the number of neural stemcells is a division-coupled process and is directlyrelated to their production of new neurons. Wepresent a scheme of the neurogenesis cascade inthe adult hippocampus that includes a proposed\"disposable stem cell\" model and accounts forthe disappearance of hippocampal neural stem", "metadata": {}}
+{"_id": "28542402", "title": "", "text": "P19 embryonal carcinoma cells.P19 cells are aline of pluripotent embryonal carcinoma able togrow continuously in serum-supplementedmedia. The differentiation of these cells can becontrolled by nontoxic drugs. Retinoic acideffectively induces the development of neurons,astroglia and microglia--cell types normallyderived from the neuroectoderm. Aggregates ofP19 cells exposed to dimethyl sulfoxidedifferentiate into endodermal and mesodermalderivatives including cardiac and skeletal muscle.P19 cells can be effectively transfected with DNAencoding recombinant genes and stable linesexpressing these genes can be readily isolated.These manipulations make P19 cells suitablematerial for investigating the molecularmechanisms governing developmental decisionmade by differentiating pluripotent cells.", "metadata": {}}
+{"_id": "28562710", "title": "", "text": "Iguanas and Salmonella marina infection inchildren: a reflection of the increasing incidenceof reptile-associated salmonellosis in the UnitedStates.OBJECTIVE To investigate clinical aspectsand risk factors for Salmonella serotype Marinainfection in the United States. METHODS Weidentified all isolates of S Marina reported in1994 to the National Salmonella SurveillanceSystem. Patients were interviewed aboutdemographic information, clinical course, diet,travel history, and contact with reptiles beforeillness. RESULTS Twenty-six (81%) of 32patients were infants (<1 year of age) and 24(75%) were male. This differs from otherSalmonella isolates reported to the Centers forDisease Control and Prevention in 1994, of which14% were from infants and 49% from malepatients. Eleven patients (34%) werehospitalized for a median of 3.5 days (range: 2to 21 days), and 1 died. Of 28 patients (88%)with reported iguana exposure, only 4 (14%)touched the reptile, and only 12 respondents", "metadata": {}}
+{"_id": "28592273", "title": "", "text": "Siblings with opposite chromosome constitutions,dup(2q)/del(7q) anddel(2q)/dup(7q).Chromosome 7q36microdeletion syndrome is a rare genomicdisorder characterized by underdevelopment ofthe brain, microcephaly, anomalies of the sexorgans, and language problems. Developmentaldelay, intellectual disability, autistic spectrumdisorders, BDMR syndrome, and unusual facialmorphology are the key features of thechromosome 2q37 microdeletion syndrome. Agenetic screening for two brothers with globaldevelopmental delay using high-resolutionchromosomal analysis and subtelomericmultiplex ligation-dependent probe amplificationrevealed subtelomeric rearrangements on thesame sites of 2q37.2 and 7q35, with reverseddeletion and duplication. Both of them showeddysmorphic facial features, severe disability ofphysical and intellectual development, andabnormal genitalia with differential abnormalitiesin their phenotypes. The family did not have", "metadata": {}}
+{"_id": "28598374", "title": "", "text": "Methods for quantifying follicular numbers withinthe mouse ovary.Accurate estimation of thenumber of ovarian follicles at various stages ofdevelopment is an important indicator of theprocess of folliculogenesis in relation to theendocrine signals and paracrine/autocrinemechanisms that control the growth andmaturation of the oocytes and their supportingfollicular cells. There are 10-fold or greaterdifferences in follicular numbers per ovary atsimilar ages and/or strains reported in earlierstudies using various methods, leading todifficulties with interpretation of ovarian functionin control vs experimental conditions. This studydescribes unbiased, assumption-freestereological methods for quantification of earlyand growing follicular numbers in the mouseovary. A fractionator approach was used tosample a defined fraction of histological sectionsof adult wild-type ovaries. Primordial andprimary follicles were counted independentlywith the optical and physical disector methods.", "metadata": {}}
+{"_id": "28614776", "title": "", "text": "Identification of functional cooperative mutationsof SETD2 in human acute leukemiaAcuteleukemia characterized by chromosomalrearrangements requires additional moleculardisruptions to develop into full-blownmalignancy, yet the cooperative mechanismsremain elusive. Using whole-genome sequencingof a pair of monozygotic twins discordant for MLL(also called KMT2A) gene–rearranged leukemia,we identified a transforming MLL-NRIP3 fusiongene and biallelic mutations in SETD2 (encodinga histone H3K36 methyltransferase). Moreover,loss-of-function point mutations in SETD2 wererecurrent (6.2%) in 241 patients with acuteleukemia and were associated with multiplemajor chromosomal aberrations. We observed aglobal loss of H3K36 trimethylation (H3K36me3)in leukemic blasts with mutations in SETD2. Inthe presence of a genetic lesion, downregulationof SETD2 contributed to both initiation andprogression during leukemia development bypromoting the self-renewal potential of leukemia", "metadata": {}}
+{"_id": "28617573", "title": "", "text": "Evidence regarding human papillomavirus testingin secondary prevention of cervical cancer.Morethan ever, clinicians need regularly updatedreviews given the continuously increasingamount of new information regarding innovativecervical cancer prevention methods. A summaryis given from recent meta-analyses andsystematic reviews on 3 possible clinicalapplications of human papillomavirus (HPV)testing: triage of women with equivocal orlow-grade cytologic abnormalities; prediction ofthe therapeutic outcome after treatment ofcervical intraepithelial neoplasia (CIN) lesions,and last not but not least, primary screening forcervical cancer and pre-cancer. Consistentevidence is available indicating that HPV-triagewith the Hybrid Capture(®) 2 assay (QiagenGaithersburg, Inc., MD, USA [previously DigeneCorp.] (HC2) is more accurate (highersensitivity, similar specificity) than repeatcytology to triage women with equivocal Papsmear results. Several other tests show at least", "metadata": {}}
+{"_id": "28633594", "title": "", "text": "International standards for fetal growth based onserial ultrasound measurements: the FetalGrowth Longitudinal Study of theINTERGROWTH-21st Project.BACKGROUND In2006, WHO produced international growthstandards for infants and children up to age 5years on the basis of recommendations from aWHO expert committee. Using the samemethods and conceptual approach, the FetalGrowth Longitudinal Study (FGLS), part of theINTERGROWTH-21(st) Project, aimed to developinternational growth and size standards forfetuses. METHODS The multicentre,population-based FGLS assessed fetal growth ingeographically defined urban populations in eightcountries, in which most of the health andnutritional needs of mothers were met andadequate antenatal care was provided. We usedultrasound to take fetal anthropometricmeasurements prospectively from 14 weeks and0 days of gestation until birth in a cohort ofwomen with adequate health and nutritional", "metadata": {}}
+{"_id": "28644298", "title": "", "text": "Role of NF-kappa B in cell survival andtranscription of latent membrane protein1-expressing or Epstein-Barr virus latencyIII-infected cells.Epstein-Barr virus (EBV) latencyIII infection converts B lymphocytes intolymphoblastoid cell lines (LCLs) by expressingEBV nuclear and membrane proteins, EBNAs,and latent membrane proteins (LMPs), whichregulate transcription through Notch and tumornecrosis factor receptor pathways. The role ofNF-kappa B in LMP1 and overall EBV latency IIItranscriptional effects was investigated bytreating LCLs with BAY11-7082 (BAY11). BAY11rapidly and irreversibly inhibited NF-kappa B,decreased mitochondrial membrane potential,induced apoptosis, and altered LCL geneexpression. BAY11 effects were similar to thoseof an NF-kappa B inhibitor, Delta N-I kappa Balpha, in effecting decreased JNK1 expressionand in microarray analyses. More than 80% ofarray elements that decreased with Delta N-Ikappa B alpha expression decreased with BAY11", "metadata": {}}
+{"_id": "28647122", "title": "", "text": "Endotoxin tolerance: new mechanisms,molecules and clinical significance.Prior exposureof innate immune cells likemonocytes/macrophages to minute amounts ofendotoxin cause them to become refractory tosubsequent endotoxin challenge, a phenomenoncalled \"endotoxin tolerance\". Clinically, this stateis associated with monocytes/macrophages insepsis patients where they contribute to\"immunosuppression\" and mortality. Themolecular mechanisms underlying endotoxintolerance remain elusive. The recent appreciationof inflammation as a self-regulating process, therelative contribution of MyD88 versus TRIFsignaling pathways in inducing activation ortolerance, plasticity of NF-kappaB function andthe role of chromatin modification andmicroRNAs in LPS-induced gene reprogrammingurges a re-evaluation of endotoxin tolerance.This review integrates these new findings into anup-to-date account of endotoxin tolerance, itsmolecular basis and clinical implications in", "metadata": {}}
+{"_id": "28651643", "title": "", "text": "Pancreatic tumor cells with mutant K-rassuppress ERK activity by MEK-dependentinduction of MAP kinasephosphatase-2.Activating mutations within theK-ras gene occur in a high percentage of humanpancreatic carcinomas. We reported previouslythat the presence of oncogenic, activated K-rasin human pancreatic carcinoma cell lines did notresult in constitutive activation of theextracellular signal-regulated kinases (ERK1 andERK2). In the present study, we furthercharacterized the ERK signaling pathway inpancreatic tumor cell lines in order to determinewhether the ERK pathway is subject to acompensatory downregulation. We found thatthe attenuation of serum-induced ERK activationwas not due to a delay in the kinetics of ERKphosphorylation. Treatment with the tyrosinephosphatase inhibitor orthovanadate increasedthe level of ERK phosphorylation, implicating avanadate-sensitive tyrosine phosphatase in thenegative regulation of ERK. Furthermore,", "metadata": {}}
+{"_id": "28697248", "title": "", "text": "E2F3 is a mediator of DNA damage-inducedapoptosis.The E2F transcription factors haveemerged as critical apoptotic effectors. Hereinwe report that the E2F family member E2F3a canbe induced by DNA damage throughtranscriptional and posttranslationalmechanisms. We demonstrate that theposttranslational induction of human E2F3a isdependent on the checkpoint kinases. Moreover,we show that human E2F3a is a substrate for thecheckpoint kinases (chk kinases) and thatmutation of the chk phosphorylation siteeliminates the DNA damage inducibility of theprotein. Furthermore, we demonstrate that E2F1and E2F2 are transcriptionally induced by DNAdamage in an E2f3-dependent manner. Finally,using both in vitro and in vivo approaches, weestablish that E2f3 is required for DNAdamage-induced apoptosis. Thus, our datareveal the novel ability of E2f3 to function as amaster regulator of the DNA damage response.", "metadata": {}}
+{"_id": "28704738", "title": "", "text": "miR-294/miR-302 promotes proliferation,suppresses G1-S restriction point, and inhibitsESC differentiation through separablemechanisms.The miR-294 and miR-302microRNAs promote the abbreviated G1 phase ofthe embryonic stem cell (ESC) cell cycle andsuppress differentiation induced by let-7. Here,we evaluated the role of the retinoblastoma (Rb)family proteins in these settings. Under normalgrowth conditions, miR-294 promoted the rapidG1-S transition independent of the Rb family. Incontrast, miR-294 suppressed the furtheraccumulation of cells in G1 in response tonutrient deprivation and cell-cell contact in anRb-dependent fashion. We uncovered fiveadditional miRNAs (miR-26a, miR-99b, miR-193,miR-199a-5p, and miR-218) that silenced ESCself-renewal in the absence of other miRNAs, allof which were antagonized by miR-294 andmiR-302. Four of the six differentiation-inducingmiRNAs induced an Rb-dependent G1accumulation. However, all six still silenced", "metadata": {}}
+{"_id": "28707489", "title": "", "text": "Bacteriophage latent-period evolution as aresponse to resource availability.Bacteriophages(phages) modify microbial communities by lysinghosts, transferring genetic material, andeffecting lysogenic conversion. To understandhow natural communities are affected it isimportant to develop predictive models. Here weconsider how variation between models--ineclipse period, latent period, adsorptionconstant, burst size, the handling of differencesin host quantity and host quality, and inmodeling strategy--can affect predictions. Firstwe compare two published models of phagegrowth, which differ primarily in terms of howthey model the kinetics of phage adsorption; oneis a computer simulation and the other is anexplicit calculation. At higher host quantities(approximately 10(8) cells/ml), both modelsclosely predict experimentally determined phagepopulation growth rates. At lower host quantities(10(7) cells/ml), the computer simulationcontinues to closely predict phage growth rates,", "metadata": {}}
+{"_id": "28712203", "title": "", "text": "Neutrophil elastase-mediated lungdisease.Elastases of both the neutrophil andmacrophage have been implicated in lungdisease initiation and progression. Although it isunlikely that these proteases evolved for thepurpose of injuring lung tissue, the elastin-richconnective tissue framework of the lungsappears to be particularly susceptible to theaction of elastolytic proteases. Assuming thatneutrophil elastase most likely plays a role in themigration of neutrophils toward a site ofinflammation and degradation of proteins frominvading organisms or other products of theinflammatory response, it is the role of inhibitorsof this protease to protect normal tissues fromits effects. In alpha-1 antitrypsin deficiency wefind an experiment of nature that disrupts thisprotease-anti-protease balance, resulting in anincreased risk of destructive lung disease.", "metadata": {}}
+{"_id": "28724565", "title": "", "text": "Role of TRPML and two-pore channels inendolysosomal cation homeostasis.The transientreceptor potential (TRP) channels TRPML1,TRPML2, and TRPML3 (also called mucolipins 1-3or MCOLN1-3) are nonselective cation channels.Mutations in the Trpml1 gene causemucolipidosis type IV in humans with clinicalfeatures including psychomotor retardation,corneal clouding, and retinal degeneration,whereas mutations in the Trpml3 gene causedeafness, circling behavior, and coat colordilution in mice. No disease-causing mutationsare reported for the Trpml2 gene. Like TRPMLchannels, which are expressed in theendolysosomal pathway, two-pore channels(TPCs), namely TPC1, TPC2, and TPC3, are foundin intracellular organelles, in particular inendosomes and lysosomes. Both TRPML channelsand TPCs may function as calcium/cation releasechannels in endosomes, lysosomes, andlysosome-related organelles with TRPMLs beingactivated by phosphatidylinositol", "metadata": {}}
+{"_id": "28738741", "title": "", "text": "Adult T-cell leukemia/lymphoma in London:clinical experience of 21 cases.Adult T-cellleukemia/lymphoma (ATLL) is uncommon in theUnited Kingdom and has so far been restricted topeople of Afro-Caribbean extraction. Between1981 and 1995, 21 cases presented to 2 innerLondon teaching hospitals where 17% of thepopulation are of Afro-Caribbean origin. Clinicalpresentations were similar to those of thedisease in HTLV-I-endemic areas. Majorresponses (CR + PR) were obtained in 10/16assessable patients (63%) treated withcombination chemotherapy. However, mediansurvival was only 5.5 months. Diseaseprogression and opportunistic infection were themajor causes of treatment failure and death.Three patients (14%) relapsed in the centralnervous system (CNS). Our cases confirm theprofound immunosuppression in ATLL. The poorprognosis of acute and lymphoma types of ATLLhighlight the need for new approaches totreatment such as zidovudine and", "metadata": {}}
+{"_id": "28783084", "title": "", "text": "Regeneration, tissue injury and the immuneresponse.The involvement of the immune systemin the response to tissue injury has raised thepossibility that it might influence tissue, organ orappendage regeneration following injury. Onehypothesis that has been discussed is thatinflammatory aspects may preclude theoccurrence of regeneration, but there is alsoevidence for more positive roles of immunecomponents. The vertebrate eye is animmunoprivileged site where inflammatoryaspects are inhibited by severalimmunomodulatory mechanisms. In variousnewt species the ocular tissues such as the lensare regenerative and it has recently been shownthat the response to local injury of the lensinvolves activation of antigen-presenting cellswhich traffic to the spleen and return to displaceand engulf the lens, thereby inducingregeneration from the dorsal iris. The activationof thrombin from prothrombin in the dorsal iris isone aspect of the injury response that is", "metadata": {}}
+{"_id": "28806780", "title": "", "text": "Poverty, Hunger, Education, and ResidentialStatus Impact Survival in HIVDespitecombination antiretroviral therapy (ART), HIVinfected people have higher mortality thannon-infected. Lower socioeconomic status (SES)predicts higher mortality in many chronicillnesses but data in people with HIV is limited.We evaluated 878 HIV infected individualsfollowed from 1995 to 2005. Cox proportionalhazards for all-cause mortality were estimatedfor SES measures and other factors. Mixedeffects analyses examined how SES impactsfactors predicting death. The 200 who died wereolder, had lower CD4 counts, and higher viralloads (VL). Age, transmission category,education, albumin, CD4 counts, VL, hunger, andpoverty predicted death in univariate analyses;age, CD4 counts, albumin, VL, and poverty in themultivariable model. Mixed models showedassociations between (1) CD4 counts witheducation and hunger; (2) albumin witheducation, homelessness, and poverty; and (3)", "metadata": {}}
+{"_id": "28809022", "title": "", "text": "The INO80 ATP-dependent chromatin remodelingcomplex is a nucleosome spacing factor.Themobilization of nucleosomes by theATP-dependent remodeler INO80 is quitedifferent from another remodeler (SWI/SNF) thatis also involved in gene activation. Unlike thatrecently shown for SWI/SNF, INO80 is unable todisassemble nucleosomes when remodeling shortnucleosomal arrays. Instead, INO80 more closelyresembles, although with notable exceptions, thenucleosome spacing activity of ISW2 and ISW1a,which are generally involved in transcriptionrepression. INO80 required a minimum of 33 to43 bp of extranucleosomal DNA for mobilizingnucleosomes, with 70 bp being optimal. INO80prefers to move mononucleosomes to the centerof DNA, like ISW2 and ISW1a, but does so withhigher precision. Unlike ISW2/1a, INO80 doesnot require the H4 tail for nucleosomemobilization; instead, the H2A histone tailnegatively regulates nucleosome movement byINO80. INO80 moved arrays of two or three", "metadata": {}}
+{"_id": "28821565", "title": "", "text": "Concentrations of tenofovir and emtricitabine insaliva: implications for preexposure prophylaxisof oral HIV acquisition.To prevent acquisition ofHIV through oral sex, drugs used forpreexposure prophylaxis (Prep) need to diffuse insaliva. We measured tenofovir (TFV) andemtricitabine (FTC) concentrationssimultaneously in the plasma and saliva of 41HIV-infected patients under stable antiretroviraltreatment. Mean ratios of saliva/plasmaconcentration were 3% (±4%) and 86.9%(±124%) for TFV and FTC, respectively.Tenofovir disoproxil fumarate (TDF) should beused in combination with FTC to prevent oralacquisition of HIV.", "metadata": {}}
+{"_id": "28845338", "title": "", "text": "Increased lean body mass as an early indicatorof olanzapine-induced weight gain in healthymen.One of the primary limitations of manypsychiatric medications is weight gain, themechanism of which remains to be fullyelucidated. We conducted a 2-week double-blindplacebo-controlled study on weight gain witholanzapine, which is frequently but unpredictablyassociated with this side effect, to address thepossible mechanisms of weight gain independentof changes in the psychiatric condition for whichit is prescribed. Healthy male volunteers wererandomly assigned to olanzapine (5 mg/day for 7days, then 10 mg/day for 7 days) or a matchingplacebo. Of the 24 participants, 19 completedthe study (olanzapine, n=13; placebo, n=6).Body weight, glucose, triglyceride, totalcholesterol, lipid, leptin, insulin, and aldosteronelevels, resting metabolic rate, body composition,physical activity, and 24-h dietary intake wereassessed. A significant increase in weight as wellas triglyceride, insulin, and leptin levels were", "metadata": {}}
+{"_id": "28894097", "title": "", "text": "QTc interval length and QT dispersion aspredictors of mortality in patients withnon-insulin-dependent diabetes.Patients withnon-insulin-dependent diabetes (NIDDM) are atindependent risk of cardiovascular death. Thereason is only partially understood. The aim ofour study was therefore to evaluate the impactof corrected QT interval length (QTc) and QTdispersion (QT-disp) on mortality in a cohort of324 Caucasian NIDDM patients. A resting12-lead ECG was recorded at baseline. Maximum(QT-max) and minimum QT (QT-min) intervalswere measured, and QT-max was corrected forheart rate (QTc-max). QT-disp was defined asthe difference between QT-max and QT-min.QTc-max was 454 (376-671) ms(1/2) (median(range)) and QT-disp 61 (0-240) ms. ProlongedQTc interval (PQTc), defined as QTc-max > 440ms(1/2), was present in 67% of the patients andprolonged QT-disp (PQT-disp), defined asQT-disp > 50 ms, was present in 51%. Duringthe 9-year follow-up period, 100 patients died", "metadata": {}}
+{"_id": "28904104", "title": "", "text": "Repriming of DNA synthesis at stalled replicationforks by human PrimPolDNA replication forksthat collapse during the process of genomicduplication lead to double-strand breaks andconstitute a threat to genomic stability. The riskof fork collapse is higher in the presence ofreplication inhibitors or after UV irradiation,which introduces specific modifications in thestructure of DNA. In these cases, forkprogression may be facilitated by error-pronetranslesion synthesis (TLS) DNA polymerases.Alternatively, the replisome may skip thedamaged DNA, leaving an unreplicated gap to berepaired after replication. This mechanismstrictly requires a priming event downstream ofthe lesion. Here we show that PrimPol, a newhuman primase and TLS polymerase, uses itsprimase activity to mediate uninterrupted forkprogression after UV irradiation and to reinitiateDNA synthesis after dNTP depletion. As anenzyme involved in tolerance to DNA damage,PrimPol might become a target for cancer", "metadata": {}}
+{"_id": "28910120", "title": "", "text": "Recombinant human tumor necrosis factoradministered as a five-day continuous infusion incancer patients: phase I toxicity and effects onlipid metabolism.Recombinant human tumornecrosis factor (rH-TNF) is a cytotoxic monokinewith pleiotropic effects. A phase I trial of rH-TNFwas initiated using a five-day continuousintravenous (IV) infusion repeated every 28days. Thirty-eight courses of therapy wereadministered to 19 patients. The starting dosewas 5 X 10(4) U/m2/d, with escalations to 1.0 X10(5), 2.0 X 10(5), 2.4 X 10(5), and 3.0 X 10(5)U/m2/d. Systemic side effects, including fever,chills, hypotension, fatigue, anorexia, andheadaches, were mild and self-limiting. At themaximum tolerated dose of 3.0 X 10(5) U/m2/d,dose-limiting hematologic toxicity wasmanifested by transient thrombocytopenia andleukopenia. Elevated bilirubin levels were alsoseen at the higher dose levels. Lipoproteinanalysis demonstrated that the five-daytreatment with rH-TNF was associated with", "metadata": {}}
+{"_id": "28928964", "title": "", "text": "Tissue-specific expression and regulation ofsexually dimorphic genes in mice.We report acomprehensive analysis of gene expressiondifferences between sexes in multiple somatictissues of 334 mice derived from an intercrossbetween inbred mouse strains C57BL/6J andC3H/HeJ. The analysis of a large number ofindividuals provided the power to detectrelatively small differences in expressionbetween sexes, and the use of an intercrossallowed analysis of the genetic control of sexuallydimorphic gene expression. Microarray analysisof 23,574 transcripts revealed that the extent ofsexual dimorphism in gene expression was muchgreater than previously recognized. Thus,thousands of genes showed sexual dimorphismin liver, adipose, and muscle, and hundreds ofgenes were sexually dimorphic in brain. Thesegenes exhibited highly tissue-specific patterns ofexpression and were enriched for distinctpathways represented in the Gene Ontologydatabase. They also showed evidence of", "metadata": {}}
+{"_id": "28931537", "title": "", "text": "The role of prevention in oncology practice:results from a 2004 survey of American Societyof Clinical Oncology members.PURPOSE In 2004,the American Society of Clinical Oncology(ASCO) Cancer Prevention Committee surveyedthe members to describe involvement in clinicalprevention activities. METHODS A previouslyadministered survey, with updated items ongenetics, chemoprevention, and survivorship,was mailed to a stratified random sample of2,000 domestic members and a conveniencesample of 3,144 international members.RESULTS A total of 49.7% of domestic memberscontacted and survey eligible responded (n =851). Nonresponders were younger (50.5 v 51.7years; P < .01); 465 international membersresponded. Overall, 35% had received formalinstruction in cancer prevention and control, andmost respondents expected increased use ofprevention, screening/early detection, and riskreduction/genetic counseling in their practices inthe next 5 years. Most reported caring for cancer", "metadata": {}}
+{"_id": "28937856", "title": "", "text": "Stress-dependent regulation of FOXOtranscription factors by the SIRT1deacetylase.The Sir2 deacetylase modulatesorganismal life-span in various species. However,the molecular mechanisms by which Sir2increases longevity are largely unknown. Weshow that in mammalian cells, the Sir2 homologSIRT1 appears to control the cellular response tostress by regulating the FOXO family of Forkheadtranscription factors, a family of proteins thatfunction as sensors of the insulin signalingpathway and as regulators of organismallongevity. SIRT1 and the FOXO transcriptionfactor FOXO3 formed a complex in cells inresponse to oxidative stress, and SIRT1deacetylated FOXO3 in vitro and within cells.SIRT1 had a dual effect on FOXO3 function:SIRT1 increased FOXO3's ability to induce cellcycle arrest and resistance to oxidative stressbut inhibited FOXO3's ability to induce cell death.Thus, one way in which members of the Sir2family of proteins may increase organismal", "metadata": {}}
+{"_id": "29015485", "title": "", "text": "TLR-Mediated Innate Production of IFN-γ byCD8+ T Cells Is Independent ofGlycolysis.CD8(+) T cells can respond tounrelated infections in an Ag-independentmanner. This rapid innate-like immune responseallows Ag-experienced T cells to alert otherimmune cell types to pathogenic intruders. Inthis study, we show that murine CD8(+) T cellscan sense TLR2 and TLR7 ligands, resulting inrapid production of IFN-γ but not of TNF-α andIL-2. Importantly, Ag-experienced T cellsactivated by TLR ligands produce sufficient IFN-γto augment the activation of macrophages. Incontrast to Ag-specific reactivation,TLR-dependent production of IFN-γ by CD8(+) Tcells relies exclusively on newly synthesizedtranscripts without inducing mRNA stability.Furthermore, transcription of IFN-γ upon TLRtriggering depends on the activation of PI3K andserine-threonine kinase Akt, and proteinsynthesis relies on the activation of themechanistic target of rapamycin. We next", "metadata": {}}
+{"_id": "29022271", "title": "", "text": "Recommendations for the presurgicalpsychosocial evaluation of bariatric surgerypatients.Psychosocial factors have significantpotential to affect long-term outcomes ofbariatric surgery, including emotionaladjustment, adherence to the recommendedpostoperative lifestyle regimen, weight lossoutcomes, and co-morbidity improvement and orresolution. Thus, it is recommended thatbariatric behavioral health clinicians withspecialized knowledge and experience beinvolved in the evaluation and care of patientsboth before and after surgery. The evaluatingclinician plays a number of important roles in themultidisciplinary treatment of the bariatricpatient. Central among these is the role ofidentifying factors that may pose challenges tooptimal surgical outcome and providingrecommendations to the patient and bariatricteam on how to address these issues. Thisdocument outlines recommendations for thepsychosocial evaluation of bariatric surgery", "metadata": {}}
+{"_id": "29023309", "title": "", "text": "Simian immunodeficiency virus–induced mucosalinterleukin-17 deficiency promotes Salmonelladissemination from the gutSalmonellatyphimurium causes a localized enteric infectionin immunocompetent individuals, whereasHIV-infected individuals develop alife-threatening bacteremia. Here we show thatsimian immunodeficiency virus (SIV) infectionresults in depletion of T helper type 17 (TH17)cells in the ileal mucosa of rhesus macaques,thereby impairing mucosal barrier functions to S.typhimurium dissemination. In SIV-negativemacaques, the gene expression profile inducedby S. typhimurium in ligated ileal loops wasdominated by TH17 responses, including theexpression of interleukin-17 (IL-17) and IL-22.TH17 cells were markedly depleted inSIV-infected rhesus macaques, resulting inblunted TH17 responses to S. typhimuriuminfection and increased bacterial dissemination.IL-17 receptor–deficient mice showed increasedsystemic dissemination of S. typhimurium from", "metadata": {}}
+{"_id": "29025270", "title": "", "text": "An adoption study of human obesity.Weexamined the contributions of genetic factorsand the family environment to human fatness ina sample of 540 adult Danish adoptees who wereselected from a population of 3580 and dividedinto four weight classes: thin, median weight,overweight, and obese. There was a strongrelation between the weight class of theadoptees and the body-mass index of theirbiologic parents - for the mothers, P less than0.0001; for the fathers, P less than 0.02. Therewas no relation between the weight class of theadoptees and the body-mass index of theiradoptive parents. Cumulative distributions of thebody-mass index of parents showed similarresults; there was a strong relation between thebody-mass index of biologic parents and adopteeweight class and no relation between the indexof adoptive parents and adoptee weight class.Furthermore, the relation between biologicparents and adoptees was not confined to theobesity weight class, but was present across the", "metadata": {}}
+{"_id": "29073751", "title": "", "text": "Redox-dependent downregulation of Rho byRacRac and Rho GTPases function as criticalregulators of actin cytoskeleton remodellingduring cell spreading and migration. Here wedemonstrate that Rac-mediated reactive oxygenspecies (ROS) production results in thedownregulation of Rho activity. Theredox-dependent decrease in Rho activity isrequired for Rac-induced formation of membraneruffles and integrin-mediated cell spreading. Thepathway linking generation of ROS todownregulation of Rho involves inhibition of thelow-molecular-weight protein tyrosinephosphatase (LMW-PTP) and then an increase inthe tyrosine phosphorylation and activation of itstarget, p190Rho-GAP. Our findings define anovel mechanism for the coupling of changes incellular redox state to the control of actincytoskeleton rearrangements by Rho GTPases.", "metadata": {}}
+{"_id": "29090823", "title": "", "text": "The epidemiology of trachoma in EasternEquatoria and Upper Nile States, southernSudan.OBJECTIVE Limited surveys and anecdotaldata indicate that trachoma is endemic in thestates of Eastern Equatoria and Upper Nile insouthern Sudan. However, its magnitude andgeographical distribution are largely unknown.We conducted surveys to ascertain theprevalence and geographical distribution oftrachoma, and to identify targets for controlinterventions. METHODS Population-basedcross-sectional surveys were conducted in ninesites in southern Sudan between September2001 and June 2004. Two-stage random clustersampling with probability proportional to sizewas used to select the sample. Trachomagrading was done using the WHO simplifiedgrading system. FINDINGS A total of 17 016persons were examined, a response rate of86.1% of the enumerated population. Prevalenceof signs of active trachoma in children aged 1-9years was: TF=53.7% (95% confidence interval", "metadata": {}}
+{"_id": "29098525", "title": "", "text": "A single residue determines the cooperativebinding property of a primosomal DNA replicationprotein, PriB, to single-stranded DNA.PriB is aprimosomal protein required for re-initiation ofreplication in bacteria. We characterized andcompared the DNA-binding properties of PriBfrom Salmonella enterica serovar TyphimuriumLT2 (StPriB) and Escherichia coli (EcPriB). Onlyone residue of EcPriB, V6, was different in StPriB(replaced by A6). Previous structural informationrevealed that this residue is located on theputative dimer-dimer interface of PriB and is notinvolved in single-stranded DNA (ssDNA)binding. The cooperative binding mechanism ofStPriB to DNA is, however, very different fromthat of EcPriB. Unlike EcPriB, which forms asingle complex with ssDNAs of various lengths,StPriB forms two or more distinct complexes.Based on these results, as well as information onstructure, binding modes for forming a stablecomplex of PriB with ssDNA of 25 nucleotides(nt), (EcPriB)25, and (StPriB)25 are proposed.", "metadata": {}}
+{"_id": "29107180", "title": "", "text": "Genomic organization and chromosomal locationof the human dsRNA adenosine deaminase gene:the enzyme for glutamate-activated ion channelRNA editing.The structure of the human geneencoding the double-stranded RNA (dsRNA)adenosine deaminase (DRADA) wascharacterized. This nuclear localized enzyme isinvolved in the RNA editing required for theexpression of certain subtypes ofglutamate-gated ion channel subunits. TheDRADA gene span 30 kb pairs and harbors 15exons. The transcription of the DRADA genedriven by the putative promoter region, whichcontains no typical TATA or CCAAT box-likesequences, is initiated at multiple sites, 164 to216 nucleotides upstream of the translationinitiation codon. The three dsRNA binding motifs(DRBM), 70 amino acid residues long, are eachencoded by two exons plus an interveningsequence that interrupts the motif at theidentical amino acid position. This finding isconsistent with the notion that the dsRNA", "metadata": {}}
+{"_id": "29107210", "title": "", "text": "\"We charge them; otherwise we cannot run thehospital\" front line workers, clients and healthfinancing policy implementation gaps inGhana.OBJECTIVES This paper examines policyimplementation gaps of user fees plusexemptions and health insurance in providingfinancial access to primary clinical care forchildren under five in Ghana. METHODS Methodsincluded analysis of routine data, focus groupdiscussions, in-depth interviews, andadministration of a structured questionnaire.RESULTS Providers modified exemptions policyimplementation arrangements, sometimes givingpartial or no exemptions. Clients who knew orsuspected exemption entitlements failed torequest them because of fear of negativereactions from providers. Providers attributedtheir modification of implementationarrangements and negative reactions to thethreat posed to the financial viability of theirinstitutions by reimbursement uncertainty anddelays. At the time of the study insurance", "metadata": {}}
+{"_id": "29124963", "title": "", "text": "EML4-ALK translocation predicts better outcomein lung adenocarcinoma patients with wild-typeEGFR.INTRODUCTION The echinodermmicrotubule-associated protein like 4-anaplasticlymphoma kinase (EML4-ALK) fusion representsa novel target in a subset of non-small cell lungcancer, especially adenocarcinoma. EML4-ALKfusion is mutually exclusive with epidermalgrowth factor receptor (EGFR) mutations. Tounderstand the impact of EML4-ALK on theprognosis of non-small cell lung cancer, weexamined EML4-ALK fusion in lungadenocarcinoma from patients with wild-typeEGFR and analyzed their clinical treatmentoutcomes. METHODS Lung adenocarcinomapatients with malignant pleural effusions havingwild-type EGFR and measurable target lesionswere enrolled for EML4-ALK analysis by reversetranscription-polymerase chain reaction anddirect sequencing. Demographic data, EML4-ALKstatus, and survival data were analyzed. We alsoperformed fluorescence in situ hybridization on", "metadata": {}}
+{"_id": "29125354", "title": "", "text": "Transcriptional Repression of Gata3 Is Essentialfor Early B Cell CommitmentThe mechanismsunderlying the silencing of alternative fatepotentials in very early B cell precursors remainunclear. Using gain- and loss-of-functionapproaches together with a synthetic Zinc-fingerpolypeptide (6ZFP) engineered to preventtranscription factor binding to a defined ciselement, we show that the transcription factorEBF1 promotes B cell lineage commitment bydirectly repressing expression of theT-cell-lineage-requisite Gata3 gene.Ebf1-deficient lymphoid progenitors exhibitedincreased T cell lineage potential and elevatedGata3 transcript expression, whereas enforcedEBF1 expression inhibited T cell differentiationand caused rapid loss of Gata3 mRNA. Notably,6ZFP-mediated perturbation of EBF1 binding to aGata3 regulatory region restored Gata3expression, abrogated EBF1-driven suppressionof T cell differentiation, and prevented B celldifferentiation via a GATA3-dependent", "metadata": {}}
+{"_id": "29134911", "title": "", "text": "Isolation and partial characterization of anunusual human immunodeficiency retrovirusfrom two persons of west-central Africanorigin.An unusual human retrovirus was isolatedfrom two patients with persistent generalizedlymphadenopathy who originate fromWest-Central Africa and are currently residing inBelgium. Although the virus shared a number ofthe same biological and morphological propertiesas human immunodeficiency retrovirus type 1(HIV-1) and HIV-2, significant antigenicdifferences could be demonstrated. Several ofthe viral proteins also differed in molecularweight from the corresponding HIV-1 and HIV-2proteins. Partial chemical cleavage of the mosthighly conserved viral proteins resulted inpatterns which differed from those of HIV-1 andHIV-2. Furthermore, nucleic acid hybridizationexperiments were capable of discriminatingbetween the virus types. Sequence analysis ofthe viral U3 region revealed a unique enhancerorganization not found in other", "metadata": {}}
+{"_id": "29148743", "title": "", "text": "Role of circulating nitrite andS-nitrosohemoglobin in the regulation of regionalblood flow in humans.To determine the relativecontributions of endothelial-derived nitric oxide(NO) vs. intravascular nitrogen oxide species inthe regulation of human blood flow, wesimultaneously measured forearm blood flow andarterial and venous levels of plasma nitrite,LMW-SNOs and HMW-SNOs, and red cellS-nitrosohemoglobin (SNO-Hb). Measurementswere made at rest and during regional inhibitionof NO synthesis, followed by forearm exercise.Surprisingly, we found significant circulatingarterial-venous plasma nitrite gradients,providing a novel delivery source forintravascular NO. Further supporting the notionthat circulating nitrite is bioactive, theconsumption of nitrite increased significantlywith exercise during the inhibition of regionalendothelial synthesis of NO. The role ofcirculating S-nitrosothiols and SNO-Hb in theregulation of basal vascular tone is less certain.", "metadata": {}}
+{"_id": "29183629", "title": "", "text": "Extra centrosomes and/or chromosomes prolongmitosis in human cellsUsing laser microsurgeryand cell fusion we have explored how additionalcentrosomes and/or chromosomes influence theduration of mitosis in human cells. We found thatdoubling the chromosome number addedapproximately 10 min to a 20 min division,whereas doubling the number of centrosomesadded approximately 30 min more. Extracentrosomes and/or chromosomes prolongmitosis by delaying satisfaction of the spindleassembly checkpoint. Thus mitosis can beprolonged by non-genetic means and extrachromosomes and centrosomes probablycontribute to the elevated mitotic index seen inmany tumours.", "metadata": {}}
+{"_id": "29185044", "title": "", "text": "Familial recurrence-pattern analysis ofnonsyndromic isolated cleft palate--a DanishRegistry study.The finding of an associationbetween genetic variation at the transforminggrowth-factor alpha (TGFA) locus andnonsyndromic isolated cleft palate (CP)represents a potentially important breakthroughin our understanding of this condition. Thepresent study was undertaken to assess thefeasibility of detecting linkage to putativeCP-susceptibility loci, such as TGFA. To this end,the familial recurrence pattern for CP wasevaluated to determine the most likely mode ofinheritance for this condition. The study tookadvantage of the high ascertainment anduniform registration of CP in Denmark. Inaddition, the study utilized estimates of familialrecurrence that were obtained by register linkageand, hence, were not subject to either recall biasor the potentially biasing influence ofnonresponders. The recurrence risks for first-,second-, and third-degree relatives of 1,364", "metadata": {}}
+{"_id": "29190724", "title": "", "text": "Gene methylation in gastric cancer.Gastriccancer is one of the most common malignanciesand remains the second leading cause ofcancer-related death worldwide. Over 70% ofnew cases and deaths occur in developingcountries. In the early years of the molecularbiology revolution, cancer research mainlyfocuses on genetic alterations, including gastriccancer. Epigenetic mechanisms are essential fornormal development and maintenance oftissue-specific gene expression patterns inmammals. Disruption of epigenetic processes canlead to altered gene function and malignantcellular transformation. Recent advancements inthe rapidly evolving field of cancer epigeneticshave shown extensive reprogramming of everycomponent of the epigenetic machinery incancer, including DNA methylation, histonemodifications, nucleosome positioning,noncoding RNAs, and microRNAs. Aberrant DNAmethylation in the promoter regions of gene,which leads to inactivation of tumor suppressor", "metadata": {}}
+{"_id": "29214508", "title": "", "text": "Klebsiella aerogenes urease gene cluster:sequence of ureD and demonstration that fouraccessory genes (ureD, ureE, ureF, and ureG)are involved in nickel metallocenterbiosynthesis.The region located immediatelyupstream from the Klebsiella aerogenes ureasestructural genes was sequenced and shown topossess an open reading frame capable ofencoding a 29.8-kDa peptide. Deletions weregenerated in this gene, denoted ureD, and ineach of the genes (ureE, ureF, and ureG) locatedimmediately downstream of the three structuralgenes. Transformation of the mutated plasmidsinto Escherichia coli resulted in high levels ofurease expression, but the enzyme was inactive(deletions in ureD, ureF, or ureG) or onlypartially active (deletions in ureE). Ureases werepurified from the recombinant cells and shown tobe identical to control enzyme when analyzed bygel filtration chromatography and sodiumdodecyl sulfate-polyacrylamide gelelectrophoresis; however, in every case the", "metadata": {}}
+{"_id": "29224825", "title": "", "text": "Hepatic polyploidy and liver growth control.Theonset of cellular polyploidy is recognized in alldifferentiated mammalian tissues. Polyploidy hasbeen noted frequently in the normal liver, as wellas in pathophysiological states of the liver. Asinsights into the significance of polyploidyaccumulate gradually, it is becoming clear thatcells belonging to high ploidy classes exhibitadvancement toward terminal differentiation andcellular senescence with greater probabilities ofapoptosis. Involvement of specific geneticabnormalities, such as impaired DNA repair, maylead to hepatocellular polyploidy. Workingmodels indicate that extensive polyploidy couldlead to organ failure, as well as to oncogenesiswith activation of precancerous cell clones.", "metadata": {}}
+{"_id": "29231620", "title": "", "text": "Disturbances in the positioning, proliferation andapoptosis of neural progenitors contribute tosubcortical band heterotopia formation.Corticalmalformations are commonly associated withintractable epilepsy and other developmentaldisorders. Our studies utilize the tish rat, aspontaneously occurring genetic model ofsubcortical band heterotopia (SBH) associatedwith epilepsy, to evaluate the developmentalevents underlying SBH formation in theneocortex. Our results demonstrate that Pax6(+)and Tbr2(+) progenitors are mislocalized intish(+/-) and tish(-/-)- neocortex throughoutneurogenesis. In addition, mislocalized tish(-/-)progenitors possess a longer cell cycle than wildtype or normally-positioned tish(-/-) progenitors,owing to a lengthened G(2)+M+G(1) time. Thismislocalization is not associated with adherensjunction breakdown or loss of radial glial polarityin the ventricular zone (VZ), as assessed byimmunohistochemistry against phalloidin (toidentify F-actin), aPKC-λ and Par3. However,", "metadata": {}}
+{"_id": "29253460", "title": "", "text": "Sex-related differences in the presentation,treatment and outcomes among patients withacute coronary syndromes: the Global Registryof Acute Coronary Events.OBJECTIVE To assesswhether sex differences exist in the angiographicseverity, management and outcomes of acutecoronary syndromes (ACS). METHODS The studycomprised 7638 women and 19 117 men withACS who underwent coronary angiography andwere included in GRACE (Global Registry of AcuteCoronary Events) from 1999-2006. Normalvessels/mild disease was defined as <50%stenosis in all epicardial vessels; advanceddisease was defined as >or=one vessel with>or=50% stenosis. RESULTS Women were olderthan men and had higher rates of cardiovascularrisk factors. Men and women presented equallywith chest pain; however, jaw pain and nauseawere more frequent among women. Womenwere more likely to have normal/mild disease(12% vs 6%, p<0.001) and less likely to haveleft-main and three-vessel disease (27% vs", "metadata": {}}
+{"_id": "29288582", "title": "", "text": "GITR, a member of the TNF receptorsuperfamily, is costimulatory to mouse Tlymphocyte subpopulations.GITR(glucocorticoid-induced TNFR family relatedgene) is a member of the TNFR superfamily(TNFRSF) that is expressed in different celltypes, including T lymphocytes. Because of ahigh homology in its cytoplasmic region withother known costimulatory members of theTNFRSF, we investigated whether GITR played acostimulatory role in T lymphocytesubpopulations. Our results show that theproliferation response of CD8+ and CD4+peripheral T cell subpopulations was potentiatedwhen a GITR costimulus was added to ananti-CD3 stimulus. Furthermore, expression ofthe main activation-induced receptor(IL-2Ralpha) and production of IL-2 andIFN-gamma were increased more with a GITRcostimulus than with anti-CD3 alone. GITRstimulation also enhanced anti-CD3-induced ERKphosphorylation, suggesting that GITR is", "metadata": {}}
+{"_id": "29321530", "title": "", "text": "PI3K and cancer: lessons, challenges andopportunitiesThe central role of phosphoinositide3-kinase (PI3K) activation in tumour cell biologyhas prompted a sizeable effort to target PI3Kand/or downstream kinases such as AKT andmammalian target of rapamycin (mTOR) incancer. However, emerging clinical data showlimited single-agent activity of inhibitorstargeting PI3K, AKT or mTOR at tolerated doses.One exception is the response to PI3Kδ inhibitorsin chronic lymphocytic leukaemia, where acombination of cell-intrinsic and -extrinsicactivities drive efficacy. Here, we review keychallenges and opportunities for the clinicaldevelopment of inhibitors targeting thePI3K–AKT–mTOR pathway. Through a greaterfocus on patient selection, increasedunderstanding of immune modulation andstrategic application of rational combinations, itshould be possible to realize the potential of thispromising class of targeted anticancer agents.", "metadata": {}}
+{"_id": "29334259", "title": "", "text": "Sequence-based species delimitation for the DNAtaxonomy of undescribed insects.Cataloging thevery large number of undescribed species ofinsects could be greatly accelerated byautomated DNA based approaches, butprocedures for large-scale species discovery fromsequence data are currently lacking. Here, weuse mitochondrial DNA variation to delimitspecies in a poorly known beetle radiation in thegenus Rivacindela from arid Australia. Among468 individuals sampled from 65 sites andmultiple morphologically distinguishable types,sequence variation in three mtDNA genes(cytochrome oxidase subunit 1, cytochrome b,16S ribosomal RNA) was strongly partitionedbetween 46 or 47 putative species identified withquantitative methods of species recognitionbased on fixed unique (\"diagnostic\") characters.The boundaries between groups were alsorecognizable from a striking increase inbranching rate in clock-constrained calibratedtrees. Models of stochastic lineage growth (Yule", "metadata": {}}
+{"_id": "29347970", "title": "", "text": "CCR6 regulates the migration of inflammatoryand regulatory T cells.Th17 and regulatory T(Treg) cells play opposite roles in autoimmunediseases. However, the mechanisms underlyingtheir proper migration to inflammatory tissuesare unclear. In this study, we report that thesetwo T cell subsets both express CCR6. CCR6expression in Th17 cells is regulated by TGF-betaand requires two nuclear receptors, RORalphaand RORgamma. Th17 cells also express theCCR6 ligand CCL20, which is inducedsynergistically by TGF-beta and IL-6, whichrequires STAT3, RORgamma and IL-21. Th17cells, by producing CCL20, promote migration ofTh17 and Treg cells in vitro in a CCR6-dependentmanner. Lack of CCR6 in Th17 cells reduces theseverity of experimental autoimmuneencephalomyelitis and Th17 and Tregrecruitment into inflammatory tissues. Similarly,CCR6 on Treg cells is also important for theirrecruitment into inflammatory tissues. Our dataindicate an important role of CCR6 in Treg and", "metadata": {}}
+{"_id": "29362104", "title": "", "text": "Inhibition of receptor-mediated calcium influx inT cells by unsaturated non-esterified fattyacids.The effect of omega-3, omega-6 andomega-9 unsaturated fatty acids (UFAs) onreceptor-mediated Ca2+ entry was investigatedin a T-cell line (JURKAT) by using anti-CD3antibodies (OKT3) to induce intracellular Ca2+ [(Ca2+]i) increase and Ca2+ influx. All the UFAs,as well as Ni2+ ions and12-O-tetradecanoylphorbol 13-acetate,decreased the OKT3-induced sustained [Ca2+]iincrease to basal levels. Although non-esterifiedfatty acids activate protein kinase C (PKC)[McPhail, Clayton & Snyderman (1984) Science224, 622-624; Murakami, Chan & Routtenberg(1986) J. Biol. Chem. 261, 15424-15429],studies using H-7 and analysis of thePKC-dependent phosphorylation of 19 and 80kDa marker substrates ruled out the involvementof PKC in UFA-induced inhibition of Ca2+ entry.Flow-cytometry analysis showed that UFAs donot interfere with antibody-receptor binding. BSA", "metadata": {}}
+{"_id": "29366489", "title": "", "text": "Deleted in liver cancer-1 (DLC-1): a tumorsuppressor not just for liver.Deleted in livercancer 1 (DLC-1), as its name implied, wasoriginally isolated as a potential tumorsuppressor gene often deleted in hepatocellularcarcinoma. Further studies have indicated thatdown-expression of DLC-1 either by genomicdeletion or DNA methylation is associated with avariety of cancer types including lung, breast,prostate, kidney, colon, uterus, ovary, andstomach. Re-expression of DLC-1 in cancer cellsregulates the structure of actin cytoskeleton andfocal adhesions and significantly inhibits cellgrowth, supporting its role as a tumorsuppressor. This tumor suppressive functionrelies on DLC-1's RhoGTPase activating protein(RhoGAP) activity and steroidogenic acuteregulatory (StAR)-related lipid transfer (START)domain, as well as its focal adhesion localization,which is recruited by the Src Homology 2 (SH2)domains of tensins in aphosphotyrosine-independent fashion. Therefore,", "metadata": {}}
+{"_id": "29367554", "title": "", "text": "Interaction of Helicobacter pylori with gastricepithelial cells is mediated by the p53 proteinfamily.BACKGROUND & AIMS Although the p53tumor suppressor has been extensively studied,many critical questions remain unansweredabout the biological functions of p53 homologs,p73 and p63. Accumulating evidence suggeststhat both p73 and p63 play important roles inregulation of apoptosis, cell differentiation, andtherapeutic drug sensitivity. METHODS Gastricepithelial cells were cocultured with Helicobacterpylori, and the roles of p63 and p73 proteinswere assessed by luciferase reporter, real-timepolymerase chain reaction, immunoblotting, andcell survival assays. Short hairpin RNA anddominant-negative mutants were used to inhibitactivity of p73 and p63 isoforms. Human andmurine gastric tissues were analyzed byimmunohistochemistry with p73 and p63antibodies and modified Steiner's silver method.RESULTS Interaction of H pylori with gastricepithelial cells leads to robust up-regulation of", "metadata": {}}
+{"_id": "29381091", "title": "", "text": "Brown and white adipose tissues: intrinsicdifferences in gene expression and response tocold exposure in miceBrown adipocytes dissipateenergy, whereas white adipocytes are an energystorage site. We explored the plasticity ofdifferent white adipose tissue depots in acquiringa brown phenotype by cold exposure. Bycomparing cold-induced genes in white fat tothose enriched in brown compared with whitefat, at thermoneutrality we defined a \"brite\"transcription signature. We identified the genes,pathways, and promoter regulatory motifsassociated with \"browning,\" as these representnovel targets for understanding this process. Forexample, neuregulin 4 was more highlyexpressed in brown adipose tissue andupregulated in white fat upon cold exposure, andcell studies showed that it is a neuriteoutgrowth-promoting adipokine, indicative of arole in increasing adipose tissue innervation inresponse to cold. A cell culture system thatallows us to reproduce the differential properties", "metadata": {}}
+{"_id": "29387024", "title": "", "text": "Continuous glucose monitoring in pregnantwomen with type 1 diabetes (CONCEPTT): amulticentre international randomised controlledtrialBACKGROUND Pregnant women with type 1diabetes are a high-risk population who arerecommended to strive for optimal glucosecontrol, but neonatal outcomes attributed tomaternal hyperglycaemia remain suboptimal.Our aim was to examine the effectiveness ofcontinuous glucose monitoring (CGM) onmaternal glucose control and obstetric andneonatal health outcomes. METHODS In thismulticentre, open-label, randomised controlledtrial, we recruited women aged 18-40 years withtype 1 diabetes for a minimum of 12 months whowere receiving intensive insulin therapy.Participants were pregnant (≤13 weeks and 6days' gestation) or planning pregnancy from 31hospitals in Canada, England, Scotland, Spain,Italy, Ireland, and the USA. We ran two trials inparallel for pregnant participants and forparticipants planning pregnancy. In both trials,", "metadata": {}}
+{"_id": "29399239", "title": "", "text": "Neutrophil extracellular traps: Is immunity thesecond function of chromatin?Neutrophilextracellular traps (NETs) are made of processedchromatin bound to granular and selectedcytoplasmic proteins. NETs are released by whiteblood cells called neutrophils, maybe as a lastresort, to control microbial infections. Thisrelease of chromatin is the result of a uniqueform of cell death, dubbed \"NETosis. \" Here wereview our understanding of how NETs are made,their function in infections and as danger signals,and their emerging importance in autoimmunityand coagulation.", "metadata": {}}
+{"_id": "29422484", "title": "", "text": "Phosphorylation of p35 and p39 by Cdk5determines the subcellular location of theholokinase in a phosphorylation-site-specificmanner.Cdk5 is a member of thecyclin-dependent kinase (Cdk) family, which isactivated by neuronal activators p35 or p39.Cdk5 regulates a variety of neuronal activitiesincluding migration, synaptic activity andneuronal death. p35 and p39 impart cytoplasmicmembrane association of p35-Cdk5 andp39-Cdk5, respectively, through theirmyristoylation, but it is not clearly understoodhow the cellular localization is related to differentfunctions. We investigated the role of Cdk5activity in the subcellular localization ofp35-Cdk5 and p39-Cdk5. Cdk5 activity affectedthe localization of p35-Cdk5 and p39-Cdk5through phosphorylation of p35 or p39. Usingunphosphorylated or phosphomimetic mutants ofp35 and p39, we found that phosphorylation atSer8, common to p35 and p39, by Cdk5regulated the cytoplasmic localization and", "metadata": {}}
+{"_id": "29423324", "title": "", "text": "Interleukin-12 and -23 Control Plasticity ofCD127(+) Group 1 and Group 3 Innate LymphoidCells in the Intestinal Lamina Propria.Humangroup 1 ILCs consist of at least threephenotypically distinct subsets, including NKcells, CD127(+) ILC1, and intraepithelialCD103(+) ILC1. In inflamed intestinal tissuesfrom Crohn's disease patients, numbers ofCD127(+) ILC1 increased at the cost of ILC3.Here we found that differentiation of ILC3 toCD127(+) ILC1 is reversible in vitro and in vivo.CD127(+) ILC1 differentiated to ILC3 in thepresence of interleukin-2 (IL-2), IL-23, and IL-1βdependent on the transcription factor RORγt, andthis process was enhanced in the presence ofretinoic acid. Furthermore, we observed inresection specimen from Crohn's disease patientsa higher proportion of CD14(+) dendritic cells(DC), which in vitro promoted polarization fromILC3 to CD127(+) ILC1. In contrast, CD14(-)DCs promoted differentiation from CD127(+)ILC1 toward ILC3. These observations suggest", "metadata": {}}
+{"_id": "29429111", "title": "", "text": "Transcriptional regulation of neuronal genes andits effect on neural functions: expression andfunction of forkhead transcription factors inneurons.Forkhead box transcription factor, classO (FOXO) is a mammalian homologue of DAF-16,which is known to regulate the lifespan ofCaenorhabditis elegans and includes subfamiliesof forkhead transcription factors such as AFX,FKHRL1, and FKHR. FKHR is phosphorylated onthree sites (Thr-24, Ser-256, and Ser-319) in aphosphatidylinositol 3-kinase(PI3K)/Akt-dependent manner, thereby inhibitingdeath signals. We here documenteddephosphorylation of FKHR following transientforebrain ischemia with its concomitanttranslocation into the nucleus in neurons in gerbiland mouse brains. The activation of FKHRpreceded delayed neuronal death in thevulnerable hippocampal regions followingischemic brain injury. The FKHR activation wasaccompanied by an increase in DNA bindingactivity for FKHR-responsive element on the Fas", "metadata": {}}
+{"_id": "29459383", "title": "", "text": "ERAAP synergizes with MHC class I molecules tomake the final cut in the antigenic peptideprecursors in the endoplasmic reticulum.Themajor histocompatibility complex class Imolecules display peptides (pMHC I) on the cellsurface for immune surveillance by CD8(+) Tcells. These peptides are generated byproteolysis of intracellular polypeptides by theproteasome in the cytoplasm and then in theendoplasmic reticulum (ER) by the ERaminopeptidase associated with antigenprocessing (ERAAP). To define the unknownmechanism of ERAAP function in vivo, weanalyzed naturally processed peptides in cellswith or without appropriate MHC I and ERAAP. Inthe absence of MHC I, ERAAP degraded theantigenic precursors in the ER. However, MHC Imolecules could bind proteolytic intermediatesand were essential for generation of the finalpeptide by ERAAP. Thus, ERAAP synergizes withMHC I to generate the final pMHC I repertoire.", "metadata": {}}
+{"_id": "29460384", "title": "", "text": "Estimates of animal and plant protein intake inUS adults: results from the Third National Healthand Nutrition Examination Survey,1988-1991.OBJECTIVE To describe the sourcesof protein intake in a sample of the US adultpopulation and among subgroups defined byrace-ethnicity, age, and gender. DESIGN TheThird National Health and Nutrition ExaminationSurvey, 1988-1991, is a stratified randomsample of the total civilian noninstitutionalizedpopulation, drawn from the 50 United States andthe District of Columbia. For all foods consumedby the participants, based on a 24-hour dietaryrecall, protein sources and the contribution ofeach protein type to the total protein intake weredetermined. SUBJECTS Adult participants in thethird National Health and Nutrition ExaminationSurvey (n = 7,924). STATISTICAL ANALYSESWeighted total, age-specific, and age-adjustedmean protein intakes were calculated using SASand WesVarPC. Statistical differences weredetermined by 2-tailed t tests. RESULTS The", "metadata": {}}
+{"_id": "29467201", "title": "", "text": "CYP18A1, a key enzyme of Drosophila steroidhormone inactivation, is essential formetamorphosis.Ecdysteroids are steroidhormones, which coordinate majordevelopmental transitions in insects. Both therises and falls in circulating levels of activehormones are important for coordinating moltingand metamorphosis, making both ecdysteroidbiosynthesis and inactivation of physiologicalrelevance. We demonstrate that Drosophilamelanogaster Cyp18a1 encodes a cytochromeP450 enzyme (CYP) with 26-hydroxylase activity,a prominent step in ecdysteroid catabolism. Aclear ortholog of Cyp18a1 exists in most insectsand crustaceans. When Cyp18a1 is transfected inDrosophila S2 cells, extensive conversion of20-hydroxyecdysone (20E) into20-hydroxyecdysonoic acid is observed. This is amulti-step process, which involves the formationof 20,26-dihydroxyecdysone as an intermediate.In Drosophila larvae, Cyp18a1 is expressed inmany target tissues of 20E. We examined the", "metadata": {}}
+{"_id": "29473081", "title": "", "text": "The sialyltransferase ST3GAL6 influences homingand survival in multiple myeloma.Glycosylation isa stepwise procedure of covalent attachment ofoligosaccharide chains to proteins or lipids, andalterations in this process, especially increasedsialylation, have been associated with malignanttransformation and metastasis. The role ofaltered sialylation in multiple myeloma (MM) celltrafficking has not been previously investigated.In the present study we identified highexpression of β-galactosideα-2,3-sialyltransferase, ST3GAL6, in MM celllines and patients. This gene plays a key role inselectin ligand synthesis in humans through thegeneration of functional sialyl Lewis X. In MRC IXpatients, high expression of this gene isassociated with inferior overall survival. In thisstudy we demonstrate that knockdown ofST3GAL6 results in a significant reduction inlevels of α-2,3-linked sialic acid on the surface ofMM cells with an associated significant reductionin adhesion to MM bone marrow stromal cells", "metadata": {}}
+{"_id": "29495185", "title": "", "text": "New developments in the epidemiology of cancerprognosis: traditional and molecular predictors oftreatment response and survival.There havebeen numerous epidemiologic investigations todetermine factors that may affect cancer risk.There is also a rich tradition of evaluatingpotential somatic changes in the cancer itself topredict recurrence and/or mortality afterdiagnosis. However, there has been relativelylittle", "metadata": {}}
+{"_id": "29504413", "title": "", "text": "Behavioral effects of estrogen receptor genedisruption in male mice.Gonadal steroidhormones regulate sexually dimorphicdevelopment of brain functions and behaviors.Their nuclear receptors offer the opportunity torelate molecular events in neurons to simpleinstinctive mammalian behaviors. We havedetermined the role of estrogen receptor (ER)activation by endogenous estrogen in thedevelopment of male-typical behaviors by theuse of transgenic estrogen-receptor-deficient(ERKO) mice. Surprisingly, in spite of the factthat they are infertile, ERKO mice showed normalmotivation to mount females but they achievedless intromissions and virtually no ejaculations.Aggressive behaviors were dramatically reducedand male-typical offensive attacks were rarelydisplayed by ERKO males. Moreover, ER genedisruption demasculinized open-field behaviors.In the brain, despite the evident loss offunctional ER protein, the androgen-dependentsystem appears to be normally present in ERKO", "metadata": {}}
+{"_id": "29509926", "title": "", "text": "High-Density Lipoproteins ExertPro-inflammatory Effects on Macrophages viaPassive Cholesterol Depletion andPKC-NF-κB/STAT1-IRF1 Signaling.Membranecholesterol modulates a variety of cell signalingpathways and functions. While cholesteroldepletion by high-density lipoproteins (HDLs) haspotent anti-inflammatory effects in various celltypes, its effects on inflammatory responses inmacrophages remain elusive. Here we showovert pro-inflammatory effects of HDL-mediatedpassive cholesterol depletion and lipid raftdisruption in murine and human primarymacrophages in vitro. These pro-inflammatoryeffects were confirmed in vivo in peritonealmacrophages from apoA-I transgenic mice,which have elevated HDL levels. In line withthese findings, the innate immune responsesrequired for clearance of P. aeruginosa bacterialinfection in lung were compromised in mice withlow HDL levels. Expression analysis, ChIP-PCR,and combinatorial pharmacological and genetic", "metadata": {}}
+{"_id": "29518440", "title": "", "text": "Hypoxia of the renal medulla--its implications fordisease.In land mammals, a major task of thekidney is to reabsorb water to allow survival in adry environment. Water conservation isenhanced by the renal medulla, whichconcentrates the urine to a level up to four timesthe osmolality of plasma. To produce this uniquegradient of osmolality, the medulla has acountercurrent system of vessels and tubulesthat dictates active reabsorption of sodium in amilieu poor in oxygen (Figure 1).1 In this review,we describe how hypoxia of the medulla mayrelate to susceptibility to acute and chronic renalinjury. The Renal Medullary ConcentratingMechanism as . . .", "metadata": {}}
+{"_id": "29526125", "title": "", "text": "Troponin concentrations for stratification ofpatients with acute coronary syndromes inrelation to therapeutic efficacy of tirofiban.PRISM Study Investigators. Platelet ReceptorInhibition in Ischemic SyndromeManagement.BACKGROUND A major challengefor physicians is to identify patients with acutecoronary syndromes who may benefit fromtreatment with glycoprotein-IIb/IIIa-receptorantagonists. We investigated whether troponinconcentrations can be used to stratify patientsfor benefit from treatment with tirofiban.METHODS We enrolled 2222 patients of thePlatelet Receptor Inhibition in IschemicSyndrome Management study with coronaryartery disease and who had had chest pain in theprevious 24 h. All patients received aspirin andwere randomly assigned treatment with tirofibanor heparin. We took baseline measurements oftroponin I and troponin T. We recorded death,myocardial infarction, or recurrent ischaemiaafter 48 h infusion treatment and at 7 days and", "metadata": {}}
+{"_id": "29557235", "title": "", "text": "Evolution and function of ubiquitin-likeprotein-conjugation systemsUbiquitin functionsby covalently modifying other proteins. In thepast few years, a surprising number of otherproteins have been identified that, despite oftenbeing only slightly similar to ubiquitin, can alsobe attached to proteins. Newly discoveredparallels between the activation of ubiquitin andthe biosynthesis of certain enzyme cofactors nowhint at the possible evolutionary origins of theubiquitin system.", "metadata": {}}
+{"_id": "29564505", "title": "", "text": "Inflammatory biomarkers and exacerbations inchronic obstructive pulmonarydisease.IMPORTANCE Exacerbations ofrespiratory symptoms in chronic obstructivepulmonary disease (COPD) have profound andlong-lasting adverse effects on patients.OBJECTIVE To test the hypothesis that elevatedlevels of inflammatory biomarkers in individualswith stable COPD are associated with anincreased risk of having exacerbations. DESIGN,SETTING, AND PARTICIPANTS Prospective cohortstudy examining 61,650 participants withspirometry measurements from the CopenhagenCity Heart Study (2001-2003) and theCopenhagen General Population Study(2003-2008). Of these, 6574 had COPD, definedas a ratio between forced expiratory volume in 1second (FEV1) and forced vital capacity below0.7. MAIN OUTCOMES AND MEASURES Baselinelevels of C-reactive protein (CRP) and fibrinogenand leukocyte count were measured inparticipants at a time when they were not", "metadata": {}}
+{"_id": "29634262", "title": "", "text": "Gene supplementation therapy for recessiveforms of inherited retinal dystrophiesOver thelast decade, gene supplementation therapy forinherited retinal degeneration has come of age.Early proof-of-concept studies in animal modelsof disease showed modest, but genuineimprovements in retinal function and/or survival.Further development of the vectors used forgene transfer to the retina has led to bettertreatment efficacy in a wide variety of animalmodels, leading in 2008 to the initiation of threeclinical trials for Leber congenital amaurosiscaused by retinal pigment epithelium 65deficiency. The results from these trials suggestthat the treatment of inherited retinal dystrophyby gene therapy can be safe and effective. Here,we examine the progress of genesupplementation therapy in the retina, anddiscuss the potential for using gene therapy totreat different forms of inherited retinaldegeneration.", "metadata": {}}
+{"_id": "29638116", "title": "", "text": "Complex Tissue and Disease Modeling usinghiPSCs.Defined genetic models based on humanpluripotent stem cells have opened new avenuesfor understanding disease mechanisms and drugscreening. Many of these models assumecell-autonomous mechanisms of disease but it ispossible that disease phenotypes or drugresponses will only be evident if all cellular andextracellular components of a tissue are presentand functionally mature. To derive optimalbenefit from such models, complex multicellularstructures with vascular components that mimictissue niches will thus likely be necessary. Herewe consider emerging research creating humantissue mimics and provide somerecommendations for moving the field forward.", "metadata": {}}
+{"_id": "29641682", "title": "", "text": "Reprogramming somatic cells towardspluripotency by cellular fusion.Pluripotent cellsarise within the inner cell mass (ICM) ofmammals and have the potential to generate allcell types of the adult organism through aprocess of commitment and ordereddifferentiation. Despite many decades ofinvestigation, the mechanisms that guide andstabilise cell fate choice as well as those that canbe engineered to promote its reversal, remainonly partially resolved. Reprogramming ofsomatic cells towards a pluripotent-like state canbe achieved by several different experimentalroutes including nuclear transfer, the supply of adefined cocktail of transcription factors, or byfusing somatic cells with a pluripotent stem cellpartner. These approaches have been used todemonstrate the remarkable intrinsic epigeneticplasticity of many terminally differentiated celltypes, as well as to define the factors that arerequired for pluripotent conversion. In thisreview we summarise some recent advances", "metadata": {}}
+{"_id": "29657303", "title": "", "text": "Anorectic drugs and pulmonary hypertensionfrom the bedside to the bench.Anorectic drugshave been used for more than 30 years as an aidin weight reduction for obese persons. The use ofaminorex, an amphetamine analog thatincreases norepinephrine levels in the centralnervous system, led to an epidemic of primarypulmonary hypertension (PPH) in Europe in thelate 1960s and early 1970s. The use offenfluramine and later dexfenfluramine [drugsthat inhibit 5-hydroxytryptamine (5-HT) releaseand reuptake and increases 5-HT and thus 5-HTsecretion in the brain] was associated with asecond epidemic of PPH. All of these drugs havebeen voluntarily withdrawn from the market. Thepathogenesis of PPH in patients treated withthese agents is uncertain, but recent evidencesuggests that potassium channel abnormalitiesand vasoactive and proliferative properties of5-HT may play a role. There is increasingexperimental evidence suggesting that aminorex,fenfluramine and dexfenfluramine inhibit", "metadata": {}}
+{"_id": "29689140", "title": "", "text": "B-catenin deficiency, but not Myc deletion,suppresses the immediate phenotypes of APCloss in the liver.Dysregulated Wnt signaling isseen in approximately 30% of hepatocellularcarcinomas; thus, finding pathways downstreamof the activation of Wnt signaling is key. Here,using cre-lox technology, we deleted the Apcgene in the adult mouse liver and observed arapid increase in nuclear beta-catenin and c-Myc,which is associated with an induction ofproliferation that led to hepatomegaly within 4days of gene deletion. To investigate thedownstream pathways responsible for thesephenotypes, we analyzed the impact ofinactivating APC in the context of deficiency ofthe potentially key effectors beta-catenin andc-Myc. beta-catenin loss rescues both theproliferation and hepatomegaly phenotypes afterAPC loss. However, c-Myc deletion, whichrescues the phenotypes of APC loss in theintestine, had no effect on the phenotypes of APCloss in the liver. The consequences of the", "metadata": {}}
+{"_id": "29691654", "title": "", "text": "Uncoupling Mitochondrial Respiration forDiabesity.Until recently, the mechanism ofadaptive thermogenesis was ascribed to theexpression of uncoupling protein 1 (UCP1) inbrown and beige adipocytes. UCP1 is known tocatalyze a proton leak of the inner mitochondrialmembrane, resulting in uncoupled oxidativemetabolism with no production of adenosinetriphosphate and increased energy expenditure.Thus increasing brown and beige adipose tissuewith augmented UCP1 expression is a viabletarget for obesity-related disorders. Recent workdemonstrates an UCP1-independent pathway touncouple mitochondrial respiration. A secretedenzyme, PM20D1, enriched in UCP1+ adipocytes,exhibits catalytic and hydrolytic activity toreversibly form N-acyl amino acids. N-acyl aminoacids act as endogenous uncouplers ofmitochondrial respiration at physiologicalconcentrations. Administration of PM20D1 or itsproducts, N-acyl amino acids, to diet-inducedobese mice improves glucose tolerance by", "metadata": {}}
+{"_id": "29723642", "title": "", "text": "A functional polymorphism in the prodynorphingene promotor is associated with temporal lobeepilepsy.The prodynorphin gene (PDYN)encoding the anticonvulsant peptide dynorphin isa strong candidate for a seizure suppressor geneand thus a possible modulator of susceptibility totemporal lobe epilepsy. We performed a casecontrol association study in 155 patients withnonlesional temporal lobe epilepsy and 202controls and found that PDYN promotorlow-expression L-alleles confer an increased riskfor temporal lobe epilepsy in patients with afamily history for seizures. Irrespective of thefamilial background, L-homozygotes display ahigher risk for secondarily generalized seizuresand status epilepticus.", "metadata": {}}
+{"_id": "29735200", "title": "", "text": "Cardiovascular and renal benefits of dry beanand soybean intake.Dry beans and soybeans arenutrient-dense, fiber-rich, and are high-qualitysources of protein. Protective and therapeuticeffects of both dry bean and soybean intake havebeen documented. Studies show that dry beanintake has the potential to decrease serumcholesterol concentrations, improve manyaspects of the diabetic state, and providemetabolic benefits that aid in weight control.Soybeans are a unique source of the isoflavonesgenistein and diadzein, which have numerousbiological functions. Soybeans and soyfoodspotentially have multifaceted health-promotingeffects, including cholesterol reduction, improvedvascular health, preserved bone mineral density,and reduction of menopausal symptoms. Soyappears to have salutary effects on renalfunction, although these effects are not wellunderstood. Whereas populations consuminghigh intakes of soy have lower prevalences ofcertain cancers, definitive experimental data are", "metadata": {}}
+{"_id": "29745822", "title": "", "text": "Nonuniform probability of glutamate release at ahippocampal synapse.A change in the probabilityof neurotransmitter release (Pr) is an importantmechanism underlying synaptic plasticity.Although Pr is often assumed to be the same forall terminals at a single synapse, this assumptionis difficult to reconcile with the nonuniform sizeand structure of synaptic terminals in the centralnervous system. Release probability wasmeasured at excitatory synapses on culturedhippocampal neurons by analysis of theprogressive block of N-methyl-D-aspartatereceptor-mediated synaptic currents by theirreversible open channel blocker MK-801.Release probability was nonuniform (range of0.09 to 0.54) for terminals arising from a singleaxon, the majority of which had a low Pr.However, terminals with high Pr are more likelyto be affected by the activity-dependentmodulation that occurs in long-term potentiation.", "metadata": {}}
+{"_id": "29785642", "title": "", "text": "An autoimmune disease, APECED, caused bymutations in a novel gene featuring twoPHD-type zinc-finger domainsAutoimmunepolyendocrinopathy-candidiasis-ectodermaldystrophy (APECED) is the only describedsystemic autoimmune disease with establishedmonogenic background, and the firstautoimmune disorder localized outside the majorhistocompatibility complex (MHC) region. Theprimary biochemical defect in APECED isunknown. We have isolated a novel gene, AIRE,encoding for a putative nuclear protein featuringtwo PHD-type zinc-finger motifs, suggesting itsinvolvement in transcriptional regulation. Fivemutations in AIRE are reported in individualswith this disorder. This is the first report of asingle-gene defect causing a systemic humanautoimmune disease, providing a tool forexploring the molecular basis of autoimmunity.", "metadata": {}}
+{"_id": "29788648", "title": "", "text": "NuA4 lysine acetyltransferase Esa1 is targeted tocoding regions and stimulates transcriptionelongation with Gcn5.NuA4, the major H4 lysineacetyltransferase (KAT) complex inSaccharomyces cerevisiae, is recruited topromoters and stimulates transcription initiation.NuA4 subunits contain domains that bindmethylated histones, suggesting that histonemethylation should target NuA4 to codingsequences during transcription elongation. Weshow that NuA4 is cotranscriptionally recruited,dependent on its physical association withelongating polymerase II (Pol II) phosphorylatedon the C-terminal domain by cyclin-dependentkinase 7/Kin28, but independently of subunits(Eaf1 and Tra1) required for NuA4 recruitment topromoters. Whereas histone methylation by Set1and Set2 is dispensable for NuA4's interactionwith Pol II and targeting to some coding regions,it stimulates NuA4-histone interaction and H4acetylation in vivo. The NuA4 KAT, Esa1,mediates increased H4 acetylation and enhanced", "metadata": {}}
+{"_id": "29806339", "title": "", "text": "Targeting mitotic exit leads to tumor regressionin vivo: Modulation by Cdk1, Mastl, and thePP2A/B55α,δ phosphatase.Targeting mitotic exithas been recently proposed as a relevanttherapeutic approach against cancer. By usinggenetically engineered mice, we show that theAPC/C cofactor Cdc20 is essential for anaphaseonset in vivo in embryonic or adult cells,including progenitor/stem cells. Ablation ofCdc20 results in efficient regression ofaggressive tumors, whereas current mitoticdrugs display limited effects. Yet, Cdc20 null cellscan exit from mitosis upon inactivation of Cdk1and the kinase Mastl (Greatwall). This mitoticexit depends on the activity of PP2A phosphatasecomplexes containing B55α or B55δ regulatorysubunits. These data illustrate the relevance ofcritical players of mitotic exit in mammals andtheir implications in the balance between celldeath and mitotic exit in tumor cells.", "metadata": {}}
+{"_id": "29807737", "title": "", "text": "DrugBank 5.0: a major update to the DrugBankdatabase for 2018DrugBank (www.drugbank.ca)is a web-enabled database containingcomprehensive molecular information aboutdrugs, their mechanisms, their interactions andtheir targets. First described in 2006, DrugBankhas continued to evolve over the past 12 years inresponse to marked improvements to webstandards and changing needs for drug researchand development. This year's update, DrugBank5.0, represents the most significant upgrade tothe database in more than 10 years. In manycases, existing data content has grown by 100%or more over the last update. For instance, thetotal number of investigational drugs in thedatabase has grown by almost 300%, thenumber of drug-drug interactions has grown bynearly 600% and the number of SNP-associateddrug effects has grown more than 3000%.Significant improvements have been made to thequantity, quality and consistency of drugindications, drug binding data as well as", "metadata": {}}
+{"_id": "29828242", "title": "", "text": "Analyzing mechanisms of alternative pre-mRNAsplicing using in vitro splicing assays.Thedevelopment of in vitro assays to analyzepre-mRNA splicing resulted in the discovery ofmany fundamental features characterizingsplicing signals and the machinery thatcompletes this process. Because in vitro assayscan be manipulated by various biochemicalapproaches, the versatility of investigatingalternative pre-mRNA splicing in the test tubeappears endless. Importantly, modifications inreaction conditions can lead to the accumulation,isolation, and characterization of reactionintermediates, a prerequisite for gainingmechanistic insights into how the spliceosomecarries out intron removal, and how regulatoryelements assist the general splicing machinery indefining splice sites and alternative exons. Theseconsiderable experimental advantages havemade the in vitro splicing system a standardassay, even though this approach is independentfrom RNA transcription and other RNA processing", "metadata": {}}
+{"_id": "29845974", "title": "", "text": "New Roles for Pharmacists in Community MentalHealth Care: A Narrative ReviewMedicines are amajor treatment modality for many mentalillnesses, and with the growing burden of mentaldisorders worldwide pharmacists are ideallypositioned to play a greater role in supportingpeople with a mental illness. This narrativereview aims to describe the evidence forpharmacist-delivered services in mental healthcare and address the barriers and facilitators toincreasing the uptake of pharmacist services aspart of the broader mental health care team.This narrative review is divided into three mainsections: (1) the role of the pharmacist in mentalhealth care in multidisciplinary teams and insupporting early detection of mental illness; (2)the pharmacists' role in supporting quality use ofmedicines in medication review, strategies toimprove medication adherence and antipsychoticpolypharmacy, and shared decision making; and(3) barriers and facilitators to theimplementation of mental health pharmacy", "metadata": {}}
+{"_id": "29851836", "title": "", "text": "UV light-induced DNA synthesis arrest in HeLacells is associated with changes inphosphorylation of human single-strandedDNA-binding protein.We show that DNAreplication activity in extracts of human HeLacells decreases following UV irradiation.Alterations in replication activity in vitro parallelthe UV-induced block in cell cycle progression ofthese cells in culture. UV irradiation also inducesspecific changes in the pattern ofphosphorylation of the 34 kDa subunit of a DNAreplication protein, human single-strandedDNA-binding protein (hSSB). The appearance ofa hyperphosphorylated form of hSSB correlateswith reduced in vitro DNA replication activity inextracts of UV-irradiated cells. Replicationactivity can be restored to these extracts in vitroby addition of purified hSSB. These resultssuggest that UV-induced DNA synthesis arrestmay be mediated in part throughphosphorylation-related alterations in the activityof hSSB, an essential component of the DNA", "metadata": {}}
+{"_id": "29863668", "title": "", "text": "P446L-importin-beta inhibits nuclear envelopeassembly by sequestering nuclear envelopeassembly factors to the microtubules.The P446Lmutant Drosophila importin-beta(P446L-imp-beta) has been reported toprohibit--in dominant negative fashion--nuclearenvelope (NE) assembly. Along elucidating themode of action of P446L-imp-beta we studied invitro NE assembly on Sepharose beads. WhileDrosophila embryo extracts support NE assemblyover Sepharose beads coated with Ran, NEassembly does not take place in extractssupplied with exogenous P446L-imp-beta. A NEalso forms over importin-beta-coated beads.Surprisingly, when immobilized to Sepharosebeads P446L-imp-beta as efficiently recruits NEvesicles as normal importin-beta. Thediscrepancy in behavior of cytoplasmic andbead-bound P446L-imp-beta appears to berelated to icreased--as compared to normalimportin-beta--microtubule (MT) binding abilityof P446L-imp-beta. While wild-type", "metadata": {}}
+{"_id": "29877890", "title": "", "text": "Histone chaperones and nucleosomeassembly.Recent structures of the nucleosomecore particle reveal details of histone-histone andhistone-DNA interactions. These structures havenow set the stage for understanding chromatinassembly and dynamics during replication andtranscription. Histone chaperones and chromatinremodeling complexes are important in both ofthese processes. The nucleosome and its proteincore, the histone octamer, have twofoldsymmetry, which histone chaperones may use tobind core histones. Recent studies suggest thatthe nucleoplasmin pentamer may mediatehistone storage, sperm chromatindecondensation and nucleosome assembly, bydimerizing to form a decamer. In this model,histone binding on the lateral surface of thechaperone involves stereospecific interactionsand a shared twofold axis.", "metadata": {}}
+{"_id": "29947146", "title": "", "text": "Intestinal methane production in obeseindividuals is associated with a higher body massindex.BACKGROUND Obesity is an epidemic thataffects 1 in 3 individuals in the United States,and recent evidence suggests that entericmicrobiota may play a significant role in thedevelopment of obesity. This study evaluated theassociation between methanogenic archaea andobesity in human subjects. METHODS Subjectswith a body mass index (BMI) of 30 kg/m² orhigher were prospectively recruited from theweight loss program of a tertiary care medicalcenter. Subjects who met the study's inclusioncriteria were asked to complete a questionnairethat included a series of visual analogue scoresfor bowel symptom severities. Subjects thenprovided a single end-expiratory breath sampleto quantitate methane levels. Bivariate andmultivariate analyses were used to determineassociations with BMI. RESULTS A total of 58patients qualified for enrollment. Twenty percentof patients (n = 12) had breath test results that", "metadata": {}}
+{"_id": "29955650", "title": "", "text": "Study of infectious intestinal disease in England:rates in the community, presenting to generalpractice, and reported to national surveillance.The Infectious Intestinal Disease StudyExecutive.OBJECTIVE To establish the incidenceand aetiology of infectious intestinal disease inthe community and presenting to generalpractitioners. Comparison with incidence andaetiology of cases reaching national laboratorybased surveillance. DESIGN Population basedcommunity cohort incidence study, generalpractice based incidence studies, and caselinkage to national laboratory surveillance.SETTING 70 general practices throughoutEngland. PARTICIPANTS 459 975 patients servedby the practices. Community surveillance of9776 randomly selected patients. MAINOUTCOME MEASURES Incidence of infectiousintestinal disease in community and reported togeneral practice. RESULTS 781 cases wereidentified in the community cohort, giving anincidence of 19.4/100 person years (95%", "metadata": {}}
+{"_id": "29981186", "title": "", "text": "Venous thrombosis in cancer patients: insightsfrom the FRONTLINE survey.BACKGROUNDVenous thromboembolism (VTE) is a commoncomplication in cancer patients and a significantcause of morbidity and mortality. However, littleinformation is available on oncologists'perceptions of the risk of VTE and itsmanagement. The Fundamental Research inOncology and Thrombosis (FRONTLINE) study isthe first comprehensive global survey ofthrombosis and cancer. The study was designedto collect data on the perceived risk and patternsof practice with regard to VTE in cancer patientsundergoing surgical and medical management oftheir malignancy and to provide information oninternational and regional practice patterns,allowing for the design of research studies toanswer the concerns of practicing clinicians.METHODS Literature reviews were performed toprovide a current evidence base against which tocompare the findings, and a survey wasdeveloped under the guidance of an advisory", "metadata": {}}
+{"_id": "30034334", "title": "", "text": "A dual function of the CRISPR-Cas system inbacterial antivirus immunity and DNArepair.Clustered Regularly Interspaced ShortPalindromic Repeats (CRISPRs) and theassociated proteins (Cas) comprise a system ofadaptive immunity against viruses and plasmidsin prokaryotes. Cas1 is a CRISPR-associatedprotein that is common to all CRISPR-containingprokaryotes but its function remains obscure.Here we show that the purified Cas1 protein ofEscherichia coli (YgbT) exhibits nuclease activityagainst single-stranded and branched DNAsincluding Holliday junctions, replication forks and5'-flaps. The crystal structure of YgbT andsite-directed mutagenesis have revealed thepotential active site. Genome-wide screens showthat YgbT physically and genetically interactswith key components of DNA repair systems,including recB, recC and ruvB. Consistent withthese findings, the ygbT deletion strain showedincreased sensitivity to DNA damage andimpaired chromosomal segregation. Similar", "metadata": {}}
+{"_id": "30041340", "title": "", "text": "Antibodies from patients with rheumatoidarthritis target citrullinated histone 4 containedin neutrophils extracellular traps.BACKGROUNDHistone deimination regulates gene function andcontributes to antimicrobial response, allowingthe formation of neutrophil extracellular traps(NETs). Deiminated proteins are target ofanti-citrullinated peptides antibodies (ACPA) inrheumatoid arthritis (RA). OBJECTIVE Theobjective of this paper is to test the hypothesisthat RA sera react with deiminated histonescontained in NETs. METHODS Neutrophils fromperipheral blood were stimulated with A23187and acid treated; NETosis was induced byphorbol myristate acetate, and NET proteinswere isolated. Sera were tested by immunobloton acid extracted proteins from neutrophils andfrom NETs, and by ELISA on deiminated histoneH4 or H4-derived peptides. Bands reactive withRA sera were excised from gels, digested withtrypsin and subjected to matrix-assisted laserdesorption/ionisation time of flight (MALDI-TOF)", "metadata": {}}
+{"_id": "30041895", "title": "", "text": "Mechanosensitive ion channel Piezo2 is importantfor enterochromaffin cell response to mechanicalforcesKEY POINTS The gastrointestinal epithelialenterochromaffin (EC) cell synthesizes the vastmajority of the body's serotonin. As a specializedmechanosensor, the EC cell releases thisserotonin in response to mechanical forces.However, the molecular mechanism of EC cellmechanotransduction is unknown. In the presentstudy, we show, for the first time, that themechanosensitive ion channel Piezo2 isspecifically expressed by the human and mouseEC cells. Activation of Piezo2 by mechanicalforces results in a characteristic ionic current, therelease of serotonin and stimulation ofgastrointestinal secretion. Piezo2 inhibition bydrugs or molecular knockdown decreasesmechanosensitive currents, serotonin releaseand downstream physiological effects. Theresults of the present study suggest that themechanosensitive ion channel Piezo2 isspecifically expressed by the EC cells of the", "metadata": {}}
+{"_id": "30058568", "title": "", "text": "Improved prognosis of thoracic aorticaneurysms: a population-based study.CONTEXTManaging thoracic aortic aneurysms identifiedincidentally by increased use of computedtomography, echocardiography, and magneticresonance imaging is problematic, especially inthe elderly. OBJECTIVE To ascertain whether thepreviously reported poor prognosis forindividuals with thoracic aortic aneurysms haschanged with better medical therapies andimproved surgical techniques that can now beapplied to aneurysm management. DESIGNPopulation-based cohort study. SETTING ANDPATIENTS All 133 patients with the diagnosis ofdegenerative thoracic aortic aneurysms amongOlmsted County, Minnesota, residents between1980 and 1994 compared with a previouslyreported cohort of similar patients between 1951and 1980. MAIN OUTCOME MEASURES Theprimary clinical end points were incidence,cumulative rupture risk, rupture risk as afunction of aneurysm size, and survival.", "metadata": {}}
+{"_id": "30101891", "title": "", "text": "Intravenous valproate is well tolerated inunstable patients with status epilepticus.Theauthors reviewed hospital records of 13 patientswith status epilepticus and hypotension whoreceived IV valproate therapy. Most patientswere elderly (74.4 +/- 12.5 [SD] years) andreceived a loading dose of valproate of 25.1 +/-5.0 mg/kg (range 14.7 to 32.7), at a rate of 36.6+/- 25.1 mg/min (range 6.3 to 100). There wereno significant changes in blood pressure, pulse,or use of vasopressors. The data suggest thatvalproate loading is well tolerated, even inpatients with cardiovascular instability.", "metadata": {}}
+{"_id": "30122260", "title": "", "text": "Interplays between ATM/Tel1 and ATR/Mec1 insensing and signaling DNA double-strandbreaks.DNA double-strand breaks (DSBs) arehighly hazardous for genome integrity becausethey have the potential to cause mutations,chromosomal rearrangements and genomicinstability. The cellular response to DSBs isorchestrated by signal transduction pathways,known as DNA damage checkpoints, which areconserved from yeasts to humans. Thesepathways can sense DNA damage and transducethis information to specific cellular targets, whichin turn regulate cell cycle transitions and DNArepair. The mammalian protein kinases ATM andATR, as well as their budding yeastcorresponding orthologs Tel1 and Mec1, act asmaster regulators of the checkpoint response toDSBs. Here, we review the early steps of DSBprocessing and the role of DNA-end structures inactivating ATM/Tel1 and ATR/Mec1 in an orderlyand reciprocal manner.", "metadata": {}}
+{"_id": "30152134", "title": "", "text": "The ‘definitive’ (and ‘primitive’) guide tozebrafish hematopoiesisProgressive advancesusing zebrafish as a model organism haveprovided hematologists with an additionalgenetic system to study blood cell formation andhematological malignancies. Despite extensiveevolutionary divergence between bony fish(teleosts) and mammals, the molecularpathways governing hematopoiesis have beenhighly conserved. As a result, most (if not all) ofthe critical hematopoietic transcription factorgenes identified in mammals have orthologues inzebrafish. As in other vertebrates, all of theteleost blood lineages are believed to originatefrom a pool of pluripotent, self-renewinghematopoietic stem cells. Here, we provide adetailed review of the timing, anatomicallocation, and transcriptional regulation ofzebrafish ‘primitive’ and ‘definitive’hematopoiesis as well as discuss a model ofT-cell leukemia and recent advances in blood celltransplantation. Given that many of the", "metadata": {}}
+{"_id": "30184745", "title": "", "text": "Steroid receptor interactions with heat shockprotein and immunophilin chaperones.We haveprovided a historical perspective on a body ofsteroid receptor research dealing with thestructure and physiological significance of theuntransformed 9S receptor that has oftenconfused both novice and expert investigators.The frequent controversies and equivocations ofearlier studies were due to the fact that thenative, hormone-free state of these receptors isa large multiprotein complex that resisteddescription for many years because of itsunstable and dynamic nature. Theuntransformed 9S state of the steroid and dioxinreceptors has provided a unique system forstudying the function of the ubiquitous,abundant, and conserved heat shock protein,hsp90. The hormonal control of receptorassociation with hsp90 provided a method ofmanipulating the receptor heterocomplex in amanner that was physiologically meaningful. Forseveral steroid receptors, binding to hsp90 was", "metadata": {}}
+{"_id": "30208015", "title": "", "text": "Molecular Characterization of Oxysterol Bindingto the Epstein-Barr Virus-induced Gene 2(GPR183)*Oxysterols are oxygenated cholesterolderivates that are emerging as a physiologicallyimportant group of molecules. Although theyregulate a range of cellular processes, only fewoxysterol-binding effector proteins have beenidentified, and the knowledge of their bindingmode is limited. Recently, the family of Gprotein-coupled seven transmembrane-spanningreceptors (7TM receptors) was added to thisgroup. Specifically, the Epstein-Barrvirus-induced gene 2 (EBI2 or GPR183) wasshown to be activated by several oxysterols,most potently by 7α,25-dihydroxycholesterol(7α,25-OHC). Nothing is known about thebinding mode, however. Using mutationalanalysis, we identify here four key residues for7α,25-OHC binding: Arg-87 in TM-II (positionII:20/2.60), Tyr-112 and Tyr-116 (positionsIII:09/3.33 and III:13/3.37) in TM-III, andTyr-260 in TM-VI (position VI:16/6.51).", "metadata": {}}
+{"_id": "30221601", "title": "", "text": "Up-regulation of neuronal calcium sensor-1(NCS-1) in the prefrontal cortex of schizophrenicand bipolar patients.The delineation of dopaminedysfunction in the mentally ill has been along-standing quest of biological psychiatry. Thepresent study focuses on a recently recognizedgroup of dopamine receptor-interacting proteinsas possible novel sites of dysfunction inschizophrenic and bipolar patients. Wedemonstrate that the dorsolateral prefrontalcortex in schizophrenia and bipolar cases fromthe Stanley Foundation NeuropathologyConsortium display significantly elevated levelsof the D2 dopamine receptor desensitizationregulatory protein, neuronal calcium sensor-1.These levels of neuronal calcium sensor-1 werenot influenced by age, gender, hemisphere,cause of death, postmortem period, alcoholconsumption, or antipsychotic and moodstabilizing medications. The present studysupports the hypothesis that schizophrenia andbipolar disorder may be associated with", "metadata": {}}
+{"_id": "30224907", "title": "", "text": "c-Abl: activation and nuclear targetsThe c-Abltyrosine kinase and its transforming variantshave been implicated in tumorigenesis and inmany important cellular processes. c-Abl islocalized in the nucleus and the cytoplasm,where it plays distinct roles. The effects of c-Ablare mediated by multiple protein-protein andprotein-DNA interactions and its tyrosine kinasedomain. At the biochemical level, the mechanismof c-Abl kinase activation and the identification ofits target proteins and cellular machineries havein part been solved. However, the phenotypicoutcomes of these molecular events remained inlarge elusive. c-Abl has been shown to regulatethe cell cycle and to induce under certainconditions cell growth arrest and apoptosis. Inthis respect the interaction of c-Abl with p53 andp73 has attracted particular attention. Recentfindings have implicated c-Abl in an ionizingirradiation signaling pathway that elicitsapoptosis. In this pathway p73 is an importantimmediate downstream effector. Here I review", "metadata": {}}
+{"_id": "30226988", "title": "", "text": "Cancer survival increases in Europe, butinternational differences remain wide.TheEUROCARE project analysed cancer survival datafrom 45 population-based cancer registries in 17European countries, revealing wide internationaldifferences in cancer survival. We calculated5-year relative survival for 1836287 patientsdiagnosed with one of 13 cancers during theperiod 1978-1989. The data, from 20 cancerregistries in 13 countries, were grouped into fourregions: Finland, Sweden, Iceland (NorthernEurope); Denmark, England and Scotland (UKand Denmark); France, The Netherlands,Germany, Italy and Switzerland (WesternEurope); Estonia and Poland (Eastern Europe),and broken down into four periods (1978-1980,1981-1983, 1984-1986, 1987-1989). For eachcancer, mean European and regional survivalwas estimated as the weighted mean of 5-yearrelative survival in each country. Survivalincreased with time for all tumours, particularlyfor cancers of testis (12% increase, i.e. from", "metadata": {}}
+{"_id": "30261663", "title": "", "text": "A nuclear translation-like factor eIF4AIII isrecruited to the mRNA during splicing andfunctions in nonsense-mediated decay.Ineukaryotes, a surveillance mechanism known asnonsense-mediated decay (NMD) degrades themRNA when a premature-termination codon(PTC) is present. NMD requires translation toread the frame of the mRNA and detect the PTC.During pre-mRNA splicing, the exon-exonjunction complex (EJC) is recruited to a region20-24 nt upstream of the exon junction on themature mRNA. The presence of a PTC upstreamfrom the EJC elicits NMD. Eukaryotic initiationfactor 4A (eIF4A) III is a nuclear protein thatinteracts physically or functionally withtranslation initiation factors eIF4G and eIF4B,respectively, and shares strikingly high identitywith the initiation factors eIF4AI/II. Here weshow that siRNA against eIF4AIII, but notagainst eIF4AI/II, inhibits NMD. Moreover,eIF4AIII, but not eIF4AI, is specifically recruitedto the EJC during splicing. The observations that", "metadata": {}}
+{"_id": "30292811", "title": "", "text": "Swaddling: a systematic review.Swaddling wasan almost universal child-care practice before the18th century. It is still tradition in certain partsof the Middle East and is gaining popularity in theUnited Kingdom, the United States, and TheNetherlands to curb excessive crying. We havesystematically reviewed all articles on swaddlingto evaluate its possible benefits anddisadvantages. In general, swaddled infantsarouse less and sleep longer. Preterm infantshave shown improved neuromusculardevelopment, less physiologic distress, bettermotor organization, and more self-regulatoryability when they are swaddled. When comparedwith massage, excessively crying infants criedless when swaddled, and swaddling can soothepain in infants. It is supportive in cases ofneonatal abstinence syndrome and infants withneonatal cerebral lesions. It can be helpful inregulating temperature but can also causehyperthermia when misapplied. Another possibleadverse effect is an increased risk of the", "metadata": {}}
+{"_id": "30297355", "title": "", "text": "Expression of the Norrie disease gene (Ndp) indeveloping and adult mouse eye, ear, andbrain.The Norrie disease gene (Ndp) codes for asecreted protein, Norrin, that activates canonicalWnt signaling by binding to its receptor,Frizzled-4. This signaling system is required fornormal vascular development in the retina andfor vascular survival in the cochlea. In mammals,the pattern of Ndp expression beyond the retinais poorly defined due to the low abundance ofNorrin mRNA and protein. Here, we characterizeNdp expression during mouse development bystudying a knock-in mouse that carries thecoding sequence of human placental alkalinephosphatase (AP) inserted at the Ndp locus(Ndp(AP)). In the CNS, Ndp(AP) expression isapparent by E10.5 and is dynamic and complex.The anatomically delimited regions of Ndp(AP)expression observed prenatally in the CNS arereplaced postnatally by widespread expression inastrocytes in the forebrain and midbrain,Bergman glia in the cerebellum, and Müller glia", "metadata": {}}
+{"_id": "30303335", "title": "", "text": "Control of NFAT Isoform Activation andNFAT-Dependent Gene Expression through TwoCoincident and Spatially Segregated IntracellularCa2+ SignalsExcitation-transcription coupling,linking stimulation at the cell surface to changesin nuclear gene expression, is conservedthroughout eukaryotes. How closely relatedcoexpressed transcription factors aredifferentially activated remains unclear. Here, weshow that two Ca2+-dependent transcriptionfactor isoforms, NFAT1 and NFAT4, requiredistinct sub-cellular InsP3 and Ca2+ signals forphysiologically sustained activation. NFAT1 isstimulated by sub-plasmalemmal Ca2+microdomains, whereas NFAT4 additionallyrequires Ca2+ mobilization from the innernuclear envelope by nuclear InsP3 receptors.NFAT1 is rephosphorylated (deactivated) moreslowly than NFAT4 in both cytoplasm andnucleus, enabling a more prolonged activationphase. Oscillations in cytoplasmic Ca2+, longconsidered the physiological form of Ca2+", "metadata": {}}
+{"_id": "30351165", "title": "", "text": "Brain region-specific up-regulation of mouseapolipoprotein E by pharmacological estrogentreatments.Cerebral apolipoprotein E (apoE) hasbeen implicated in neuronal protection andrepair. Due to the variable levels and types ofestrogen receptors within different brain regions,the effect of estrogen on apoE and themechanism of this effect may vary withindifferent regions. Ovariectomized femaleC57BL/6 mice were treated with pharmacologicallevels of 17 beta-estradiol or placebo for 5 days,resulting in supraphysiological plasma levels ofestradiol in the treated mice. ApoE and glialfibrillary acidic protein (GFAP) levels weremeasured in the cortex, hippocampus anddiencephalon. 17 beta-Estradiol up-regulatedapoE but not GFAP in the cortex anddiencephalon, whereas in the hippocampus,GFAP and apoE were equally up-regulated.Treatment of estrogen receptor (ER) alphaknockout mice with 17 beta-estradiol ortreatment of C57BL/6 mice with 17", "metadata": {}}
+{"_id": "30353437", "title": "", "text": "ATM and ataxia telangiectasia.Ataxiatelangiectasia (AT) has long intrigued thebiomedical research community owing to thespectrum of defects that are characteristic of thedisease, including neurodegeneration, immunedysfunction, radiosensitivity and cancerpredisposition. Following the identification ofmutations in ATM (ataxia telangiectasia,mutated) as the underlying cause of the disease,biochemical analysis of this protein kinase hasshown that it is a crucial nexus for the cellularresponse to DNA double-stranded breaks. ManyATM kinase substrates are important players inthe cellular responses that prevent cancer.Accordingly, AT is a disease that results fromdefects in the response to specific types of DNAdamage. Thus, although it is a rareneurodegenerative disease, understanding thebiology of AT will lead to a greater understandingof the fundamental processes that underpincancer and neurodegeneration.", "metadata": {}}
+{"_id": "30369606", "title": "", "text": "A novel immortalized human endometrial stromalcell line with normal progestationalresponse.Obtaining primary human endometrialstromal cells (HESCs) for in vitro studies islimited by the scarcity of adequate humanmaterial and the inability to passage these cellsin culture for long periods. Immortalization ofthese cells would greatly facilitate studies;however, the process of immortalization oftenresults in abnormal karyotypes and aberrantfunctional characteristics. To meet this need, wehave introduced telomerase into cultured HESCsto prevent the normal shortening of telomeresobserved in adult somatic cells during mitosis.We have now developed and analyzed a newlyimmortalized HESC line that contains no clonalchromosomal structural or numericalabnormalities. In addition, when compared withthe primary unpassaged parent cells, the newcell line displayed similar biochemical endpointsafter treatment with ovarian steroids. Classicaldecidualization response to estradiol plus", "metadata": {}}
+{"_id": "30379039", "title": "", "text": "Comparison of the intrinsic kinase activity andsubstrate specificity of c-Abl and Bcr-Abl.Westudied the intrinsic tyrosine kinase activity andsubstrate specificity of c-Abl and Bcr-Abl proteintyrosine kinases (PTKs) using the peptidesubstrates discovered from a syntheticcombinatorial peptide library. Our data indicatethat the phosphorylation of these peptides byBcr-Abl was consistently stronger than that byc-Abl. Bcr-Abl also showed substrate preferencetowards those peptides with one or more positivecharges.", "metadata": {}}
+{"_id": "30398773", "title": "", "text": "Strong association between respiratory viralinfection early after hematopoietic stem celltransplantation and the development oflife-threatening acute and chronic alloimmunelung syndromes.Alloimmune lung syndromes(allo-LS), including idiopathic pneumoniasyndrome, bronchiolitis obliterans syndrome, andbronchiolitis obliterans organizing pneumonia,are severe complications after hematopoieticstem cell transplantation (HSCT). In our cohortof 110 pediatric patients, 30 had allo-LS(27.3%), 18 with idiopathic pneumoniasyndrome and 12 with bronchiolitis obliteranssyndrome. Multivariate analysis showed thatrespiratory viral infection early after HSCT is animportant predictor for the development ofallo-LS (P <.0001). This was true for all virusestested. In multivariate analysis, allo-LS was theonly predictor for higher mortality (P = .04).Paradoxically, prolonged administration ofimmunosuppressive agents because of acutegraft-versus-host disease had a protective effect", "metadata": {}}
+{"_id": "30437264", "title": "", "text": "Hepatitis C virus blocks interferon effectorfunction by inducing protein kinase Rphosphorylation.Hepatitis C virus (HCV) is asingle-stranded RNA virus encoding a singlepolyprotein whose translation is driven by aninternal ribosome entry site (IRES). HCVinfection strongly induces antiviralinterferon-stimulated gene (ISG) expression inthe liver, yet it persists, suggesting that HCV canblock ISG effector function. We now show thatHCV infection triggers phosphorylation andactivation of the RNA-dependent protein kinasePKR, which inhibits eukaryotic translationinitiation factor eIF2 alpha and attenuates ISGprotein expression despite normal ISG mRNAinduction. ISG protein induction is restored andthe antiviral effects of interferon are enhancedwhen PKR expression is suppressed ininterferon-treated infected cells. Whereas hostprotein translation, including antiviral ISGs, issuppressed by activated PKR, HCVIRES-dependent translation is not. These results", "metadata": {}}
+{"_id": "30464859", "title": "", "text": "The influence of denervation on grafted hindlimbregeneration of larval Xenopus laevis.The aim ofthe present research is to ascertain whether inlarval Xenopus laevis nerve-independence for theregeneration of early stage limbs andnerve-dependence of late stage limbs observedin a previous work (Filoni and Paglialunga, '90) isrelated to extrinsic (systemic) factors or tointrinsic changes taking place in the limb cellsthemselves during development. In this paperthe regenerative capacity of early and late stagehindlimbs under the same extrinsic conditions,insofar as both are grafted onto the denervatedhindlimbs of host larvae at the samedevelopmental stage, is studied. All the graftedlimbs are amputated after the host larvae havereached stage 57-58 (according to Nieuwkoopand Faber, '56). In experiment I, the graftedlimb is amputated at stage 52, at the thigh level;in experiment II, the grafted limb is amputatedat stage 54-55, at the tarsalia level; inexperiment III the grafted limb is amputated at", "metadata": {}}
+{"_id": "30468386", "title": "", "text": "Adult c-Kit(+) progenitor cells are necessary formaintenance and regeneration of olfactoryneurons.The olfactory epithelium houseschemosensory neurons, which transmit odorinformation from the nose to the brain. In adultmammals, the olfactory epithelium is a uniquelyrobust neuroproliferative zone, with the ability toreplenish its neuronal and non-neuronalpopulations due to the presence of germinalbasal cells. The stem and progenitor cells ofthese germinal layers, and their regulatorymechanisms, remain incompletely defined. Herewe show that progenitor cells expressing c-Kit, areceptor tyrosine kinase marking stem cells in avariety of embryonic tissues, are required formaintenance of the adult neuroepithelium.Mouse genetic fate-mapping analyses show thatembryonically, a c-Kit(+) population contributesto olfactory neurogenesis. In adults underconditions of normal turnover, there is relativelysparse c-Kit(+) progenitor cell (ckPC) activity.However, after experimentally induced", "metadata": {}}
+{"_id": "30471052", "title": "", "text": "Neurogenin3: a master regulator of pancreaticislet differentiation and regeneration.The basichelix-loop-helix transcription factor neurogenin-3(Ngn3, Neurog3) is critical for the developmentof the endocrine cells of the islets. Eitherdisrupted or forced expression of Ngn3 early inmouse pancreas development abrogates theformation of islets. The successive waves ofNgn3 expression that occur during the primaryand secondary transitions of endocrine celldevelopment temporally determine the fourdistinct endocrine cell lineages, α, β, PP, and δcells that express glucagon, insulin, pancreaticpolypeptide, and somatostatin, respectively.During islet regeneration after injury of the adultmouse pancreas, such as by duct ligation orstreptozotocin, Ngn3 is activated induct-associated stem/progenitor cells thattransform into alpha and/or beta cells (Xu et al,Collombat et al). The important role of Ngn3 as amaster regulator of endocrine pancreasdevelopment directs attention to finding", "metadata": {}}
+{"_id": "30492966", "title": "", "text": "Detection of Mycoplasmas in Patients withAmyotrophic Lateral SclerosisAmyotrophicLateral Sclerosis (ALS) is a progressivedegenerative  disease of the motor neurons andthe cause is unknown. Diverse factors suchas  genetic defects, nutritional deficiencies, headtrauma, environmental toxin,  autoimmuneresponses and viral and bacterial infections areinvolved. Mycoplasmas  have been implicated ascausal agents of different illnesses in human.The  purpose of this study was to investigate thepresence of mycoplasmas in  the bloodstream ofpatients with ALS. Patients with ALS and healthyindividuals  were included in the study. A bloodsample was taken in tubes with orwithout  anticoagulant. Mycoplasmas weredetected by culture or direct PCR, andthe  presence of antibodies IgM and IgG againstLAMPs of these microorganisms by  Westernblot. Cultures for aerobic facultative bacteriawere also done. Blood samples  from 13 patientsand 44 healthy individuals were screened. All", "metadata": {}}
+{"_id": "30500829", "title": "", "text": "Correlation and variable importance in randomforestsThis paper is about variable selection withthe random forests algorithm in presence ofcorrelated predictors. In high-dimensionalregression or classification frameworks, variableselection is a difficult task, that becomes evenmore challenging in the presence of highlycorrelated predictors. Firstly we provide atheoretical study of the permutation importancemeasure for an additive regression model. Thisallows us to describe how the correlationbetween predictors impacts the permutationimportance. Our results motivate the use of theRecursive Feature Elimination (RFE) algorithmfor variable selection in this context. Thisalgorithm recursively eliminates the variablesusing permutation importance measure as aranking criterion. Next various simulationexperiments illustrate the efficiency of the RFEalgorithm for selecting a small number ofvariables together with a good prediction error.Finally, this selection algorithm is tested on the", "metadata": {}}
+{"_id": "30507607", "title": "", "text": "An Oct4-Centered Protein Interaction Network inEmbryonic Stem CellsTranscription factors, suchas Oct4, are critical for establishing andmaintaining pluripotent cell identity. Whereas thegenomic locations of several pluripotencytranscription factors have been reported, thespectrum of their interaction partners isunderexplored. Here, we use an improvedaffinity protocol to purify Oct4-interactingproteins from mouse embryonic stem cells(ESCs). Subsequent purification of Oct4 partnersSall4, Tcfcp2l1, Dax1, and Esrrb resulted in anOct4 interactome of 166 proteins, includingtranscription factors and chromatin-modifyingcomplexes with documented roles inself-renewal, but also many factors notpreviously associated with the ESC network. Wefind that Esrrb associated with the basaltranscription machinery and also detectinteractions between transcription factors andcomponents of the TGF-beta, Notch, and Wntsignaling pathways. Acute depletion of Oct4", "metadata": {}}
+{"_id": "30534237", "title": "", "text": "GABA(B) receptor 1 polymorphism (G1465A) isassociated with temporal lobeepilepsy.BACKGROUND Dysfunction ofgamma-aminobutyric acid (GABA) (B) receptorshas been implicated in the pathogenesis oftemporal lobe epilepsy (TLE). OBJECTIVE Toevaluate the genetic contribution of clonedhuman GABA(B) receptors to TLE. METHODS Theauthors genotyped 141 patients (78 women and63 men; mean age = 49.1 +/- 18.0 years) withnonlesional TLE and 372 age- and sex-matchednormal individuals for the known polymorphismG1465A in the human GABA(B) receptor 1[GABA(B[1])] gene. RESULTS There was a highlysignificant overrepresentation of the G1465Aheterozygote in patients with TLE compared withcontrols. The A/G genotype was found in 17% ofthe 141 patients with TLE and in only 0.5% ofthe 372 controls (p < 0.0001). The authors alsofound that patients carrying the A allele had asignificantly higher risk (p = 0.003, OR = 6.47,95% CI = 2.02 to 20.76) of developing", "metadata": {}}
+{"_id": "30543439", "title": "", "text": "Crystal structure, biochemical and cellularactivities demonstrate separate functions ofMTH1 and MTH2Deregulated redox metabolismin cancer leads to oxidative damage to cellularcomponents including deoxyribonucleosidetriphosphates (dNTPs). Targeting dNTP poolsanitizing enzymes, such as MTH1, is a highlypromising anticancer strategy. The MTH2protein, known as NUDT15, is described as thesecond human homologue of bacterial MutT with8-oxo-dGTPase activity. We present the firstNUDT15 crystal structure and demonstrate thatNUDT15 prefers other nucleotide substrates over8-oxo-dGTP. Key structural features areidentified that explain different substratepreferences for NUDT15 and MTH1. We find thatdepletion of NUDT15 has no effect onincorporation of 8-oxo-dGTP into DNA and doesnot impact cancer cell survival in cell linestested. NUDT17 and NUDT18 were also profiledand found to have far less activity than MTH1against oxidized nucleotides. We show that", "metadata": {}}
+{"_id": "30553457", "title": "", "text": "De novo expression of Trpm4 initiates secondaryhemorrhage in spinal cord injuryThe role oftransient receptor potential M4 (Trpm4), anunusual member of the Trp family of ionchannels, is poorly understood. Using rodentmodels of spinal cord injury, we studiedinvolvement of Trpm4 in the progressiveexpansion of secondary hemorrhage associatedwith capillary fragmentation, the mostdestructive mechanism of secondary injury in thecentral nervous system. Trpm4 mRNA andprotein were abundantly upregulated incapillaries preceding their fragmentation andformation of petechial hemorrhages. Trpm4expression in vitro rendered COS-7 cells highlysusceptible to oncotic swelling and oncotic deathfollowing ATP depletion. After spinal cord injury,in vivo gene suppression in rats treated withTrpm4 antisense or in Trpm4−/− mice preservedcapillary structural integrity, eliminatedsecondary hemorrhage, yielded a threefold tofivefold reduction in lesion volume and produced", "metadata": {}}
+{"_id": "30580263", "title": "", "text": "Differential expression of bcl-2 in intestinalepithelia. Correlation with attenuation ofapoptosis in colonic crypts and the incidence ofcolonic neoplasia.The cell-positional incidence ofboth spontaneous and damage-inducedapoptosis of epithelial cells was assessed inlongitudinal sections of the crypts of smallintestine and colon of BDF1 mice. This wascompared, using immunohistochemistry, withthe pattern of expression of bcl-2, a suppressorof apoptosis. In the small intestine, apoptosiswas maximal around cell position 4 from thebase of the crypt; this closely corresponds to theposition considered to contain the stem cells. Inthe colon, however, apoptosis was not confinedto the area considered to harbour the stem cells(position 1 and 2). Instead, apoptosis wasattenuated and distributed along the length ofthe crypt. Some cells at the base of murinecolonic crypts expressed bcl-2 protein, whereasbcl-2 was absent in the crypts of the smallintestine. Most pertinently, bcl-2 was absent", "metadata": {}}
+{"_id": "30639847", "title": "", "text": "Aortic stiffness, blood pressure progression, andincident hypertension.CONTEXT Vascularstiffness increases with advancing age and is amajor risk factor for age-related morbidity andmortality. Vascular stiffness and blood pressurepulsatility are related; however, temporalrelationships between vascular stiffening andblood pressure elevation have not been fullydelineated. OBJECTIVE To examine temporalrelationships among vascular stiffness, centralhemodynamics, microvascular function, andblood pressure progression. DESIGN, SETTING,AND PARTICIPANTS Longitudinalcommunity-based cohort study conducted inFramingham, Massachusetts. The presentinvestigation is based on the 2 latestexamination cycles (cycle 7: 1998-2001; cycle 8:2005-2008 [last visit: January 25, 2008]) of theFramingham Offspring study (recruited:1971-1975). Temporal relationships amongblood pressure and 3 measures of vascularstiffness and pressure pulsatility derived from", "metadata": {}}
+{"_id": "30655442", "title": "", "text": "The EMBL nucleotide sequence database.TheEMBL Nucleotide Sequence Database(http://www.ebi.ac.uk/embl. html ) constitutesEurope's primary nucleotide sequence resource.DNA and RNA sequences are directly submittedfrom researchers and genome sequencing groupsand collected from the scientific literature andpatent applications (Fig. 1). In collaboration withDDBJ and GenBank the database is produced,maintained and distributed at the EuropeanBioinformatics Institute. Database releases areproduced quarterly and are distributed onCD-ROM. EBI's network services allow access tothe most up-to-date data collection via Internetand World Wide Web interface, providingdatabase searching and sequence similarityfacilities plus access to a large number ofadditional databases.", "metadata": {}}
+{"_id": "30658796", "title": "", "text": "Anaphase catastrophe is a target for cancertherapy.Neoplastic cells are genetically unstable.Strategies that target pathways affectinggenome instability can be exploited to disrupttumor cell growth, potentially with limitedconsequences to normal cells. Chromosomalinstability (CIN) is one type of genome instabilitycharacterized by mitotic defects that increase therate of chromosome mis-segregation. CIN isfrequently caused by extra centrosomes thattransiently disrupt normal bipolar spindlegeometry needed for accurate chromosomesegregation. Tumor cells survive with extracentrosomes because of biochemical pathwaysthat cluster centrosomes and promotechromosome segregation on bipolar spindles.Recent work shows that targeted inhibition ofthese pathways prevents centrosome clusteringand forces chromosomes to segregate to multipledaughter cells, an event triggering apoptosis thatwe refer to as anaphase catastrophe. Anaphasecatastrophe specifically kills tumor cells with", "metadata": {}}
+{"_id": "30675656", "title": "", "text": "Dishevelled Activates JNK and Discriminatesbetween JNK Pathways in Planar Polarity andwingless SignalingFrizzled family proteins havebeen described as receptors of Wnt signalingmolecules. In Drosophila, the two known Frizzledproteins are associated with distinctdevelopmental processes. Genesis of epithelialplanar polarity requires Frizzled, whereas Dfz2affects morphogenesis by wingless-mediatedsignaling. Dishevelled is required in bothsignaling pathways. Here, we use genetic andoverexpression assays to show that Dishevelledactivates JNK cascades. Rescue analysis revealsdifferent protein domain requirements inDishevelled for the two pathways; the C-terminalDEP domain is essential to rescue planar polaritydefects and induce JNK signaling. Furthermore,the planar polarity-specific dsh1 allele is mutatedin the DEP domain. Our results indicate thatdifferent Wnt/Fz signals activate distinctintracellular pathways, and Dishevelleddiscriminates among them by distinct domain", "metadata": {}}
+{"_id": "30714190", "title": "", "text": "Genome-wide lineage-specific transcriptionalnetworks underscore Ikaros-dependent lymphoidpriming in hematopoietic stem cells.Themechanisms regulating lineage potential duringearly hematopoiesis were investigated. First, acascade of lineage-affiliated gene expressionsignatures, primed in hematopoietic stem cells(HSCs) and differentially propagated inlineage-restricted progenitors, was identified.Lymphoid transcripts were primed as early as theHSC, together with myeloid and erythroidtranscripts. Although this multilineage primingwas resolved upon subsequent lineagerestrictions, an unexpected cosegregation oflymphoid and myeloid gene expression andpotential past a nominal myeloid restriction pointwas identified. Finally, we demonstrated thatwhereas the zinc finger DNA-binding factorIkaros was required for induction of lymphoidlineage priming in the HSC, it was also necessaryfor repression of genetic programs compatiblewith self-renewal and multipotency downstream", "metadata": {}}
+{"_id": "30720103", "title": "", "text": "Vitamin D status: measurement, interpretation,and clinical application.Vitamin D, the sunshinevitamin, is now recognized not only for itsimportance in promoting bone health in childrenand adults but also for other health benefits,including reducing the risk of chronic diseasessuch as autoimmune diseases, common cancer,and cardiovascular disease. Vitamin D made inthe skin or ingested in the diet is biologicallyinert and requires 2 successive hydroxylationsfirst in the liver on carbon 25 to form25-hydroxyvitamin D [25(OH)D], and then in thekidney for a hydroxylation on carbon 1 to formthe biologically active form of vitamin D,1,25-dihydroxyvitamin D [1,25(OH)(2)D]. Withthe identification of 25(OH)D and 1,25(OH)(2)D,methods were developed to measure thesemetabolites in the circulation. Serum 25(OH)D isthe barometer for vitamin D status. Serum1,25(OH)(2)D provides no information aboutvitamin D status and is often normal or evenincreased as the result of secondary", "metadata": {}}
+{"_id": "30741007", "title": "", "text": "Lessons from the past: managing insecticideresistance in malaria control and eradicationprogrammes.The distribution ofinsecticide-treated bednets to help combat theburden of malaria in sub-Saharan Africa hasaccelerated in the past 5 years. Additionally,many countries are also considering, or havealready begun, indoor residual sprayingcampaigns. These are positive developments,since vector control has repeatedly proven to bean effective means of reducing malariatransmission. However, the sustainability ofthese insecticide-based interventions relies onthe continuing susceptibility of the anophelesvectors to the limited number of availableinsecticides. Continual monitoring for early signsof insecticide resistance and the adoption ofcarefully considered resistance managementstrategies are therefore required. Regrettably,this essential monitoring component is frequentlygiven a low priority in the push to meetambitious coverage targets. We outline the key", "metadata": {}}
+{"_id": "30774694", "title": "", "text": "T helper 2 cytokines inhibit autophagic control ofintracellular Mycobacteriumtuberculosis.Autophagy is a recently recognizedimmune effector mechanism against intracellularpathogens. The role of autophagy in innateimmunity has been well established, but theextent of its regulation by the adaptive immuneresponse is less well understood. The T helper 1(Th1) cell cytokine IFN-gamma inducesautophagy in macrophages to eliminateMycobacterium tuberculosis. Here, we reportthat Th2 cytokines affect autophagy inmacrophages and their ability to controlintracellular M. tuberculosis. IL-4 and IL-13abrogated autophagy and autophagy-mediatedkilling of intracellular mycobacteria in murine andhuman macrophages. Inhibition ofstarvation-induced autophagy by IL-4 and IL-13was dependent on Akt signaling, whereas theinhibition of IFN-gamma-induced autophagy wasAkt independent and signal transducer andactivator of transcription 6 (STAT6) dependent.", "metadata": {}}
+{"_id": "30786800", "title": "", "text": "Lipid-based nutrient supplement increases thebirth size of infants of primiparous women inGhana.BACKGROUND The InternationalLipid-Based Nutrient Supplements Projectdeveloped a small-quantity (20 g/d) lipid-basednutrient supplement (LNS) for pregnant andlactating women. OBJECTIVE We evaluated theeffects of prenatal LNS supplementation on fetalgrowth. DESIGN In a community-based, partiallydouble-blind, individually randomized controlledtrial, 1320 women ≤20 wk pregnant received 60mg Fe/400 μg folic acid (IFA), or 1-2Recommended Dietary Allowances of 18micronutrients, including 20 mg Fe (MMN), orLNS with the same micronutrients as the MMNgroup, plus 4 minerals and macronutrientscontributing 118 kcal (LNS) daily until delivery.Fetal growth was compared across groups byusing intention-to-treat analysis. The primaryoutcome was birth length. RESULTS This analysisincluded 1057 women (IFA = 349, MMN = 354,LNS = 354). Groups did not differ significantly in", "metadata": {}}
+{"_id": "30805636", "title": "", "text": "Peroxisome proliferator-activated receptor ligandbezafibrate for prevention of type 2 diabetesmellitus in patients with coronary arterydisease.BACKGROUND Recent studies haveshown that type 2 diabetes is preventable byboth lifestyle interventions and medications thatinfluence primary glucose metabolism. Whetherpharmacological interventions that influenceprimary lipid metabolism can also delaydevelopment of type 2 diabetes is unknown. Thegoal of this study was to evaluate the effect ofthe peroxisome proliferator-activated receptorligand bezafibrate on the progression of impairedfasting glucose phase to type 2 diabetes inpatients with coronary artery disease over a6.2-year follow-up period. METHODS ANDRESULTS The study sample comprised 303nondiabetic patients 42 to 74 years of age with afasting blood glucose level of 110 to 125 mg/dL(6.1 to 6.9 mmol/L). The patients received either400 mg bezafibrate retard (156 patients) orplacebo (147 patients) once a day. No patients", "metadata": {}}
+{"_id": "30813140", "title": "", "text": "Familial occurrence of chronic tension-typeheadache.Chronic tension-type headache (CTTH)assessed by proband report was evaluated in afamily study of CTTH. A clinical interview offirst-degree relatives by a physician was used asindex of validity. Familial occurrence of CTTH infirst-degree relatives was also investigated.Patterns of familial aggregation of CTTH wereassessed by calculating the population relativerisk. A neurological resident carried out all theinterviews of probands and their first-degreerelatives. The operational diagnostic criteria ofthe International Headache Society were used.The 122 probands had 377 first-degree relatives.Sensitivity, specificity, predictive values, andchance-corrected agreement rate for thediagnosis CTTH were 68%, 86%, 53% (PVpos),92% (PVneg), and 0.48, respectively. The lowsensitivity of CTTH assessed by proband reportindicates that a clinical interview by a physicianis necessary in family studies of CTTH. Clinicallyinterviewed parents, siblings, and children had a", "metadata": {}}
+{"_id": "30835854", "title": "", "text": "Complex formation of SMAP/KAP3, a KIF3A/BATPase motor-associated protein, with a humanchromosome-associated polypeptide.We haverecently isolated SMAP (Smg GDS-associatedprotein; Smg GDS: small G protein GDPdissociation stimulator) as a novel SmgGDS-associated protein, which has Armadillorepeats and is phosphorylated by Src tyrosinekinase. SMAP is a human counterpart of mouseKAP3 (kinesin superfamily-associated protein)that is associated with mouse KIF3A/B (a kinesinsuperfamily protein), which functions as amicrotubule-based ATPase motor for organelletransport. We isolated here a SMAP-interactingprotein from a human brain cDNA library,identified it to be a human homolog of XenopusXCAP-E (Xenopus chromosome-associatedpolypeptide), a subunit of condensins thatregulate the assembly and structuralmaintenance of mitotic chromosomes, andnamed it HCAP (Human chromosome-associatedpolypeptide). Tissue and subcellular distribution", "metadata": {}}
+{"_id": "30844602", "title": "", "text": "Surveillance for foodborne-diseaseoutbreaks--United States,1993-1997.PROBLEM/CONDITION Since 1973,CDC has maintained a collaborative surveillanceprogram for collection and periodic reporting ofdata on the occurrence and causes offoodborne-disease outbreaks (FBDOs) in theUnited States. REPORTING PERIOD COVEREDThis summary reviews data from January 1993through December 1997. DESCRIPTION OFSYSTEM The Foodborne-Disease OutbreakSurveillance System reviews data concerningFBDOs, defined as the occurrence of two or morecases of a similar illness resulting from theingestion of a common food. State and localpublic health departments have primaryresponsibility for identifying and investigatingFBDOs. State, local, and territorial healthdepartments use a standard form to report theseoutbreaks to CDC. RESULTS During 1993-1997,a total of 2,751 outbreaks of foodborne diseasewere reported (489 in 1993, 653 in 1994, 628 in", "metadata": {}}
+{"_id": "30861948", "title": "", "text": "Nuclear-cytoplasmic shuttling of C-ABL tyrosinekinase.The ubiquitously expressed nonreceptortyrosine kinase c-Abl contains three nuclearlocalization signals, however, it is found in boththe nucleus and the cytoplasm of proliferatingfibroblasts. A rapid and transient loss of c-Ablfrom the nucleus is observed upon the initialadhesion of fibroblasts onto a fibronectin matrix,suggesting the possibility of nuclear export[Lewis, J., Baskaran, R. , Taagepera, S.,Schwartz, M. & Wang, J. (1996) Proc. Natl. Acad.Sci. USA 93, 15174-15179]. Here we show thatthe C terminus of c-Abl does indeed contain afunctional nuclear export signal (NES) with thecharacteristic leucine-rich motif. The c-Abl NEScan functionally complement an NES-defectiveHIV Rev protein (RevDelta3NI) and can mediatethe nuclear export of glutathione-S-transferase.The c-Abl NES function is sensitive to the nuclearexport inhibitor leptomycin B. Mutation of asingle leucine (L1064A) in the c-Abl NESabrogates export function. The NES-mutated", "metadata": {}}
+{"_id": "30884033", "title": "", "text": "Regulation of embryonic stem cell pluripotencyby heat shock protein 90.Deciphering themolecular basis of stem cell pluripotency isfundamental to the understanding of stem cellbiology, early embryonic development, and tothe clinical application of regenerative medicine.We report here that the molecular chaperoneheat shock protein 90 (Hsp90) is essential formouse embryonic stem cell (ESC) pluripotencythrough regulating multiple pluripotency factors,including Oct4, Nanog, and signal transducer andactivator of transcription 3. Inhibition of Hsp90by either17-N-Allylamino-17-demethoxygeldanamycin ormiRNA led to ESC differentiation. Overexpressionof Hsp90β partially rescued the phenotype; inparticular, the levels of Oct4 and Nanog wererestored. Notably, Hsp90 associated with Oct4and Nanog in the same cellular complex andprotected them from degradation by theubiquitin proteasome pathway, suggesting thatOct4 and Nanog are potential novel Hsp90 client", "metadata": {}}
+{"_id": "30908508", "title": "", "text": "CD4+CD25+Foxp3+Regulatory T Cells ProtectEndothelial Function Impaired by Oxidized LowDensity Lipoprotein via the KLF-2 TranscriptionFactorObjective: To investigate the regulation ofCD4+CD25+ Regulatory T cells (Tregs) onpro-inflammatory adhesion molecules,Krüppel-Like Factor-2 (KLF-2) and itsdownstream transcriptional targets in humanumbilical vein endothelial cells (HUVECs)impaired by ox-LDL and the mechanisms of it.Methods and results: HUVECs were cultured inthe continuous presence of ox-LDL(0 mg/L,25mg/L,50 mg/L,100 mg/L) for 4, 6, 12 and 24hours to allow identification of early-andlate-induced genes, respectively, whereasnon-stimulated controls were taken at 0 hours.The expression of pro-inflammatory adhesionmolecules such as vascular cell adhesionmolecule-1 (VCAM-1), intracellular adhesionmolecule-1 (ICAM-1), E-selectin, KLF-2 and itstarget genes eNOS, PAI-1 were determined byreal time RT-PCR and/or western-blot analysis.", "metadata": {}}
+{"_id": "30915421", "title": "", "text": "Metformin Normalizes Type 2 Diabetes-InducedDecrease in Cell Proliferation and NeuroblastDifferentiation in the Rat Dentate GyrusIn thisstudy, we observed the effects of metformin, oneof the most widely prescribed drugs for thetreatment of type 2 diabetes, on cell proliferationand neuroblast differentiation in the subgranularzone of the hippocampal dentate gyrus (SZDG)in Zucker diabetic fatty (ZDF) rats, which are amodel for type 2 diabetes. For this, metforminwas administered orally once a day to14-week-old ZDF rats for 2 weeks and theanimals were sacrificed at 16 weeks of age.During this period, blood glucose levels werehigher in the vehicle-treated ZDF rats than in theZucker lean control (ZLC) rats. Metformintreatment significantly decreased the bloodglucose levels from 15.5 weeks of age. In theSZDG, Ki67 (a marker for cell proliferation)- anddoublecortin (DCX, a marker for differentiatedneuroblasts)-immunoreactive cells were muchlower in the vehicle-treated ZDF rats than in the", "metadata": {}}
+{"_id": "30919024", "title": "", "text": "Molecular mechanisms underlying tumordormancy.Evidence suggests that dormant,microscopic tumors are not only common, butare highly prevalent in otherwise healthyindividuals. Due to their small size andnon-invasive nature, these dormant tumorsremain asymptomatic and, in most cases,undetected. With advances in diagnostic imagingand molecular biology, it is now becoming clearthat such neoplasms can remain in anasymptomatic, dormant stage for considerableperiods of time without expanding in size.Although a number of processes may play a rolein thwarting the expansion of microscopictumors, one critical mechanism behind tumordormancy is the ability of the tumor populationto induce angiogenesis. Although cancer canarise through multiple pathways, it is assumedthat essentially most tumors begin asmicroscopic, non-angiogenic neoplasms whichcannot expand in size until vasculature isestablished. It is now becoming clear that cancer", "metadata": {}}
+{"_id": "30933307", "title": "", "text": "The myeloid transcription factor GATA-2regulates the viral UL144 gene during humancytomegalovirus latency in an isolate-specificmanner.It is generally accepted that, followingprimary infection, human cytomegalovirus(HCMV) establishes lifelong latency in CD34(+)progenitor cells and other derivative cells of themyeloid lineage. In this study, we show that theviral UL144 gene is expressed during latentinfection in two cell types of the myeloid lineage,CD34(+) and CD14(+) monocytes, and that theUL144 protein is functional in latently infectedmonocytes. However, this latency-associatedexpression of UL144 occurs only in certainisolates of HCMV and depends on the presence offunctional GATA-2 transcription factor bindingsites in the UL144 promoter, in contrast to theviral latency-associated gene LUNA, which wealso show is regulated by GATA-2 but expresseduniformly during latent infection independent ofthe virus isolate. Taken together, these datasuggest that the HCMV latency-associated", "metadata": {}}
+{"_id": "30981192", "title": "", "text": "How to control residual cardiovascular riskdespite statin treatment: focusing onHDL-cholesterol.Lowering low-densitylipoprotein-cholesterol (LDL-C) is the primarytarget in the management of dyslipidemia inpatients at high risk of cardiovascular disease.However, patients who have achieved LDL-Clevels below the currently recommended targetsmay still experience cardiovascular events. Thismay result, in part, from elevated triglyceride(TG) levels and low levels of high-densitylipoprotein-cholesterol (HDL-C). Low HDL-C andhigh TG levels are common and are recognizedas independent risk factors for cardiovascularmorbidity and mortality. Furthermore,atherogenic dyslipidemia, characterized by lowlevels of HDL-C, high TG, and small, dense LDLparticles, is a typical phenotype of dyslipidemiain subjects with insulin resistance and metabolicsyndrome. Therefore, to reduce further the riskof coronary heart disease (CHD), raising HDL-Cand lowering TG may be the secondary", "metadata": {}}
+{"_id": "30983338", "title": "", "text": "The prevalence of congenital malformations isstill higher in pregnant women withpregestational diabetes despite near-normalHbA1c: a literature review.AIMS/HYPOTHESISWe assessed the association between congenitalmalformations and maternal hyperglycemia inpregnant women with pregestational (type 1 ortype 2) diabetes and investigated if the rate ofcongenital malformations was similar in womenwith near-normal glycemic control compared tothe background population. We also assessed theassociation between congenital malformationsand maternal hyperglycemia in pregnant womenwith pregestational diabetes with special focuson women with near-normal HbA1c in earlypregnancy. MATERIALS AND METHODS This is aliterature review based on an electronic literaturesearch of the databases PubMed, Cochrane,Embase and Web of Science conducted in July2017 using the search terms diabetes,pregnancy, HbA1c or glycemic control andcongenital anomaly or congenital anomaly. We", "metadata": {}}
+{"_id": "31001322", "title": "", "text": "Local and systemic insulin resistance resultingfrom hepatic activation of IKK-beta andNF-kappaB.We show that NF-kappaB andtranscriptional targets are activated in liver byobesity and high-fat diet (HFD). We havematched this state of chronic, subacute'inflammation' by low-level activation ofNF-kappaB in the liver of transgenic mice,designated LIKK, by selectively expressingconstitutively active IKK-b in hepatocytes. Thesemice exhibit a type 2 diabetes phenotype,characterized by hyperglycemia, profoundhepatic insulin resistance, and moderatesystemic insulin resistance, including effects inmuscle. The hepatic production ofproinflammatory cytokines, including IL-6,IL-1beta and TNF-alpha, was increased in LIKKmice to a similar extent as induced by HFD in inwild-type mice. Parallel increases were observedin cytokine signaling in liver and mucscle of LIKKmice. Insulin resistance was improved bysystemic neutralization of IL-6 or salicylate", "metadata": {}}
+{"_id": "31019903", "title": "", "text": "Homelessness and health.Homelessness affectstens of thousands of canadians and hasimportant health implications. Homeless peopleare at increased risk of dying prematurely andsuffer from a wide range of health problems,including seizures, chronic obstructive pulmonarydisease, musculoskeletal disorders, tuberculosis,and skin and foot problems. Homeless peoplealso face significant barriers that impair theiraccess to health care. More research is needed toidentify better ways to deliver care to thispopulation.", "metadata": {}}
+{"_id": "31070360", "title": "", "text": "Serum metabolomics in animal models andhuman disease.PURPOSE OF REVIEW The aim ofthis study is to highlight some recent uses ofserum metabolomics in human and animalstudies. The main themes are the importance ofunderstanding the underlying variation in humanmetabolism and the use of serum metabolomicsin disease profiling. RECENT FINDINGS Severalstudies have attempted to use serummetabolomics to develop noninvasive biomarkersof disease and/or track the consequences ofnutritional and genetic interventions. Manyadvances have been made with commonchanges being identified in ageing, themenopause and cancer but several problems ofinterpretation have emerged from these studies.These include the small sample sizes in mosthuman studies and the differences betweenhuman and rodent metabolomes. However, ametabolic screen of over 1000 'healthy' humans(the Humsermet project) has highlighted manyvariables that may be used to refine the", "metadata": {}}
+{"_id": "31107919", "title": "", "text": "Differential Requirement of the ExtracellularDomain in Activation of Class B GProtein-coupled Receptors.G protein-coupledreceptors (GPCRs) from the secretin-like (classB) family are key players in hormonalhomeostasis and are important drug targets forthe treatment of metabolic disorders andneuronal diseases. They consist of a largeN-terminal extracellular domain (ECD) and atransmembrane domain (TMD) with the GPCRsignature of seven transmembrane helices. ClassB GPCRs are activated by peptide hormones withtheir C termini bound to the receptor ECD andtheir N termini bound to the TMD. It is thoughtthat the ECD functions as an affinity trap to bindand localize the hormone to the receptor. This inturn would allow the hormone N terminus toinsert into the TMD and induce conformationalchanges of the TMD to activate downstreamsignaling. In contrast to this prevailing model,we demonstrate that human class B GPCRs varywidely in their requirement of the ECD for", "metadata": {}}
+{"_id": "31141365", "title": "", "text": "Genome-wide maps of histone modificationsunwind in vivo chromatin states of the hairfollicle lineage.Using mouse skin, where bountifulreservoirs of synchronized hair follicle stem cells(HF-SCs) fuel cycles of regeneration, we explorehow adult SCs remodel chromatin in response toactivating cues. By profiling global mRNA andchromatin changes in quiescent and activatedHF-SCs and their committed, transit-amplifying(TA) progeny, we show that polycomb-group(PcG)-mediated H3K27-trimethylation featuresprominently in HF-lineage progression bymechanisms distinct from embryonic-SCs. InHF-SCs, PcG represses nonskin lineages and HFdifferentiation. In TA progeny, nonskin regulatorsremain PcG-repressed, HF-SC regulators acquireH3K27me3-marks, and HF-lineage regulatorslose them. Interestingly, genes poised inembryonic stem cells, active in HF-SCs, andPcG-repressed in TA progeny encode not onlykey transcription factors, but also signalingregulators. We document their importance in", "metadata": {}}
+{"_id": "31148090", "title": "", "text": "Two classes of endogenous small RNAs inTetrahymena thermophila.Endogenous smallRNAs function in RNA interference (RNAi)pathways to guide RNA cleavage, translationalrepression, or methylation of DNA or chromatin.In Tetrahymena thermophila, developmentallyregulated DNA elimination is governed by anRNAi mechanism involving approximately27-30-nucleotide (nt) RNAs. Here wecharacterize the sequence features of theapproximately 27-30-nt RNAs and aapproximately 23-24-nt RNA class representing asecond RNAi pathway. The approximately23-24-nt RNAs accumulate strain-specificallymanner and map to the genome in clusters thatare antisense to predicted genes. These findingsreveal the existence of distinct endogenous RNAipathways in the unicellular T. thermophila, acomplexity previously demonstrated only inmulticellular organisms.", "metadata": {}}
+{"_id": "31154082", "title": "", "text": "The binding of maize DHN1 to lipid vesicles. Gainof structure and lipid specificity.Dehydrins(DHNs; late embryogenesis abundant D-11) area family of plant proteins induced in response toabiotic stresses such as drought, lowtemperature, and salinity or during the latestages of embryogenesis. Spectral and thermalproperties of these proteins in purified formsuggest that they are \"intrinsically unstructured.\" However, DHNs contain at least one copy of aconsensus 15-amino acid sequence, the \"Ksegment,\" which resembles a class A2amphipathic alpha-helical, lipid-binding domainfound in other proteins such as apolipoproteinsand alpha-synuclein. The presence of the Ksegment raises the question of whether DHNsbind lipids, bilayers, or phospholipid vesicles.Here, we show that maize (Zea mays) DHNDHN1 can bind to lipid vesicles that containacidic phospholipids. We also observe that DHN1binds more favorably to vesicles of smallerdiameter than to larger vesicles, and that the", "metadata": {}}
+{"_id": "31166180", "title": "", "text": "Requirement of heterochromatin for cohesion atcentromeres.Centromeres are heterochromatic inmany organisms, but the mitotic function of thissilent chromatin remains unknown. During celldivision, newly replicated sister chromatids mustcohere until anaphase whenScc1/Rad21-mediated cohesion is destroyed. Inmetazoans, chromosome arm cohesins dissociateduring prophase, leaving centromeres as theonly linkage before anaphase. It is not knownwhat distinguishes centromere cohesion fromarm cohesion. Fission yeast Swi6 (aHeterochromatin protein 1 counterpart) is acomponent of silent heterochromatin. Here weshow that this heterochromatin is specificallyrequired for cohesion between sistercentromeres. Swi6 is required for association ofRad21-cohesin with centromeres but not alongchromosome arms and, thus, acts to distinguishcentromere from arm cohesion. Therefore, onefunction of centromeric heterochromatin is toattract cohesin, thereby ensuring sister", "metadata": {}}
+{"_id": "31200375", "title": "", "text": "Gene expression in human skeletal muscle:alternative normalization method and effect ofrepeated biopsiesThe reversetranscriptase-polymerase chain reaction(RT-PCR) method has lately become widely usedto determine transcription and mRNA content inrodent and human muscle samples. However,the common use of endogenous controls forcorrecting for variance in cDNA between samplesis not optimal. Specifically, we investigated (1) anew normalization method based on determiningthe cDNA content by the flourophores PicoGreenand OliGreen, (2) effect of repeated musclebiopsies on mRNA gene expression, and (3) thespatial heterogeneity in mRNA expression acrossthe muscle. Standard curves using oligostandards revealed a high degree of sensitivityand linearity (2.5–45 ng; R 2>0.99) withOliGreen reagent, as was the case for OliGreenanalyses with standard curves constructed fromserial dilutions of representative RT samples (R 2>0.99 for a ten times dilution range of a", "metadata": {}}
+{"_id": "31208367", "title": "", "text": "The Impact of Location of Progressive VisualField Loss on Longitudinal Changes in Quality ofLife of Patients with Glaucoma.PURPOSE Toevaluate the association between rates ofprogressive loss in different regions of the visualfield and longitudinal changes in quality of life(QoL). DESIGN Prospective, observational cohortstudy. PARTICIPANTS The study included 236patients with glaucomatous visual field lossfollowed for an average of 4.3±1.5 years.METHODS All subjects had the 25-item NationalEye Institute Visual Functioning Questionnaire(NEI VFQ-25) performed annually and standardautomated perimetry (SAP) at 6-month intervals.Subjects were included if they had a minimum of2 NEI VFQ-25 and 5 SAP tests during follow-up.Evaluation of rates of visual field change wasperformed using 4 different regions (centralinferior, central superior, peripheral inferior, andperipheral superior) of the integrated binocularvisual field. The association between change inNEI VFQ-25 Rasch-calibrated scores and change", "metadata": {}}
+{"_id": "31229233", "title": "", "text": "Use of thiazolidinediones and the risk of bladdercancer among people with type 2 diabetes: ameta-analysis.BACKGROUND Patients with type2 diabetes have a 40% increased risk of bladdercancer. Thiazolidinediones, especiallypioglitazone, may increase the risk. Weconducted a systematic review andmeta-analysis to evaluate the risk of bladdercancer among adults with type 2 diabetes takingthiazolidinediones. METHODS We searched keybiomedical databases (including MEDLINE,Embase and Scopus) and sources of greyliterature from inception through March 2012 forpublished and unpublished studies, withoutlanguage restrictions. We included randomizedcontrolled trials (RCTs), cohort studies andcase-control studies that reported incidentbladder cancer among people with type 2diabetes who ever (v. never) were exposed topioglitazone (main outcome), rosiglitazone orany thiazolidinedione. RESULTS Of the 1787studies identified, we selected 4 RCTs, 5 cohort", "metadata": {}}
+{"_id": "31272411", "title": "", "text": "Immune signaling by RIG-I-like receptors.TheRIG-I-like receptors (RLRs) RIG-I, MDA5, andLGP2 play a major role in pathogen sensing ofRNA virus infection to initiate and modulateantiviral immunity. The RLRs detect viral RNAligands or processed self RNA in the cytoplasm totrigger innate immunity and inflammation and toimpart gene expression that serves to controlinfection. Importantly, RLRs cooperate insignaling crosstalk networks with Toll-likereceptors and other factors to impart innateimmunity and to modulate the adaptive immuneresponse. RLR regulation occurs at a variety oflevels ranging from autoregulation to ligand andcofactor interactions and posttranslationalmodifications. Abberant RLR signaling ordysregulation of RLR expression is nowimplicated in the development of autoimmunediseases. Understanding the processes of RLRsignaling and response will provide insights toguide RLR-targeted therapeutics for antiviral andimmune-modifying applications.", "metadata": {}}
+{"_id": "31293581", "title": "", "text": "Ionizing radiation-induced long-term expressionof senescence markers in mice is independent ofp53 and immune status.Exposure to IR has beenshown to induce the formation of senescencemarkers, a phenotype that coincides with lifelongdelayed repair and regeneration of irradiatedtissues. We hypothesized that IR-inducedsenescence markers could persist long-term invivo, possibly contributing to the permanentreduction in tissue functionality. Here, we showthat mouse tissues exposed to a sublethal doseof IR display persistent (up to 45 weeks, themaximum time analyzed) DNA damage foci andincreased p16(INK4a) expression, two hallmarksof cellular senescence and aging. BrdU-labelingexperiments revealed that IR-induced damagedcells are preferentially eliminated, at leastpartially, in a tissue-dependent manner.Unexpectedly, the accumulation of damaged cellswas found to occur independent from the DNAdamage response modulator p53, and from anintact immune system, as their levels were", "metadata": {}}
+{"_id": "31304956", "title": "", "text": "Cranial neural crest and the building of thevertebrate headHead development in vertebratesinvolves a complex series of molecular andmorphogenetic events that generate acoordinated pattern of cartilages, bones andnerves, and result in species-specific craniofacialmorphologies. A specialized cell type of neuralorigin, the neural crest, is central to this process,as it provides the main source of craniofacialmesenchyme. The degree of patterninginformation that is intrinsic to the neural cresthas been recently debated, and new advanceshave underscored the influence of environmentalsignalling on the transcriptional readout thatcoordinates craniofacial morphogenesis in spaceand time.", "metadata": {}}
+{"_id": "31311495", "title": "", "text": "Tamoxifen resistance in MCF7 cells promotesEMT-like behaviour and involves modulation ofbeta-catenin phosphorylation.We have previouslydemonstrated that, following acquisition ofendocrine resistance, breast cancer cells displayan altered growth rate together with increasedaggressive behaviour in vitro. Sincedysfunctional cell-cell adhesive interactions canpromote an aggressive phenotype, weinvestigated the integrity of this protein complexin our breast cancer model of tamoxifenresistance. In culture, tamoxifen-resistant MCF7(TamR) cells grew as loosely packed colonieswith loss of cell-cell junctions and demonstratedaltered morphology characteristic of cellsundergoing epithelial-to-mesenchymal transition(EMT). Neutralising E-cadherin functionpromoted the invasion and inhibited theaggregation of endocrine-sensitive MCF7 cells,whilst having little effect on the behaviour ofTamR cells. Additionally, TamR cells hadincreased levels of tyrosine-phosphorylated", "metadata": {}}
+{"_id": "31313782", "title": "", "text": "Expression profiles of Toll-like receptors innon-small cell lung cancer and idiopathicpulmonary fibrosis.Patients with idiopathicpulmonary fibrosis (IPF) have a higherincidence             of lung cancer. The role ofToll-like receptors (TLRs), a key component ofthe             innate immunity, in interstitial lungdiseases (ILDs) and lung cancerpathogenesis             is not clarified. TLR2,TLR3, TLR4, TLR7, TLR8 and TLR9 mRNAexpression was quantitatively             measuredby real-time reverse transcriptase polymerasechain reaction (RT-PCR)             inbronchoalveolar lavage fluid (BALF) of 16 IPFpatients, 16 non-small cell lung             cancer(NSCLC) patients and 9 control subjects. TLR2,TLR3, TLR4 and TLR9 protein             expressionwas assessed on BALF T-lymphocytes using flowcytometry. TLR3 mRNA             expression wassignificantly higher in NSCLC compared to IPF(p=0.023) and controls             (p=0.001). TLR7mRNA expression levels were significantly higher", "metadata": {}}
+{"_id": "31324978", "title": "", "text": "A protein farnesyltransferase inhibitorameliorates disease in a mouse model ofprogeria.Progerias are rare genetic diseasescharacterized by premature aging. Severalprogeroid disorders are caused by mutations thatlead to the accumulation of a lipid-modified(farnesylated) form of prelamin A, a protein thatcontributes to the structural scaffolding for thecell nucleus. In progeria, the accumulation offarnesyl-prelamin A disrupts this scaffolding,leading to misshapen nuclei. Previous studieshave shown that farnesyltransferase inhibitors(FTIs) reverse this cellular abnormality. Wetested the efficacy of an FTI (ABT-100) inZmpste24-deficient mice, a mouse model ofprogeria. The FTI-treated mice exhibitedimproved body weight, grip strength, boneintegrity, and percent survival at 20 weeks ofage. These results suggest that FTIs may havebeneficial effects in humans with progeria.", "metadata": {}}
+{"_id": "31347396", "title": "", "text": "A rare mutation in UNC5C predisposes tolate-onset Alzheimer's disease and increasesneuronal cell deathWe have identified a rarecoding mutation, T835M (rs137875858), in theUNC5C netrin receptor gene that segregated withdisease in an autosomal dominant pattern in twofamilies enriched for late-onset Alzheimer'sdisease and that was associated with diseaseacross four large case-control cohorts (odds ratio= 2.15, Pmeta = 0.0095). T835M alters aconserved residue in the hinge region of UNC5C,and in vitro studies demonstrate that thismutation leads to increased cell death in humanHEK293T cells and in rodent neurons.Furthermore, neurons expressing T835M UNC5Care more susceptible to cell death from multipleneurotoxic stimuli, including β-amyloid (Aβ),glutamate and staurosporine. On the basis ofthese data and the enriched hippocampalexpression of UNC5C in the adult nervoussystem, we propose that one possiblemechanism in which T835M UNC5C contributes", "metadata": {}}
+{"_id": "31363207", "title": "", "text": "Treatment of active tuberculosis inHIV-coinfected patients: a systematic review andmeta-analysis.BACKGROUND Patients withhuman immunodeficiency virus (HIV) infectionand tuberculosis have an increased risk of death,treatment failure, and relapse. METHODS Asystematic review and meta-analysis ofrandomized, controlled trials and cohort studieswas conducted to evaluate the impact of durationand dosing schedule of rifamycin and use ofantiretroviral therapy in the treatment of activetuberculosis in HIV-positive patients. In includedstudies, the initial tuberculosis diagnosis, failure,and/or relapse were microbiologically confirmed,and patients received standardized rifampin- orrifabutin-containing regimens. Pooled cumulativeincidence of treatment failure, death duringtreatment, and relapse were calculated usingrandom-effects models. Multivariablemeta-regression was performed using negativebinomial regression. RESULTS After screening5158 citations, 6 randomized trials and 21 cohort", "metadata": {}}
+{"_id": "31387717", "title": "", "text": "Crystal structure and association behaviour ofthe GluR2 amino-terminal domain.Fast excitatoryneurotransmission is mediated largely byionotropic glutamate receptors (iGluRs),tetrameric, ligand-gated ion channel proteinscomprised of three subfamilies, AMPA, kainateand NMDA receptors, with each subfamilysharing a common, modular-domainarchitecture. For all receptor subfamilies, activechannels are exclusively formed by assemblagesof subunits within the same subfamily, amolecular process principally encoded by theamino-terminal domain (ATD). However, themolecular basis by which the ATD guidessubfamily-specific receptor assembly is notknown. Here we show that AMPA receptor GluR1-and GluR2-ATDs form tightly associated dimersand, by the analysis of crystal structures of theGluR2-ATD, propose mechanisms by which theATD guides subfamily-specific receptorassembly.", "metadata": {}}
+{"_id": "31407112", "title": "", "text": "Deficiency in l-serine deaminase results inabnormal growth and cell division of Escherichiacoli K-12.The loss of the ability to deaminatel-serine severely impairs growth and cell divisionin Escherichia coli K-12. A strain from which thethree genes (sdaA, sdaB, tdcG) coding for thisorganism's three l-serine deaminases had beendeleted grows well in glucose minimal mediumbut, on subculture into minimal medium withglucose and casamino acids, it makes very large,abnormally shaped cells, many of which lyse.When inoculated into Luria-Bertani (LB) brothwith or without glucose, it makes very longfilaments. Provision of S-adenosylmethioninerestores cell division in LB broth with glucose,and repairs much of the difficulty in growth inmedium with casamino acids. We suggest thatreplication of E. coli is regulated by methylation,that an unusually high intracellular l-serineconcentration, in the presence of other aminoacids, starves the cell for S-adenosylmethionineand that it is the absence of", "metadata": {}}
+{"_id": "31439189", "title": "", "text": "Stem cell characteristics in prostate cancer celllines.BACKGROUND Recent studies indicate thepresence of a small, stem-like cell population inseveral human cancers that is crucial for thetumour (re)population. OBJECTIVE Sixestablished prostate cancer (PCa) celllines-DU145, DuCaP, LAPC-4, 22Rv1, LNCaP, andPC-3-were examined for their stem cellproperties in vitro. DESIGN, SETTINGS, ANDPARTICIPANTS The colony-forming efficiency andself-renewal ability of morphologicallydistinguishable holoclones and paraclones weretested with low-density plating and serialpassaging. Expression of the putative stem cellmarker CD133 and breast cancer resistanceprotein (BCRP) was examined with flowcytometry, and immunohistochemical stainingswere made for CD133, alpha2-integrin, nestin,BCRP, cytokeratin 5 (CK5), and cytokeratin 18(CK18). RESULTS AND LIMITATIONS Five out ofsix cell lines formed clear holo-, mero-, andparaclones. Unlike paraclones, we can maintain", "metadata": {}}
+{"_id": "31460499", "title": "", "text": "Resistance to antimicrobials in humans andanimals.Overusing antibiotics is not the onlycause and reducing use is not the onlysolution   W arning signs of antimicrobialresistance, chinks in the antimicrobial armour,began to appear in the middle of the lastcentury, and by the 1990s various reports hadsignalled the dangers of excessive orinappropriate use of antibiotics in clinicalmedicine and of the use of antibiotics in animalfeed as growth promoters.1–3 Overuse ofantimicrobials emerged as the main culprit, andreducing their use was seen as the answer. But itmay not be that simple. The idea that reducingantibiotic use would redress the problem formedpart of a positive response on the part of theUnited Kingdom government to the House ofLords report,1 including a public informationcampaign, surveillance of resistance along thefood chain, targets with respect to hospitalacquired infections, and setting up of anoverarching advisory body on all aspects of", "metadata": {}}
+{"_id": "31495049", "title": "", "text": "Unmet needs and depressive symptoms amonglow--income older adults.Previous studies havefound that declining health, decreased socialinteraction, and inadequate financial resourceswere significant risk factors for late-lifedepression, and social support from families andfriends and religiosity were significant protectivefactors. In this study, we examined if low-incomeolder adults' perceived unmet need for home-and community-based services for manyaging-associated problems would beindependently associated with their depressivesymptoms, controlling for these known risk andprotective factors. We interviewed a total of 213community-residing older adults to assess theirdepressive symptoms, using the GeriatricDepression Scale (GDS), and unmet needs in theareas of personal assistance, instrumental andenvironmental support, emotional support, andother facilitative/enabling services. We foundthat the number of unmet needs wassignificantly positively associated with these", "metadata": {}}
+{"_id": "31514338", "title": "", "text": "A key role for Ctf4 in coupling the MCM2-7helicase to DNA polymerase alpha within theeukaryotic replisome.The eukaryotic replisome isa crucial determinant of genome stability, but itsstructure is still poorly understood. We foundpreviously that many regulatory proteinsassemble around the MCM2-7 helicase at yeastreplication forks to form the replisomeprogression complex (RPC), which might linkMCM2-7 to other replisome components. Here,we show that the RPC associates with DNApolymerase alpha that primes each Okazakifragment during lagging strand synthesis. Ourdata indicate that a complex of the GINS andCtf4 components of the RPC is crucial to coupleMCM2-7 to DNA polymerase alpha. Others havefound recently that the Mrc1 subunit of RPCsbinds DNA polymerase epsilon, whichsynthesises the leading strand at DNA replicationforks. We show that cells lacking both Ctf4 andMrc1 experience chronic activation of the DNAdamage checkpoint during chromosome", "metadata": {}}
+{"_id": "31543713", "title": "", "text": "Data analysis methods for detection ofdifferential protein expression in two-dimensionalgel electrophoresis.The recent development ofmicroarray technology has led statisticians andbioinformaticians to develop new statisticalmethodologies for comparing different biologicalsamples. The objective is to identify a smallnumber of differentially expressed genes fromamong thousands. In quantitative proteomics,analysis of protein expression usingtwo-dimensional gel electrophoresis shows somesimilarities with transcriptomic studies. Thus, thegoal of this study was to evaluate different dataanalysis methodologies widely used in arrayanalysis using different proteomic data sets ofhundreds of proteins. Even with few replications,the significance analysis of microarrays methodappeared to be more powerful than the Student'st test in truly declaring differentially expressedproteins. This procedure will avoid wasting timedue to false positives and losing information withfalse negatives.", "metadata": {}}
+{"_id": "31554917", "title": "", "text": "A clinical approach to circadian rhythm sleepdisorders.Circadian rhythm sleep disorders arecharacterized by complaints of insomnia andexcessive sleepiness that are primarily due toalterations in the internal circadian timingsystem or a misalignment between the timing ofsleep and the 24-h social and physicalenvironment. In addition to physiological andenvironmental factors, maladaptive behaviorsoften play an important role in the developmentof many of the circadian rhythm sleep disorders.This review will focus on the clinical approach tothe diagnosis and management of the variouscircadian rhythm sleep disorders, includingdelayed sleep phase disorder, advanced sleepphase disorder, non-entrained type, irregularsleep-wake rhythm, shift work sleep disorder andjet lag disorder. Diagnostic tools such as sleepdiaries and wrist activity monitoring are oftenuseful in confirming the diagnosis. Becausebehavioral and environmental factors often areinvolved in the development of these conditions,", "metadata": {}}
+{"_id": "31560225", "title": "", "text": "SIVrcm infection of macaques.In a prior report,we described the isolation and characterization ofSIVrcm, a distinct primate lentivirus found in ahousehold pet Red-Capped Mangabey (RCM) inGabon. SIVrcm is divergent from HIV-1 andHIV-2/SIV families of primate lentiviruses. In thisreport, additional in vitro replication studies andthe results of SIVrcm infection in macaques arepresented. SIVrcm causes little cytopathiceffedct in Molt 4 Clone 8 cells and in rhesus andhuman PBMCs. In vivo, SIVrcm isnon-pathogenic after 200 days in rhesusmacaques and after one year in cynomolgousmacaques, but does cause a chronic infection inboth macaques.", "metadata": {}}
+{"_id": "31562330", "title": "", "text": "Integrating nutrition security with treatment ofpeople living with HIV: lessons fromKenya.BACKGROUND The increased caloricrequirements of HIV-positive individuals,undesirable side effects of treatment that may beworsened by malnutrition (but alleviated bynutritional support), and associated declines inadherence and possible increased drugresistance are all justifications for developingbetter interventions to strengthen the nutritionsecurity of individuals receiving antiretroviraltreatment. OBJECTIVE To highlight key benefitsand challenges relating to interventions aimed atstrengthening the nutrition security of peopleliving with HIV who are receiving antiretroviraltreatment. METHODS Qualitative research wasundertaken on a short-term nutritionintervention linked to the provision of freeantiretroviral treatment for people living with HIVin western Kenya in late 2005 and early 2006.RESULTS Patients enrolled in the food programwhile on treatment regimens self-reported", "metadata": {}}
+{"_id": "31564409", "title": "", "text": "Acylated and desacyl ghrelin stimulate lipidaccumulation in human visceraladipocytesObjectives:The orexigenic hormoneghrelin circulates mainly in two forms, acylatedand desacyl ghrelin. We evaluated the impact ofobesity and obesity-associated type 2 diabetes(T2D) on ghrelin forms and the potential role ofacylated and desacyl ghrelin in the control ofadipogenesis in humans. Methods:Plasmaconcentrations of the different ghrelin formswere measured in 80 subjects. The expression ofthe ghrelin receptor (growth hormonesecretagogue receptor, GHS-R) was analyzed inomental adipose tissue using western blot andimmunohistochemistry, and the effect ofacylated ghrelin and desacyl ghrelin (0.1–1000pmol l−1) on adipogenesis was determined invitro in omental adipocytes. Results:Circulatingconcentrations of acylated ghrelin wereincreased, whereas desacyl ghrelin levels weredecreased, in obesity and obesity-associatedT2D. Body mass index, waist circumference,", "metadata": {}}
+{"_id": "31591262", "title": "", "text": "Significant correlation between LKB1 and LGR5gene expression and the association with poorrecurrence-free survival in rectal cancer afterpreoperative chemoradiotherapyThe aim of thepresent study was to investigate whether thegene expression levels of LKB1 and LGR5correlated with clinical outcome in patients withlocally advanced rectal cancer treated withpreoperative chemoradiotherapy (CRT). Residualcancer cells were obtained from 52 patients withlocally advanced rectal cancer treated withpreoperative CRT. Total RNA was then isolatedfrom formalin-fixed, paraffin-embeddedspecimens using microdissection. The expressionlevels of LKB1 and LGR5 genes were measuredusing real-time reverse-transcription polymerasechain reaction and by immunohistochemistry. Inaddition, in vitro studies were performed usingcolon cancer cell lines to study the serial changesof LKB1, LGR5 and PRKAA1 (AMPK) geneexpression levels after irradiation. Our datademonstrate that specimens obtained from", "metadata": {}}
+{"_id": "31612088", "title": "", "text": "Evaluating the impact of pharmacists in mentalhealth: a systematic review.Efforts to improvethe outcomes of patients with mental illnessoften have involved incorporating the skills of avariety of health care professionals intocollaborative care models. For over 30 years,clinical pharmacists have contributed to thesecare models in capacities ranging from educatorto consultant to provider. This systematic reviewevaluates the quantity and quality of medicalliterature examining the impact of pharmacists inmental health from 1972-2003. Although weidentified approximately 35 publicationsdescribing the roles of clinical pharmacists in thisregard, only 16 were of sufficient scientific rigorto permit evaluation and comparison. The 16studies were divided equally between inpatientand outpatient settings and were conducted in avariety of health care organizations (e.g.,Veterans Administration, health maintenanceorganizations, community mental health clinics,and nursing homes). Nine of the studies", "metadata": {}}
+{"_id": "31616203", "title": "", "text": "Multicenter phase II study of lapatinib in patientswith brain metastases from HER2-positive breastcancer.PURPOSE Brain metastases develop inone third of patients with advanced HER2+breast cancer. Effective therapy for patients withcentral nervous system (CNS) progression aftercranial radiation is extremely limited andrepresents a major clinical challenge. Lapatinib,an epidermal growth factor receptor/HER2inhibitor, was associated with regressions of CNSlesions in a small phase 2 trial. The current studywas done to further evaluate the CNS activity oflapatinib. The study was later amended to allowpatients who progressed on lapatinib the optionof receiving lapatinib plus capecitabine.EXPERIMENTAL DESIGN Eligible patients hadHER2+ breast cancer, progressive brainmetastases, prior trastuzumab, and cranialradiotherapy. The primary end point was CNSobjective response, defined as >or=50%volumetric reduction of CNS lesion(s) in theabsence of increasing steroid use, progressive", "metadata": {}}
+{"_id": "31624828", "title": "", "text": "Control of signaling-mediated clearance ofapoptotic cells by the tumor suppressor p53Theinefficient clearance of dying cells can lead toabnormal immune responses, such as unresolvedinflammation and autoimmune conditions. Weshow that tumor suppressor p53 controlssignaling-mediated phagocytosis of apoptoticcells through its target, Death Domain1α(DD1α), which suggests that p53 promotes boththe proapoptotic pathway and postapoptoticevents. DD1α appears to function as anengulfment ligand or receptor that engages inhomophilic intermolecular interaction atintercellular junctions of apoptotic cells andmacrophages, unlike other typical scavengerreceptors that recognize phosphatidylserine onthe surface of dead cells. DD1α-deficient miceshowed in vivo defects in clearing dying cells,which led to multiple organ damage indicative ofimmune dysfunction. p53-induced expression ofDD1α thus prevents persistence of cell corpsesand ensures efficient generation of precise", "metadata": {}}
+{"_id": "31634628", "title": "", "text": "Circulating tumor DNA as a non-invasivesubstitute to metastasis biopsy for tumorgenotyping and personalized medicine in aprospective trial across all tumor types.Cell-freetumor DNA (ctDNA) has the potential to enablenon-invasive diagnostic tests for personalizedmedicine in providing similar molecularinformation as that derived from invasive tumorbiopsies. The histology-independent phase IISHIVA trial matches patients with targetedtherapeutics based on previous screening ofmultiple somatic mutations using metastaticbiopsies. To evaluate the utility of ctDNA in thistrial, as an ancillary study we performed de novodetection of somatic mutations using plasmaDNA compared to metastasis biopsies in 34patients covering 18 different tumor types,scanning 46 genes and more than 6800 COSMICmutations with a multiplexed next-generationsequencing panel. In 27 patients, 28 of 29mutations identified in metastasis biopsies(97%) were detected in matched ctDNA. Among", "metadata": {}}
+{"_id": "31682248", "title": "", "text": "TGF-beta suppresses tumor progression in coloncancer by inhibition of IL-6trans-signaling.Alterations of TGF-beta signalinghave been described in colorectal cancer,although the molecular consequences are largelyunknown. By using transgenic miceoverexpressing TGF-beta or a dominant-negativeTGF-betaRII, we demonstrate that TGF-betasignaling in tumor infiltrating T lymphocytescontrols the growth of dysplastic epithelial cellsin experimental colorectal cancer, as determinedby histology and a novel system forhigh-resolution chromoendoscopy. At themolecular level, TGF-beta signaling in T cellsregulated STAT-3 activation in tumor cells viaIL-6. IL-6 signaling required tumor cell-derivedsoluble IL-6R rather than membrane boundIL-6R and suppression of suchTGF-beta-dependent IL-6 trans-signalingprevented tumor progression in vivo. Takentogether, our data provide novel insights intoTGF-beta signaling in colorectal cancer and", "metadata": {}}
+{"_id": "31715818", "title": "", "text": "New opportunities: the use of nanotechnologiesto manipulate and track stemcells.Nanotechnologies are emerging platformsthat could be useful in measuring,understanding, and manipulating stem cells.Examples include magnetic nanoparticles andquantum dots for stem cell labeling and in vivotracking; nanoparticles, carbon nanotubes, andpolyplexes for the intracellular delivery ofgenes/oligonucleotides and protein/peptides;and engineered nanometer-scale scaffolds forstem cell differentiation and transplantation. Thisreview examines the use of nanotechnologies forstem cell tracking, differentiation, andtransplantation. We further discuss their utilityand the potential concerns regarding theircytotoxicity.", "metadata": {}}
+{"_id": "31761981", "title": "", "text": "The emergence of order in the Drosophila pupalretina.During pupation, long-range order isimposed on the autonomously developingommatidia which compose the Drosophila eye.To accomplish this, eight additional cell typesarise: the primary, secondary, and tertiarypigment cells, and the four cells that form thebristle. These cells form an interweaving latticebetween ommatidia. The lattice is refined whenexcess cells are removed to bring neighboringommatidia into register. Recent evidencesuggests that in larval development, localcontacts direct cell fate. The same appears to betrue during pupal development: the contacts acell makes predict the cell type it will become.Cells which contact the anterior or posterior conecells in an ommatidium invariably becomeprimary pigment cells. Cells which contactprimary pigment cells from different ommatidiabecome secondary and tertiary pigment cells.Bristle development is in several ways distinctfrom ommatidial development. The four cells of", "metadata": {}}
+{"_id": "31803596", "title": "", "text": "Gene expression analysis by cDNA microarray inoral squamous cell carcinoma.BACKGROUNDOral squamous cell carcinoma (OSCC) iscommon type of human cancer, but little isknown about the molecular mechanisms decidingon this malignancy. Comprehensive geneexpression profiling is essential forunderstanding OSCC. METHODS cDNAmicroarray was used to analyze expressionpatterns of 16 617 genes in nine OSCC patients.RESULTS Forty-seven genes with alteredexpression among all cases were extracted. Theontology of these 47 genes was classified into 10categories. To validate the microarray data, theexpression of genes, including TGFBI, FADD andDUSP1 was analyzed by reversetranscriptase-polymerase chain reaction(RT-PCR). By hierarchical clustering analysis, thenine cases were divided into two clusters.CONCLUSIONS The 47 genes are suggested ashaving a functional significance in oral squamouscell carcinogenesis. It is also suggested that the", "metadata": {}}
+{"_id": "31834381", "title": "", "text": "Risk factors associated with symptoms ofgastroesophageal reflux.BACKGROUND Althoughpatients with gastroesophageal reflux are ofteninstructed to change their lifestyle,population-based data on the risk factors forreflux in the United States are lacking. METHODSWe performed a cross-sectional study in an age-and gender-stratified random sample of thepopulation of Olmsted County, Minnesota.Residents aged 25 to 74 years were mailed avalid self-report questionnaire that measuredreflux symptoms and potential risk factors.Logistic regression was used to estimate theodds ratios (OR) with 95% confidence intervals(CI) for reflux symptoms (heartburn or acidregurgitation) associated with potential riskfactors. RESULTS Overall, 1,524 (72%) of 2,118eligible subjects responded. A body mass index>30 kg/m2 (OR = 2.8; CI, 1.7 to 4.5), reportingan immediate family member with heartburn ordisease of the esophagus or stomach (OR = 2.6;CI, 1.8 to 3.7), a past history of smoking (OR =", "metadata": {}}
+{"_id": "31844040", "title": "", "text": "A mathematical investigation of the effects ofinhibitor therapy on three putativephosphorylation cascades governing thetwo-component system of the agroperon.Two-component systems (TCSs) arewidely employed by bacteria to sense specificexternal signals and conduct an appropriateresponse via a phosphorylation cascade withinthe cell. The TCS of the agr operon in thebacterium Staphylococcus aureus forms part of aregulatory process termed quorum sensing, acell-to-cell communication mechanism used toassess population density. Since S. aureusmanipulates this \"knowledge\" in order toco-ordinate production of its armoury of exotoxinvirulence factors required to promote infection, itis important to understand fully how this processworks. We present three models of the agroperon, each incorporating a differentphosphorylation cascade for the TCS since theprecise nature of the cascade is not fullyunderstood. Using numerical and asymptotic", "metadata": {}}
+{"_id": "31851367", "title": "", "text": "Coregulators in nuclear estrogen receptor action:from concept to therapeutic targeting.Estrogensare key regulators of growth, differentiation, andthe physiological functions of a wide range oftarget tissues, including the male and femalereproductive tracts, breast, and skeletal,nervous, cardiovascular, digestive and immunesystems. The majority of these biologicalactivities of estrogens are mediated through twogenetically distinct receptors, ERalpha andERbeta, which function as hormone-inducibletranscription factors. Over the past decade, ithas become increasingly clear that therecruitment of coregulatory proteins to ERs isrequired for ER-mediated transcriptional andbiological activities. These \"coactivator\"complexes enable the ERs to respondappropriately: 1) to hormones orpharmacological ligands, 2) interpret extra- andintra-cellular signals, 3) catalyze the process ofchromatin condensation and 4) to communicatewith the general transcription apparatus at target", "metadata": {}}
+{"_id": "31882215", "title": "", "text": "Autophagy and mTORC1 regulate the stochasticphase of somatic cell reprogrammingWe describerobust induction of autophagy during thereprogramming of mouse fibroblasts to inducedpluripotent stem cells by four reprogrammingfactors (Sox2, Oct4, Klf4 and c-Myc), henceforth4F. This process occurs independently of p53activation, and is mediated by the synergisticdownregulation of mechanistic target ofrapamycin complex 1 (mTORC1) and theinduction of autophagy-related genes. The 4Fcoordinately repress mTORC1, but bifurcate intheir regulation of autophagy-related genes, withKlf4 and c-Myc inducing them but Sox2 and Oct4inhibiting them. On one hand, inhibition ofmTORC1 facilitates reprogramming by promotingcell reshaping (mitochondrial remodelling andcell size reduction). On the other hand, mTORC1paradoxically impairs reprogramming bytriggering autophagy. Autophagy does notparticipate in cell reshaping in reprogrammingbut instead degrades p62, whose accumulation", "metadata": {}}
+{"_id": "31884697", "title": "", "text": "Lithium Therapy Improves Neurological Functionand Hippocampal Dendritic Arborization in aSpinocerebellar Ataxia Type 1 MouseModelBackground  Spinocerebellar ataxia type 1(SCA1) is a dominantly inheritedneurodegenerative disorder characterized byprogressive motor and cognitive dysfunction.Caused by an expanded polyglutamine tract inataxin 1 (ATXN1), SCA1 pathogenesis involves amultifactorial process that likely begins withmisfolding of ATXN1, which has functionalconsequences on its interactions, leading totranscriptional dysregulation. Because lithiumhas been shown to exert neuroprotective effectsin a variety of conditions, possibly by affectinggene expression, we tested the efficacy oflithium treatment in a knock-in mouse model ofSCA1 (Sca1154Q/2Q mice) that replicates manyfeatures of the human disease. Methods andFindings  Sca1154Q/2Q mice and their wild-typelittermates were fed either regular chow or chowthat contained 0.2% lithium carbonate. Dietary", "metadata": {}}
+{"_id": "31889025", "title": "", "text": "The progression from hypertension to congestiveheart failure.OBJECTIVES - To study the relativeand population-attributable risks of hypertensionfor the development of congestive heart failure(CHF), to assess the time course of progressionfrom hypertension to CHF, and to identify riskfactors that contribute to the development ofovert heart failure in hypertensive subjects.DESIGN - Inception cohort study. SETTING -General community. PARTICIPANTS - OriginalFramingham Heart Study and FraminghamOffspring Study participants aged 40 to 89 yearsand free of CHF. To reflect more contemporaryexperience, the starting point of this study wasJanuary 1, 1970. EXPOSURE MEASURES -Hypertension (blood pressure of at least 140 mmHg systolic or 90 mm Hg diastolic or current useof medications for treatment of high bloodpressure) and other potential CHF risk factorswere assessed at periodic clinic examinations.OUTCOME MEASURE - The development of CHF.RESULTS - A total of 5143 eligible subjects", "metadata": {}}
+{"_id": "31890716", "title": "", "text": "Association of plasma resistin with glomerularfiltration rate and albuminuria in hypertensiveadults.Resistin, a recently discoveredproinflammatory cytokine, has been variablyassociated with insulin resistance, inflammation,and renal dysfunction. We investigated theassociation of plasma resistin with estimatedglomerular filtration rate and albuminuria in1575 hypertensive adults without knowncoronary heart disease or stroke (857 blacks and718 non-Hispanic whites). Resistin wasmeasured by a solid phase sandwichimmunoassay, estimated glomerular filtrationrate was estimated from serum creatinine, andalbuminuria was expressed as urinealbumin:creatinine ratio. After adjustment forcoronary heart disease risk factors (age, sex,body mass index, smoking history, systolic bloodpressure, diabetes, and total and high-densitylipoprotein cholesterol) and use ofrenin-angiotensin blockers and statins, higherplasma resistin levels were associated with lower", "metadata": {}}
+{"_id": "31902059", "title": "", "text": "Large-scale candidate gene scan reveals the roleof chemoreceptor genes in host plantspecialization and speciation in the peaaphid.Understanding the drivers of speciation iscritical to interpreting patterns of biodiversity.The identification of the genetic changesunderlying adaptation and reproductive isolationis necessary to link barriers to gene flow to thecausal origins of divergence. Here, we present anovel approach to the genetics of speciation,which should complement the commonly usedapproaches of quantitative trait locus mappingand genome-wide scans for selection. Wepresent a large-scale candidate gene approachby means of sequence capture, applied toidentifying the genetic changes underlyingreproductive isolation in the pea aphid, a modelsystem for the study of ecological speciation.Targeted resequencing enabled us to scale upthe candidate gene approach, specifically testingfor the role of chemosensory gene families inhost plant specialization. Screening for the", "metadata": {}}
+{"_id": "31902335", "title": "", "text": "The cancer stem cell hypothesis: a guide topotential molecular targets.Common cancertheories hold that tumor is an uncontrolledsomatic cell proliferation caused by theprogressive addition of random mutations incritical genes that control cell growth.Nevertheless, various contradictions related tothe mutation theory have been reportedpreviously. These events may be elucidated bythe persistence of residual tumor cells, calledCancer Stem Cells (CSCs) responsible fortumorigenesis, tumor maintenance, tumorspread, and tumor relapse. Herein, wesummarize the current understanding of CSCs,with a focus on the possibility to identify specificmarkers of CSCs, and discuss the clinicalapplication of targeting CSCs for cancertreatment.", "metadata": {}}
+{"_id": "31933981", "title": "", "text": "Serum amyloid A: An acute-phase proteininvolved in tumour pathogenesisThe synthesis ofacute-phase protein serum amyloid A (SAA) islargely regulated by inflammation- associatedcytokines and a high concentration of circulatingSAA may represent an ideal marker for acuteand chronic inflammatory diseases. However,SAA is also synthesized in extrahepatic tissues,e.g. human carcinoma metastases and cancercell lines. An increasing body of in vitro datasupports the concept of involvement of SAA incarcinogenesis and neoplastic diseases.Accumulating evidence suggests that SAA mightbe included in a group of biomarkers to detect apattern of physiological events that reflect thegrowth of malignancy and host response. Thisreview is meant to provide a broad overview ofthe many ways that SAA could contribute totumour development, and accelerate tumourprogression and metastasis, and to gain a betterunderstanding of this acute-phase reactant as apossible link between chronic inflammation and", "metadata": {}}
+{"_id": "31942055", "title": "", "text": "Body size and outcomes on peritoneal dialysis inthe United States.BACKGROUND Beingoverweight is often cited as a relativecontraindication to peritoneal dialysis. Ourprimary objective was to determine whetheractual mortality rates support this opinion.METHODS Retrospective cohort study of UnitedStates Medicare patients initiating dialysisbetween 1995 and 2000 (N = 418,021; 11%peritoneal dialysis). RESULTS Seven percentwere underweight [body mass index (BMI) <18.5 kg/m2], 27% were overweight (BMI 25.0 to29.9 kg/m2), and 23% were obese (BMI> 29.9kg/m2) at dialysis initiation. Compared to thosewith normal BMI, the adjusted odds of initiatingperitoneal dialysis were 0.70 (P < 0.05) inunderweight, 1.12 (P < 0.05) in overweight, and0.87 (P < 0.05) in obese subjects. Amongperitoneal dialysis patients, adjusted mortalityhazard ratios in the first, second, and third yearwere 1.45 (P < 0.05), 1.28 (P < 0.05), and 1.17for the underweight, respectively; 0.84 (P <", "metadata": {}}
+{"_id": "31962403", "title": "", "text": "The anaphase promoting complex/cyclosome: amachine designed to destroyThe anaphasepromoting complex/cyclosome (APC/C) is aubiquitin ligase that has essential functions inand outside the eukaryotic cell cycle. It is themost complex molecular machine that is knownto catalyse ubiquitylation reactions, and itcontains more than a dozen subunits thatassemble into a large 1.5-MDa complex. Recentdiscoveries have revealed an unexpectedmultitude of mechanisms that control APC/Cactivity, and have provided a first insight intohow this unusual ubiquitin ligase recognizes itssubstrates.", "metadata": {}}
+{"_id": "32001951", "title": "", "text": "Regulation of the expression of alkalinephosphatase in a human breast-cancer cellline.Treatment of the cultured humanbreast-cancer cells BC-M1 with dexamethasoneinduced a placental-type alkaline phosphatase(ALP). Both the ALP activity and the mRNA levelin the cells were increased. The induction of ALPactivity by dexamethasone was time- anddose-dependent. The accumulation of ALP mRNAwas inhibited by both actinomycin D andcycloheximide, indicating that its induction is acomplex event and may involve other regulatoryproteins. Retinoic acid showed opposing effectswith dexamethasone on the expression ofalkaline phosphatase. Retinoic acid (RA) andphorbol 12-myristate 13-acetate alsosubstantially reduced thedexamethasone-induced expression of ALP.Studies on thermostability and sensitivity tovarious amino acid inhibitors indicated that theBC-M1 ALP is most similar to the placental form.Northern hybridization analysis also revealed", "metadata": {}}
+{"_id": "32012666", "title": "", "text": "Declining tuberculosis notification trendassociated with strengthened TB and expandedHIV care in Swaziland.This retrospectiveobservational review documents the efforts ofthe Swaziland National Tuberculosis (TB) ControlProgramme between 2004 and 2014. Theobjective is to describe the disparity betweenactual declines in case notification and increasesin estimated incidence. The review of policiesand practices shows the most influential factorsassociated with the decrease in TB casenotification to be an increase in access toantiretroviral therapy for co-infected TB patients,the general success of TB and humanimmunodeficiency virus service integration in thecountry and improvements in implementation ofall components of directly observed treatment,active case finding, and rapid diagnosis usingnew technologies.", "metadata": {}}
+{"_id": "32023005", "title": "", "text": "Advances in techniques of testing mycobacterialdrug sensitivity, and the use of sensitivity testsin tuberculosis control programmes.In a paperarising out of an informal internationalconsultation of specialists in the bacteriology oftuberculosis held in 1961, an attempt was madeto formulate criteria, and specify technicalprocedures, for reliable tests of sensitivity (theabsolute-concentration method, theresistance-ratio method and the proportionmethod) to the 3 main antituberculosis drugs(isoniazid, streptomycin and p-aminosalicylicacid). Seven years later, a further consultationwas held to review the latest developments inthe field and to suggest how sensitivity testsmight be put to practical use in tuberculosiscontrol programmes. The participants reachedagreement on how to define drug sensitivity andresistance, and stressed the importance of usinga discrimination approach to the calibration ofsensitivity tests. Their views are contained in thepresent paper, which also includes descriptions", "metadata": {}}
+{"_id": "32084655", "title": "", "text": "Time from finding abnormality onmass-screening to final diagnosis of lungcancer.Mass-screening for lung cancer is rather aunique system in Japan. This study illustratestime from finding abnormality on mass-screeningto final diagnosis of lung cancer. Among the 517patients with lung cancer who were admitted toour hospital over a 10-year period up toDecember 2001, 83 (16.1%) were detected bymass-screening. We reviewed medical records ofthe 83 patients and determined the intervalsfrom the mass-screening to the pathologicaldiagnosis with clinical staging. Time from themass-screening to the date of hospital visit was<2 months in 62 (74.7%) cases. Five (6.0%)patients visited hospital more than 6 monthsafter the mass-screening. With respect to theinterval, there was no statistical difference ingender (p=0.0680) and age (p=0.1532). Among60 patients who were referred from outside, onaverage, patients visited our hospital 0.5 monthafter they first sought medical attention at", "metadata": {}}
+{"_id": "32101982", "title": "", "text": "Krüppel-like factor 2 (KLF2) regulates B-cellreactivity, subset differentiation, and traffickingmolecule expression.The transcription factorKrüppel-like factor 2 (KLF2) is critical for normaltrafficking of T lymphocytes, but its role in B cellsis unclear. We report that B cell-specific KLF2deficiency leads to decreased expression of thetrafficking molecules CD62L and β7-integrin, yetexpression of sphingosine-1 phosphate receptor1 (which is a critical target of KLF2 in T cells)was, unexpectedly, minimally altered.Unexpectedly, Klf2 deletion led to a drasticreduction in the B1 B-cell pool and a substantialincrease in transitional and marginal zone B-cellnumbers. In addition, we observed thatKLF2-deficient B cells showed increasedapoptosis and impaired proliferation after B-cellreceptor cross-linking. Gene expression analysisindicated that KLF2-deficient follicular B cellsdisplay numerous characteristics shared bynormal marginal zone B cells, including reducedexpression of several signaling molecules that", "metadata": {}}
+{"_id": "32159283", "title": "", "text": "Antibiotics and risk of subsequent first-timeacute myocardial infarction.CONTEXT Increasingevidence supports the hypothesis of a causalassociation between certain bacterial infectionsand increased risk of developing acutemyocardial infarction. If such a causalassociation exists, subjects who used antibioticsactive against the bacteria, regardless ofindication, might be at lower risk of developingacute myocardial infarction than nonusers.OBJECTIVE To determine whether previous useof antibiotics decreases the risk of developing afirst-time acute myocardial infarction. DESIGNPopulation-based case-control analysis. SETTINGThe United Kingdom-based General PracticeResearch Database comprising 350 generalpractices. PATIENTS A total of 3315 casepatients aged 75 years or younger with adiagnosis of first-time acute myocardialinfarction between 1992 and 1997 and 13139controls without myocardial infarction matchedto cases for age, sex, general practice attended,", "metadata": {}}
+{"_id": "32170702", "title": "", "text": "Thrombopoietin/MPL signaling regulateshematopoietic stem cell quiescence andinteraction with the osteoblasticniche.Maintenance of hematopoietic stem cells(HSCs) depends on interaction with their niche.Here we show that the long-term (LT)-HSCsexpressing the thrombopoietin (THPO) receptor,MPL, are a quiescent population in adult bonemarrow (BM) and are closely associated withTHPO-producing osteoblastic cells. THPO/MPLsignaling upregulated beta1-integrin andcyclin-dependent kinase inhibitors in HSCs.Furthermore, inhibition and stimulation ofTHPO/MPL pathway by treatments with anti-MPLneutralizing antibody, AMM2, and with THPOshowed reciprocal regulation of quiescence ofLT-HSC. AMM2 treatment reduced the number ofquiescent LT-HSCs and allowed exogenous HSCengraftment without irradiation. By contrast,exogenous THPO transiently increased quiescentHSC population and subsequently induced HSCproliferation in vivo. Altogether, these", "metadata": {}}
+{"_id": "32177659", "title": "", "text": "Interlaboratory reproducibility and proficiencytesting within the human papillomavirus cervicalcancer screening program in Catalonia, Spain.InCatalonia, a screening protocol for cervicalcancer, including human papillomavirus (HPV)DNA testing using the Digene Hybrid Capture 2(HC2) assay, was implemented in 2006. In orderto monitor interlaboratory reproducibility, aproficiency testing (PT) survey of the HPVsamples was launched in 2008. The aim of thisstudy was to explore the repeatability of the HC2assay's performance. Participating laboratoriesprovided 20 samples annually, 5 randomlychosen samples from each of the followingrelative light unit (RLU) intervals: <0.5, 0.5 to0.99, 1 to 9.99, and ≥10. Kappa statistics wereused to determine the agreement levels betweenthe original and the PT readings. The nature andorigin of the discrepant results were calculatedby bootstrapping. A total of 946 specimens wereretested. The kappa values were 0.91 forpositive/negative categorical classification and", "metadata": {}}
+{"_id": "32181055", "title": "", "text": "The role of regulatory variation in complex traitsand diseaseWe are in a phase of unprecedentedprogress in identifying genetic loci that causevariation in traits ranging from growth andfitness in simple organisms to disease inhumans. However, a mechanistic understandingof how these loci influence traits is lacking for themajority of loci. Studies of the genetics of geneexpression have emerged as a key tool forlinking DNA sequence variation to phenotypes.Here, we review recent insights into themolecular nature of regulatory variants anddescribe their influence on the transcriptome andthe proteome. We discuss conceptual advancesfrom studies in model organisms and presentexamples of complete chains of causality thatlink individual polymorphisms to changes in geneexpression, which in turn result in physiologicalchanges and, ultimately, disease risk.", "metadata": {}}
+{"_id": "32194449", "title": "", "text": "Adhesion disengagement uncouples intrinsic andextrinsic forces to drive cytokinesis in epithelialtissues.Cytokinesis entails cell invagination by acontractile actomyosin ring. In epithelia,E-cadherin-mediated adhesion connects thecortices of contacting cells; thus, it is unclearhow invagination occurs, how the new junctionforms, and how tissue integrity is preserved.Investigations in Drosophila embryos first showthat apicobasal cleavage is polarized:invagination is faster from the basal than fromthe apical side. Ring contraction but not itspolarized constriction is controlled by septinfilaments and Anillin. Polarized cleavage is dueinstead to mechanical anchorage of the ring toE-cadherin complexes. Formation of the newjunction requires local adhesion disengagementin the cleavage furrow, followed by newE-cadherin complex formation at the newinterface. E-cadherin disengagement depends onthe tension exerted by the cytokinetic ring andby neighboring cells. We uncover intrinsic and", "metadata": {}}
+{"_id": "32250572", "title": "", "text": "The epithelial inward rectifier channel Kir7.1displays unusual K+ permeation properties.Ratand human cDNAs were isolated that bothencoded a 360 amino acid polypeptide with atertiary structure typical of inwardly rectifyingK+ channel (Kir) subunits. The new proteins,termed Kir7.1, were <37% identical to other Kirsubunits and showed various unique residues atconserved sites, particularly near the poreregion. High levels of Kir7.1 transcripts weredetected in rat brain, lung, kidney, and testis. Insitu hybridization of rat brain sectionsdemonstrated that Kir7.1 mRNA was absent fromneurons and glia but strongly expressed in thesecretory epithelial cells of the choroid plexus (asconfirmed by in situ patch-clampmeasurements). In cRNA-injected Xenopusoocytes Kir7.1 generated macroscopic Kircurrents that showed a very shallow dependenceon external K+ ([K+]e), which is in markedcontrast to all other Kir channels. At a holdingpotential of -100 mV, the inward current through", "metadata": {}}
+{"_id": "32263707", "title": "", "text": "Oral fingolimod (FTY720) for relapsing multiplesclerosis.BACKGROUND Fingolimod (FTY720) is anew oral immunomodulating agent underevaluation for the treatment of relapsing multiplesclerosis. METHODS We randomly assigned 281patients to receive oral fingolimod, at a dose of1.25 mg or 5.0 mg, or a placebo once daily, andwe followed these patients for 6 months withmagnetic resonance imaging (MRI) and clinicalevaluations (core study, months 0 to 6). Theprimary end point was the total number ofgadolinium-enhanced lesions recorded onT(1)-weighted MRI at monthly intervals for 6months. In an extension study in which theinvestigators and patients remained unaware ofthe dose assignments (months 7 to 12), patientswho received placebo underwent randomizationagain to one of the fingolimod doses. RESULTS Atotal of 255 patients completed the core study.The median total number ofgadolinium-enhanced lesions on MRI was lowerwith 1.25 mg of fingolimod (1 lesion, P<0.001)", "metadata": {}}
+{"_id": "32275758", "title": "", "text": "Nonoverlapping functions of DNA polymerasesmu, lambda, and terminaldeoxynucleotidyltransferase duringimmunoglobulin V(D)J recombination in vivo.DNApolymerases mu (pol mu), lambda (pol lambda),and terminal deoxynucleotidyltransferase (TdT)are enzymes of the pol X family that sharehomology in sequence and functional domainorganization. We showed previously that pol muparticipates in light chain but surprisingly notheavy chain gene rearrangement. We show herethat immunoglobulin heavy chain junctions frompol lambda-deficient animals have shorter lengthwith normal N-additions, thus indicating that pollambda is recruited during heavy chainrearrangement at a step that precedes the actionof TdT. In contrast to previous in vitro studies,analysis of animals with combined inactivation ofthese enzymes revealed no overlapping orcompensatory activities for V(D)J recombinationbetween pol mu, pol lambda, and TdT. Thiscomplex usage of polymerases with distinct", "metadata": {}}
+{"_id": "32322418", "title": "", "text": "Moderate regular exercise increases basalproduction of nitric oxide in elderlywomen.Vascular endothelial cells produce nitricoxide (NO), which is a potent vasodilatorsubstance and is thought to haveantiatherosclerotic properties. Therefore, it hasalso been proposed that NO may be useful toregulate vascular tonus and prevent progressionof atherosclerosis. On the other hand, NOactivity reduces with aging. We previouslyreported that the plasma nitrite/nitrate (NOx:the stable end product of NO) concentration wassignificantly increased by intense aerobicexercise training in healthy young humans. Wehypothesized that lifestyle modification (e.g.,even mild regular exercise training) can increaseNO production in previously sedentary olderhumans. We measured the plasma NOxconcentration before and after a mild aerobicexercise training regimen (cycling on a legergometer at 80% ventilatory threshold for 30min, 5 days/week) for 3 months in elderly", "metadata": {}}
+{"_id": "32324430", "title": "", "text": "Competition between target sites of regulatorsshapes post-transcriptional generegulationPost-transcriptional gene regulation(PTGR) of mRNA turnover, localization andtranslation is mediated by microRNAs (miRNAs)and RNA-binding proteins (RBPs). Theseregulators exert their effects by binding tospecific sequences within their target mRNAs.Increasing evidence suggests that competitionfor binding is a fundamental principle of PTGR.Not only can miRNAs be sequestered andneutralized by the targets with which theyinteract through a process termed 'sponging',but competition between binding sites ondifferent RNAs may also lead to regulatorycrosstalk between transcripts. Here, wequantitatively model competition effects underphysiological conditions and review the role ofendogenous sponges for PTGR in light of the keyfeatures that emerge.", "metadata": {}}
+{"_id": "32328114", "title": "", "text": "Primary prevention of ischemic stroke: Astatement for healthcare professionals from theStroke Council of the American HeartAssociation.Stroke ranks as the third leadingcause of death in the United States. It is nowestimated that there are more than 700 000incident strokes annually and 4.4 million strokesurvivors.1 2 The economic burden of stroke wasestimated by the American Heart Association tobe $51 billion (direct and indirect costs) in1999.3 Despite the advent of treatment ofselected patients with acute ischemic stroke withtissue plasminogen activator and the promise ofother experimental therapies, the best approachto reducing the burden of stroke remainsprevention.4 5 High-risk or stroke-proneindividuals can be identified and targeted forspecific interventions.6 This is important becauseepidemiological data suggest a substantialleveling off of prior declines in stroke-relatedmortality and a possible increase in strokeincidence.7 8   The Stroke Council of the", "metadata": {}}
+{"_id": "32353339", "title": "", "text": "Chimeric live, attenuated vaccine againstJapanese encephalitis (ChimeriVax-JE): phase 2clinical trials for safety and immunogenicity,effect of vaccine dose and schedule, and memoryresponse to challenge with inactivated Japaneseencephalitis antigen.ChimeriVax-JE is a live,attenuated vaccine against Japaneseencephalitis, using yellow fever (YF) 17D vaccineas a vector. In a double-blind phase 2 trial, 99adults received vaccine, placebo, or YF 17Dvaccine (YF-VAX). ChimeriVax-JE was welltolerated, with no differences in adverse eventsbetween treatment groups. Viremias resultingfrom administration of ChimeriVax-JE andYF-VAX were of short duration and low titer; 82(94%) of 87 subjects administered graded doses(1.8-5.8 log(10)) of ChimeriVax-JE developedneutralizing antibodies. A second dose,administered 30 days later, had no boostereffect. Previous inoculation with YF did notinterfere with ChimeriVax-JE, but there was asuggestion (not statistically significant) that", "metadata": {}}
+{"_id": "32357890", "title": "", "text": "Global prevalence of anxiety disorders: asystematic review andmeta-regression.BACKGROUND The literaturedescribing the global prevalence of anxietydisorders is highly variable. A systematic reviewand meta-regression were undertaken toestimate the prevalence of anxiety disorders andto identify factors that may influence theseestimates. The findings will inform the newGlobal Burden of Disease study. Method Asystematic review identified prevalence studiesof anxiety disorders published between 1980 and2009. Electronic databases, reference lists,review articles and monographs were searchedand experts then contacted to identify missingstudies. Substantive and methodological factorsassociated with inter-study variability wereidentified through meta-regression analyses andthe global prevalence of anxiety disorders wascalculated adjusting for study methodology.RESULTS The prevalence of anxiety disorderswas obtained from 87 studies across 44", "metadata": {}}
+{"_id": "32372280", "title": "", "text": "Expression of optineurin, a glaucoma-linkedgene, is influenced by elevated intraocularpressure.Optineurin (optic neuropathy inducingprotein; OPTN) was recently linked to 16.7% offamilies with primary open-angle glaucoma. Thefunction of OPTN in the eye is not known, but ispresent in the trabecular meshwork, which isresponsible for maintenance of intraocularpressure (IOP). To gain insight into the role ofOPTN in the development of glaucoma westudied its expression in response to factorsknown to be associated with the disease:elevated IOP, tumor necrosis factor-alpha(TNFalpha), and dexamethasone (DEX). Weperformed the treatments in human organcultures under conditions mimickingphysiological pressure. We find OPTNsignificantly upregulated after 2, 4, and 7 days ofsustained elevated IOP. OPTN expression is alsoinduced 2.3-fold by TNFalpha and 2.6-fold byprolonged DEX treatment. These resultsdemonstrate that OPTN is part of the", "metadata": {}}
+{"_id": "32390525", "title": "", "text": "Prevention of malaria in long-termtravelers.CONTEXT Long-term travelers, definedhere as those traveling for periods of 6 monthsor longer, face particular challenges regardingmalaria prevention. Current guidelines formalaria prevention primarily address preventionof Plasmodium falciparum infections inshort-term travelers. OBJECTIVES To examinethe risk of malaria in long-term travelers, recentdevelopments in personal protective measures,and the safety and tolerability of malariachemoprophylaxis during long-term use and toconsider prevention strategies includingcontinuous chemoprophylaxis, stand-byemergency self-treatment, seasonal prophylaxis,and strategies to prevent primary infection andrelapses from P vivax malaria. EVIDENCEACQUISITION Comprehensive search of scientificpublications including MEDLINE via both OVIDand PubMED for relevant studies and articleswith a cutoff date of July 2006, using the searchterms long-term travel and malaria prevention,", "metadata": {}}
+{"_id": "32408470", "title": "", "text": "Activation of AMPKα2 in adipocytes is essentialfor nicotine-induced insulin resistance invivoCigarette smoking promotes body weightreduction in humans while paradoxically alsopromoting insulin resistance (IR) andhyperinsulinemia. However, the mechanismsbehind these effects are unclear. Here we showthat nicotine, a major constituent of cigarettesmoke, selectively activates AMP-activatedprotein kinase α2 (AMPKα2) in adipocytes, whichin turn phosphorylates MAP kinasephosphatase-1 (MKP1) at serine 334, initiatingits proteasome-dependent degradation. Thenicotine-dependent reduction of MKP1 inducesthe aberrant activation of both p38mitogen-activated protein kinase and c-JunN-terminal kinase, leading to increasedphosphorylation of insulin receptor substrate 1(IRS1) at serine 307. Phosphorylation of IRS1leads to its degradation, protein kinase Binhibition, and the loss of insulin-mediatedinhibition of lipolysis. Consequently, nicotine", "metadata": {}}
+{"_id": "32421068", "title": "", "text": "Availability of evidence of benefits on overallsurvival and quality of life of cancer drugsapproved by European Medicines Agency:retrospective cohort study of drug approvals2009-13Objective To determine the availabilityof data on overall survival and quality of lifebenefits of cancer drugs approved in Europe.Design Retrospective cohort study. SettingPublicly accessible regulatory and scientificreports on cancer approvals by the EuropeanMedicines Agency (EMA) from 2009 to 2013.Mainoutcome measures Pivotal and postmarketingtrials of cancer drugs according to their designfeatures (randomisation, crossover, blinding),comparators, and endpoints. Availability andmagnitude of benefit on overall survival orquality of life determined at time of approval andafter market entry. Validated European Societyfor Medical Oncology Magnitude of ClinicalBenefit Scale (ESMO-MCBS) used to assess theclinical value of the reported gains in publishedstudies of cancer drugs. Results From 2009 to", "metadata": {}}
+{"_id": "32423829", "title": "", "text": "A cluster randomized, controlled trial of breastand cervix cancer screening in Mumbai, India:methodology and interim results after threerounds of screening.Cervix and Breast cancersare the most common cancers among womenworldwide and extract a large toll in developingcountries. In May 1998, supported by a grantfrom the NCI (US), the Tata Memorial Hospital,Mumbai, India, started a cluster-randomized,controlled, screening-trial for cervix and breastcancer using trained primary health workers toprovide health-education, visual-inspection ofcervix (with 4% acetic acid-VIA) and clinicalbreast examination (CBE) in the screening arm,and only health education in the control arm.Four rounds of screening at 2-year intervals willbe followed by 8 years of monitoring forincidence and mortality from cervix and breastcancers. The methodology and interim resultsafter three rounds of screening are presentedhere. Good randomization was achieved betweenthe screening (n = 75360) and control arms (n =", "metadata": {}}
+{"_id": "32450297", "title": "", "text": "Evidence for energy-dependent accumulation ofparaquat into rat lungTHE herbicide paraquat(N,N′-dimethyl 4,4′-bipyridilium) can producewidespread oedema and fibrosis in the humanlung after accidental ingestion1–3. In thosecases where death occurs after several weeks,there are no apparent pulmonary changes duringthe first few days following ingestion. Animalexperiments in a variety of species have shownthe lung to be the major target organ4–6. Afteradministration of paraquat to animals, the lunghas a high initial concentration and retainsparaquat7–9. This retention appears to berelated to the development of lung damage7 (L.L. Smith and M. S. Rose, unpublished work). Themechanism of retention of paraquat by the lungis at present not understood.", "metadata": {}}
+{"_id": "32454714", "title": "", "text": "Role of gut commensal microflora in thedevelopment of experimental autoimmuneencephalomyelitis.Mucosal tolerance has beenconsidered a potentially important pathway forthe treatment of autoimmune disease, includinghuman multiple sclerosis and experimentalconditions such as experimental autoimmuneencephalomyelitis (EAE). There is limitedinformation on the capacity of commensal gutbacteria to induce and maintain peripheralimmune tolerance. Inbred SJL and C57BL/6 micewere treated orally with a broad spectrum ofantibiotics to reduce gut microflora. Reduction ofgut commensal bacteria impaired thedevelopment of EAE. Intraperitonealantibiotic-treated mice showed no significantdecline in the gut microflora and developed EAEsimilar to untreated mice, suggesting thatreduction in disease activity was related toalterations in the gut bacterial population.Protection was associated with a reduction ofproinflammatory cytokines and increases in", "metadata": {}}
+{"_id": "32462603", "title": "", "text": "Epidemiology of surgically managed pelvic organprolapse and urinary incontinence.OBJECTIVE Todetermine the incidence of surgically managedpelvic organ prolapse and urinary incontinence ina population-based cohort, and to describe theirclinical characteristics. METHODS Ourretrospective cohort study included all patientsundergoing surgical treatment for prolapse andincontinence during 1995; all were members ofKaiser Permanente Northwest, which included149,554 women age 20 or older. A standardizeddata-collection form was used to review allinpatient and outpatient charts of the 395women identified. Variables examined includedage, ethnicity, height, weight, vaginal parity,smoking history, medical history, and surgicalhistory, including the preoperative evaluation,procedure performed, and details of all priorprocedures. Analysis included calculation ofage-specific and cumulative incidences anddetermination of the number of primaryoperations compared with repeat operations", "metadata": {}}
+{"_id": "32463364", "title": "", "text": "Antihypertensive classes, cognitive decline andincidence of dementia: a networkmeta-analysis.OBJECTIVES Prevention ofcognitive decline and dementia with bloodpressure lowering treatments has showninconsistent results. We compared the effects ofdifferent classes of antihypertensive drugs on theincidence of dementia, and on cognitive function.METHODS We conducted a systematic reviewand included 19 randomized trials (18 515individuals) and 11 studies (831 674 individuals)analysing the effects of antihypertensivetreatment on cognition and on the incidence ofdementia, respectively, in hypertensive patientswithout prior cerebrovascular disorders. Networkmeta-analysis was used for the comparison ofantihypertensive classes. RESULTSAntihypertensive treatment, regardless of thedrug class, had benefits on overall cognition[effect size 0.05, 95% confidence interval (CI)0.02-0.07] and all cognitive functions exceptlanguage. Antihypertensive treatment reduced", "metadata": {}}
+{"_id": "32481310", "title": "", "text": "Abnormal hemoglobins in a quarter millionpeople.Hemolysates of erythrocytes from morethan a quarter million people in Alabama wereelectrophoresed on cellulose acetate, pH 8.4, andthose samples exhibiting an abnormality werealso electrophoresed in citrate agar, pH 6.0. Theglobin chains of mutants other than Hb S and Cwere electrophoresed in urea-mercaptoethanolbuffers at both pH 8.9 and pH 6.0, and 60 ofthem were also analyzed structurally. Of about6000 samples from whites, only three containedabnormal hemoglobins--Hb D Los Angeles, Hb JBaltimore, and one unidentified. Of 249,000samples from blacks, about 29,000 containedelectrophoretically detectable abnormalities,most of them associated with Hb S or C, presentin a frequency of about 9% and 3%,respectively. About 1000 samples resolved intopatterns of potential clinical significance. Twentyother mutant hemoglobins were detected, invarious genetic combinations in 164 kindreds;four of these-Hb Alabama, Montgomery,", "metadata": {}}
+{"_id": "32532238", "title": "", "text": "Cellular adaptation to mechanical stress: role ofintegrins, Rho, cytoskeletal tension andmechanosensitive ion channels.To understandhow cells sense and adapt to mechanical stress,we applied tensional forces to magneticmicrobeads bound to cell-surface integrinreceptors and measured changes in beaddisplacement with sub-micrometer resolutionusing optical microscopy. Cells exhibited fourtypes of mechanical responses: (1) animmediate viscoelastic response; (2) earlyadaptive behavior characterized bypulse-to-pulse attenuation in response tooscillatory forces; (3) later adaptive cellstiffening with sustained (>15 second) staticstresses; and (4) a large-scale repositioningresponse with prolonged (>1 minute) stress.Importantly, these adaptation responses differedbiochemically. The immediate and earlyresponses were affected by chemicallydissipating cytoskeletal prestress (isometrictension), whereas the later adaptive response", "metadata": {}}
+{"_id": "32533299", "title": "", "text": "Cutting edge: Candida albicans hyphae formationtriggers activation of the Nlrp3inflammasome.The proinflammatory cytokineIL-1beta plays an important role in antifungalimmunity; however, the mechanisms by whichfungal pathogens trigger IL-1beta secretion areunclear. In this study we show that infection withCandida albicans is sensed by the Nlrp3inflammasome, resulting in the subsequentrelease of IL-1beta. The ability of C. albicans toswitch from a unicellular yeast form into afilamentous form is essential for activation of theNlrp3 inflammasome, as C. albicans mutantsincapable of forming hyphae were defective intheir ability to induce macrophage IL- 1betasecretion. Nlrp3-deficient mice alsodemonstrated increased susceptibility toinfection with C. albicans, which is consistentwith a key role for Nlrp3 in innate immuneresponses to the pathogen C. albicans.", "metadata": {}}
+{"_id": "32534305", "title": "", "text": "Type 2 diabetes and subsequent incidence ofbreast cancer in the Nurses' HealthStudy.OBJECTIVE Hyperinsulinemia maypromote mammary carcinogenesis. Insulinresistance has been linked to an increased risk ofbreast cancer and is also characteristic of type 2diabetes. We prospectively evaluated theassociation between type 2 diabetes and invasivebreast cancer incidence in the Nurses' HealthStudy. RESEARCH DESIGN AND METHODS Atotal of 116,488 female nurses who were 30-55years old and free of cancer in 1976 werefollowed through 1996 for the occurrence of type2 diabetes and through 1998 for incidentinvasive breast cancer, verified by medicalrecords and pathology reports. RESULTS During2.3 million person-years of follow-up, weidentified 6,220 women with type 2 diabetes and5,189 incident cases of invasive breast cancer.Women with type 2 diabetes had a modestlyelevated incidence of breast cancer (hazard ratio[HR] = 1.17; 95% CI 1.01-1.35) compared with", "metadata": {}}
+{"_id": "32556431", "title": "", "text": "Virus-encoded microRNAs.MicroRNAs (miRNAs)are the subject of enormous interest. They aresmall non-coding RNAs that play a regulatoryrole in numerous and diverse cellular processessuch as immune function, apoptosis andtumorigenesis. Several virus families have beenshown to encode miRNAs, and an appreciationfor their roles in the viral infectious cyclecontinues to grow. Despite the identification ofnumerous (>225) viral miRNAs, an in depthfunctional understanding of most virus-encodedmiRNAs is lacking. Here we focus on a few viralmiRNAs with well-defined functions. We usethese examples to extrapolate general themes ofviral miRNA activities including autoregulation ofviral gene expression, avoidance of hostdefenses, and a likely important role inmaintaining latent and persistent infections. Wehypothesize that although the molecularmechanisms and machinery are similar, themajority of viral miRNAs may utilize a targetstrategy that differs from host miRNAs. That is,", "metadata": {}}
+{"_id": "32587939", "title": "", "text": "Wolfram syndrome 1 and adenylyl cyclase 8interact at the plasma membrane to regulateinsulin production and secretionEndoplasmicreticulum (ER) stress causes pancreatic β-celldysfunction and contributes to β-cell loss and theprogression of type 2 diabetes. Wolframsyndrome 1 (WFS1) has been shown to be animportant regulator of the ER stress signallingpathway; however, its role in β-cell functionremains unclear. Here we provide evidence thatWFS1 is essential for glucose- and glucagon-likepeptide 1 (GLP-1)-stimulated cyclic AMPproduction and regulation of insulin biosynthesisand secretion. Stimulation with glucose causesWFS1 translocation from the ER to the plasmamembrane, where it forms a complex withadenylyl cyclase 8 (AC8), an essentialcAMP-generating enzyme in the β-cell thatintegrates glucose and GLP-1 signalling. ERstress and mutant WFS1 inhibit complexformation and activation of AC8, reducing cAMPsynthesis and insulin secretion. These findings", "metadata": {}}
+{"_id": "32598644", "title": "", "text": "Two Rice GRAS Family Genes Responsive toN-Acetylchitooligosaccharide Elicitor are Inducedby Phytoactive Gibberellins: Evidence forCross-Talk Between Elicitor and GibberellinSignaling in Rice CellsIn this study, we presentdata showing that two members of the GRASfamily of genes from rice, CIGR1 andCIGR2(chitin-inducible gibberellin-responsive),inducible by the potent elicitorN-acetylchitooligosaccharide (GN), are rapidlyinduced by exogenous gibberellins. The patternof mRNA accumulation was dependent on thedose and biological activity of the gibberellins,suggesting that the induction of the genes bygibberellin is mediated by a biological receptorcapable of specific recognition and signaltransduction upon perception of the phytoactivecompounds. Further pharmacological analysisrevealed that the CIGR1 and CIGR2 mRNAaccumulation by treatment with gibberellin isdependent upon proteinphosphorylation/dephosphorylation events. In", "metadata": {}}
+{"_id": "32611468", "title": "", "text": "Ghrelin's second life: from appetite stimulator toglucose regulator.Ghrelin, a 28 amino acidpeptide hormone produced by the stomach, wasthe first orexigenic hormone to be discoveredfrom the periphery. The octanoyl modification atSer³, mediated by ghrelin O-acyltransferase(GOAT), is essential for ghrelin's biologicalactivity. Ghrelin stimulates food intake throughbinding to its receptor (GRLN-R) on neurons inthe arcuate nucleus of the hypothalamus. Ghrelinis widely expressed throughout the body;accordingly, it is implicated in several otherphysiological functions, which include growthhormone release, gastric emptying, and bodyweight regulation. Ghrelin and GRLN-Rexpression are also found in the pancreas,suggesting a local physiological role. Accordingly,several recent studies now point towards animportant role for ghrelin and its receptor in theregulation of blood glucose homeostasis, which isthe main focus of this review. Severalmechanisms of this regulation by ghrelin have", "metadata": {}}
+{"_id": "32638085", "title": "", "text": "Histone acetylation and deacetylation inyeastHistone acetylation and deacetylation in theyeast Saccharomyces cerevisiae occur bytargeting acetyltransferase and deacetylaseenzymes to gene promoters and, in anuntargeted and global manner, by affecting mostnucleosomes. Recently, new roles for histoneacetylation have been uncovered, not only intranscription but also in DNA replication, repairand heterochromatin formation. Interestingly,specific acetylatable lysines can function asbinding sites for regulatory factors. Moreover,histone deacetylation is not only repressive butcan be required for gene activity.", "metadata": {}}
+{"_id": "32665136", "title": "", "text": "Neuroinflammation in spinal cord injury:therapeutic targets for neuroprotection andregeneration.Traumatic spinal cord injurytriggers a complex local inflammatory reactioncapable of enhancing repair and exacerbatingpathology. The composition and effectorpotential of the post-injury cellular and molecularimmune cascade changes as a function of timeand distance from the lesion. Production alongthis time-space continuum of cytokines,proteases, and growth factors establishesdynamic environments that lead to the death,damage, repair or growth of affected neuronsand glia. Microenvironmental cues, therefore,generated by the cells therein, may determinethese distinct fates of repair versus pathology.To harness repair, it is necessary to manipulatethe assembly and phenotype of cells thatcomprise the neuroinflammatory response toinjury. Here, the potential of theneuroinflammatory response to cause outcomessuch as pain, regeneration, and functional", "metadata": {}}
+{"_id": "32671519", "title": "", "text": "Evaluation of systemic amyloidosis byscintigraphy with 123I-labeled serum amyloid Pcomponent.BACKGROUND In systemicamyloidosis the distribution and progression ofdisease have been difficult to monitor, becausethey can be demonstrated only by biopsy. Serumamyloid P component (SAP) is a normalcirculating plasma protein that is deposited onamyloid fibrils because of its specific bindingaffinity for them. We investigated whetherlabeled SAP could be used to locate amyloiddeposits. METHODS Purified human SAP labeledwith iodine-123 was given intravenously to 50patients with biopsy-proved systemicamyloidosis--25 with the AL (primary) type and25 with the AA (secondary) type--and to 26control patients with disease and 10 healthysubjects. Whole-body images and regional viewswere obtained after 24 hours and read in ablinded fashion. RESULTS In the patients withamyloidosis the 123I-SAP was localized rapidlyand specifically in amyloid deposits. The", "metadata": {}}
+{"_id": "32697244", "title": "", "text": "The Neurovascular Unit Coming of Age: AJourney through Neurovascular Coupling inHealth and DiseaseThe concept of theneurovascular unit (NVU), formalized at the 2001Stroke Progress Review Group meeting of theNational Institute of Neurological Disorders andStroke, emphasizes the intimate relationshipbetween the brain and its vessels. Since then,the NVU has attracted the interest of theneuroscience community, resulting inconsiderable advances in the field. Here thecurrent state of knowledge of the NVU will beassessed, focusing on one of its most vital roles:the coupling between neural activity and bloodflow. The evidence supports a conceptual shift inthe mechanisms of neurovascular coupling, froma unidimensional process involvingneuronal-astrocytic signaling to local bloodvessels to a multidimensional one in whichmediators released from multiple cells engagedistinct signaling pathways and effector systemsacross the entire cerebrovascular network in a", "metadata": {}}
+{"_id": "32712381", "title": "", "text": "Effects of MAL61 and MAL62 overexpression onmaltose fermentation of baker's yeast in leandough.The predominant fermentable sugar inlean dough is maltose. To improve the leaveningability of baker's yeast in lean dough, maltosemetabolism should be improved. Maltase(alpha-glucosidase, encoded by MAL62) andmaltose permease (encoded by MAL61) are themajor factors involved in maltose metabolism.The major rate-limiting factor in maltosemetabolism and leavening ability of baker's yeastremains unclear. In this work, MAL61 and/orMAL62 overexpression strains were constructedto investigate the decisive factor for maltosemetabolism of industrial baker's yeast in leandough. Our results show that elevated maltosepermease activity by MAL61 overexpressionyielded less improvement in maltosefermentation compared to elevated maltaseactivity by MAL62 overexpression. Significantincrease in maltase activity by MAL62overexpression could result in a 44% increase in", "metadata": {}}
+{"_id": "32720933", "title": "", "text": "Human papillomavirus genotype 31 does notexpress detectable microRNA levels during latentor productive virus replication.It has recentlybecome clear that several pathogenic DNAviruses express virally encoded microRNAs ininfected cells. In particular, numerous microRNAshave been identified in a range of human andanimal herpesviruses, and individual microRNAshave also been identified in members of thepolyoma- and adenovirus families. Although theirfunctions remain largely unknown, it seems likelythat these viral microRNAs play an important rolein viral replication in vivo. Here we present ananalysis of the microRNAs expressed in humancells during the latent and productive phases ofthe human papillomavirus genotype 31 (HPV31)replication cycle. Although over 500 cellularmicroRNAs were cloned and identified, not asingle HPV31-specific microRNA was obtained.We therefore concluded that HPV31, and possiblyhuman papillomaviruses in general, does notexpress viral microRNAs.", "metadata": {}}
+{"_id": "32721137", "title": "", "text": "Integrated genomic profiling of endometrialcarcinoma associates aggressive tumors withindicators of PI3 kinase activation.Although 75%of endometrial cancers are treated at an earlystage, 15% to 20% of these recur. Weperformed an integrated analysis ofgenome-wide expression and copy-number datafor primary endometrial carcinomas withextensive clinical and histopathological data todetect features predictive of recurrent disease.Unsupervised analysis of the expression datadistinguished 2 major clusters with strikinglydifferent phenotypes, including significantdifferences in disease-free survival. To identifypossible mechanisms for these differences, weperformed a global genomic survey ofamplifications, deletions, and loss ofheterozygosity, which identified 11 significantlyamplified and 13 significantly deleted regions.Amplifications of 3q26.32 harboring theoncogene PIK3CA were associated with poorprognosis and segregated with the aggressive", "metadata": {}}
+{"_id": "32742683", "title": "", "text": "Alteration of the Antitumor Immune Response byCancer-Associated FibroblastsAmong cellspresent in the tumor microenvironment,activated fibroblasts termed cancer-associatedfibroblasts (CAFs), play a critical role in thecomplex process of tumor-stroma interaction.CAFs, one of the prominent stromal cellpopulations in most types of human carcinomas,have been involved in tumor growth,angiogenesis, cancer stemness, extracellularmatrix remodeling, tissue invasion, metastasis,and even chemoresistance. During the pastdecade, these activated tumor-associatedfibroblasts have also been involved in themodulation of the anti-tumor immune responseon various levels. In this review, we describe ourcurrent understanding of how CAFs accomplishthis task as well as their potential therapeuticimplications.", "metadata": {}}
+{"_id": "32743723", "title": "", "text": "Confusion and memory loss from capsular genuinfarction: a thalamocortical disconnectionsyndrome?We examined six patients with anabrupt change in behavior after infarctioninvolving the inferior genu of the internalcapsule. The acute syndrome featuredfluctuating alertness, inattention, memory loss,apathy, abulia, and psychomotor retardation,suggesting frontal lobe dysfunction. Contralateralhemiparesis and dysarthria were generally mild,except when the infarct extended into theposterior limb. Neuropsychological testing in fivepatients with left-sided infarcts revealed severeverbal memory loss. Additional cognitive deficitsconsistent with dementia occurred in fourpatients. A right-sided infarct caused transientimpairment in visuospatial memory. Functionalbrain imaging in three patients showed a focalreduction in hemispheric perfusion mostprominent in the ipsilateral inferior and medialfrontal cortex. We infer that the capsular genuinfarct interrupted the inferior and anterior", "metadata": {}}
+{"_id": "32766786", "title": "", "text": "Neoadjuvant androgen ablation before radicalprostatectomy in cT2bNxMo prostate cancer:5-year results.PURPOSE In the initial report ofthe Lupron Depot Neoadjuvant Prostate CancerStudy Group patients who received 3 months ofandrogen deprivation had a significant decreasein the positive margin rate. We monitored thesepatients for 5 years and to our knowledgepresent the longest followup of any neoadjuvanttrial. MATERIALS AND METHODS Amulti-institutional prospective randomized trialwas performed between February 1992 and April1994 involving patients with stage cT2b prostatecancer, including 138 who received 3 months ofleuprolide plus flutamide before radicalprostatectomy and 144 who underwent radicalprostatectomy only. Patients were followed every6 months with serum prostate specific antigen(PSA) testing for 5 years. Biochemical recurrencewas defined as PSA greater than 0.4 ng./ml.RESULTS At 5 years there was no difference inthe biochemical recurrence rate. PSA was less", "metadata": {}}
+{"_id": "32770503", "title": "", "text": "Full-length transcriptome assembly fromRNA-Seq data without a referencegenome.Massively parallel sequencing of cDNAhas enabled deep and efficient probing oftranscriptomes. Current approaches fortranscript reconstruction from such data oftenrely on aligning reads to a reference genome,and are thus unsuitable for samples with apartial or missing reference genome. Here wepresent the Trinity method for de novo assemblyof full-length transcripts and evaluate it onsamples from fission yeast, mouse and whitefly,whose reference genome is not yet available. Byefficiently constructing and analyzing sets of deBruijn graphs, Trinity fully reconstructs a largefraction of transcripts, including alternativelyspliced isoforms and transcripts from recentlyduplicated genes. Compared with other de novotranscriptome assemblers, Trinity recovers morefull-length transcripts across a broad range ofexpression levels, with a sensitivity similar tomethods that rely on genome alignments. Our", "metadata": {}}
+{"_id": "32776084", "title": "", "text": "Growth restricted in vitro culture conditions alterthe imprinted gene expression patterns of mouseembryonic stem cells.Embryonic stem (ES)cell-derived clones and chimeras are oftenassociated with growth abnormalities during fetaldevelopment, leading to the production ofover/under-weight offspring that show elevatedneonatal mortality and morbidity. Due to the roleplayed by imprinted genes in controlling fetalgrowth, much of the blame is pointed atimproper epigenetic reprogramming of cells usedin the procedures. We have analyzed theexpression pattern of two growth regulatoryimprinted genes, namely insulin like growthfactor II (Igf2) and H19, in mouse ES cellscultured under growth restricted conditions andafter in vitro aging. Culture of cells withserum-depleted media (starvation) and at highcell density (confluence) increased theexpression of both imprinted genes and led toaberrant methylation profiles of differentiallymethylated regions in key regulatory sites of Igf2", "metadata": {}}
+{"_id": "32777637", "title": "", "text": "When is antipsychotic polypharmacy supportedby research evidence? Implications forQI.BACKGROUND Concurrent use of multiplestanding antipsychotics (antipsychoticpolypharmacy) is increasingly common amongboth inpatients and outpatients. Although thishas often been cited as a potentialquality-of-care problem, reviews of researchevidence on antipsychotic polypharmacy havenot distinguished between appropriate versusinappropriate use. METHODS A MEDLINE searchfrom 1966 to December 2007 was completed toidentify studies comparing changes in symptoms,functioning, and/or side effects between patientstreated with multiple antipsychotics and patientstreated with a single antipsychotic. The studieswere reviewed in two groups on the basis ofwhether prescribing was concordant withguideline recommendations formultiple-antipsychotic use. RESULTS A review ofthe literature, including three randomizedcontrolled trials, found no support for the use of", "metadata": {}}
+{"_id": "32787042", "title": "", "text": "The Liverpool uveal melanoma liver metastasespathway: outcome following liver resection.AIMTo determine the outcome of patients thatunderwent liver resection for metastases fromuveal melanoma. METHODS Over a 9-yearperiod, patients referred with uveal melanomametastases were included. Following treatmentof primary uveal melanoma, high-risk patientswere offered to be enrolled into a 6-monthlynon-contrast liver magnetic resonance imaging(MRI) surveillance. Following detection of livermetastases, patients were staged with acontrast-enhanced (Primovist(®)) liver MRI,computer tomography (CT) of the thorax andstaging laparoscopy. RESULTS 155 patients werereferred with uveal melanoma liver metastases,of which 17 (11.0%) patients had liver resectionand one patient was treated with percutaneousradio-frequency ablation. The majority ofpatients undergoing liver resection were treatedwith multiple metastectomies (n = 8) and threepatients had major liver resections. The overall", "metadata": {}}
+{"_id": "32797183", "title": "", "text": "Smooth muscle lineage diversity in the chickembryo. Two types of aortic smooth muscle celldiffer in growth and receptor-mediatedtranscriptional responses to transforming growthfactor-beta.Lineage analysis studies in the avianembryo have identified two types of smoothmuscle cells (SMCs) in the tunica media of largeelastic arteries; one that originates within thecardiac neural crest and is ectoderm in origin(Ect) and another that arises from localmesenchyme of mesodermal origin (Mes). Todetermine if differences in primary embryoniclineage can give rise to SMCs with stabledifferences in growth and differentiationproperties, we isolated Ect and Mes SMCs fromthe Day 14 chick embryo aorta. We report thatdespite different primary embryonic origins, Ectand Mes SMCs express nearly identical levels ofseven SMC differentiation markers in vitro,consistent with their common smooth muscledevelopmental fates in vivo. By contrast, EctSMCs displayed a greater capacity for growth in", "metadata": {}}
+{"_id": "32827351", "title": "", "text": "THE USE OF LEAD CITRATE AT HIGH pH AS ANELECTRON-OPAQUE STAIN IN ELECTRONMICROSCOPYAqueous solutions of lead salts (1,2) and saturated solutions of lead hydroxide (1)have been used as stains to enhance theelectron-scattering properties of components ofbiological materials examined in the electronmicroscope. Saturated solutions of leadhydroxide (1), while staining more intensely thaneither lead acetate or monobasic lead acetate (l ,2), form insoluble lead carbonate upon exposureto air. The avoidance of such precipitates whichcontaminate surfaces of sections during staininghas been the stimulus for the development ofelaborate procedures for exclusion of air orcarbon dioxide (3, 4). Several modifications ofWatson's lead hydroxide stain (1) have recentlyappeared (5-7). All utilize relatively high pH(approximately 12) and one contains smallamounts of tartrate (6), a relatively weakcomplexing agent (8), in addition to lead. Thesemodified lead stains are less liable to", "metadata": {}}
+{"_id": "32850528", "title": "", "text": "Amylase, Lipase, and Acute Pancreatitis in PeopleWith Type 2 Diabetes Treated With Liraglutide:Results From the LEADER RandomizedTrial.OBJECTIVE To evaluate serum amylase andlipase levels and the rate of acute pancreatitis inpatients with type 2 diabetes and highcardiovascular risk randomized to liraglutide orplacebo and observed for 3.5-5.0 years.RESEARCH DESIGN AND METHODS A total of9,340 patients with type 2 diabetes wererandomized to either liraglutide or placebo(median observation time 3.84 years). Fastingserum lipase and amylase were monitored. Acutepancreatitis was adjudicated in a blindedmanner. RESULTS Compared with the placebogroup, liraglutide-treated patients had increasesin serum lipase and amylase of 28.0% and 7.0%,respectively. Levels were increased at 6 monthsand then remained stable. During the study, 18(0.4% [1.1 events/1,000 patient-years ofobservation] [PYO]) liraglutide-treated and 23(0.5% [1.7 events/1,000 PYO]) placebo patients", "metadata": {}}
+{"_id": "32852283", "title": "", "text": "Zoledronic acid is unable to induce apoptosis, butslows tumor growth and prolongs survival fornon-small-cell lung cancers.BACKGROUNDAlthough zoledronic acid (ZOL), athird-generation nitrogen-containingbisphosphonate, has been identified as anattractive therapeutic agent against breastcancer, prostate cancer, multiple myeloma aswell as small-cell lung cancer (SCLC), as best aswe are aware, the anti-tumor effect of ZOL uponnon-small-cell lung cancer (NSCLC) remains tobe effectively investigated. This study examinedthe effects of ZOL upon the line-1 tumor cell,using a murine lung adenocarcinoma cell linesimilar to the behavior of human lungadenocarcinoma. METHODS We investigated theanti-tumor effects of ZOL (3-100 microM) online-1 tumor cells in vitro, including cellularproliferation, by means of an MTT assay,cell-cycle analysis by flow cytometry and byassessing the level of apoptosis by annexinV/propidium iodide (PI) and", "metadata": {}}
+{"_id": "32906513", "title": "", "text": "A central role for central tolerance.Recentelucidation of the role of central tolerance inpreventing organ-specific autoimmunity haschanged our concepts of self/nonselfdiscrimination. This paradigmatic shift is largelyattributable to the discovery of promiscuousexpression of tissue-restricted self-antigens(TRAs) by medullary thymic epithelial cells(mTECs). TRA expression in mTECs mirrorsvirtually all tissues of the body, irrespective ofdevelopmental or spatio-temporal expressionpatterns. This review summarizes currentknowledge on the cellular and molecularregulation of TRA expression in mTECs, outlinesrelevant mechanisms of antigen presentationand modes of tolerance induction, and discussesimplications for the pathogenesis of autoimmunediseases and other biological processes such asfertility, pregnancy, puberty, and tumor defense.", "metadata": {}}
+{"_id": "32909242", "title": "", "text": "Contribution of traditional healers to a ruraltuberculosis control programme in Hlabisa, SouthAfrica.SETTING The rural health district ofHlabisa, KwaZulu-Natal, SouthAfrica.   OBJECTIVES To assess the acceptabilityand effectiveness of traditional healers assupervisors of tuberculosis (TB) treatment in anexisting directly observed treatment,short-course (DOTS) programme. DESIGN Anobservational study comparing treatmentoutcomes among new TB patients in the threeintervention sub-districts offered the additionaloption of traditional healers for directly observedtreatment (DOT) supervision with those in theremainder of the district offered the standardrange of options for DOT supervision (healthfacility, community health worker and laypersons). A comparison was also made oftreatment outcomes between different optionsfor DOT supervision. RESULTS A total of 3461 TBpatients were registered in Hlabisa District fromApril 1999 to December 2000, of whom 2823", "metadata": {}}
+{"_id": "32922179", "title": "", "text": "Alzheimer's disease: the two-hithypothesis.There are many lines of evidenceshowing that oxidative stress and aberrantmitogenic changes have important roles in thepathogenesis of Alzheimer's disease (AD).However, although both oxidative stress and cellcycle-related abnormalities are early events,occurring before any cytopathology, the relationbetween these two events, and their role inpathophysiology was, until recently, unclear.However, on the basis of studies of mitogenicand oxidative stress signalling pathways in AD,we proposed a \"two-hit hypothesis\" which statesthat although either oxidative stress orabnormalities in mitotic signalling canindependently serve as initiators, both processesare necessary to propagate diseasepathogenesis. In this paper, we summariseevidence for oxidative stress and abnormalmitotic alterations in AD and explain the two-hithypothesis by describing how both mechanismsare necessary and invariant features of disease.", "metadata": {}}
+{"_id": "32927401", "title": "", "text": "Toll-like receptor 7 mediates pruritusToll-likereceptors are typically expressed in immune cellsto regulate innate immunity. We found thatfunctional Toll-like receptor 7 (TLR7) wasexpressed in C-fiber primary sensory neuronsand was important for inducing itch (pruritus),but was not necessary for eliciting mechanical,thermal, inflammatory and neuropathic pain inmice. Our results indicate that TLR7 mediatesitching and is a potential therapeutic target foranti-itch treatment in skin disease conditions.", "metadata": {}}
+{"_id": "32927475", "title": "", "text": "Antigen presentation by major histocompatibilitycomplex class I-B molecules.Class I-b genesconstitute the majority of MHC class I loci. Thesemonomorphic or oligomorphic molecules havebeen described in many organisms; they arebest characterized in the mouse, which containsa substantial number of potentially intact genes.Two main characteristics differentiate class I-bfrom class I-a molecules: limited polymorphismand lower cell surface expression. Thesedistinguishing features suggest possiblegeneralizations regarding the evolution andfunction of this class. Additionally, class I-bproteins tend to have shorter cytoplasmicdomains or in some cases may be secreted ormay substitute a lipid anchor for thetransmembrane domain. Some are alsoexpressed in a limited distribution of cells ortissues. At least six mouse MHC class I-bmolecules have been shown to present antigensto alpha beta or gamma delta T cells. Recentadvances have provided insight into the", "metadata": {}}
+{"_id": "32955023", "title": "", "text": "Pdgfrβ+ Mural Preadipocytes Contribute toAdipocyte Hyperplasia Induced by High-Fat-DietFeeding and Prolonged Cold Exposure in AdultMice.The expansion of white adipose tissue(WAT) in obesity involves de novo differentiationof new adipocytes; however, the cellular origin ofthese cells remains unclear. Here, we utilizeZfp423(GFP) reporter mice to characterizeadipose mural (Pdgfrβ(+)) cells with varyinglevels of the preadipocyte commitment factorZfp423. We find that adipose tissue containsdistinct mural populations, with levels of Zfp423distinguishing adipogenic from inflammatory-likemural cells. Using our \"MuralChaser\" lineagetracking system, we uncover adiposeperivascular cells as developmental precursors ofadipocytes formed in obesity, with adipogenesisand precursor abundance regulated in adepot-dependent manner. Interestingly,Pdgfrβ(+) cells do not significantly contribute tothe initial cold-induced recruitment of beigeadipocytes in WAT; it is only after prolonged cold", "metadata": {}}
+{"_id": "32969964", "title": "", "text": "Effect of clinical guidelines on medical practice: asystematic review of rigorousevaluations.Although interest in clinicalguidelines has never been greater, uncertaintypersists about whether they are effective. Thedebate has been hampered by the lack of arigorous overview. We have identified 59published evaluations of clinical guidelines thatmet defined criteria for scientific rigour; 24investigated guidelines for specific clinicalconditions, 27 studied preventive care, and 8looked at guidelines for prescribing or for supportservices. All but 4 of these studies detectedsignificant improvements in the process of careafter the introduction of guidelines and all but 2of the 11 studies that assessed the outcome ofcare reported significant improvements. Weconclude that explicit guidelines do improveclinical practice, when introduced in the contextof rigorous evaluations. However, the size of theimprovements in performance variedconsiderably.", "metadata": {}}
+{"_id": "32975424", "title": "", "text": "Threonine as a carbon source for Escherichiacoli.Threonine can be used aerobically as the solesource of carbon and energy by mutants ofEscherichia coli K-12. The pathway used involvesthe conversion of threonine via threoninedehydrogenase to aminoketobutyric acid, whichis further metabolized by aminoketobutyric acidligase, forming acetyl coenzyme A and glycine. Astrain devoid of serine transhydroxymethylaseuses this pathway and excretes glycine as awaste product. Aminoketobutyric acid ligaseactivity was demonstrated after passage of crudeextracts through Sephadex G100.", "metadata": {}}
+{"_id": "32985041", "title": "", "text": "Protein S-nitrosylation: a physiological signal forneuronal nitric oxideNitric oxide (NO) has beenlinked to numerous physiological andpathophysiological events that are not readilyexplained by the well established effects of NOon soluble guanylyl cyclase. Exogenous NOS-nitrosylates cysteine residues in proteins, butwhether this is an important function ofendogenous NO is unclear. Here, using a newproteomic approach, we identify a population ofproteins that are endogenously S-nitrosylated,and demonstrate the loss of this modification inmice harbouring a genomic deletion of neuronalNO synthase (nNOS). Targets of NO includemetabolic, structural and signalling proteins thatmay be effectors for neuronally generated NO.These findings establish protein S-nitrosylationas a physiological signalling mechanism fornNOS.", "metadata": {}}
+{"_id": "33030946", "title": "", "text": "Hypoxia\u0000Sensitive COMMD1 IntegratesSignaling and Cellular Metabolism in HumanMacrophages and SuppressesOsteoclastogenesisSummary Hypoxia augmentsinflammatory responses and osteoclastogenesisby incompletely understood mechanisms. Weidentified COMMD1 as a cell\u0000intrinsic negativeregulator of osteoclastogenesis that issuppressed by hypoxia. In human macrophages,COMMD1 restrained induction of NF\u0000&kgr;Bsignaling and a transcription factorE2F1\u0000dependent metabolic pathway by thecytokine RANKL. Downregulation of COMMD1protein expression by hypoxia augmentedRANKL\u0000induced expression of inflammatory andE2F1 target genes and downstreamosteoclastogenesis. E2F1 targets includedglycolysis and metabolic genes including CKBthat enabled cells to meet metabolic demands inchallenging environments, as well asinflammatory cytokine\u0000driven target genes.Expression quantitative trait locus analysis linked", "metadata": {}}
+{"_id": "33036897", "title": "", "text": "Production of tyrosol by Candida albicansbiofilms and its role in quorum sensing andbiofilm development.Tyrosol and farnesol arequorum-sensing molecules produced by Candidaalbicans which accelerate and block,respectively, the morphological transition fromyeasts to hyphae. In this study, we haveinvestigated the secretion of tyrosol by C.albicans and explored its likely role in biofilmdevelopment. Both planktonic (suspended) cellsand biofilms of four C. albicans strains, includingthree mutants with defined defects in the Efg 1and Cph 1 morphogenetic signaling pathways,synthesized extracellular tyrosol during growthat 37 degrees C. There was a correlationbetween tyrosol production and biomass for bothcell types. However, biofilm cells secreted atleast 50% more tyrosol than did planktonic cellswhen tyrosol production was related to cell dryweight. The addition of exogenous farnesol to awild-type strain inhibited biofilm formation by upto 33% after 48 h. Exogenous tyrosol appeared", "metadata": {}}
+{"_id": "33063763", "title": "", "text": "Regulated nucleo/cytoplasmic exchange of HOG1MAPK requires the importin beta homologs NMD5and XPO1.MAP kinase signaling modules serve totransduce extracellular signals to the nucleus ofeukaryotic cells, but little is known about howsignals cross the nuclear envelope. Exposure ofyeast cells to increases in extracellularosmolarity activates the HOG1 MAP kinasecascade, which is composed of three tiers ofprotein kinases, namely the SSK2, SSK22 andSTE11 MAPKKKs, the PBS2 MAPKK, and theHOG1 MAPK. Using green fluorescent protein(GFP) fusions of these kinases, we found thatHOG1, PBS2 and STE11 localize to the cytoplasmof unstressed cells. Following osmotic stress,HOG1, but neither PBS2 nor STE11, translocatesinto the nucleus. HOG1 translocation occurs veryrapidly, is transient, and correlates with thephosphorylation and activation of the MAP kinaseby its MAPKK. HOG1 phosphorylation isnecessary and sufficient for nucleartranslocation, because a catalytically inactive", "metadata": {}}
+{"_id": "33068577", "title": "", "text": "FBW7 regulates endothelial functions bytargeting KLF2 for ubiquitination anddegradationF-box and WD repeatdomain-containing 7 (FBW7), thesubstrate-binding subunit of E3 ubiquitin ligaseSCFFBW7 (a complex of SKP1, cullin-1 andFBW7), plays important roles in variousphysiological and pathological processes.Although FBW7 is required for vasculardevelopment, its function in the endotheliumremains to be investigated. In this study, weshow that FBW7 is an important regulator ofendothelial functions, including angiogenesis,leukocyte adhesion and the endothelial barrierintegrity. Using RNA interference, we found thatthe depletion of FBW7 markedly impairsangiogenesis in vitro and in vivo. We identifiedthe zinc finger transcription factor Krüppel-likefactor 2 (KLF2) as a physiological target of FBW7in endothelial cells. Knockdown of FBW7expression resulted in the accumulation ofendogenous KLF2 protein in endothelial cells.", "metadata": {}}
+{"_id": "33076846", "title": "", "text": "Role of RhoA-specific guanine exchange factorsin regulation of endomitosis inmegakaryocytes.Polyploidization can precede thedevelopment of aneuploidy in cancer.Polyploidization in megakaryocytes (Mks), incontrast, is a highly controlled developmentalprocess critical for efficient platelet productionvia unknown mechanisms. Using primary cells,we demonstrate that the guanine exchangefactors GEF-H1 and ECT2, which are oftenoverexpressed in cancer and are essential forRhoA activation during cytokinesis, must bedownregulated for Mk polyploidization. The first(2N-4N) endomitotic cycle requires GEF-H1downregulation, whereas subsequent cycles(>4N) require ECT2 downregulation. Exogenousexpression of both GEF-H1 and ECT2 preventsendomitosis, resulting in proliferation of 2N Mks.Furthermore, we have shown that themechanism by which polyploidization isprevented in Mks lacking Mkl1, which is mutatedin megakaryocytic leukemia, is via elevated", "metadata": {}}
+{"_id": "33118292", "title": "", "text": "Optimal therapy for reduction oflipoprotein(a).WHAT IS KNOWN AND OBJECTIVEThere is a growing body of experimental andclinical evidence for the atherogenic andpro-thrombotic potential of Lipoprotein(a)[Lp(a)], as well as for its causative role incoronary heart disease and stroke. We commenton novel strategies for reducing Lp(a) levels.COMMENT Irrespective of the underlyingbiological mechanisms explaining theathero-thrombotic potential of this lipoprotein,most work has focused on the identification ofsuitable therapies for hyperlipoproteinemia(a).These include apheresis techniques, nicotinicacid and statins. None of these strategies havebeen shown to be definitely effective orconvenient for the patient and new strategies arebeing attempted. Promising results are emergingwith therapeutic interventions targeting the'inflammatory pathways' by inhibition ofInterleukin-6 (IL-6) signalling with naturalcompounds (e.g., Ginko biloba) or the IL-6", "metadata": {}}
+{"_id": "33127778", "title": "", "text": "Early gastric cancer and dysplasia.Since theconcept of early gastric cancer was firstdescribed in Japan in 1962, its treatment hasevolved from curative surgical resection toendoscopic resection, initially with polypectomyto more recently with endoscopic submucosaldissection. As worldwide experience with theseendoscopic techniques evolve and gainacceptance, studies have confirmed itscomparable effectiveness with historical surgicaloutcomes in carefully selected patients. Thecriteria for endoscopic resection have expandedto offer more patients improved quality of life,avoiding the morbidity and mortality associatedwith surgery. This article summarizes theevolutional role of endoscopic and surgicaltherapy in early gastric cancer.", "metadata": {}}
+{"_id": "33135135", "title": "", "text": "The impact of homelessness on children.Thisarticle reviews and critiques community-basedresearch on the effects of homelessness onchildren. Homeless children confront seriousthreats to their ability to succeed and their futurewell-being. Of particular concern are healthproblems, hunger, poor nutrition, developmentaldelays, anxiety, depression, behavioralproblems, and educational underachievement.Factors that may mediate the observedoutcomes include inadequate shelter conditions,instability in residences and shelters, inadequateservices, and barriers to accessing services thatare available. Public policy initiatives are neededto meet the needs of homeless children.", "metadata": {}}
+{"_id": "33169058", "title": "", "text": "Strategies of microbial cheater control.Thepotential benefits of cooperation inmicroorganisms can be undermined by geneticconflict within social groups, which can take theform of 'cheating'. For cooperation to succeed asan evolutionary strategy, the negative effects ofsuch conflict must somehow be either preventedor mitigated. To generate an interpretiveframework for future research in microbialbehavioural ecology, here we outline a widerange of hypothetical mechanisms by whichcheaters might be constrained.", "metadata": {}}
+{"_id": "33203108", "title": "", "text": "Golden Hours in Severe Paraquat Poisoning-TheRole of Early HaemoperfusionTherapy.INTRODUCTION Paraquat is a commonlyingested poison especially in Southern India.There is no antidote for paraquat poison andconsumption is often fatal. The usual cause ofdeath is either acute lung injury or multi-organfailure. AIM To evaluate the role of earlyhaemoperfusion as a therapy in paraquatpoisoned patients. MATERIALS AND METHODSThis study was a retrospective analysis ofpatients admitted to a Tertiary Medical CollegeHospital between January 2012 and December2015 with history of paraquat consumption,comparing outcomes in those who received onlygastric lavage and symptomatic treatment withthose who received haemoperfusion as atherapy. The role of early haemoperfusion (≤ 6hours) vs late haemoperfusion (> 6 hours) inparaquat poisoned patients was also compared.The data of these patients was extracted andanalysed with respect to age, sex, mode of", "metadata": {}}
+{"_id": "33257464", "title": "", "text": "Changes in the prevalence of cerebral palsy forchildren born very prematurely within apopulation-based program over 30years.CONTEXT Although cerebral palsy (CP)among extremely premature infants has beenreported as a major morbidity outcome, thereare difficulties comparing published CP ratesfrom many sites over various birth years.OBJECTIVE To assess the changes inpopulation-based, gestational age-specificprevalence rates of CP among extremelypremature infants over 30 years. DESIGNProspective population-based longitudinaloutcome study. SETTING AND PARTICIPANTS InNorthern Alberta, 2318 infants 20 to 27 weeks'gestational age with birth weights of 500 to 1249g were liveborn from 1974 through 2003. By 2years of age, 1437 (62%) had died, 23 (1%)were lost to follow-up, and 858 (37%) hadreceived multidisciplinary neurodevelopmentalassessment. MAIN OUTCOME MEASUREPopulation-based prevalence rates of CP were", "metadata": {}}
+{"_id": "33339202", "title": "", "text": "Desferrioxamine treatment of porphyria cutaneatarda in a patient with HIV and chronic renalfailure.Porphyria cutanea tarda (PCT) can occurin HIV patients. Current evidence suggests thatHIV infection may interfere with the hepaticcytochrome oxidase system, leading to porphyrinmetabolism impairment. Moreover, chronichemodialysis in renal failure may be a risk factorfor PCT. In addition to the contributory factorsfor PCT associated to HIV infection, it is possiblethat porphyrin accumulation secondary to renalfailure may play a role in the expression of thisdisease. We report a case of PCT in an HIV-1infected patient under blood dialysis, refractoryto antimalarials and controlled withdesferrioxamine.", "metadata": {}}
+{"_id": "33387953", "title": "", "text": "Mutations in G protein beta subunits promotetransformation and kinase inhibitorresistanceActivating mutations in genes encodingG protein α (Gα) subunits occur in 4-5% of allhuman cancers, but oncogenic alterations in Gβsubunits have not been defined. Here wedemonstrate that recurrent mutations in the Gβproteins GNB1 and GNB2 confercytokine-independent growth and activatecanonical G protein signaling. Multiple mutationsin GNB1 affect the protein interface that bindsGα subunits as well as downstream effectors anddisrupt Gα interactions with the Gβγ dimer.Different mutations in Gβ proteins clusteredpartly on the basis of lineage; for example, all 11GNB1 K57 mutations were in myeloid neoplasms,and seven of eight GNB1 I80 mutations were in Bcell neoplasms. Expression of patient-derivedGNB1 variants in Cdkn2a-deficient mouse bonemarrow followed by transplantation resulted ineither myeloid or B cell malignancies. In vivotreatment with the dual PI3K-mTOR inhibitor", "metadata": {}}
+{"_id": "33390472", "title": "", "text": "Isolation of major pancreatic cell types andlong-term culture-initiating cells using novelhuman surface markers.We have developed anovel panel of cell-surface markers for theisolation and study of all major cell types of thehuman pancreas. Hybridomas were selectedafter subtractive immunization of Balb/C micewith intact or dissociated human islets andassessed for cell-type specificity and cell-surfacereactivity by immunohistochemistry and flowcytometry. Antibodies were identified by specificbinding of surface antigens on islet(panendocrine or alpha-specific) and nonisletpancreatic cell subsets (exocrine and duct).These antibodies were used individually or incombination to isolate populations of alpha, beta,exocrine, or duct cells from primary humanpancreas by FACS and to characterize thedetailed cell composition of human isletpreparations. They were also employed to showthat human islet expansion cultures originatedfrom nonendocrine cells and that insulin", "metadata": {}}
+{"_id": "33397197", "title": "", "text": "Re-engineered CD40 receptor enables potentpharmacological activation of dendritic-cellcancer vaccines in vivoModest clinical outcomesof dendritic-cell (DC) vaccine trials call for therefinement of DC vaccine design. Although manypotential antigens have been identified,development of methods to enhance antigenpresentation by DCs has lagged. We haveengineered a potent, drug-inducible CD40(iCD40) receptor that permits temporallycontrolled, lymphoid-localized, DC-specificactivation. iCD40 is comprised of amembrane-localized cytoplasmic domain of CD40fused to drug-binding domains. This allows it torespond to a lipid-permeable, high-affinitydimerizer drug while circumventingectodomain-dependent negative-feedbackmechanisms. These modifications permitprolonged activation of iCD40-expressing DCs invivo, resulting in more potent CD8+ T-celleffector responses, including the eradication ofpreviously established solid tumors, relative to", "metadata": {}}
+{"_id": "33409100", "title": "", "text": "Effect of homocysteine lowering on mortality andvascular disease in advanced chronic kidneydisease and end-stage renal disease: arandomized controlled trial.CONTEXT Highplasma homocysteine levels are a risk factor formortality and vascular disease in observationalstudies of patients with chronic kidney disease.Folic acid and B vitamins decrease homocysteinelevels in this population but whether they lowermortality is unknown. OBJECTIVE To determinewhether high doses of folic acid and B vitaminsadministered daily reduce mortality in patientswith chronic kidney disease. DESIGN, SETTING,AND PARTICIPANTS Double-blind randomizedcontrolled trial (2001-2006) in 36 USDepartment of Veterans Affairs medical centers.Median follow-up was 3.2 years for 2056participants aged 21 years or older withadvanced chronic kidney disease (estimatedcreatinine clearance < or =30 mL/min) (n =1305) or end-stage renal disease (n = 751) andhigh homocysteine levels (> or = 15", "metadata": {}}
+{"_id": "33417012", "title": "", "text": "Treated individuals who progress to action ormaintenance for one behavior are more likely tomake similar progress on another behavior:coaction results of a pooled data analysis ofthree trials.OBJECTIVE This study compared, intreatment and control groups, the phenomena ofcoaction, which is the probability that takingeffective action on one behavior is related totaking effective action on a second behavior.METHODS Pooled data from three randomizedtrials of Transtheoretical Model (TTM) tailoredinterventions (n=9461), completed in the U.S. in1999, were analyzed to assess coaction in threebehavior pairs (diet and sun protection, diet andsmoking, and sun protection and smoking). Oddsratios (ORs) compared the likelihood of takingaction on a second behavior compared to takingaction on only one behavior. RESULTS Acrossbehavior pairs, at 12 and 24 months, the ORs forthe treatment group were greater on an absolutebasis than for the control group, with two beingsignificant. The combined ORs at 12 and 24", "metadata": {}}
+{"_id": "33458992", "title": "", "text": "Trabecular bone score as an indicator for skeletaldeterioration in diabetes.CONTEXT Trabecularbone score (TBS) is a novel texture index thatevaluates the pixel gray-level variations inlumbar spine dual-energy X-ray absorptiometryimages and is related to bone microarchitectureindependent of bone mineral density (BMD).OBJECTIVE We investigated lumbar spine TBS asan indicator for skeletal deterioration in diabetes.DESIGN AND SETTING Cross-sectional data werecollected from subjects participating in anongoing prospective, community-based, cohortstudy from 2009 to 2010. PARTICIPANTS Weincluded 1229 men and 1529 postmenopausalwomen older than 50 years in the Ansungcohort. OUTCOME MEASURES Biochemicalparameters, lumbar spine TBS, and BMD fromdual-energy X-ray absorptiometry images weremeasured. RESULTS Lumbar spine TBS waslower in men with diabetes than in nondiabeticmen (1.287 ± 0.005 vs 1.316 ± 0.003, P <.001), whereas lumbar spine BMD was higher in", "metadata": {}}
+{"_id": "33499189", "title": "", "text": "Full activation of the T cell receptor requires bothclustering and conformational changes at CD3.Tcell receptor (TCR-CD3) triggering involves bothreceptor clustering and conformational changesat the cytoplasmic tails of the CD3 subunits. Themechanism by which TCRalphabeta ligandbinding confers conformational changes to CD3 isunknown. By using well-defined ligands, weshowed that induction of the conformationalchange requires both multivalent engagementand the mobility restriction of the TCR-CD3imposed by the plasma membrane. Theconformational change is elicited by cooperativerearrangements of two TCR-CD3 complexes anddoes not require accompanying changes in thestructure of the TCRalphabeta ectodomains. Thisconformational change at CD3 reverts uponligand dissociation and is required for T cellactivation. Thus, our permissive geometry modelprovides a molecular mechanism thatrationalizes how the information of ligand bindingto TCRalphabeta is transmitted to the CD3", "metadata": {}}
+{"_id": "33507866", "title": "", "text": "Class III PI3K Vps34 plays an essential role inautophagy and in heart and liver function.Acritical regulator of autophagy is the Class IIIPI3K Vps34 (also called PIK3C3). Although Vps34is known to play an essential role in autophagy inyeast, its role in mammals remains elusive. Toelucidate the physiological function of Vps34 andto determine its precise role in autophagy, wehave generated Vps34(f/f) mice, in whichexpression of Cre recombinase results in adeletion of exon 4 of Vps34 and a frame shiftcausing a deletion of 755 of the 887 amino acidsof Vps34. Acute ablation of Vps34 in MEFs uponadenoviral Cre infection results in adiminishment of localized generation ofphosphatidylinositol 3-phosphate and blockadeof both endocytic and autophagic degradation.Starvation-induced autophagosome formation isblocked in both Vps34-null MEFs and liver.Liver-specific Albumin-Cre;Vps34(f/f) micedeveloped hepatomegaly and hepatic steatosis,and impaired protein turnover. Ablation of Vps34", "metadata": {}}
+{"_id": "33533307", "title": "", "text": "Sex-based differences in the effect of digoxin forthe treatment of heart failure.BACKGROUND TheDigitalis Investigation Group trial reported thattreatment with digoxin did not decrease overallmortality among patients with heart failure anddepressed left ventricular systolic function,although it did reduce hospitalizations slightly.Even though the epidemiologic features, causes,and prognosis of heart failure vary between menand women, sex-based differences in the effectof digoxin were not evaluated. METHODS Weconducted a post hoc subgroup analysis toassess whether there were sex-based differencesin the effect of digoxin therapy among the 6800patients in the Digitalis Investigation Groupstudy. The presence of an interaction betweensex and digoxin therapy with respect to theprimary end point of death from any cause wasevaluated with the use of Mantel-Haenszel testsof heterogeneity and a multivariable Coxproportional-hazards model, adjusted fordemographic and clinical variables. RESULTS", "metadata": {}}
+{"_id": "33535222", "title": "", "text": "Recipient-type specific CD4+CD25+ regulatory Tcells favor immune reconstitution and controlgraft-versus-host disease while maintaininggraft-versus-leukemia.CD4+CD25+ regulatory Tcells (Treg's) play a pivotal role in preventingorgan-specific autoimmune diseases and ininducing tolerance to allogeneic organtransplants. We and others recentlydemonstrated that high numbers of Treg's canalso modulate graft-versus-host disease (GVHD)if administered in conjunction with allogeneichematopoietic stem cell transplantation in mice.In a clinical setting, it would be impossible toobtain enough freshly purified Treg's from asingle donor to have a therapeutic effect. Thus,we performed regulatory T cell expansion ex vivoby stimulation with allogeneic APCs, which hasthe additional effect of producingalloantigen-specific regulatory T cells. Here weshow that regulatory T cells specific forrecipient-type alloantigens control GVHD whilefavoring immune reconstitution. Irrelevant", "metadata": {}}
+{"_id": "33535447", "title": "", "text": "Expression of the gene encoding thechemorepellent semaphorin III is induced in thefibroblast component of neural scar tissueformed following injuries of adult but notneonatal CNS.This study evaluates theexpression of the chemorepellent semaphorin III(D)/collapsin-1 (sema III) following lesions tothe rat CNS. Scar tissue, formed afterpenetrating injuries to the lateral olfactory tract(LOT), cortex, perforant pathway, and spinalcord, contained numerous spindle-shaped cellsexpressing high levels of sema III mRNA. Theproperties of these cells were investigated indetail in the lesioned LOT. Most sema IIImRNA-positive cells were located in the core ofthe scar and expressed proteins characteristic forfibroblast-like cells. Neuropilin-1, a sema IIIreceptor, was expressed in injured neurons withprojections to the lesion site, in a subpopulationof scar-associated cells and in blood vesselsaround the scar. In contrast to lesions made inthe mature CNS, LOT transection in neonates did", "metadata": {}}
+{"_id": "33554389", "title": "", "text": "The relationship of the level of cyclic amp todifferentiation in primary cultures of chick musclecells.Abstract The effect of increased levels ofcAMP upon the differentiation of primary culturesof chick myo blasts has been investigated. 0.1mM But 2 cAMP or 1 mM3-isobutyl-1-methylxanthine was added to thecultures 24 h after plating and maintainedthroughout the 70 h period of culture examined.Both reagents were found to markedly delay thetime of fusion of the myoblasts but had noobservable effect upon the increase in activity ofcreatine phosphokinase. Morphologicalexamination of the cells revealed no difference inthe relative numbers of myoblasts andfibroblasts between the control, But 2 cAMP and3-isobutyl-1-methylxanthine cultures, but thelatter reagent appeared to cause some inhibitionof cell proliferation.", "metadata": {}}
+{"_id": "33569870", "title": "", "text": "Intact endothelial autophagy is required tomaintain vascular lipid homeostasis.Thephysiological role of autophagic flux within thevascular endothelial layer remains poorlyunderstood. Here, we show that in primaryendothelial cells, oxidized and native LDLstimulates autophagosome formation. Moreover,by both confocal and electron microscopy, excessnative or modified LDL appears to be engulfedwithin autophagic structures. Transientknockdown of the essential autophagy geneATG7 resulted in higher levels of intracellular(125) I-LDL and oxidized LDL (OxLDL)accumulation, suggesting that in endothelialcells, autophagy may represent an importantmechanism to regulate excess, exogenous lipids.The physiological importance of theseobservations was assessed using mice containinga conditional deletion of ATG7 within theendothelium. Following acute intravenousinfusion of fluorescently labeled OxLDL, micelacking endothelial expression of ATG7", "metadata": {}}
+{"_id": "33634749", "title": "", "text": "Induction of circadian gene expression in humansubcutaneous adipose-derived stemcells.OBJECTIVE Genes encoding the circadiantranscriptional apparatus exhibit robustoscillatory expression in murine adipose tissues.This study tests the hypothesis that humansubcutaneous adipose-derived stem cells (ASCs)provide an in vitro model in which to monitor theactivity of the core circadian transcriptionalapparatus. RESEARCH METHODS ANDPROCEDURES Primary cultures ofundifferentiated or adipocyte-differentiated ASCswere treated with dexamethasone, rosiglitazone,or 30% fetal bovine serum. The response ofundifferentiated ASCs to dexamethasone wasfurther evaluated in the presence of lithiumchloride. Lithium inhibits glycogen synthasekinase 3, a key component of the circadianapparatus. Total RNA was harvested at 4-hourintervals over 48 hours and examined byreal-time reverse transcription polymerase chainreaction (RT-PCR). RESULTS", "metadata": {}}
+{"_id": "33638477", "title": "", "text": "BCL9 promotes tumor progression by conferringenhanced proliferative, metastatic, andangiogenic properties to cancer cells.Severalcomponents of the Wnt signaling cascade havebeen shown to function either as tumorsuppressor proteins or as oncogenes in multiplehuman cancers, underscoring the relevance ofthis pathway in oncogenesis and the need forfurther investigation of Wnt signalingcomponents as potential targets for cancertherapy. Here, using expression profiling analysisas well as in vitro and in vivo functional studies,we show that the Wnt pathway component BCL9is a novel oncogene that is aberrantly expressedin human multiple myeloma as well as coloncarcinoma. We show that BCL9 enhancesbeta-catenin-mediated transcriptional activityregardless of the mutational status of the Wntsignaling components and increases cellproliferation, migration, invasion, and themetastatic potential of tumor cells by promotingloss of epithelial and gain of mesenchymal-like", "metadata": {}}
+{"_id": "33667484", "title": "", "text": "Programmed cell death pathways in cancer: areview of apoptosis, autophagy and programmednecrosis.Programmed cell death (PCD), referringto apoptosis, autophagy and programmednecrosis, is proposed to be death of a cell in anypathological format, when mediated by anintracellular program. These three forms of PCDmay jointly decide the fate of cells of malignantneoplasms; apoptosis and programmed necrosisinvariably contribute to cell death, whereasautophagy can play either pro-survival orpro-death roles. Recent bulk of accumulatingevidence has contributed to a wealth ofknowledge facilitating better understanding ofcancer initiation and progression with the threedistinctive types of cell death. To be able todecipher PCD signalling pathways may aiddevelopment of new targeted anti-cancertherapeutic strategies. Thus in this review, wepresent a brief outline of apoptosis, autophagyand programmed necrosis pathways andapoptosis-related microRNA regulation, in", "metadata": {}}
+{"_id": "33669399", "title": "", "text": "Loss of gametophytic self-incompatibility withevolution of inbreeding depression.Gametophyticself-incompatibility (SI) in plants is a widespreadmechanism preventing self-fertilization and theensuing inbreeding depression, but it oftenevolves to self-compatibility. We analyze geneticmechanisms for the breakdown of gametophyticSI, incorporating a dynamic model for theevolution of inbreeding depression allowing forpartial purging of nearly recessive lethalmutations by selfing, and accounting for pollenlimitation and sheltered load linked to theS-locus. We consider two mechanisms for thebreakdown of gametophytic SI: a nonfunctionalS-allele and an unlinked modifier locus thatinactivates the S-locus. We show that, under awide range of conditions, self-compatible allelescan invade a self-incompatible population.Conditions for invasion are always less stringentfor a nonfunctional S-allele than for a modifierlocus. The spread of self-compatible genotypes isfavored by extremely high or low selfing rates, a", "metadata": {}}
+{"_id": "33677323", "title": "", "text": "The oncogenic microRNA miR-22 targets theTET2 tumor suppressor to promotehematopoietic stem cell self-renewal andtransformation.MicroRNAs are frequentlyderegulated in cancer. Here we show thatmiR-22 is upregulated in myelodysplasticsyndrome (MDS) and leukemia and its aberrantexpression correlates with poor survival. Toexplore its role in hematopoietic stem cellfunction and malignancy, we generatedtransgenic mice conditionally expressing miR-22in the hematopoietic compartment. These micedisplayed reduced levels of global5-hydroxymethylcytosine (5-hmC) and increasedhematopoietic stem cell self-renewalaccompanied by defective differentiation.Conversely, miR-22 inhibition blockedproliferation in both mouse and human leukemiccells. Over time, miR-22 transgenic micedeveloped MDS and hematological malignancies.We also identify TET2 as a key target of miR-22in this context. Ectopic expression of TET2", "metadata": {}}
+{"_id": "33684572", "title": "", "text": "Transmission of atherosclerosis susceptibilitywith gut microbial transplantation.Recent studiesindicate both clinical and mechanistic linksbetween atherosclerotic heart disease andintestinal microbial metabolism of certain dietarynutrients producing trimethylamine N-oxide(TMAO). Here we test the hypothesis that gutmicrobial transplantation can transmit cholinediet-induced TMAO production andatherosclerosis susceptibility. First, a strongassociation was noted between atheroscleroticplaque and plasma TMAO levels in a mousediversity panel (n = 22 strains, r = 0.38; p =0.0001). An atherosclerosis-prone and highTMAO-producing strain, C57BL/6J, and anatherosclerosis-resistant and lowTMAO-producing strain, NZW/LacJ, were selectedas donors for cecal microbial transplantation intoapolipoprotein e null mice in which residentintestinal microbes were first suppressed withantibiotics. Trimethylamine (TMA) and TMAOlevels were initially higher in recipients on", "metadata": {}}
+{"_id": "33720691", "title": "", "text": "The complete primary structure of thespermadhesin AWN, a zona pellucida-bindingprotein isolated from boar spermatozoa.AWN is aboar protein which originates in secretions of themale accessory glands and which becomessperm surface-associated upon ejaculation. It isone of the components thought to mediatesperm adhesion to the egg's zona pellucidathrough a carbohydrate-recognition mechanism.AWN may, thus, participate in the initial eventsof fertilization in the pig. In this report wedescribe its complete primary structure bycombination of protein-chemical and massspectrometric methods. AWN exists as twoisoforms, AWN-1 and AWN-2, which differ in thatAWN-2 is N-terminally acetylated. The aminoacid sequence of AWN contains 133 amino acidresidues and two disulphide bridges betweennearest-neighbour cysteine residues. Analysis ofthe amino acid sequence of the AWN proteinsshowed significant similarity only to AQN-1 andAQN-3, two other boar spermadhesins.", "metadata": {}}
+{"_id": "33723822", "title": "", "text": "What influences government adoption ofvaccines in developing countries? A policyprocess analysis.This paper proposes aframework for examining the process by whichgovernment consideration and adoption of newvaccines takes place, with specific reference todeveloping country settings. The cases of earlyHepatitis B vaccine adoption in Taiwan andThailand are used to explore the relevance ofexplanatory factors identified in the literature aswell as the need to go beyond a variable-centricfocus by highlighting the role of policy contextand process in determining the pace and extentof adoption. The cases suggest the feasibility andimportance of modeling 'causal diversity'-thecomplex set of necessary and sufficientconditions leading to particular decisionaloutcomes-in a broad range of country contexts.A better understanding of the lenses throughwhich government decision-makers filterinformation, and of the arenas in which criticaldecisions are shaped and taken, may assist both", "metadata": {}}
+{"_id": "33733520", "title": "", "text": "Benzodiazepines and injurious falls in communitydwelling elders.BACKGROUND Benzodiazepinesare frequently used medications in the elderly, inwhom they are associated with an increased riskof falling, with sometimes dire consequences.OBJECTIVE To estimate the impact ofbenzodiazepine-associated injurious falls in apopulation of elderly persons. METHOD A nestedcase-control study was conducted using datacollected during 10 years of follow-up of theFrench PAQUID (Personnes Agées QUID)community-based cohort. The main outcomemeasure was the occurrence of an injurious fall,which was defined as a fall resulting inhospitalization, fracture, head trauma or death.Controls (3 : 1) were frequency-matched tocases. Benzodiazepine exposure was the use ofbenzodiazepines over the previous 2 weeksreported at the follow-up visit preceding the fall.RESULTS Benzodiazepine use was significantlyassociated with the occurrence of injurious falls,with a significant interaction with age. The", "metadata": {}}
+{"_id": "33740844", "title": "", "text": "Effect of women's nutrition before and duringearly pregnancy on maternal and infantoutcomes: a systematic review.Currentunderstanding of biologic processes indicatesthat women's nutritional status before andduring early pregnancy may play an importantrole in determining early developmentalprocesses and ensuring successful pregnancyoutcomes. We conducted a systematic review ofthe evidence for the impact of maternal nutritionbefore and during early pregnancy (<12 weeksgestation) on maternal, neonatal and child healthoutcomes and included 45 articles (nineintervention trials and 32 observational studies)that were identified through PubMed andEMBASE database searches and examiningreview articles. Intervention trials andobservational studies show that periconceptional(<12 weeks gestation) folic acid supplementationsignificantly reduced the risk of neural tubedefects. Observational studies suggest thatpreconceptional and periconceptional intake of", "metadata": {}}
+{"_id": "33792330", "title": "", "text": "Kinesin-2 controls development and patterning ofthe vertebrate skeleton by Hedgehog- andGli3-dependent mechanisms.Hedgehog signalingplays an essential role in patterning of thevertebrate skeleton. Here we demonstrate thatconditional inactivation of the Kif3a subunit ofthe kinesin-2 intraflagellar transport motor inmesenchymal skeletal progenitor cells results insevere patterning defects in the craniofacialarea, the formation of split sternum and thedevelopment of polydactyly. These deformitiesare reminiscent of those previously described inmice with deregulated hedgehog signaling. Weshow that in Kif3a-deficient mesenchymal tissuesboth the repressor function of Gli3 transcriptionfactor and the activation of the Shhtranscriptional targets Ptch and Gli1 arecompromised. Quantitative analysis of geneexpression demonstrates that the Gli1 transcriptlevel is dramatically reduced, whereas Gli3expression is not significantly affected bykinesin-2 depletion. However, the motor appears", "metadata": {}}
+{"_id": "33796570", "title": "", "text": "Ablation of NF1 function in neurons inducesabnormal development of cerebral cortex andreactive gliosis in the brain.Neurofibromatosistype 1 (NF1) is a prevalent genetic disorder thataffects growth properties of neural-crest-derivedcell populations. In addition, approximatelyone-half of NF1 patients exhibit learningdisabilities. To characterize NF1 function both invitro and in vivo, we circumvent the embryoniclethality of NF1 null mouse embryos bygenerating a conditional mutation in the NF1gene using Cre/loxP technology. Introduction ofa Synapsin I promoter driven Cre transgenicmouse strain into the conditional NF1background has ablated NF1 function in mostdifferentiated neuronal populations. These micehave abnormal development of the cerebralcortex, which suggests that NF1 has anindispensable role in this aspect of CNSdevelopment. Furthermore, although they aretumor free, these mice display extensiveastrogliosis in the absence of conspicuous", "metadata": {}}
+{"_id": "33835579", "title": "", "text": "Pathology of postprimary tuberculosis in humansand mice: contradiction of long-heldbeliefs.Tuberculosis remains one of the world'sleading infectious causes of death.Approximately 80% of all disease is due topostprimary (secondary) tuberculosis in the lung.Unfortunately, tissues of developing lesions areseldom available and there are no recognizedmodels of postprimary tuberculosis. In thepreantibiotic era when tissues were moreabundant, several investigators described earlypostprimary tuberculosis as a lipid pneumoniaquite different from the caseating granulomascommonly described today. We usedhistopathologic, immunohistochemical and acidfast stains to examine tissues from severalpeople with untreated primary and postprimarytuberculosis and compared the findings withthose of mice with reactivation tuberculosis. Theresults confirmed that developing postprimarytuberculosis begins as a lipid pneumoniaaccompanied by bronchial obstruction in which", "metadata": {}}
+{"_id": "33872649", "title": "", "text": "Secondary aerosolization of viable Bacillusanthracis spores in a contaminated US SenateOffice.CONTEXT Bioterrorist attacks involvingletters and mail-handling systems inWashington, DC, resulted in Bacillus anthracis(anthrax) spore contamination in the HartSenate Office Building and other facilities in theUS Capitol's vicinity. OBJECTIVE To provideinformation about the nature and extent ofindoor secondary aerosolization of B anthracisspores. DESIGN Stationary and personal airsamples, surface dust, and swab samples werecollected under semiquiescent (minimalactivities) and then simulated active officeconditions to estimate secondary aerosolizationof B anthracis spores. Nominal sizecharacteristics, airborne concentrations, andsurface contamination of B anthracis particles(colony-forming units) were evaluated. RESULTSViable B anthracis spores reaerosolized undersemiquiescent conditions, with a markedincrease in reaerosolization during simulated", "metadata": {}}
+{"_id": "33884866", "title": "", "text": "Fingolimod provides long-term protection inrodent models of cerebral ischemia.OBJECTIVEThe sphingosine-1-phosphate (S1P) receptoragonist fingolimod (FTY720), that has shownefficacy in advanced multiple sclerosis clinicaltrials, decreases reperfusion injury in heart,liver, and kidney. We therefore tested thetherapeutic effects of fingolimod in severalrodent models of focal cerebral ischemia. Toassess the translational significance of thesefindings, we asked whether fingolimod improvedlong-term behavioral outcomes, whether delayedtreatment was still effective, and whetherneuroprotection can be obtained in a secondspecies. METHODS We used rodent models ofmiddle cerebral artery occlusion and cell-culturemodels of neurotoxicity and inflammation toexamine the therapeutic potential andmechanisms of neuroprotection by fingolimod.RESULTS In a transient mouse model, fingolimodreduced infarct size, neurological deficit, edema,and the number of dying cells in the core and", "metadata": {}}
+{"_id": "33904473", "title": "", "text": "Induced regeneration—the progress and promiseof direct reprogramming for heartrepairRegeneration of cardiac tissue has thepotential to transform cardiovascular medicine.Recent advances in stem cell biology and directreprogramming, or transdifferentiation, haveproduced powerful new tools to advance thisgoal. In this Review we examine keydevelopments in the generation of newcardiomyocytes in vitro as well as the excitingprogress that has been made toward in vivoreprogramming of cardiac tissue. We alsoaddress controversies and hurdles that challengethe field.", "metadata": {}}
+{"_id": "33904789", "title": "", "text": "\"Sandwich\"-type immunoassay ofcarcinoembryonic antigen in patients receivingmurine monoclonal antibodies for diagnosis andtherapy.Measurements of carcinoembryonicantigen (CEA) in blood increased dramatically insome patients who were receiving injections ofmonoclonal antibody. CEA titers were measuredwith a monoclonal antibody-baseddouble-determinant enzyme immunoassay inwhich untreated plasma specimens were dilutedwith an equal volume of buffer containing mouseserum. Increasing CEA titers were accompaniedby the appearance and coincident increase intiters of human antibody against mouse Ig(HAMA). Adsorption of these sera withsolid-phase anti-human IgG or Protein A restoredantigen titers to pretreatment values; evidentlythe serum factor eliciting false-positive CEA titerswas most probably HAMA. Neither addition ofundiluted mouse serum to the assay mixture norpretreatment by heating plasma specimens to 70degrees C effectively abolished HAMA", "metadata": {}}
+{"_id": "33911859", "title": "", "text": "Mutant dynactin in motor neurondiseaseImpaired axonal transport in motorneurons has been proposed as a mechanism forneuronal degeneration in motor neuron disease.Here we show linkage of a lower motor neurondisease to a region of 4 Mb at chromosome2p13. Mutation analysis of a gene in this intervalthat encodes the largest subunit of the axonaltransport protein dynactin showed a singlebase-pair change resulting in an amino-acidsubstitution that is predicted to distort thefolding of dynactin's microtubule-bindingdomain. Binding assays show decreased bindingof the mutant protein to microtubules. Ourresults show that dysfunction ofdynactin-mediated transport can lead to humanmotor neuron disease.", "metadata": {}}
+{"_id": "33912020", "title": "", "text": "Thioredoxin mediates oxidation-dependentphosphorylation of CRMP2 and growth conecollapse.Semaphorin3A (Sema3A) is a repulsiveguidance molecule for axons, which acts byinducing growth cone collapse throughphosphorylation of CRMP2 (collapsin responsemediator protein 2). Here, we show a role forCRMP2 oxidation and thioredoxin (TRX) in theregulation of CRMP2 phosphorylation and growthcone collapse. Sema3A stimulation generatedhydrogen peroxide (H2O2) through MICAL(molecule interacting with CasL) and oxidizedCRMP2, enabling it to form a disulfide-linkedhomodimer through cysteine-504. OxidizedCRMP2 then formed a transient disulfide-linkedcomplex with TRX, which stimulated CRMP2phosphorylation by glycogen synthase kinase-3,leading to growth cone collapse. We alsoreconstituted oxidation-dependentphosphorylation of CRMP2 in vitro, using alimited set of purified proteins. Our results notonly clarify the importance of H2O2 and CRMP2", "metadata": {}}
+{"_id": "33912748", "title": "", "text": "Pathologic indicators of degradation andinflammation in human osteoarthritic cartilageare abrogated by exposure to n-3 fattyacids.OBJECTIVE To determine if n-3polyunsaturated fatty acid (PUFA)supplementation (versus treatment with n-6polyunsaturated or other fatty acid supplements)affects the metabolism of osteoarthritic (OA)cartilage. METHODS The metabolic profile ofhuman OA cartilage was determined at the timeof harvest and after 24-hour exposure to n-3PUFAs or other classes of fatty acids, followed byexplant culture for 4 days in the presence orabsence of interleukin-1 (IL-1). Parametersmeasured were glycosaminoglycan release,aggrecanase and matrix metalloproteinase(MMP) activity, and the levels of expression ofmessenger RNA (mRNA) for mediators ofinflammation, aggrecanases, MMPs, and theirnatural tissue inhibitors (tissue inhibitors ofmetalloproteinases [TIMPs]). RESULTSSupplementation with n-3 PUFA (but not other", "metadata": {}}
+{"_id": "33918970", "title": "", "text": "Interactive effects of oligofructose and obesitypredisposition on gut hormones and microbiotain diet-induced obese rats.OBJECTIVEOligofructose (OFS) is a prebiotic that reducesenergy intake and fat mass via changes in gutsatiety hormones and microbiota. The effects ofOFS may vary depending on predisposition toobesity. The aim of this study was to examinethe effect of OFS in diet-induced obese (DIO)and diet-resistant (DR) rats. METHODS Adult,male DIO, and DR rats were randomized to:high-fat/high-sucrose (HFS) diet or HFS diet +10% OFS for 6 weeks. Body composition, foodintake, gut microbiota, plasma gut hormones,and cannabinoid CB(1) receptor expression inthe nodose ganglia were measured. RESULTSOFS reduced body weight, energy intake, and fatmass in both phenotypes (P < 0.05). Select gutmicrobiota differed in DIO versus DR rats (P <0.05), the differences being eliminated by OFS.OFS did not modify plasma ghrelin or CB(1)expression in nodose ganglia, but plasma levels", "metadata": {}}
+{"_id": "33920995", "title": "", "text": "RKIKK motif in the intracellular domain is criticalfor spatial and dynamic organization of ICAM-1:functional implication for the leukocyte adhesionand transmigration.No direct evidence has beenreported whether the spatial organization ofICAM-1 on the cell surface is linked to itsphysiological function in terms of leukocyteadhesion and transendothelial migration (TEM).Here we observed that ICAM-1 by itself directlyregulates the de novo elongation of microvilli andis thereby clustered on the microvilli. However,truncation of the intracellular domain resulted inuniform cell surface distribution of ICAM-1.Mutation analysis revealed that the C-terminal21 amino acids are dispensable, whereas asegment of 5 amino acids ((507)RKIKK(511)) inthe NH-terminal third of intracellular domain, isrequired for the proper localization and dynamicdistribution of ICAM-1 and the association ofICAM-1 with F-actin, ezrin, and moesin.Importantly, deletion of the (507)RKIKK(511)significantly delayed the LFA-1-dependent", "metadata": {}}
+{"_id": "33934971", "title": "", "text": "Immunology of the tick-host interaction and thecontrol of ticks and tick-borne diseases.The firstexperimental vaccination against ticks wascarried out 60 years ago. Since then, progresshas been slow, although the recent commercialrelease of a recombinant vaccine againstBoophilus microplus is significant. The nature ofnaturally acquired protective immunity againstticks is poorly understood, particularly in theimportant, domesticated ruminant hosts.Characterization of the antigens of naturallyacquired immunity remains limited, althoughmore has been achieved with 'concealed'antigens. Crucial questions remain about thetrue impact of tick-induced immunosuppressionand the effect of immunity on the transmission oftick-borne diseases, despite some fascinatingand important recent results, as discussed hereby Peter Willadsen and Frans Jongejan.", "metadata": {}}
+{"_id": "33955641", "title": "", "text": "Rapid method for the isolation of lipoproteinsfrom human serum by precipitation withpolyanions.Procedures are described for theisolation of lipoproteins from human serum byprecipitation with polyanions and divalentcations. A mixture of low and very low densitylipoproteins can be prepared withoutultracentrifugation by precipitation with heparinand either MnCl(2) alone or MgCl(2) plussucrose. In both cases the precipitation isreversible, selective, and complete. The highlyconcentrated isolated lipoproteins are free ofother plasma proteins as judged byimmunological and electrophoretic methods. Thelow density and very low density lipoproteins canthen be separated from each other byultracentrifugation. The advantage of the methodis that large amounts of lipoproteins can beprepared with only a single preparativeultracentrifugation. Polyanions other thanheparin may also be used; when the precipitationof the low and very low density lipoproteins is", "metadata": {}}
+{"_id": "33960383", "title": "", "text": "The role of oral antidiabetic agents: why andwhen to use an early-phase insulin secretionagent in Type II diabetes mellitusAbstractEvidence obtained in the 1990's stronglysupports the notion that glycaemic control isimportant not only in Type I (insulin-dependent),but also in Type II (non-insulin-dependent)diabetes mellitus. Although measurement ofHbA1c is the standard for assessing the effect ofglucose control in the occurrence and preventionof diabetic sequelae, more recent evidenceindicates that other glucose parameters are alsoimportant. Postchallenge and postprandialhyperglycaemic peaks seem to be prospectivedeterminants of vascular damage in early Type IIdiabetes. Currently, there is no overall acceptedstandard approach for the pharmacologicalmanagement of Type II diabetes. The UnitedKingdom Prospective Diabetes Study has shownthat reaching a near-normal glycaemic target iscritically important and the pharmacotherapy ofthis progressive disease is difficult. Loss of", "metadata": {}}
+{"_id": "33986200", "title": "", "text": "Layered hydrogels accelerate iPSC-derivedneuronal maturation and reveal migrationdefects caused by MeCP2 dysfunction.Probing awide range of cellular phenotypes inneurodevelopmental disorders usingpatient-derived neural progenitor cells (NPCs)can be facilitated by 3D assays, as 2D systemscannot entirely recapitulate the arrangement ofcells in the brain. Here, we developed apreviously unidentified 3D migration anddifferentiation assay in layered hydrogels toexamine how these processes are affected inneurodevelopmental disorders, such as Rettsyndrome. Our soft 3D system mimics the brainenvironment and accelerates maturation ofneurons from human induced pluripotent stemcell (iPSC)-derived NPCs, yieldingelectrophysiologically active neurons within just3 wk. Using this platform, we revealed agenotype-specific effect of methyl-CpG-bindingprotein-2 (MeCP2) dysfunction on iPSC-derivedneuronal migration and maturation (reduced", "metadata": {}}
+{"_id": "33986507", "title": "", "text": "Inducible gene expression: diverse regulatorymechanismsThe rapid activation of geneexpression in response to stimuli occurs largelythrough the regulation of RNA polymeraseII-dependent transcription. In this Review, wediscuss events that occur during the transcriptioncycle in eukaryotes that are important for therapid and specific activation of gene expressionin response to external stimuli. In addition toregulated recruitment of the transcriptionmachinery to the promoter, it has now beenshown that control steps can include chromatinremodelling and the release of pausedpolymerase. Recent work suggests that somecomponents of signal transduction cascades alsoplay an integral part in activating transcription attarget genes.", "metadata": {}}
+{"_id": "33989422", "title": "", "text": "On the origins of ultra-fine anaphasebridges.Comment on: Chan KL, Palmai-Pallag T,Ying S, Hickson ID. Replication stress inducessister-chromatid bridging at fragile site loci inmitosis. Nat Cell Biol 2009; 11:753-60.", "metadata": {}}
+{"_id": "34016944", "title": "", "text": "Resistance to gefitinib in PTEN-nullHER-overexpressing tumor cells can beovercome through restoration of PTEN functionor pharmacologic modulation of constitutivephosphatidylinositol 3'-kinase/Akt pathwaysignaling.PURPOSE Tyrosine kinase (TK)inhibitors are emerging as a promising newapproach to the treatment of HERoverexpressing tumors, however optimal use ofthese agents awaits further definition of thedownstream signaling pathways that mediatetheir effects. We reported previously that bothEGFR- and Her2-overexpressing tumors aresensitive to the new EGFR-selective TK inhibitorgefitinib (ZD1839, \"Iressa\"), and sensitivity tothis agent correlated with its ability todown-regulate Akt. However,EGFR-overexpressing MDA-468 cells, which lackPTEN function, are resistant to ZD1839, andZD1839 is unable to down-regulate Akt activityin these cells. EXPERIMENTAL DESIGN To studythe role of PTEN function, we generated MDA468", "metadata": {}}
+{"_id": "34016987", "title": "", "text": "Transcriptome analysis reveals humancytomegalovirus reprograms monocytedifferentiation toward an M1macrophage.Monocytes are primary targets forhuman CMV (HCMV) infection and are proposedto be responsible for hematogenousdissemination of the virus. Monocytes acquiredifferent functional traits during polarization tothe classical proinflammatory M1 macrophage orthe alternative antiinflammatory M2macrophage. We hypothesized that HCMVinduced a proinflammatory M1 macrophagefollowing infection to promote viral disseminationbecause, biologically, a proinflammatory stateprovides the tools to drive infected monocytesfrom the blood into the tissue. To test thishypothesis of monocyte conversion from anormal quiescent phenotype to an inflammatoryphenotype, we used Affymetrix Microarray toacquire a transcriptional profile of infectedmonocytes at a time point our data emphasizedis a key temporal regulatory point following", "metadata": {}}
+{"_id": "34025053", "title": "", "text": "Antithymocyte globulin treatment for patientswith recent-onset type 1 diabetes: 12-monthresults of a randomised, placebo-controlled,phase 2 trial.BACKGROUND Type 1 diabetesresults from T-cell-mediated destruction of βcells. Findings from preclinical studies and pilotclinical trials suggest that antithymocyte globulin(ATG) might be effective for reducing thisautoimmune response. We assessed the safetyand efficacy of rabbit ATG in preserving isletfunction in participants with recent-onset type 1diabetes, and report here our 12-month results.METHODS For this phase 2, randomised,placebo-controlled, clinical trial, we enrolledpatients with recent-onset type 1 diabetes, aged12-35 years, and with a peak C-peptide of 0.4nM or greater on mixed meal tolerance test from11 sites in the USA. We used a computergenerated randomisation sequence to randomlyassign patients (2:1, with permuted-blocks ofsize three or six and stratified by study site) toreceive either 6.5 mg/kg ATG or placebo over a", "metadata": {}}
+{"_id": "34034749", "title": "", "text": "The nucleosome family: dynamic andgrowing.Ever since the discovery of thenucleosome in 1974, scientists have stumbledupon discrete particles in which DNA is wrappedaround histone complexes of differentstoichiometries: octasomes, hexasomes,tetrasomes, \"split\" half-nucleosomes, and,recently, bona fide hemisomes. Do all theseparticles exist in vivo? Under what conditions?What is their physiological significance in thecomplex DNA transactions in the eukaryoticnucleus? What are their dynamics? This reviewsummarizes research spanning more than threedecades and provides a new meaning to the term\"nucleosome. \" The nucleosome can no longer beviewed as a single static entity: rather, it is afamily of particles differing in their structural anddynamic properties, leading to differentfunctionalities.", "metadata": {}}
+{"_id": "34054472", "title": "", "text": "Association between serum corin levels and riskof acute myocardial infarction.BACKGROUNDAccumulating evidence has indicated that corinplays critical roles in regulating salt-waterbalance, blood pressure and cardiac function byactivating natriuretic peptides. The presentcase-control study was designed to evaluate theassociation of serum soluble corin with acutemyocardial infarction (AMI). METHODS Weenrolled 856 consecutive AMI patients and 856control subjects and explored the possiblerelation between serum corin levels and AMI riskusing logistic regression model. RESULTSPatients with AMI had higher BMI, were lessphysically active, and were more likely to havehistories of hypertension, diabetes,hyperlipidemia and smoking compared with thecontrols. Serum levels of corin were remarkablyreduced in AMI patients (825±263pg/ml)compared with those in healthy controls(1246±425pg/ml). Odds ratios of ST elevation(STEMI) and non-ST elevation myocardial", "metadata": {}}
+{"_id": "34066665", "title": "", "text": "Crosstalk between the estrogen receptor and theHER tyrosine kinase receptor family: molecularmechanism and clinical implications for endocrinetherapy resistance.Breast cancer evolution andtumor progression are governed by the complexinteractions between steroid receptor [estrogenreceptor (ER) and progesterone receptor] andgrowth factor receptor signaling. In recent years,the field of cancer therapy has witnessed theemergence of multiple strategies targeting thesespecific cancer pathways and key molecules (ERand growth factor receptors) to arrest tumorgrowth and achieve tumor eradication; treatmentsuccess, however, has varied and both de novo(up front) and acquired resistance have proven achallenge. Recent studies of ER biology haverevealed new insights into ER action in breastcancer and have highlighted the role of anintimate crosstalk between the ER and HERfamily signaling pathways as a fundamentalcontributor to the development of resistance toendocrine therapies against the ER pathway. The", "metadata": {}}
+{"_id": "34071621", "title": "", "text": "Nuclear PTEN functions as an essential regulatorof SRF-dependent transcription to control smoothmuscle differentiationVascular diseaseprogression is associated with marked changes invascular smooth muscle cell (SMC) phenotypeand function. SMC contractile gene expressionand, thus differentiation, is under directtranscriptional control by the transcription factor,serum response factor (SRF); however, themechanisms dynamically regulating SMCphenotype are not fully defined. Here we reportthat the lipid and protein phosphatase, PTEN,has a novel role in the nucleus by functioning asan indispensible regulator with SRF to maintainthe differentiated SM phenotype. PTEN interactswith the N-terminal domain of SRF andPTEN-SRF interaction promotes SRF binding toessential promoter elements in SM-specificgenes. Factors inducing phenotypic switchingpromote loss of nuclear PTEN throughnucleo-cytoplasmic translocation resulting inreduced myogenically active SRF, but enhanced", "metadata": {}}
+{"_id": "34074902", "title": "", "text": "SEROSURVEY FOR FELINE LEUKEMIA VIRUS ANDLENTIVIRUSES IN CAPTIVE SMALL NEOTROPICFELIDS IN SÃO PAULO STATE, BRAZILAbstractFeline leukemia virus (FeLV), Gammaretrovirus,and feline immunodeficiency virus, a Lentivirus,are members of the family Retroviridae, and mayestablish persistent infections in the domestic cat(Felis catus). Cytoproliferative andcytosuppressive disorders may result frominfection with these viruses. Morbidity andmortality rates are high in domestic catsworldwide. Infection of endangered neotropicsmall felids with these viruses could bedevastating. To investigate the prevalence ofFeLV and feline lentiviruses in neotropic smallfelids kept in captivity in São Paulo state, Brazil,serum samples from 104 animals belonging tothe species Leopardus pardalis, Leopardustigrinus, Leopardus wiedii, Herpailurusyaguarondi, and Oncifelis geoffroyi were testedfor FeLV and feline lentiviruses by commerciallyavailable immunoassays. All results were", "metadata": {}}
+{"_id": "34101101", "title": "", "text": "Comparing the metabolism of quercetin in rats,mice and gerbilsSeveral species of rodents areused to investigate the metabolism of quercetinin vivo. However, it is unclear whether they are aproper animal model. Thus, we compared themetabolism of quercetin in Wistar rats (rats),Balb/c mice (mice) and Mongolian gerbils(gerbils). We determined the levels of quercetinmetabolites, quercetin-3-glucuronide (Q3G),quercetin-3′-sulfate (Q3′S) and methyl-quercetinisorhamnetin (IH), in the plasma, lungs andlivers of three species of animals byhigh-performance liquid chromatography afteracute and/or chronic quercetin administration.The metabolic enzyme activities in the intestinalmucosal membrane and liver were alsoinvestigated. First, we found that after acutequercetin administration, the Q3′S level was thehighest in gerbils. However, after long-termsupplementation (20 weeks), Q3G was thedominant metabolite in the plasma, lungs andlivers followed by IH and Q3′S in all animals,", "metadata": {}}
+{"_id": "34103335", "title": "", "text": "Cytokinesis failure generating tetraploidspromotes tumorigenesis in p53-null cellsAlong-standing hypothesis on tumorigenesis isthat cell division failure, generating geneticallyunstable tetraploid cells, facilitates thedevelopment of aneuploid malignancies. Here wetest this idea by transiently blocking cytokinesisin p53-null (p53-/-) mouse mammary epithelialcells (MMECs), enabling the isolation of diploidand tetraploid cultures. The tetraploid cells hadan increase in the frequency ofwhole-chromosome mis-segregation andchromosomal rearrangements. Only thetetraploid cells were transformed in vitro afterexposure to a carcinogen. Furthermore, in theabsence of carcinogen, only the tetraploid cellsgave rise to malignant mammary epithelialcancers when transplanted subcutaneously intonude mice. These tumours all containednumerous non-reciprocal translocations and an8–30-fold amplification of a chromosomal regioncontaining a cluster of matrix metalloproteinase", "metadata": {}}
+{"_id": "34105878", "title": "", "text": "Claspin, a Chk1-regulatory protein, monitorsDNA replication on chromatin independently ofRPA, ATR, and Rad17.Claspin is required for theATR-dependent activation of Chk1 in Xenopusegg extracts containing incompletely replicatedDNA. We show here that Claspin associates withchromatin in a regulated manner during S phase.Binding of Claspin to chromatin depends on thepre-replication complex (pre-RC) and Cdc45 butnot on replication protein A (RPA). Thesedependencies suggest that binding of Claspinoccurs around the time of initial DNA unwindingat replication origins. By contrast, both ATR andRad17 require RPA for association with DNA.Claspin, ATR, and Rad17 all bind to chromatinindependently. These findings suggest thatClaspin plays a role in monitoring DNA replicationduring S phase. Claspin, ATR, and Rad17 maycollaborate in checkpoint regulation by detectingdifferent aspects of a DNA replication fork.", "metadata": {}}
+{"_id": "34121231", "title": "", "text": "Cold-related respiratory symptoms in the generalpopulation.INTRODUCTION Cold-relatedrespiratory symptoms are common amongnorthern populations, especially among peoplesuffering from respiratory diseases. However,the prevalence of such symptoms in the generalpopulation and the threshold temperatures atwhich the symptoms start to emerge are poorlyknown. OBJECTIVES The present studydetermined the prevalence and thresholdtemperatures of self-reported respiratorysymptoms related to cold, separately for healthypeople and those with respiratory disease.MATERIALS AND METHODS Six thousand fivehundred ninety-one men and women aged 25years-74 years from the national FINRISK studywere queried about cold-related respiratorysymptoms. The results were expressed asage-adjusted prevalence figures and coefficientsfrom multivariate regressions. RESULTSCold-related respiratory symptoms were moreoften reported by people with asthma (men", "metadata": {}}
+{"_id": "34139429", "title": "", "text": "Carvedilol for children and adolescents with heartfailure: a randomized controlled trial.CONTEXTAlthough beta-blockers improve symptoms andsurvival in adults with heart failure, little isknown about these medications in children andadolescents. OBJECTIVE To prospectivelyevaluate the effects of carvedilol in children andadolescents with symptomatic systemicventricular systolic dysfunction. DESIGN,SETTING, AND PARTICIPANTS A multicenter,randomized, double-blind, placebo-controlledstudy of 161 children and adolescents withsymptomatic systolic heart failure from 26 UScenters. In addition to treatment withconventional heart failure medications, patientswere assigned to receive placebo or carvedilol.Enrollment began in June 2000 and the last dosewas given in May 2005 (each patient receivedmedication for 8 months). INTERVENTIONSPatients were randomized in a 1:1:1 ratio totwice-daily dosing with placebo, low-dosecarvedilol (0.2 mg/kg per dose if weight <62.5", "metadata": {}}
+{"_id": "34189936", "title": "", "text": "The circadian clock gene BMAL1 is a noveltherapeutic target for malignant pleuralmesothelioma.Malignant pleural mesothelioma(MPM) is a highly aggressive neoplasm arisingfrom the mesothelial cells lining the parietalpleura and it exhibits poor prognosis. Althoughthere has been significant progress in MPMtreatment, development of more efficienttherapeutic approaches is needed. BMAL1 is acore component of the circadian clock machineryand its constitutive overexpression in MPM hasbeen reported. Here, we demonstrate thatBMAL1 may serve as a molecular target for MPM.The majority of MPM cell lines and a subset ofMPM clinical specimens expressed higher levelsof BMAL1 compared to a nontumorigenicmesothelial cell line (MeT-5A) and normalparietal pleural specimens, respectively. A serumshock induced a rhythmical BMAL1 expressionchange in MeT-5A but not in ACC-MESO-1,suggesting that the circadian rhythm pathway isderegulated in MPM cells. BMAL1 knockdown", "metadata": {}}
+{"_id": "34198365", "title": "", "text": "Mechanism and Regulation of DNA-ProteinCrosslink Repair by the DNA-DependentMetalloprotease SPRTNCovalent DNA-proteincrosslinks (DPCs) are toxic DNA lesions thatinterfere with essential chromatin transactions,such as replication and transcription. Little wasknown about DPC-specific repair mechanismsuntil the recent identification of a DPC-processingprotease in yeast. The existence of a DPCprotease in higher eukaryotes is inferred fromdata in Xenopus laevis egg extracts, but itsidentity remains elusive. Here we identify themetalloprotease SPRTN as the DPC proteaseacting in metazoans. Loss of SPRTN results infailure to repair DPCs and hypersensitivity toDPC-inducing agents. SPRTN accomplishes DPCprocessing through a unique DNA-inducedprotease activity, which is controlled by severalsophisticated regulatory mechanisms. Cellular,biochemical, and structural studies define a DNAswitch triggering its protease activity, a ubiquitinswitch controlling SPRTN chromatin accessibility,", "metadata": {}}
+{"_id": "34198460", "title": "", "text": "'Zero is not good for me': implications ofinfertility in Ghana.BACKGROUND Given the highvalue placed on children in sub-Saharan Africa,previous research suggests that infertilityincreases the risk of psychological distress andmarital conflict, encourages risky sexual behaviorand deprives infertile individuals and couples ofan important source of economic and socialcapital. This paper explores the implications ofinfertility for women in Ghana, West Africa.METHODS Semi-structured interview datacollected from 107 women (aged 21-48 years,mean 33 years) seeking treatment ingynecological and obstetric clinics in Accra,Ghana, are analyzed. Based on iterative opencoding of the interviews, the focus of the analysisis on mental health, marital instability, socialinteraction and gendered experiences. RESULTSInfertile women report facing severe socialstigma, marital strain and a range of mentalhealth difficulties. Many women feel that theyshoulder a disproportionate share of the blame", "metadata": {}}
+{"_id": "34208005", "title": "", "text": "Ethical dilemmas in a randomized trial of asthmatreatment: can Bayesian statistical analysisexplain the results?OBJECTIVES The originalobjective was to determine whether the use ofbilevel positive airway pressure (BiPAP)ventilation would reduce the need forendotracheal intubation, the length of hospitalstay, and hospital charges in patients with statusasthmaticus. The development of physiciantreatment bias made patient enrollment difficult.The article subsequently describes the use ofBayesian statistics to explain study results whenthis bias occurs. METHODS This study was aprospective, randomized controlled clinical trialconducted over a 34.5-month period at an urbanuniversity hospital with an emergencydepartment census of 94,000 annual visits.Patients remaining in status asthmaticus afterinitial standard treatment with inhaledbeta-agonists and steroids were randomized toreceive BiPAP ventilation plus standard treatmentversus standard treatment alone (non-BiPAP),", "metadata": {}}
+{"_id": "34227917", "title": "", "text": "Mental health in prison populations. Areview--with special emphasis on a study ofDanish prisoners on remand.OBJECTIVE Toreview the literature on mental health andpsychiatric morbidity in prison populations andrelate findings to a Danish study on remandprisoners. METHOD The literature is reviewedand subdivided in the following section: validityof psychometrics in prison populations,prevalence of psychiatric disorders prior toimprisonment, incidence of psychiatric disordersduring imprisonment, psychopathy related topsychiatric comorbidity, dependence syndromeswith special emphasis on differentadministrations of heroin use (smoke vs.injection). The results are compared with alongitudinal Danish study on remand prisoners ineither solitary confinement (SC) or non-SC.RESULTS Many factors must be taken intoconsideration when dealing with prisoners andmental health, e.g. international differences, theprison setting, demographics and methodological", "metadata": {}}
+{"_id": "34228604", "title": "", "text": "Why females live longer than males: control oflongevity by sex hormones.Females live longerthan males in many species, including humans.We have traced a possible explanation for thisphenomenon to the beneficial action ofestrogens, which bind to estrogen receptors andincrease the expression of longevity-associatedgenes, including those encoding the antioxidantenzymes superoxide dismutase and glutathioneperoxidase. As a result, mitochondria fromfemales produce fewer reactive oxygen speciesthan those from males. Administering estrogenshas serious drawbacks, however--they arefeminizing (and thus cannot be administered tomales) and may increase the incidence of seriousdiseases such as uterine cancer inpostmenopausal women. Phytoestrogens, whichare present in soy or wine, may have some ofthe favorable effects of estrogens without theirundesirable effects. Study of gender differencesin longevity may help us to understand the basicprocesses of aging and to devise practical", "metadata": {}}
+{"_id": "34254203", "title": "", "text": "The pre-B-cell receptor: selector of fittingimmunoglobulin heavy chains for the B-cellrepertoireIn this Opinion article, I address therole of the pre-B-cell receptor (pre-BCR) in thedevelopment of antigen-specific B cells in termsof immunoglobulin heavy chain (IgH)variable-region repertoire selection, precursorB-cell differentiation and proliferation, and IgHallelic exclusion. Comparisons with the role of thepre-T-cell receptor (pre-TCR) in T-celldevelopment raise provocative questions. Whydo B- and T-cell lineages both use a surrogatechain — the surrogate light chain and thepre-TCR α-chain, respectively — as a step todevelop their repertoires of antigen-recognizingcells? What are the functions of the pre-BCR andpre-TCR in lymphocyte differentiation andantigen-receptor allelic exclusion? This article,together with the accompanying article by Haraldvon Boehmer, hopes to answer some of thesequestions.", "metadata": {}}
+{"_id": "34258065", "title": "", "text": "Helicobacter species methods and protocols.Introduction.Helicobacter infection is a chronicpersistent condition which is responsible for themajority of cases of gastric and duodenal ulcers,and gastric cancer. The study of the bacteria, theinteraction of the bacteria with the host, and thehost immune response has greatly benefitedfrom standardization of culture techniques andanimal models. The following chapters willdescribe the clinical aspects of infection andtouch on the important techniques for optimalinvestigation of this infection.", "metadata": {}}
+{"_id": "34268160", "title": "", "text": "Effectiveness of statin-eluting stent on earlyinflammatory response and neointimal thicknessin a porcine coronary model.BACKGROUNDDrug-eluting stent (DES) implantation is routineduring coronary revascularization because DESsignificantly reduce rates of restenosis and targetlesion revascularization compared with baremetal stent (BMS). However, available DES havelimitations, such as late thrombosis because ofdelayed healing with poorer endothelializationand persistent local inflammation. Statins caninhibit cell proliferation, inflammation, andrestore endothelial function. The present studyevaluated the ability of stent-based cerivastatindelivery to reduce stent-induced inflammatoryresponses and adverse effects on endothelialfunction, and to inhibit neointimal hyperplasia ina porcine coronary model. METHODS ANDRESULTS Pigs were randomized into groups inwhich the coronary arteries (9 pigs, 18coronaries in each group) had either acerivastatin-eluting stent (CES) or a BMS. All", "metadata": {}}
+{"_id": "34287602", "title": "", "text": "Genetic variation in West Nile virus fromnaturally infected mosquitoes and birds suggestsquasispecies structure and strong purifyingselection.Intrahost genetic diversity wasanalysed in naturally infected mosquitoes andbirds to determine whether West Nile virus(WNV) exists in nature as a quasispecies and toquantify selective pressures within and betweenhosts. WNV was sampled from ten infected birdsand ten infected mosquito pools collected onLong Island, NY, USA, during the peak of the2003 WNV transmission season. A 1938 ntfragment comprising the 3' 1159 nt of the WNVenvelope (E) coding region and the 5' 779 nt ofthe non-structural protein 1 (NS1) coding regionwas amplified and cloned and 20 clones perspecimen were sequenced. Results from thisanalysis demonstrate that WNV infections arederived from a genetically diverse population ofgenomes in nature. The mean nucleotidediversity was 0.016 % within individualspecimens and the mean percentage of clones", "metadata": {}}
+{"_id": "34316341", "title": "", "text": "Overlapping patterns of IGF2 and H19 expressionduring human development: biallelic IGF2expression correlates with a lack of H19expression.The spatial patterns of IGF2 and H19gene expression are strikingly similar duringparts of human embryonic/fetal and earlypostnatal development. Notable exceptions werefound with the ciliary anlage of the embryonicretina and the choroid plexus/leptomeninges,where transcripts from the IGF2 but not the H19locus could be detected. Moreover, in contrast tothe other tissue samples examined, the choroidplexus/leptomeninges expressed both parentalIGF2 alleles. Whilst RNase protection analysisrevealed a weak activity of the P1 promoter inthe choroid plexus/leptomeninges, the P2, P3and P4 promoters were all active wherever IGF2was expressed. We discuss these observationswith respect to a hypothesized coordinatedcontrol of the reciprocally imprinted and closelylinked IGF2 and H19 loci.", "metadata": {}}
+{"_id": "34328964", "title": "", "text": "Intimal smooth muscle cell proliferation afterballoon catheter injury. The role of basicfibroblast growth factor.The localization andsynthesis of basic fibroblast growth factor (bFGF)in the rat carotid artery were investigated attimes of chronic smooth muscle cell proliferation.Immunocytochemical staining showed thepresence of bFGF in the uninjured arterial wall,and after balloon injury, this cellular staining wasdecreased. Western and northern blot analyseslikewise showed that the amount of bFGF proteinand mRNA decreased after injury. A neutralizingantibody to bFGF was administered 4 and 5 daysafter injury and was found to have no effect onintimal smooth muscle cell proliferation. Thesedata suggest that an increase in the expressionof bFGF is not necessary for chronic smoothmuscle cell proliferation observed after ballooncatheter injury and that bFGF is not the majormitogen responsible for intimal smooth musclecell proliferation.", "metadata": {}}
+{"_id": "34338075", "title": "", "text": "Prevention of central venous catheter-associatedthrombosis: a meta-analysis.PURPOSEAnticoagulant prophylaxis in patients with centralvenous catheters is controversial. We performeda meta-analysis of randomized controlled trials ofanticoagulant prophylaxis in patients with centralvenous catheters. METHODS MEDLINE andEMBASE were searched up to May 2006,supplemented by manual searches of conferenceproceedings and bibliographies. RESULTS Fifteentrials were included. Unfractionated heparininfusion, oral fixed low-dose vitamin Kantagonist, and subcutaneouslow-molecular-weight heparin were evaluated.For all catheter-associated deep vein thrombosis(symptomatic and asymptomatic combined), thesummary relative risks ranged from 0.31 to 0.73(all achieved statistical significance). Forsymptomatic deep vein thrombosis, thesummary relative risks ranged from 0.28 to0.72, but did not achieve statistical significancefor any individual regimen. CONCLUSION", "metadata": {}}
+{"_id": "34369306", "title": "", "text": "Long-term efficacy of nicotine replacementtherapy for smoking cessation in adolescents: arandomized controlled trial.BACKGROUND Adouble-blind RCT on the short-term efficacy ofnicotine patches compared to placebo patchesamong Dutch adolescents was conducted. Thefindings demonstrated that nicotine patches areefficacious for smoking cessation atend-of-treatment; however, only in highlycompliant participants. We tested whether theeffects of NRT also held in 6- (T7) and 12-month(T8) follow-up assessments. METHODSAdolescents aged 12-18 years, who smoked atleast seven cigarettes a day and who weremotivated to quit smoking were recruited atschool yards and randomly assigned to either anicotine patch (n=182) or a placebo patch(n=180) condition according to a computergenerated list. Participants (N=257, age: 16.7 ±1.13 years) attended an information meetingfollowed by a 6- or 9-week treatment. Smokingcessation, compliance, and potential covariates", "metadata": {}}
+{"_id": "34378726", "title": "", "text": "Interferon gamma in autoimmunity: Acomplicated player on a complex stage.Earlyviews of autoimmune disease cast IFNγ as aprototypic pro-inflammatory factor. It is nowclear that IFNγ is capable of both pro- andanti-inflammatory activities with the functionaloutcome dependent on the physiological andpathological setting examined. Here, the majorimmune modulatory activities of IFNγ arereviewed and current evidence for the impact ofIFNγ on pathology and regulation of severalautoimmune diseases and disease models issummarized.", "metadata": {}}
+{"_id": "34386619", "title": "", "text": "The first gene of the Bacillus subtilis clpC operon,ctsR, encodes a negative regulator of its ownoperon and other class III heat shock genes.TheBacillus subtilis clpC operon is regulated by twostress induction pathways relying on eithersigmaB or a class III stress induction mechanismacting at a sigmaA-like promoter. When the clpCoperon was placed under the control of theisopropyl-beta-D-thiogalactopyranoside(IPTG)-inducible Pspac promoter, dramaticrepression of the natural clpC promoters fused toa lacZ reporter gene was noticed after IPTGinduction. This result strongly indicated negativeregulation of the clpC operon by one of its geneproducts. Indeed, the negative regulator couldbe identified which is encoded by the first geneof the clpC operon, ctsR, containing a predictedhelix-turn-helix DNA-binding motif. Deletion ofctsR abolished the negative regulation andresulted in high expression of both the clpCoperon and the clpP gene under nonstressedconditions. Nevertheless, a further increase in", "metadata": {}}
+{"_id": "34436231", "title": "", "text": "Role for c-myc in activation-induced apoptoticcell death in T cell hybridomas.Immature T cellsand some T cell hybridomas undergo apoptoticcell death when activated through the T cellreceptor complex, a phenomenon that isprobably related to antigen induced negativeselection of developing T cells. Thisactivation-induced apoptosis depends on activeprotein and RNA synthesis in the dying cells,although none of the genes required for thisprocess have previously been identified.Antisense oligonucleotides corresponding toc-myc block the constitutive expression of c-Mycprotein in T cell hybridomas and interfere with allaspects of activation-induced apoptosis withoutaffecting lymphokine production in these cells.These data indicate that c-myc expression is anecessary component of activation-inducedapoptosis.", "metadata": {}}
+{"_id": "34439544", "title": "", "text": "Examining BCL-2 family function with largeunilamellar vesicles.The BCL-2 (B cellCLL/Lymphoma) family is comprised ofapproximately twenty proteins that collaborateto either maintain cell survival or initiateapoptosis(1). Following cellular stress (e.g., DNAdamage), the pro-apoptotic BCL-2 familyeffectors BAK (BCL-2 antagonistic killer 1) and/orBAX (BCL-2 associated X protein) becomeactivated and compromise the integrity of theouter mitochondrial membrane (OMM), thoughthe process referred to as mitochondrial outermembrane permeabilization (MOMP)(1). AfterMOMP occurs, pro-apoptotic proteins (e.g.,cytochrome c) gain access to the cytoplasm,promote caspase activation, and apoptosisrapidly ensues(2). In order for BAK/BAX toinduce MOMP, they require transient interactionswith members of another pro-apoptotic subset ofthe BCL-2 family, the BCL-2 homology domain 3(BH3)-only proteins, such as BID(BH3-interacting domain agonist)(3-6).", "metadata": {}}
+{"_id": "34445160", "title": "", "text": "The Hippo pathway effector YAP controls mousehepatic stellate cell activation.BACKGROUND &AIMS Hepatic stellate cell activation is awound-healing response to liver injury. However,continued activation of stellate cells duringchronic liver damage causes excessive matrixdeposition and the formation of pathological scartissue leading to fibrosis and ultimately cirrhosis.The importance of sustained stellate cellactivation for this pathological process is wellrecognized, and several signalling pathways thatcan promote stellate cell activation have beenidentified, such as the TGFβ-, PDGF-, andLPS-dependent pathways. However, themechanisms that trigger and drive the earlysteps in activation are not well understood.METHODS AND RESULTS We identified the Hippopathway and its effector YAP as a key pathwaythat controls stellate cell activation. YAP is atranscriptional co-activator and we found that itdrives the earliest changes in gene expressionduring stellate cell activation. Activation of", "metadata": {}}
+{"_id": "34469966", "title": "", "text": "Human Monocytes Engage an AlternativeInflammasome Pathway.Interleukin-1β (IL-1β) isa cytokine whose bioactivity is controlled byactivation of the inflammasome. However, inresponse to lipopolysaccharide, humanmonocytes secrete IL-1β independently ofclassical inflammasome stimuli. Here, we reportthat this constituted a species-specific responsethat is not observed in the murine system.Indeed, in human monocytes, lipopolysaccharidetriggered an \"alternative inflammasome\" thatrelied on NLRP3-ASC-caspase-1 signaling, yetwas devoid of any classical inflammasomecharacteristics including pyroptosome formation,pyroptosis induction, and K(+) effluxdependency. Genetic dissection of the underlyingsignaling pathway in a monocytetransdifferentiation system revealed thatalternative inflammasome activation waspropagated by TLR4-TRIF-RIPK1-FADD-CASP8signaling upstream of NLRP3. Importantly,involvement of this signaling cascade was limited", "metadata": {}}
+{"_id": "34481589", "title": "", "text": "The use of biosimilars in immune-mediateddisease: A joint Italian Society of Rheumatology(SIR), Italian Society of Dermatology(SIDeMaST), and Italian Group of InflammatoryBowel Disease (IG-IBD) position paper.Biologicalagents are widely used in rheumatology,dermatology and inflammatory bowel disease.Evidence about their efficacy and safety hasbeen strengthened for all those therapeuticindications over the last decade. Biosimilaragents are monoclonal antibodies similar topreviously approved biologics. In the EuropeanUnion, they have been approved for all theindications in the management ofimmune-mediated inflammatory diseases(IMIDs), although data only in rheumatoidarthritis and ankylosing spondylitis are currentlyavailable. Direct evidence on efficacy, safety,and immunogenicity of biosimilars is mandatoryin psoriasis, psoriatic arthritis, and inflammatorybowel disease, as well as in children. Based onthe current evidence in the literature, we present", "metadata": {}}
+{"_id": "34498093", "title": "", "text": "The coordination of cyclic microtubuleassociation/dissociation and tail swing ofcytoplasmic dynein.The dynein motor domain iscomposed of a tail, head, and stalk and isthought to generate a force to microtubules byswinging the tail against the head during itsATPase cycle. For this \"power stroke,\" dynein hasto coordinate the tail swing with microtubuleassociation/dissociation at the tip of the stalk.Although a detailed picture of the former processis emerging, the latter process remains to beelucidated. By using the single-headedrecombinant motor domain of Dictyosteliumcytoplasmic dynein, we address the questions ofhow the interaction of the motor domain with amicrotubule is modulated by ATPase steps, howthe two mechanical cycles (the microtubuleassociation/dissociation and tail swing) arecoordinated, and which ATPase site among themultiple sites in the motor domain regulates thecoordination. Based on steady-state andpre-steady-state measurements, we", "metadata": {}}
+{"_id": "34498325", "title": "", "text": "A conserved modified wobble nucleoside(mcm5s2U) in lysyl-tRNA is required for viabilityin yeast.Transfer RNAs specific for Gln, Lys, andGlu from all organisms (except Mycoplasma) andorganelles have a 2-thiouridine derivative(xm(5)s(2)U) as wobble nucleoside. These tRNAsread the A- and G-ending codons in the splitcodon boxes His/Gln, Asn/Lys, and Asp/Glu. Ineukaryotic cytoplasmic tRNAs the conservedconstituent (xm(5)-) in position 5 of uridine is5-methoxycarbonylmethyl (mcm(5)). A protein(Tuc1p) from yeast resembling the bacterialprotein TtcA, which is required for the synthesisof 2-thiocytidine in position 32 of the tRNA, wasshown instead to be required for the synthesis of2-thiouridine in the wobble position (position34). Apparently, an ancient member of the TtcAfamily has evolved to thiolate U34 in tRNAs oforganisms from the domains Eukarya andArchaea. Deletion of the TUC1 gene togetherwith a deletion of the ELP3 gene, which results inthe lack of the mcm(5) side chain, removes all", "metadata": {}}
+{"_id": "34537906", "title": "", "text": "The molecular requirements for cytokinesis.Afteranaphase onset, animal cells build an actomyosincontractile ring that constricts the plasmamembrane to generate two daughter cellsconnected by a cytoplasmic bridge. The bridge isultimately severed to complete cytokinesis.Myriad techniques have been used to identifyproteins that participate in cytokinesis invertebrates, insects, and nematodes. Aconserved core of about 20 proteins areindividually involved with cytokinesis in mostanimal cells. These components are found in thecontractile ring, on the central spindle, within theRhoA pathway, and on vesicles that expand themembrane and sever the bridge. Cytokinesisinvolves additional proteins, but they, or theirrequirement in cytokinesis, are not conservedamong animal cells.", "metadata": {}}
+{"_id": "34544514", "title": "", "text": "Ibuprofen for the treatment of patent ductusarteriosus in preterm or low birth weight (orboth) infants.BACKGROUND Indomethacin isused as standard therapy to close a patentductus arteriosus (PDA) but is associated withreduced blood flow to several organs. Ibuprofen,another cyclo-oxygenase inhibitor, may be aseffective as indomethacin with fewer adverseeffects. OBJECTIVES To determine theeffectiveness and safety of ibuprofen comparedwith indomethacin, other cyclo-oxygenaseinhibitor, placebo or no intervention for closing apatent ductus arteriosus in preterm, low birthweight, or preterm and low birth weight infants.SEARCH METHODS We searched The CochraneLibrary, MEDLINE, EMBASE, Clincialtrials.gov,Controlled-trials.com, andwww.abstracts2view.com/pas in May 2014.SELECTION CRITERIA Randomised orquasi-randomised controlled trials of ibuprofenfor the treatment of a PDA in newborn infants.DATA COLLECTION AND ANALYSIS Data", "metadata": {}}
+{"_id": "34559336", "title": "", "text": "A gradient of template dependence definesdistinct biological roles for family X polymerasesin nonhomologous end joining.Three Pol X familymembers have been linked to nonhomologousend joining (NHEJ) in mammals.Template-independent TdT promotes diversityduring NHEJ-dependent repair of V(D)Jrecombination intermediates, but the roles of thetemplate-dependent polymerases mu andlambda in NHEJ remain unclear. We show herethat pol mu and pol lambda are similarlyrecruited by NHEJ factors to fill gaps when endshave partially complementary overhangs,suggesting equivalent roles promoting accuracyin NHEJ. However, only pol mu promotesaccuracy during immunoglobulin kapparecombination. This distinctive in vivo rolecorrelates with the TdT-like ability of pol mu, butnot pol lambda, to act when primer termini lackcomplementary bases in the template strand.However, unlike TdT, synthesis by pol mu in thiscontext is primarily instructed by a template", "metadata": {}}
+{"_id": "34582256", "title": "", "text": "Involvement of sympathetic nervous system andbrown fat in endotoxin-induced fever in rats.Theobject of this study was to assess the role ofbrown adipose tissue (BAT) and the sympatheticnervous system in the rise in heat productionassociated with endotoxin-induced fever. Oxygenconsumption (VO2) was found to be significantlyincreased (28%) over a 4-h period after twodoses of endotoxin (Escherichia colilipopolysaccharide, 0.3 mg/100 g body wt) given24 h apart. Injection of a mixedbeta-adrenoceptor antagonist (propranolol)reduced VO2 by 14% in endotoxin-treated rats,whereas the selective beta 1- (atenolol) or beta2- (ICI 118551) antagonists suppressed VO2 by10%. These drugs did not affect VO2 in controlanimals. BAT thermogenic activity assessed frommeasurements of in vitro mitochondrialguanosine 5'-diphosphate (GDP) binding waselevated by 54% in interscapular BAT and by171% in other BAT depots. Surgical denervationof one lobe of the interscapular depot prevented", "metadata": {}}
+{"_id": "34603465", "title": "", "text": "Metabolic, Epigenetic, and TransgenerationalEffects of Gut Bacterial CholineConsumption.Choline is an essential nutrient andmethyl donor required for epigenetic regulation.Here, we assessed the impact of gut microbialcholine metabolism on bacterial fitness and hostbiology by engineering a microbial communitythat lacks a single choline-utilizing enzyme. Ourresults indicate that choline-utilizing bacteriacompete with the host for this nutrient,significantly impacting plasma and hepatic levelsof methyl-donor metabolites and recapitulatingbiochemical signatures of choline deficiency. Miceharboring high levels of choline-consumingbacteria showed increased susceptibility tometabolic disease in the context of a high-fatdiet. Furthermore, bacterially induced reductionof methyl-donor availability influenced globalDNA methylation patterns in both adult mice andtheir offspring and engendered behavioralalterations. Our results reveal anunderappreciated effect of bacterial choline", "metadata": {}}
+{"_id": "34604584", "title": "", "text": "Genome-wide analysis reveals SR proteincooperation and competition in regulatedsplicing.SR proteins are well-characterized RNAbinding proteins that promote exon inclusion bybinding to exonic splicing enhancers (ESEs).However, it has been unclear whether regulatoryrules deduced on model genes apply generally toactivities of SR proteins in the cell. Here, wereport global analyses of two prototypical SRproteins, SRSF1 (SF2/ASF) and SRSF2 (SC35),using splicing-sensitive arrays and CLIP-seq onmouse embryo fibroblasts (MEFs). Unexpectedly,we find that these SR proteins promote bothinclusion and skipping of exons in vivo, but theirbinding patterns do not explain such oppositeresponses. Further analyses reveal that loss ofone SR protein is accompanied by coordinatedloss or compensatory gain in the interaction ofother SR proteins at the affected exons.Therefore, specific effects on regulated splicingby one SR protein actually depend on a complexset of relationships with multiple other SR", "metadata": {}}
+{"_id": "34615397", "title": "", "text": "Human tuberculous granulomas induceperipheral lymphoid follicle-like structures toorchestrate local host defence in the lung.Thehuman tuberculous granuloma provides themorphological basis for local immune processescentral to the outcome of tuberculosis. Becauseof the scarcity of information in human patients,the aim of the present study was to gain insightsinto the functional and structural properties ofinfiltrated tissue. To this end, the mycobacterialload in lesions and dissemination to differenttissue locations were investigated, as well asdistribution, biological functions, and interactionsof host immune cells. Analysis of earlygranuloma formation in formerly healthy lungtissue revealed a spatio-temporal sequence ofcellular infiltration to sites of mycobacterialinfection. A general structure of the developinggranuloma was identified, comprising an innercell layer with few CD8(+) cells surrounding thenecrotic centre and an outer area of lymphocyteinfiltration harbouring mycobacteria-containing", "metadata": {}}
+{"_id": "34630025", "title": "", "text": "Eosinophil pathogenicity mechanisms andtherapeutics in neuromyelitis optica.Eosinophilsare abundant in inflammatory demyelinatinglesions in neuromyelitis optica (NMO). We usedcell culture, ex vivo spinal cord slices, and in vivomouse models of NMO to investigate the role ofeosinophils in NMO pathogenesis and thetherapeutic potential of eosinophil inhibitors.Eosinophils cultured from mouse bone marrowproduced antibody-dependent cell-mediatedcytotoxicity (ADCC) in cell cultures expressingaquaporin-4 in the presence of NMOautoantibody (NMO-IgG). In the presence ofcomplement, eosinophils greatly increased cellkilling by a complement-dependent cell-mediatedcytotoxicity (CDCC) mechanism. NMO pathologywas produced in NMO-IgG-treated spinal cordslice cultures by inclusion of eosinophils or theirgranule toxins. The second-generationantihistamines cetirizine and ketotifen, whichhave eosinophil-stabilizing actions, greatlyreduced NMO-IgG/eosinophil-dependent", "metadata": {}}
+{"_id": "34733465", "title": "", "text": "Association of cystic fibrosis with abnormalities infatty acid metabolism.BACKGROUND Patientswith cystic fibrosis have altered levels of plasmafatty acids. We previously demonstrated thatarachidonic acid levels are increased anddocosahexaenoic acid levels are decreased inaffected tissues from cystic fibrosis-knockoutmice. In this study we determined whetherhumans with mutations in the cystic fibrosistransmembrane conductance regulator (CFTR)gene have a similar fatty acid defect in tissuesexpressing CFTR. METHODS Fatty acids fromnasal- and rectal-biopsy specimens, nasalepithelial scrapings, and plasma were analyzedfrom 38 subjects with cystic fibrosis andcompared with results in 13 obligateheterozygotes, 24 healthy controls, 11 subjectswith inflammatory bowel disease, 9 subjects withupper respiratory tract infection, and 16 subjectswith asthma. RESULTS The ratio of arachidonicto docosahexaenoic acid was increased inmucosal and submucosal nasal-biopsy specimens", "metadata": {}}
+{"_id": "34735369", "title": "", "text": "Actin dynamics and cell-cell adhesion inepithelia.Recent advances in the field ofintercellular adhesion highlight the importance ofadherens junction association with theunderlying actin cytoskeleton. In skin epithelialcells a dynamic feature of adherens junctionformation involves filopodia, which physicallyproject into the membrane of adjacent cells,catalyzing the clustering of adherens junctionprotein complexes at their tips. In turn, actinpolymerization is stimulated at the cytoplasmicinterface of these complexes. Although themechanism remains unclear, the VASP/Menafamily of proteins seems to be involved inorganizing actin polymerization at these sites. Invivo, adherens junction formation appears to relyupon filopodia in processes where epithelialsheets must be physically moved closer to formstable intercellular connections, for example, inventral closure in embryonic development orwound healing in the postnatal animal.", "metadata": {}}
+{"_id": "34747208", "title": "", "text": "Lamin A-dependent nuclear defects in humanaging.Mutations in the nuclear structural proteinlamin A cause the premature aging syndromeHutchinson-Gilford progeria (HGPS). Whetherlamin A plays any role in normal aging isunknown. We show that the same molecularmechanism responsible for HGPS is active inhealthy cells. Cell nuclei from old individualsacquire defects similar to those of HGPS patientcells, including changes in histone modificationsand increased DNA damage. Age-related nucleardefects are caused by sporadic use, in healthyindividuals, of the same cryptic splice site inlamin A whose constitutive activation causesHGPS. Inhibition of this splice site reverses thenuclear defects associated with aging. Theseobservations implicate lamin A in physiologicalaging.", "metadata": {}}
+{"_id": "34753204", "title": "", "text": "Zmpste24 deficiency in mice causes spontaneousbone fractures, muscle weakness, and aprelamin A processing defect.Zmpste24 is anintegral membrane metalloproteinase of theendoplasmic reticulum. Biochemical studies oftissues from Zmpste24-deficient mice(Zmpste24(-/-)) have indicated a role forZmpste24 in the processing of CAAX-typeprenylated proteins. Here, we report thepathologic consequences of Zmpste24 deficiencyin mice. Zmpste24(-/-) mice gain weight slowly,appear malnourished, and exhibit progressivehair loss. The most striking pathologic phenotypeis multiple spontaneous bone fractures-akin tothose occurring in mouse models of osteogenesisimperfecta. Cortical and trabecular bone volumesare significantly reduced in Zmpste24(-/-) mice.Zmpste24(-/-) mice also manifested muscleweakness in the lower and upper extremities,resembling mice lacking the farnesylated CAAXprotein prelamin A. Prelamin A processing wasdefective both in fibroblasts lacking Zmpste24", "metadata": {}}
+{"_id": "34760396", "title": "", "text": "Human and other faeces as breeding media ofthe trachoma vector Musca sorbens.The flyMusca sorbens Wiedemann (Diptera: Muscidae)apparently transmits Chlamydia trachomatis,causing human trachoma. The literatureindicates that M. sorbens breeds predominantlyin isolated human faeces on the soil surface, butnot in covered pit latrines. We sought to identifybreeding media of M. sorbens in a rural Gambianvillage endemic for trachoma. Test breedingmedia were presented for oviposition onsoil-filled buckets and monitored for adultemergence. Musca sorbens emerged fromhuman (6/9 trials), calf (3/9), cow (3/9), dog(2/9) and goat (1/9) faeces, but not from horsefaeces, composting kitchen scraps or a soilcontrol (0/9 of each). After adjusting for mass ofmedium, the greatest number of flies emergedfrom human faeces (1426 flies/kg). Median timefor emergence was 9 (inter quartile range =8-9.75) days post-oviposition. Of all fliesemerging from faeces 81% were M. sorbens.", "metadata": {}}
+{"_id": "34818263", "title": "", "text": "Current Health and Environmental Status of theMaasai People in Sub-Saharan AfricaAs timepasses, the AIDS pandemic continues to spike,affecting an estimated 38.6 million peopleworldwide. In response, a satellite health clinic isbeing d esigned by two Cal Poly students toserve the Maasai people living in the Kajiadodistrict in Southern Kenya. The Maasai havetraditionally lived as pastoralists, surviving off oftheir cattle with which they share their water,increasing the risk for contamination. However,as the population of Kenya increases, the landthe Maasai have traditionally used for grazing isshrink ing. For this reason, some have turned tofarming to maintain their liveli hood. Thesefactors have contributed to the desertificationand deforestation of their region. As the lifestyleof the Maasai evolves, they rely more on maizethan meat and dairy products for their nutrients.All of these changes have contributed to theevolution of the Maasai culture. We will addressthese changes in order to better understand the", "metadata": {}}
+{"_id": "34846352", "title": "", "text": "Identification and characterization of a widelyexpressed form of adenylyl cyclase.A novelmammalian adenylyl cyclase was identified byreverse transcription-polymerase chain reactionamplification using degenerate primers based ona conserved region of previously describedadenylyl cyclases (Premont, R. T. (1994)Methods Enzymol. 238, 116-127). The full-lengthcDNA sequence obtained from mouse brainpredicts a 1353-amino acid protein possessing a12-membrane span topology, and containing tworegions of high similarity with the catalyticdomains of adenylyl cyclases. Comparison of thisnovel adenylyl cyclase with the eight previouslydescribed mammalian enzymes indicates thatthis type 9 adenylyl cyclase sequence is the mostdivergent, defining a sixth distinct subclass ofmammalian adenylyl cyclases. The AC9 gene hasbeen localized to human chromosome band16p13.3-13.2. The 8.5-kb mRNA encoding thetype 9 adenylyl cyclase is widely distributed,being readily detected in all tissues tested, and is", "metadata": {}}
+{"_id": "34854444", "title": "", "text": "Expression of Golli mRNA during development inprimary immune lymphoid organs of the ratThegene-of-the-oligodendrocyte lineage (Golli)-MBPtranscription unit contains three Golli-specificexons together with eight exons of the \"classical\"myelin basic protein (MBP) gene, yieldingalternatively spliced proteins which share aminoacid sequence with MBP. Unlike MBP, a lateantigen expressed only in the nervous system,Golli gene products are expressed pre- andpost-natally at many sites. In this study, wedetermined the sequence of Golli in rat byRT-PCR and 5' RACE and showed that Gollisequences are expressed in primary lymphoidorgans as early as e16.5, which could explain theanergic rat T cell response we previouslyobserved in Golli-induced meningitis.", "metadata": {}}
+{"_id": "34873974", "title": "", "text": "Diagnostic accuracy of single baselinemeasurement of Elecsys Troponin Thigh-sensitive assay for diagnosis of acutemyocardial infarction in emergency department:systematic review and meta-analysisOBJECTIVETo obtain summary estimates of the accuracy ofa single baseline measurement of the ElecsysTroponin T high-sensitive assay (RocheDiagnostics) for the diagnosis of acutemyocardial infarction in patients presenting tothe emergency department. DESIGN Systematicreview and meta-analysis of diagnostic testaccuracy studies. DATA SOURCES Medline,Embase, and other relevant electronic databaseswere searched for papers published betweenJanuary 2006 and December 2013. STUDYSELECTION Studies were included if theyevaluated the diagnostic accuracy of a singlebaseline measurement of Elecsys Troponin Thigh-sensitive assay for the diagnosis of acutemyocardial infarction in patients presenting tothe emergency department with suspected acute", "metadata": {}}
+{"_id": "34876410", "title": "", "text": "Pericyte differentiation.Pericytes are defined invivo by their location: They are embedded withinthe basement membrane of microvessels. Theyform an integral part of the microvascular walland are believed to participate in angiogenesis,although their precise role is not clear. Pericytesderived from the retinal microvasculature havebeen cultured and identified by a series ofphenotypic characteristics that clearlydistinguishes them from other stromal cells suchas smooth muscle cells. Pericytes in vitro formmulticellular nodules rich in extracellular matrix.This matrix becomes mineralized in the presenceof growth medium containing serum, withoutexogenous beta-glycerophosphate. These resultsindicate that pericytes represent primitivemesenchymal cells able to differentiate into anosteogenic phenotype. Pericyte differentiationalso is defined by alterations in their response totransforming growth factor beta 1 and changesin the synthesis and/or deposition of variousextracellular matrix proteins such as laminin,", "metadata": {}}
+{"_id": "34905328", "title": "", "text": "Membrane association of the CD3ε signalingdomain is required for optimal T celldevelopment and function.The TCR:CD3 complextransduces signals that are critical for optimal Tcell development and adaptive immunity. Inresting T cells, the CD3ε cytoplasmic tailassociates with the plasma membrane via aproximal basic-rich stretch (BRS). In this study,we show that mice lacking a functionalCD3ε-BRS exhibited substantial reductions inthymic cellularity and limited CD4- CD8-double-negative (DN) 3 to DN4 thymocytetransition, because of enhanced DN4 TCRsignaling resulting in increased cell death andTCR downregulation in all subsequentpopulations. Furthermore, positive, but notnegative, T cell selection was affected in micelacking a functional CD3ε-BRS, which led tolimited peripheral T cell function andsubstantially reduced responsiveness to influenzainfection. Collectively, these results indicate thatmembrane association of the CD3ε signaling", "metadata": {}}
+{"_id": "34935825", "title": "", "text": "A new era in ovulation induction.OBJECTIVE Toevaluate the efficacy of aromatase inhibitors inovulation induction, superovulation, and IVF.DESIGN A literature search was conducted withthe key words \"aromatase inhibitor,\" \"letrozole,\"\"anastrazole,\" \"ovulation induction,\" \"ovulation,\"and \"superovulation\" in MEDLINE, EMBASE, andthe Cochrane Database of systematic reviews.RESULT(S) Ovulation induction with letrozole isassociated with an ovulation rate of 70%-84%and a pregnancy rate of 20%-27% per cycle. Inone study, ovulation and pregnancy rates withletrozole seemed to be higher than those ofanastrazole. In superovulation, letrozole isassociated with few developing follicles and thickendometrium. The use of letrozole forsuperovulation is associated with a pregnancyrate higher than with the use of clomiphenecitrate (CC) (16.7% vs. 5.6%). The addition ofletrozole to FSH treatment leads to a decreasedFSH requirement. The pregnancy rate fortreatment with letrozole and FSH was similar to", "metadata": {}}
+{"_id": "34982259", "title": "", "text": "Of lineage and legacy: the development ofmammalian hematopoietic stem cellsThehematopoietic system is one of the first complextissues to develop in the mammalian conceptus.Of particular interest in the field ofdevelopmental hematopoiesis is the origin ofadult bone marrow hematopoietic stem cells.Tracing their origin is complicated because bloodis a mobile tissue and because hematopoieticcells emerge from many embryonic sites. Theorigin of the adult mammalian blood systemremains a topic of lively discussion and intenseresearch. Interest is also focused ondevelopmental signals that induce the adulthematopoietic stem cell program, as these mayprove useful for generating and expanding theseclinically important cell populations ex vivo. Thisreview presents a historical overview of and themost recent data on the developmental origins ofhematopoiesis.", "metadata": {}}
+{"_id": "35004872", "title": "", "text": "Long crocidolite asbestos fibers cause polyploidyby sterically blocking cytokinesis.Asbestos hasbeen described as a physical carcinogen in thatits carcinogenic effects appear to be relatedprimarily to fiber dimensions. It has beenhypothesized that long asbestos fibers mayinterfere with chromosome distribution duringcell division, causing genomic changes that leadto cell transformation and neoplasticprogression. Using high-resolution time-lapselight microscopy and serial-section electronmicroscopy, we have followed individualcrocidolite asbestos fibers through the laterstages of cell division in LLC-MK2 epithelial cells,and have detailed for the first time their effect oncytokinesis. We found that long fibers (15-55microgram), trapped by the cleavage furrow,sterically blocked cytokinesis, sometimesresulting in the formation of a binucleated cell.The ends of blocking fibers were usually foundwithin invaginations of the newly formed nuclei.Nuclear envelope-fiber attachment was evident", "metadata": {}}
+{"_id": "35008773", "title": "", "text": "Neural induction and early patterning invertebrates.In vertebrates, the development ofthe nervous system is triggered by signals froma powerful 'organizing' region of the earlyembryo during gastrulation. Thisphenomenon--neural induction--was originallydiscovered and given conceptual definition byexperimental embryologists working withamphibian embryos. Work on the molecularcircuitry underlying neural induction, also in thesame model system, demonstrated thatelimination of ongoing transforming growthfactor-β (TGFβ) signaling in the ectoderm is thehallmark of anterior neural-fate acquisition. Thisobservation is the basis of the 'default' model ofneural induction. Endogenous neural inducersare secreted proteins that act to inhibit TGFβligands in the dorsal ectoderm. In the ventralectoderm, where the signaling ligands escape theinhibitors, a non-neural fate is induced.Inhibition of the TGFβ pathway has now beendemonstrated to be sufficient to directly induce", "metadata": {}}
+{"_id": "35022568", "title": "", "text": "What's in the 'treatment gap'? Ethnographicperspectives on addiction and global mentalhealth from China, Russia, and the UnitedStates.Recent years have seen the emergence ofa 'global mental health' agenda, focused onproviding evidence-based interventions formental illnesses in low- and middle-incomecountries. Anthropologists and culturalpsychiatrists have engaged in vigorous debatesabout the appropriateness of this agenda. In thisarticle, we reflect on these debates, drawing onethnographic fieldwork on the management ofsubstance use disorders in China, Russia, andthe United States. We argue that the logic of'treatment gaps,' which guides much researchand intervention under the rubric of globalmental health, partially obscures the complexassemblages of institutions, therapeutics,knowledges, and actors framing and managingaddiction (as well as other mental health issues)in any particular setting.", "metadata": {}}
+{"_id": "35062452", "title": "", "text": "Generation of mice deficient in both KLF3/BKLFand KLF8 reveals a genetic interaction and a rolefor these factors in embryonic globin genesilencing.Krüppel-like factors 3 and 8 (KLF3 andKLF8) are highly related transcriptionalregulators that bind to similar sequences of DNA.We have previously shown that in erythroid cellsthere is a regulatory hierarchy within the KLFfamily, whereby KLF1 drives the expression ofboth the Klf3 and Klf8 genes and KLF3 in turnrepresses Klf8 expression. While the erythroidroles of KLF1 and KLF3 have been explored, thecontribution of KLF8 to this regulatory networkhas been unknown. To investigate this, we havegenerated a mouse model with disrupted KLF8expression. While these mice are viable, albeitwith a reduced life span, mice lacking both KLF3and KLF8 die at around embryonic day 14.5(E14.5), indicative of a genetic interactionbetween these two factors. In the fetal liver, Klf3Klf8 double mutant embryos exhibit greaterdysregulation of gene expression than either of", "metadata": {}}
+{"_id": "35079452", "title": "", "text": "Mycobacterium tuberculosis phagosomematuration arrest: selective targeting ofPI3P-dependent membrane trafficking.The abilityof Mycobacterium tuberculosis to enter hostmacrophages, and reside in a phagosome, whichdoes not mature into a phagolysosome, is centralto the spread of tuberculosis and the associatedpandemic involving billions of people worldwide.Tuberculosis can be viewed as a disease with asignificant intracellular trafficking and organellarbiogenesis component. Current understanding ofthe block in M. tuberculosis phagosomematuration also sheds light on fundamentalaspects of phagolysosome biogenesis. Thematuration block involves interference with therecruitment and function of rabs, rab effectors(phosphatidylinositol 3-kinases and tetheringmolecules such as EEA1), SNAREs (Syntaxin 6and cellubrevin) and Ca2+/calmodulin signaling.M. tuberculosis analogs of mammalianphosphatidylinositols interfere with thesesystems and associated processes.", "metadata": {}}
+{"_id": "35085326", "title": "", "text": "SvpA, a novel surface virulence-associatedprotein required for intracellular survival ofListeria monocytogenes.A previously unknownprotein, designated SvpA (surfacevirulence-associated protein) and implicated inthe virulence of the intracellular pathogenListeria monocytogenes, was identified. This 64kDa protein, encoded by svpA, is both secretedin culture supernatants and surface-exposed, asshown by immunogold labelling of whole bacteriawith an anti-SvpA antibody. Analysis of thepeptide sequence revealed that SvpA contains aleader peptide, a predicted C-terminaltransmembrane region and a positively chargedtail resembling that of the surface protein ActA,suggesting that SvpA might partially reassociatewith the bacterial surface by its C-terminalmembrane anchor. An allelic mutant wasconstructed by disrupting svpA in the wild-typestrain LO28. The virulence of this mutant wasstrongly attenuated in the mouse, with a 2 logdecrease in the LD50 and restricted bacterial", "metadata": {}}
+{"_id": "35087728", "title": "", "text": "Measuring adherence to highly activeantiretroviral therapy: implications for researchand practice.Highly active antiretroviral therapy(HAART) has radically changed the course of HIVdisease, producing substantial reductions in bothHIV-related morbidity and mortality. However,the complexity of the typical daily HAARTregimen is substantial, and high levels ofadherence are essential for complete andlong-term viral suppression and the avoidance ofdrug resistance. The complexity of HAART hasmade the assessment of medication adherenceof paramount importance. Even though variousmethods are in use, each measures only a subsetof adherence behaviors, and each measure haslimited predictive validity. Given the individualand public health concerns associated withadherence to HAART, there is a need for thecontinued development and validation ofmeasures of medication adherence.", "metadata": {}}
+{"_id": "35100235", "title": "", "text": "Survival rates of tropical and temperatepasserines: a Trinidadianperspective.Mark-recapture data collected usingmist nets over a 10-yr period in Trinidad wereused to estimate adult survival rates for 17species of forest passerines. Trinidadian survivalrates (mean 65%, range 45%-85%) weresignificantly higher than published estimates forEuropean (mean survival 52%, range 32%-71%)and North American (mean survival 53%, range29%-63%) passerines of similar body size(equivalent to 45% higher mean life expectancyin Trinidad). These findings were confirmed aftercontrolling for phylogeny using a method ofindependent contrasts. Transient and/or youngbirds were an important feature of the Trinidaddata, and studies that fail to allow for thepresence of such birds risk underestimating adultsurvival. This study lends support to thehypothesis that avian survival rates are higher inthe humid tropics, although the magnitude of thedifference may be smaller than previously", "metadata": {}}
+{"_id": "35149431", "title": "", "text": "P0 glycoprotein peptides 56–71 and 180–199dose-dependently induce acute and chronicexperimental autoimmune neuritis in Lewis ratsassociated with epitope spreadingTwo syntheticperipheral nerve myelin P0 protein peptides, animmunodominant (amino acids 180-199) and acryptic (amino acids 56-71) one, induced anacute or chronic course of experimentalautoimmune neuritis (EAN) in Lewis rats, whengiven at low dose (50-100 microg/rat) or highdose (250 microg/rat), respectively.Corresponding to the different clinical course,pathological changes and immune responseswere found: (1) Onset of clinical signs of P0peptide 56-71 (P0 56-71) induced EAN was 1-3days later than in P0 peptide 180-199 (P0180-199) induced EAN at all immunizing doses,whereas the peak of the disease occurred at asimilar time point post immunization (p.i.), i.e. atdays 14-16 p.i. in P0 56-71 induced EAN and atday 16 p.i. in P0 180-199 induced EAN. (2)Intramolecular epitope spreading as assessed by", "metadata": {}}
+{"_id": "35186640", "title": "", "text": "Interaction between broad-spectrum antibioticsand the combined oral contraceptive pill. Aliterature review.There is considerable variationin opinion about the importance of druginteractions between the combined oralcontraceptive pill (COCP) and broad-spectrumantibiotics. Clinical practice varies widely,especially between doctors in Europe and thosein the US. Rifampicin and griseofulvin inducehepatic enzymes and do appear to have agenuine interaction with the COCP, leading toreduced efficacy. The situation with thebroad-spectrum antibiotics is less clear. Thereare relatively few prospective studies of thepharmacokinetics of concurrent COCP andantibiotic use and few, if any, demonstrate aconvincing basis for any reduced contraceptiveefficacy. There is evidence, however, thatvariable contraceptive steroid handling couldmake some women, at some times, moresusceptible to COCP failure. Given the seriousconsequences of unwanted pregnancy, the", "metadata": {}}
+{"_id": "35231675", "title": "", "text": "CLIP-170 interacts with dynactin complex andthe APC-binding protein EB1 by differentmechanisms.CLIP-170 is a \"cytoplasmic linkerprotein\" implicated in endosome-microtubuleinteractions and in control of microtubuledynamics. CLIP-170 localizes dynamically togrowing microtubule plus ends, colocalizing withthe dynein activator dynactin and theAPC-binding protein EB1. This shared \"plus-endtracking\" behavior suggests that CLIP-170 mightinteract with dynactin and/or EB1. We have usedsite-specific mutagenesis of CLIP-170 and atransfection/colocalization assay to address thisquestion in mammalian tissue culture cells. Ourresults indicate that CLIP-170 interacts, directlyor indirectly, with both dynactin and EB1. Wefind that the CLIP-170/dynactin interaction ismediated by the second metal binding motif ofthe CLIP-170 tail. In contrast, the CLIP-170/EB1interaction requires neither metal binding motif.In addition, our experiments suggest that theCLIP-170/dynactin interaction occurs via the", "metadata": {}}
+{"_id": "35256900", "title": "", "text": "Subcapsular encounter andcomplement-dependent transport of immunecomplexes by lymph node B cellsThe mechanismof B cell–antigen encounter in lymphoid tissues isincompletely understood. It is also unclear howimmune complexes are transported to folliculardendritic cells. Here, using real-time two-photonmicroscopy we noted rapid delivery of immunecomplexes through the lymph to macrophages inthe lymph node subcapsular sinus. B cellscaptured immune complexes by a complementreceptor–dependent mechanism frommacrophage processes that penetrated thefollicle and transported the complexes tofollicular dendritic cells. Furthermore, cognate Bcells captured antigen-containing immunecomplexes from macrophage processes andmigrated to the T zone. Our findings identifymacrophages lining the subcapsular sinus as animportant site of B cell encounter with immunecomplexes and show that intrafollicular B cellmigration facilitates the transport of immune", "metadata": {}}
+{"_id": "35271381", "title": "", "text": "Exercise training-induced adaptations in thecoronary circulation.Aerobic exercise traininginduces an increase in coronary blood flowcapacity that is associated with altered control ofcoronary vascular resistance and, therefore,coronary blood flow. The relative importance ofmetabolic, myogenic, endothelium-mediated,and neurohumoral control systems variesthroughout the coronary arterial tree, and thesecontrol systems contribute in parallel toregulating coronary vascular resistance todiffering degrees at each level in the coronaryarterial tree. In addition to this nonuniformity ofthe relative importance of vascular controlsystems in the coronary arterial tree, it appearsthat exercise training-induced adaptations arealso distributed spatially, in a nonuniformmanner throughout the coronary tree. As aresult, it is necessary to examinetraining-induced adaptations throughout thecoronary arterial tree. Adaptations inendothelium-mediated control play a role in", "metadata": {}}
+{"_id": "35301079", "title": "", "text": "Hepatic intra-arterial versus intravenousfotemustine in patients with liver metastasesfrom uveal melanoma (EORTC 18021): amulticentric randomized trial.BACKGROUND Inuveal melanoma (UM) with metastatic diseaselimited to the liver, the effect of an intrahepatictreatment on survival is unknown. Weinvestigated prospectively the efficacy andtoxicity of hepatic intra-arterial (HIA) versussystemic (IV) fotemustine in patients with livermetastases from UM. PATIENTS AND METHODSPatients were randomly assigned to receiveeither IV or HIA fotemustine at 100 mg/m(2) ondays 1, 8, 15 (and 22 in HIA arm only) asinduction, and after a 5-week rest period every 3weeks as maintenance. Primary end point wasoverall survival (OS). Response rate (RR),progression-free survival (PFS) and safety weresecondary end points. RESULTS Accrual wasstopped after randomization of 171 patientsbased on the results of a futility OS analysis. Atotal of 155 patients died and 16 were still alive", "metadata": {}}
+{"_id": "35314705", "title": "", "text": "Comparison of survival between cerebellar andsupratentorial glioblastoma patients:surveillance, epidemiology, and end results(SEER) analysis.BACKGROUND Cerebellarglioblastoma multiforme (cGBM) is rare, andalthough there is a general belief that thesetumors have a worse prognosis thansupratentorial GBM (sGBM), few studies havebeen published to support this belief. OBJECTIVETo investigate the effect of cerebellar location onsurvival through a case-control design comparingoverall survival time of cGBM and sGBM patients.METHODS The Surveillance, Epidemiology, andEnd Results (SEER) registry was used to identify132 patients with cGBM (1973-2008). EachcGBM patient was matched with an sGBM patientfrom among 20,848 sGBM patients on the basisof age, extent of resection, decade of diagnosis,and radiation therapy using propensity scorematching. RESULTS Within the cGBM, 37% wereolder than 65 years of age, 62% were men, and87% were white. Most patients underwent", "metadata": {}}
+{"_id": "35321950", "title": "", "text": "Staphylococcus aureus and Candida albicansinfection (animal experiments).During a certainperiod of the course of infection in white miceinoculated intraperitoneally with the pure cultureof a proteolysing strain of Candida albicans,Staphylococcus aureus and C. albicans both,were isolated simultaneously from the peritonealabscesses, especially those adhering to thestomach, duodenum, pancreas and the upperpart of small intestine. This concommitantoccurrence of the two pathogens was furthercorroborated by histopathological examinationwhich revealed large number of staphylococcipresent in the close neighbourhood of Candidacells, usually in the center of the granulomatacaused by the fungus. In view of the facts thatthe proteolytic end-products of C. albicans canoffer a good substratum for the growth of S.aureus and the latter may be isolated from theintestinal tract of apparently healthy mice,possibly as a constituent of the transientmicroflora, the co-existence of these two", "metadata": {}}
+{"_id": "35329820", "title": "", "text": "Three common functional polymorphisms inmicroRNA encoding genes in the susceptibility tohepatocellular carcinoma: a systematic reviewand meta-analysis.Emerging evidences haveshown that common genetic polymorphisms inmicroRNAs may be associated with thedevelopment of hepatocellular carcinoma (HCC);but individually published studies and previousmeta-analyses revealed inconclusive results. Theaims of this review and meta-analysis are toassess whether common single-nucleotidepolymorphisms (SNPs) in the genes encoding themicroRNAs are associated with susceptibility toHCC development and clinicopathologiccharacteristics of hepatitis B virus (HBV) relatedHCC. A computerized search was performed inPubMed, Embase, Web of Science and ChinaBioMedicine (CBM) databases to identify relevantarticles published before January 1st 2013. Tencase-control studies were assessed with a totalof 3437 cases and 3437 healthy controls. Threecommon functional SNPs in miRNA-encoding", "metadata": {}}
+{"_id": "35345807", "title": "", "text": "Isonicotinamide enhances Sir2 protein-mediatedsilencing and longevity in yeast by raisingintracellular NAD+ concentration.Sirtuins are anevolutionarily conserved family ofNAD(+)-dependent protein deacetylases thatfunction in the regulation of gene transcription,cellular metabolism, and aging. Their activityrequires the maintenance of an adequateintracellular NAD(+) concentration through thecombined action of NAD(+) biosynthesis andsalvage pathways. Nicotinamide (NAM) is a keyNAD(+) precursor that is also a byproduct andfeedback inhibitor of the deacetylation reaction.In Saccharomyces cerevisiae, the nicotinamidasePnc1 converts NAM to nicotinic acid (NA), whichis then used as a substrate by the NAD(+)salvage pathway enzyme NAphosphoribosyltransferase (Npt1).Isonicotinamide (INAM) is an isostere of NAMthat stimulates yeast Sir2 deacetylase activity invitro by alleviating the NAM inhibition. In thisstudy, we determined that INAM stimulates Sir2", "metadata": {}}
+{"_id": "35395662", "title": "", "text": "Similar activation of signal transductionpathways by the herpesvirus-encoded chemokinereceptors US28 and ORF74.The virally encodedchemokine receptors US28 from humancytomegalovirus and ORF74 from humanherpesvirus 8 are both constitutively active. Weshow that both receptors constitutively activatethe transcription factors nuclear factor ofactivated T cells (NFAT) and cAMP responseelement binding protein (CREB) and that bothpathways are modulated by their respectiveendogenous receptor ligands. By addition ofspecific pathway modulators against the Gprotein subunit Galphai, phospholipase C, proteinkinase C, calcineurin, p38 MAP kinase, andMEK1, we find that the constitutive andligand-dependent inductions are mediated bymultiple yet similar pathways in both receptors.The NFAT and CREB transcription factors andtheir upstream activators are known inducers ofhost and virally encoded genes. We propose thatthe activity of these virally encoded chemokine", "metadata": {}}
+{"_id": "35443524", "title": "", "text": "The therapeutic promise of the cancer stem cellconcept.Cancer stem cells (CSCs) are asubpopulation of tumor cells that selectivelypossess tumor initiation and self-renewalcapacity and the ability to give rise to bulkpopulations of nontumorigenic cancer cellprogeny through differentiation. As we discusshere, they have been prospectively identified inseveral human malignancies, and their relativeabundance in clinical cancer specimens has beencorrelated with malignant disease progression inhuman patients. Furthermore, recent findingssuggest that clinical cancer progression driven byCSCs may contribute to the failure of existingtherapies to consistently eradicate malignanttumors. Therefore, CSC-directed therapeuticapproaches might represent translationallyrelevant strategies to improve clinical cancertherapy, in particular for those malignancies thatare currently refractory to conventionalanticancer agents directed predominantly attumor bulk populations.", "metadata": {}}
+{"_id": "35448676", "title": "", "text": "3'-End processing of pre-mRNA ineukaryotes.3'-Ends of almost all eukaryoticmRNAs are generated by endonucleolyticcleavage and addition of a poly(A) tail. Inmammalian cells, the reaction depends on thesequence AAUAAA upstream of the cleavage site,a degenerate GU-rich sequence elementdownstream of the cleavage site and stimulatorysequences upstream of AAUAAA. Six factors havebeen identified that carry out the two reactions.With a single exception, they have been purifiedto homogeneity and cDNAs for 11 subunits havebeen cloned. Some of the cooperativeRNA-protein and protein-protein interactionswithin the processing complex have beenanalyzed, but many details, including the identityof the endonuclease, remain unknown. Severalexamples of regulated polyadenylation are beinganalyzed at the molecular level. In the yeastSaccharomyces cerevisiae, sequences directingcleavage and polyadenylation are moredegenerate than in metazoans, and a", "metadata": {}}
+{"_id": "35467590", "title": "", "text": "Structure and developmental regulation ofGolli-mbp, a 105-kilobase gene thatencompasses the myelin basic protein gene andis expressed in cells in the oligodendrocytelineage in the brain.We have identified a noveltranscription unit of 105 kilobases (called theGolli-mbp gene) that encompasses the mousemyelin basic protein (MBP) gene. Three uniqueexons within this gene are alternatively splicedinto MBP exons and introns to produce a familyof MBP gene-related mRNAs that are underindividual developmental regulation. ThesemRNAs are temporally expressed within cells ofthe oligodendrocyte lineage at progressivestages of differentiation. Thus, the MBP gene is apart of a more complex gene structure, theproducts of which may play a role inoligodendrocyte differentiation prior tomyelination. One Golli-mbp mRNA that encodesa protein antigenically related to MBP is alsoexpressed in the spleen and other non-neuraltissues.", "metadata": {}}
+{"_id": "35495268", "title": "", "text": "Cardiovascular effects of intensive lifestyleintervention in type 2 diabetes.BACKGROUNDWeight loss is recommended for overweight orobese patients with type 2 diabetes on the basisof short-term studies, but long-term effects oncardiovascular disease remain unknown. Weexamined whether an intensive lifestyleintervention for weight loss would decreasecardiovascular morbidity and mortality amongsuch patients. METHODS In 16 study centers inthe United States, we randomly assigned 5145overweight or obese patients with type 2diabetes to participate in an intensive lifestyleintervention that promoted weight loss throughdecreased caloric intake and increased physicalactivity (intervention group) or to receivediabetes support and education (control group).The primary outcome was a composite of deathfrom cardiovascular causes, nonfatal myocardialinfarction, nonfatal stroke, or hospitalization forangina during a maximum follow-up of 13.5years. RESULTS The trial was stopped early on", "metadata": {}}
+{"_id": "35520219", "title": "", "text": "Early loss of interneurons and delayedsubunit-specific changes in GABA(A)-receptorexpression in a mouse model of mesial temporallobe epilepsy.Unilateral injection of kainic acid(KA) into the dorsal hippocampus of adult miceinduces spontaneous recurrent partial seizuresand replicates histopathological changesobserved in human mesial temporal lobeepilepsy (MTLE) (Bouilleret V et al., Neuroscience1999; 89:717-729). Alterations in pre- andpostsynaptic components of GABAergicneurotransmission were investigatedimmunohistochemically at different time points(1-120 days) in this mouse model of MTLE.Markers of GABAergic interneurons(parvalbumin, calbindin-D28k, and calretinin),the type-1 GABA transporter (GAT1), and majorGABA(A)-receptor subunits expressed in thehippocampal formation were analyzed. Acutely,KA injection produced a profound loss of hilarcells but only limited damage to CA1 and CA3pyramidal cells. In addition, parvalbumin and", "metadata": {}}
+{"_id": "35521287", "title": "", "text": "Cardiorespiratory adaptation during sleep ininfants and children.The cardiorespiratory controlsystem undergoes functional maturation afterbirth. Until this process is completed, thecardiorespiratory system is unstable, placinginfants at risk for cardiorespiratory disturbances,especially during sleep. The profound influence ofstates of alertness on respiratory and cardiaccontrol has been the focus of intense scrutinyduring the last decade. The effects of rapid-eyemovement (REM) sleep on various mechanismsinvolved in cardiorespiratory control are ofparticular significance during the postnatalperiod since newborns spend much of their timein this sleep state. In fullterm newborns, REMsleep occupies more than 50% of total sleeptime, and this percentage is even greater inpreterm newborns. From term to six months ofage, the proportion of REM sleep decreases.Since respiratory and cardiac disturbances areknown to occur selectively during REM sleep, thepredominance of REM sleep may be a risk factor", "metadata": {}}
+{"_id": "35531883", "title": "", "text": "A Common Signal Patch Drives AP-1Protein-dependent Golgi Export of InwardlyRectifying Potassium Channels.Nearly allmembers of the inwardly rectifying potassium(Kir) channel family share a cytoplasmic domainstructure that serves as an unusual AP-1 clathrinadaptor-dependent Golgi export signal in one Kirchannel, Kir2.1 (KCNJ2), raising the questionwhether Kir channels share a common Golgiexport mechanism. Here we explore this idea,focusing on two structurally and functionallydivergent Kir family members, Kir2.3 (KCNJ4)and Kir4.1/5.1 (KCNJ10/16), which have \u000050%amino identity. We found that Golgi export ofboth channels is blocked upon siRNA-mediatedknockdown of the AP-1 γ subunit, as predictedfor the common AP-1-dependent traffickingprocess. A comprehensive mutagenic analysis,guided by homology mapping in atomicresolution models of Kir2.1, Kir2.3, andKir4.1/5.1, identified a common structure thatserves as a recognition site for AP-1 binding and", "metadata": {}}
+{"_id": "35534019", "title": "", "text": "Statins in the treatment of polycythaemia veraand allied disorders: an antithrombotic andcytoreductive potential?Thrombohaemorrhagiccomplications are major clinical problems in theclassical chronic Ph-negative myeloproliferativedisorders (CMPDs), polycytaemia vera (PV),essential thrombocythaemia (ET) and idiopathicmyelofibrosis (IMF), contributing significantly tomorbidity and mortality. Pathophysiologicallythese disorders are characterized by clonalmyeloproliferation, myeloaccumulation and apropensity to develop myelofibrosis andneoangiogenesis in both the bone marrow andspleen. Based upon in vitro and in vivo studies ofthe effects of statins (antithrombotic,antiproliferative, proapoptotic andantiangiogenic), this review focuses on thetranslation of these effects into potential clinicalbenefits of statin therapy in patients with CMPDs.", "metadata": {}}
+{"_id": "35543846", "title": "", "text": "Metabolic analysis of senescent humanfibroblasts reveals a role for AMP in cellularsenescence.Cellular senescence is considered amajor tumour-suppressor mechanism inmammals, and many oncogenic insults, such asthe activation of the ras proto-oncogene, triggerinitiation of the senescence programme.Although it was shown that activation of thesenescence programme involves theup-regulation of cell-cycle regulators such as theinhibitors of cyclin-dependent kinases p16INK4Aand p21CIP-1, the mechanisms underlying thesenescence response remain to be resolved. Inthe case of stress-induced prematuresenescence, reactive oxygen species areconsidered important intermediates contributingto the phenotype. Moreover, distinct alterationsof the cellular carbohydrate metabolism areknown to contribute to oncogenic transformation,as is best documented for the phenomenon ofaerobic glycolysis. These findings suggest thatmetabolic alterations are involved in", "metadata": {}}
+{"_id": "35612665", "title": "", "text": "Identification of an H2-M3-restricted Listeriaepitope: implications for antigen presentation byM3.Using expression cloning, we have identifiedan H2-M3-restricted epitope of the intracellularbacterial pathogen Listeria monocytogenes.Picomolar concentrations of an amino-terminalN-formylated hexapeptide, fMIGWII, targetedcells for lysis by CD8+ cytotoxic T cells, while thenonformylated peptide was approximately100-fold less active. The sequence of the 185 aaprotein source of this epitope predicts atransmembrane protein that retains its Nterminus and assumes an N(out)-C(in) topology.This membrane orientation offers an explanationfor the protection of the epitope fromdeformylases present in the bacterial cell andsuggests an explanation for the ability ofphagocytes to present H2-M3-restricted bacterialepitopes via a vacuolar TAP-independentmechanism.", "metadata": {}}
+{"_id": "35621259", "title": "", "text": "High-resolution peripheral quantitative computedtomographic imaging of cortical and trabecularbone microarchitecture in patients with type 2diabetes mellitus.CONTEXT Cross-sectionalepidemiological studies have found that patientswith type 2 diabetes mellitus (T2DM) have ahigher incidence of certain fragility fracturesdespite normal or elevated bone mineral density(BMD). OBJECTIVE In this study, high-resolutionperipheral quantitative computed tomographywas applied to characterize cortical andtrabecular microarchitecture and biomechanics inthe peripheral skeleton of female patients withT2DM. DESIGN AND SETTING A cross-sectionalstudy was conducted in patients with T2DMrecruited from a diabetic outpatient clinic.PARTICIPANTS Elderly female patients (age,62.9 ± 7.7 yr) with a history of T2DM (n = 19)and age- and height-matched controls (n = 19)were recruited. OUTCOME MEASURES Subjectswere imaged using high-resolution peripheralquantitative computed tomography at the distal", "metadata": {}}
+{"_id": "35651106", "title": "", "text": "Critical role of CD28 in protective immunityagainst Salmonella typhimurium.Efficient T cellactivation requires both TCR signals andcostimulatory signals. CD28 is one of themolecules that provide costimulatory signals forT cells. We used mice deficient in CD28expression (CD28-/- mice) to analyze the role ofCD28 in the immune response against theintracellular bacterium Salmonella typhimurium,the causative agent of murine typhoid fever.CD28-/- mice were highly susceptible to infectionwith wild-type S. typhimurium and even failed tocontrol infection with attenuated aroA- S.typhimurium. More detailed analysis revealedthat CD28-/- animals did not mount aT-dependent Ab response and were highlyimpaired in the production of IFN-gamma. Thus,CD28 cosignaling is crucial for immunity againstS. typhimurium. To our knowledge, this is thefirst report describing an essential role for CD28in protective immunity against an intracellularmicrobial pathogen.", "metadata": {}}
+{"_id": "35660758", "title": "", "text": "D3 phosphoinositides and outside-in integrinsignaling by glycoprotein IIb-IIIa mediateplatelet actin assembly and filopodial extensioninduced by phorbol 12-myristate13-acetate.Phorbol 12-myristate 13-acetate(PMA) uncaps a small number of thefast-growing (barbed) ends of actin filaments,thereby eliciting slow actin assembly andextension of filopodia in human blood platelets.These reactions, which also occur in response toimmunologic perturbation of the integringlycoprotein (GP) IIb-IIIa, are sensitive to thephosphoinositide 3-kinase inhibitor wortmannin.Platelets deficient in GPIIb-IIIa integrins or withGPIIb-IIIa function inhibited by calcium chelationor the peptide RGDS have diminished PMAresponsiveness. The effects of PMA contrast withthrombin receptor stimulation by >/=5 microMthrombin receptor-activating peptide (TRAP),which causes rapid and massivewortmannin-insensitive actin assembly andlamellar and filopodial extension. However, we", "metadata": {}}
+{"_id": "35684881", "title": "", "text": "`Gain of function' phenotype of tumor-derivedmutant p53 requires theoligomerization/nonsequence-specific nucleicacid-binding domainTumor-derived p53 mutantscan transcriptionally activate a number ofpromoters of genes involved in cellularproliferation. For this transactivation, mutantp53 does not use the wild-type p53 DNA-bindingsite, suggesting a mechanism of transactivationthat is independent of direct DNA binding. Herewe describe our analysis of the domainrequirements for mutant p53 to transactivatepromoters of the human epidermal growth factorreceptor (EGFR), human multiple drug resistance1 (MDR-1) and human proliferating cell nuclearantigen (PCNA) genes. We also report theidentification of a structural domain required forthe `gain of function' property of mutantp53-281G. `Gain of function' is measured as thetumorigenicity (in nude mice) of 10(3) murinecells expressing mutant p53 constitutively. Wehave generated internal deletion mutants of", "metadata": {}}
+{"_id": "35711485", "title": "", "text": "Banana contains a diverse array of endogenousbadnaviruses.Banana streak disease is caused byseveral distinct badnavirus species, one of whichis Banana streak Obino l'Ewai virus. Bananastreak Obino l'Ewai virus has severely hinderedinternational banana (Musa spp.) breedingprogrammes, as new hybrids are frequentlyinfected with this virus, curtailing any furtherexploitation. This infection is thought to arisefrom viral DNA integrated in the nuclear genomeof Musa balbisiana (B genome), one of the wildspecies contributing to many of the bananacultivars currently grown. In order to determinewhether the DNA of other badnavirus species isintegrated in the Musa genome, PCR-amplifiedDNA fragments from Musa acuminata, M.balbisiana and Musa schizocarpa, as well ascultivars 'Obino l'Ewai' and 'Klue Tiparot', werecloned. In total, 103 clones were sequenced andall had similarity to open reading frame III in thebadnavirus genome, although there wasremarkable variation, with 36 distinct sequences", "metadata": {}}
+{"_id": "35714909", "title": "", "text": "Pregnancy in women with type 1 diabetes: havethe goals of St. Vincent declaration been metconcerning foetal and neonatalcomplications?OBJECTIVE In 1989 the St.Vincent declaration set a five-year target forapproximating outcomes of pregnancies inwomen with diabetes to those of the backgroundpopulation. We investigated and quantified therisk of adverse pregnancy outcomes in pregnantwomen with type 1 diabetes (T1DM) to evaluateif the goals of the 1989 St. Vincent Declarationhave been obtained concerning foetal andneonatal complications. METHODS Twelvepopulation-based studies published within thelast 10 years with in total 14,099 women withT1DM and 4,035,373 women from thebackground population were identified. Theprevalence of four foetal and neonatalcomplications was compared. RESULTS Inwomen with T1DM versus the backgroundpopulation, congenital malformations occurred in5.0% (2.2-9.0) (weighted mean and range)", "metadata": {}}
+{"_id": "35724562", "title": "", "text": "BP control and left ventricular hypertrophyregression in children with CKD.In adult patientswith CKD, hypertension is linked to thedevelopment of left ventricular hypertrophy, butwhether this association exists in children withCKD has not been determined conclusively. Toassess the relationship between BP and leftventricular hypertrophy, we prospectivelyanalyzed data from the Chronic Kidney Diseasein Children cohort. In total, 478 subjects wereenrolled, and 435, 321, and 142 subjectsremained enrolled at years 1, 3, and 5,respectively. Echocardiograms were obtained 1year after study entry and then every 2 years;BP was measured annually. A linear mixed modelwas used to assess the effect of BP on leftventricular mass index, which was measured atthree different visits, and a mixed logistic modelwas used to assess left ventricular hypertrophy.These models were part of a joint longitudinaland survival model to adjust for informativedropout. Predictors of left ventricular mass index", "metadata": {}}
+{"_id": "35747505", "title": "", "text": "Nicotinic Acid Adenine Dinucleotide 2'-Phosphate(NAADP) Binding Proteins inT-Lymphocytes.Nicotinic acid adeninedinucleotide phosphate (NAADP) is a messengerthat regulates calcium release from intracellularacidic stores. Although several channels,including two-pore channels (TPC), ryanodinereceptor (RYR) and mucolipin (TRP-ML1) havebeen implicated in NAADP regulation of calciumsignaling, the NAADP receptor has not beenidentified. In this study, the photoaffinity probe,[32P]-5-azido-NAADP ([32P]-5-N3-NAADP), wasused to study NAADP binding proteins in extractsfrom NAADP responsive Jurkat T-lymphocytes.[32P]-5-N3-NAADP photolabeling of Jurkat S100cytosolic fractions resulted in the labeling of atleast ten distinct proteins. Several of these S100proteins, including a doublet at 22/23 kDa andsmall protein at 15 kDa displayed selectivity forNAADP as the labeling was protected by inclusionof unlabeled NAADP, whereas the structurallysimilar NADP required much higher", "metadata": {}}
+{"_id": "35760786", "title": "", "text": "Loss of subcellular lipid transport due to ARV1deficiency disrupts organelle homeostasis andactivates the unfolded protein response.TheARV1-encoded protein mediates sterol transportfrom the endoplasmic reticulum (ER) to theplasma membrane. Yeast ARV1 mutantsaccumulate multiple lipids in the ER and aresensitive to pharmacological modulators of bothsterol and sphingolipid metabolism. Usingfluorescent and electron microscopy, wedemonstrate sterol accumulation, subcellularmembrane expansion, elevated lipid dropletformation, and vacuolar fragmentation in ARV1mutants. Motif-based regression analysis ofARV1 deletion transcription profiles indicatesactivation of Hac1p, an integral component ofthe unfolded protein response (UPR).Accordingly, we show constitutive splicing ofHAC1 transcripts, induction of a UPR reporter,and elevated expression of UPR targets in ARV1mutants. IRE1, encoding the unfolded proteinsensor in the ER lumen, exhibits a lethal genetic", "metadata": {}}
+{"_id": "35764259", "title": "", "text": "IL-28, IL-29 and their class II cytokine receptorIL-28RCytokines play a critical role in modulatingthe innate and adaptive immune systems. Here,we have identified from the human genomicsequence a family of three cytokines, designatedinterleukin 28A (IL-28A), IL-28B and IL-29, thatare distantly related to type I interferons (IFNs)and the IL-10 family. We found that like type IIFNs, IL-28 and IL-29 were induced by viralinfection and showed antiviral activity. However,IL-28 and IL-29 interacted with a heterodimericclass II cytokine receptor that consisted of IL-10receptor β (IL-10Rβ) and an orphan class IIreceptor chain, designated IL-28Rα. This newlydescribed cytokine family may serve as analternative to type I IFNs in providing immunityto viral infection.", "metadata": {}}
+{"_id": "35766603", "title": "", "text": "High-dose recombinant tumor necrosis factoralpha in combination with interferon gamma andmelphalan in isolation perfusion of the limbs formelanoma and sarcoma.PURPOSE To determinethe toxicity and the therapeutic efficacy of thecombination of the recombinant tumor necrosisfactor alpha (rTNF alpha), recombinantinterferon gamma (rIFN-gamma), andmelphalan, we designed a protocol usingisolation limb perfusion (ILP) with hyperthermiafor in-transit metastases of melanoma andrecurrent sarcoma. The triple combination waschosen because of the reported synergisticantitumor effect of rTNF alpha with IFN-gammaand of rTNF alpha with alkylating agents.PATIENTS AND METHODS Twenty-three patientsreceived a total of 25 ILPs with the triplecombination. There were 19 females and fourmales with either multiple progressive in-transitmelanoma metastases of the extremities (stageIIIa or IIIab; 19 patients) or recurrent soft tissuesarcoma (five). The rTNF alpha was injected as a", "metadata": {}}
+{"_id": "35768199", "title": "", "text": "Methanosphaera stadtmaniae gen. nov., sp.nov.: a species that forms methane by reducingmethanol with hydrogenMethanosphaerastadtmaniae is a non-motile, Gram-positivespherical-shaped organism that obtains energyfor growth by using hydrogen to reducemethanol to methane. It does not producemethane from hydrogen and carbon dioxide,formate, acetate or methylamines and cannotgrow with hydrogen and carbon monoxide,nitrate, fumarate, sulfate or choline. Its pHoptimum is 6.5 to 6.9 and its temperatureoptimum is 36° to 40° C. It is not inhibited bybile salts, inhibitors of the synthesis of folic acidcoenzymes, cephalothin or clindamycin but isinhibited by metronidazole, bacitracin, monensin,lasalocid, or bromoethanesulfonate. It requiresacetate, carbon dioxide, isoleucine, ammonium,and thiamin for growth and biotin is stimulatory.It does not contain cytochromes and the mol %G+C of its DNA is 25.8. The composition of itscell wall and 16 S rRNA and its immunological", "metadata": {}}
+{"_id": "35777860", "title": "", "text": "Generation of induced pluripotent stem cellsfrom Asian patients with chronicneurodegenerative diseases.Induced pluripotentstem (iPS) cells derived from disease patientsare an invaluable resource for biomedicalresearch and may provide a source forreplacement therapies. In this study, we havegenerated iPS cells from Asian patients withchronic degenerative diseases of the nervoussystem, including spinal muscular atrophy(SMA), Parkinson disease (PD) and amyotrophiclateral sclerosis (ALS) by transduction with fourfactors (KLF4, SOX2, OCT4 and c-MYC). All of theiPS cells showed pluripotency similar to that ofhuman embryonic stem cells (hESCs) and wereable to differentiate into various somatic celltypes in vitro and in vivo. Furthermore, the iPScells also can be committed to differentiate intoneural cells, the cell type that is affected inchronic degenerative diseases. Therefore, thepatient-specific iPS cells we generated offer acellular model in which to investigate disease", "metadata": {}}
+{"_id": "35811036", "title": "", "text": "Embryonic-like stem cell derived from adult bonemarrow: immature morphology, cell surfacemarkers, ultramicrostructure and differentiationinto multinucleated fibers in vitro.Embryonic-likestem cell (ELSC), expressing part of surfacemarkers of human embryonic stem cells, may bea better candidate for cell therapy ofdegenerative muscular disease thanmesenchymal stem cell (MSC). We isolated ELSCand MSC from bone marrow, respectively, andcompared their differences in the characteristicsand the capacity of myogenic differentiation.Results showed that ELSC could be isolatedsuccessfully from 3 adult bone marrow samplesby using serum-free medium with 10ng/ml basicfibroblast growth factor (bFGF). At the same celldensity, MSC could also be isolated from thesame samples by using DMEM/F12 mediumcontaining 10% new cattle serum. However,ELSC appeared as small, morphologicallyslenderer, upregulated expression of SSEA-4 andultramicroscopically more immature than MSC", "metadata": {}}
+{"_id": "35828148", "title": "", "text": "Kinetic evidence for rapid oxidation of(-)-epicatechin by humanmyeloperoxidase.Apocynin has been reported torequire dimerization by myeloperoxidase (MPO)to inhibit leukocyte NADPH oxidase.(-)-Epicatechin, a dietary flavan-3-ol, has beenidentified as a 'prodrug' of apocynin-likemetabolites that inhibit endothelial NADPHoxidase activity and elevate the cellular level ofnitric oxide. Since (-)-epicatechin has tentativelybeen identified as substrate of MPO, we studiedthe one-electron oxidation of (-)-epicatechin byMPO. By using multi-mixing stopped-flowtechnique, we demonstrate that (-)-epicatechinis one of the most efficient electron donors forheme peroxidases investigated so far. Secondorder rate constants for the(-)-epicatechin-mediated conversion ofMPO-compound I to compound II and compoundII to resting enzyme were estimated to be 1.9 x10(7) and 4.5 x 10(6) M(-1)s(-1), respectively(pH 7, 25 degrees C). The data indicate that", "metadata": {}}
+{"_id": "35861290", "title": "", "text": "Using the yeast gene deletion collection tocustomize gene expression.Substitute TeacherDespite the relative ease of genomemanipulation in S. cerevisiae, researchers arealways looking to learn still more convenient andrapid methods for substituting yeast promoters.Replacing a gene's native promoter with aheterolo-gous promoter of choice allowsregulated expression and simplifies the task ofdiscerning functional relevance. Although a hostof clever chromosomal insertion strategies havebeen described over the years, the advent of theS. cerevisiae Genome Deletion Project providesan incredible resource for a further streamlinedworkflow. The strategy, explained by Liko et al.on p. 728 is appealingly simple. The genomedeletion project resulted in a collection of strainsin which a single ORF is replaced with akanamycin resistance module. Although thepurpose of the collection is to have acomprehensive resource of essentially allpossible knockouts, the authors point out that for", "metadata": {}}
+{"_id": "35884026", "title": "", "text": "Tyrosine phosphorylation and regulation of theAMPA receptor by SRC family tyrosinekinases.Phosphorylation of AMPA receptors is amajor mechanism for the regulation of receptorfunction and underlies several forms of synapticplasticity in the CNS. Although serine andthreonine phosphorylation of AMPA receptors hasbeen well studied, the potential role of tyrosinephosphorylation of AMPA receptors has not beeninvestigated. Here, we show that the GluR2subunit of AMPA receptors is tyrosinephosphorylated in vitro and in vivo by Src familytyrosine kinases on tyrosine 876 near its Cterminus. In addition, GluR agonist treatment ofcultured cortical neurons increasedphosphorylation of tyrosine 876. The associationwith GluR2-interacting molecules GRIP1/2 wasdecreased by tyrosine phosphorylation of GluR2,whereas PICK1 interaction was not influenced.Moreover, mutation of tyrosine 876 eliminatedAMPA- and NMDA-induced internalization of theGluR2 subunit. These data indicate that tyrosine", "metadata": {}}
+{"_id": "35962023", "title": "", "text": "tBid induces alterations of mitochondrial fattyacid oxidation flux by malonyl-CoA-independentinhibition of carnitinepalmitoyltransferase-1Recent studies suggest aclose relationship between cell metabolism andapoptosis. We have evaluated changes in lipidmetabolism on permeabilized hepatocytestreated with truncated Bid (tBid) in the presenceof caspase inhibitors and exogenous cytochromec. The measurement of β-oxidation flux bylabeled palmitate demonstrates that tBid inhibitsβ-oxidation, thereby resulting in theaccumulation of palmitoyl-coenzyme A (CoA) anddepletion of acetyl-carnitine and acylcarnitines,which is pathognomonic for inhibition of carnitinepalmitoyltransferase-1 (CPT-1). We also showthat tBid decreases CPT-1 activity by amechanism independent of both malonyl-CoA,the key inhibitory molecule of CPT-1, and Bakand/or Bax, but dependent on cardiolipindecrease. Overexpression of Bcl-2, which is ableto interact with CPT-1, counteracts the effects", "metadata": {}}
+{"_id": "35987381", "title": "", "text": "CD8+ T cells are activated in anantigen-independent manner in HIV-infectedindividuals.Hyperactivation of T cells, particularlyof CD8(+) T cells, is a hallmark of chronic HIV 1(HIV-1) infection. Little is known about theantigenic specificities and the mechanisms bywhich HIV-1 causes activation of CD8(+) T cellsduring chronic infection. We report that CD8(+)T cells were activated during in vivo HIV-1replication irrespective of their Ag specificity.Cytokines present during untreated HIV-1infection, most prominently IL-15, triggeredproliferation and expression of activationmarkers in CD8(+) T cells, but not CD4(+) Tcells, in the absence of TCR stimulation.Moreover, LPS or HIV-1-activated dendritic cells(DCs) stimulated CD8(+) T cells in anIL-15-dependent but Ag-independent manner,and IL-15 expression was highly increased inDCs isolated from viremic HIV-1 patients,suggesting that CD8(+) T cells are activated byinflammatory cytokines in untreated HIV-1", "metadata": {}}
+{"_id": "35993767", "title": "", "text": "Cancer-associated fibroblasts promotehepatocellular carcinoma metastasis throughchemokine-activated hedgehog and TGF-βpathways.Fibroblasts are rich in the surroundingmicroenvironment of hepatocellular carcinoma(HCC) because most HCCs occur in fibrotic orcirrhotic livers. However, the role ofcancer-associated fibroblasts (CAFs) in HCCmetastasis remains obscure. Here, we reportedthat CAFs promote the migration and invasion ofHCC cells in vitro and facilitate the HCCmetastasis to the bone, brain and lung inNOD/SCID mice. The RayBio human chemokineantibody array revealed that CAFs secret higherlevels of CCL2, CCL5, CCL7 and CXCL16 thanperi-tumor fibroblasts. CCL2 and CCL5 increasethe migration but not the invasion of HCC cells,while CCL7 and CXCL16 promote both migrationand invasion of HCC cells. Moreover, CCL2 andCCL5 stimulate the activation of the hedgehog(Hh) pathway, while CCL7 and CXCL16 enhancethe activity of the transforming growth factor-β", "metadata": {}}
+{"_id": "36003142", "title": "", "text": "Mortality risk in patients with dementia treatedwith antipsychotics versus other psychiatricmedications.OBJECTIVE Mortality rates in theyear following new antipsychotic medicationstarts for neuropsychiatric symptoms ofdementia were compared with rates after startsof other psychiatric medications. METHOD Theretrospective, cohort study used national datafrom the Department of Veterans Affairs (fiscalyears 2001-2005) on patients older than 65years who began outpatient treatment withpsychiatric medication following a dementiadiagnosis (N=10,615). Twelve-month mortalityrates were compared in patients takingantipsychotics and those taking other psychiatricmedications. The authors controlled forconfounding by using multivariate models andpropensity-scoring methods. Secondary analysesincluded a no-medication group and examinationof mortality causes. RESULTS All groups takingantipsychotics had significantly higher mortalityrates (22.6%-29.1%) than patients taking", "metadata": {}}
+{"_id": "36025357", "title": "", "text": "Glutathione: overview of its protective roles,measurement, and biosynthesis.This review isthe introduction to a special issue concerning,glutathione (GSH), the most abundant lowmolecular weight thiol compound synthesized incells. GSH plays critical roles in protecting cellsfrom oxidative damage and the toxicity ofxenobiotic electrophiles, and maintaining redoxhomeostasis. Here, the functions and GSH andthe sources of oxidants and electrophiles, theelimination of oxidants by reduction andelectrophiles by conjugation with GSH are brieflydescribed. Methods of assessing GSH status inthe cells are also described. GSH synthesis andits regulation are addressed along withtherapeutic approaches for manipulating GSHcontent that have been proposed. The purposehere is to provide a brief overview of some of theimportant aspects of glutathione metabolism aspart of this special issue that will provide a morecomprehensive review of the state of knowledgeregarding this essential molecule.", "metadata": {}}
+{"_id": "36033696", "title": "", "text": "A wellness class for inpatients with psychoticdisorders.OBJECTIVE The purpose of this projectwas to educate inpatients with psychoticdisorders, many of whom were takingsecond-generation antipsychotics, about lifestylechanges they can make to combat weight gain.METHOD All inpatients on a Veterans Affairsacute inpatient schizophrenia treatment unitwere invited to a 30-minute, didacticpresentation given by a medical student and apsychology student under the supervision of theprimary investigator. The topics covered includedthe health benefits of maintaining an ideal bodyweight by selecting foods according to the USDAFood Pyramid, determining adequate foodportions, choosing healthy meals outside thehome, and beginning and adhering to anexercise program. Subjects completed a 13-itemquiz concerning their knowledge of food andnutrition before and after the presentation todetermine its efficacy in teaching patients thematerial. RESULTS Fifty patients completed both", "metadata": {}}
+{"_id": "36066871", "title": "", "text": "Heterochromatin integrity affects chromosomereorganization after centromere dysfunction.Thecentromere is essential for the inheritance ofgenetic information on eukaryotic chromosomes.Epigenetic regulation of centromere identity hasbeen implicated in genome stability, karyotypeevolution, and speciation. However, little isknown regarding the manner in whichcentromere dysfunction affects the chromosomalarchitectures. Here we show that in the fissionyeast Schizosaccharomyces pombe, theconditional deletion of the centromere producessurvivors that carry either aneocentromere-acquired chromosome at thesubtelomeric region or an acentric chromosomerescued by intertelomere fusion with either ofthe remaining chromosomes. The ratio ofneocentromere formation to telomere fusion isconsiderably decreased by the inactivation ofgenes involved in RNA interference-dependentheterochromatin formation. By affecting themodes of chromosomal reorganization, the", "metadata": {}}
+{"_id": "36082224", "title": "", "text": "Expansion and deletion of CTG repeats fromhuman disease genes are determined by thedirection of replication in E. coliSeveral humanhereditary neurological and neurodegenerativedisease genes are associated with the expansionof CTG repeats. Here we show that the frequencyof genetic expansions or deletions in Escherichiacoli depends on the direction of replication. Largeexpansions occur predominantly when the CTGsare in the leading strand template rather thanthe lagging strand. However, deletions are moreprominant when the CTGs are in the oppositeorientation. Most deletions generated products ofdefined size classes. Strand slippage coupledwith non–classical DMA structures may accountfor these observations and relate toexpansion–deletion mechanisms in eukaryoticchromosomes for disease genes.", "metadata": {}}
+{"_id": "36089763", "title": "", "text": "Neutrophil extracellular traps capture and killCandida albicans yeast and hyphalforms.Neutrophils phagocytose and kill microbesupon phagolysosomal fusion. Recently we foundthat activated neutrophils form extracellularfibres that consist of granule proteins andchromatin. These neutrophil extracellular traps(NETs) degrade virulence factors and kill Grampositive and negative bacteria. Here we show forthe first time that Candida albicans, a eukaryoticpathogen, induces NET-formation and issusceptible to NET-mediated killing. C. albicansis the predominant aetiologic agent of fungalinfections in humans, particularly inimmunocompromised hosts. One major virulencetrait of C. albicans is its ability to reversiblyswitch from singular budding cells to filamentoushyphae. We demonstrate that NETs kill bothyeast-form and hyphal cells, and that granulecomponents mediate fungal killing. Takentogether our data indicate that neutrophils trapand kill ascomycetous yeasts by forming NETs.", "metadata": {}}
+{"_id": "36111909", "title": "", "text": "Katanin p60-like1 promotes microtubule growthand terminal dendrite stability in the larval classIV sensory neurons of Drosophila.Dendrite shapeis considered a defining component of neuronalfunction. Yet, the mechanisms specifying diversedendritic morphologies, and the extent to whichtheir function depends on these morphologies,remain unclear. Here, we demonstrate arequirement for the microtubule-severing proteinkatanin p60-like 1 (Kat-60L1) in regulating theelaborate dendrite morphology and nocifensivefunctions of Drosophila larval class IV dendriticarborization neurons. Kat-60L1 mutants exhibitdiminished responsiveness to noxiousmechanical and thermal stimuli. Class IVdendrite branch number and length are alsoreduced, supporting a correspondence betweenneuronal function and the full extent of thedendritic arbor. These arborization defects occurparticularly in late larval development, and liveimaging reveals that Kat-60L1 is required fordynamic, filopodia-like nascent branches to", "metadata": {}}
+{"_id": "36124058", "title": "", "text": "Update on technical issues concerningcomplementary feeding of young children indeveloping countries and implications forintervention programs.This paper provides anupdate to the 1998 WHO/UNICEF report oncomplementary feeding. New research findingsare generally consistent with the guidelines inthat report, but the adoption of new energy andmicronutrient requirements for infants and youngchildren will result in lower recommendationsregarding minimum meal frequency and energydensity of complementary foods, and will alterthe list of \"problem nutrients. \" Withoutfortification, the densities of iron, zinc, andvitamin B6 in complementary foods are ofteninadequate, and the intake of other nutrientsmay also be low in some populations. Strategiesfor obtaining the needed amounts of problemnutrients, as well as optimizing breastmilk intakewhen other foods are added to the diet, arediscussed. The impact of complementary feedinginterventions on child growth has been variable,", "metadata": {}}
+{"_id": "36178047", "title": "", "text": "Decrease of learning capacity in offspring withincreasing paternal age in the rat.The same 15male Wistar rats at the ages of 2.5, 6, 10, 14,18, and 22 months were successively randomlymated with 2.5-month-old females. In a separateexperiment, 15 male Wistar rats at the age of2.5 months and 15 at the age of 23 months weresimultaneously randomly mated with2.5-month-old females. Offspring were evaluatedin regard to the mean number per litter, sexratio, frequency of gross external malformations,growth pattern, and mortality in the first 13weeks of life and reproductive capacity at 13weeks of age. They were also evaluated forspontaneous activity and emotionality with anopen field test and for learning capacity with anavoidance conditioning test, both carried outbetween 10 and 13 weeks of age. Only learningcapacity of the offspring, expressed inpercentage of success for male or female,decreased consistently and significantly as thefather's age increased. But females did not seem", "metadata": {}}
+{"_id": "36180468", "title": "", "text": "Processing of the beta-amyloid precursor.Multiple proteases generate and degradepotentially amyloidogenic fragments.Proteolyticprocessing of the beta-amyloid precursorproteins (APP) is required for release of thebeta/A4 protein and its deposition into theamyloid plaques characteristic of aging andAlzheimer's disease. We have examined theinvolvement of acidic intracellular compartmentsin APP processing in cultured human cells. Theuse of acidotropic agents and inhibitors to aspecific class of lysosomal protease, coupled withmetabolic labeling and immunoprecipitation,revealed that APP is degraded within an acidiccompartment to produce at least 12COOH-terminal fragments. Nine likely containthe entire beta/A4 domain and, therefore, arepotentially amyloidogenic. Treatment with E64 orZ-Phe-Ala-CHN2 irreversibly blocked activities ofthe lysosomal cysteine proteases cathepsins Band L but did not inhibit the lysosomal asparticprotease cathepsin D and did not alter the", "metadata": {}}
+{"_id": "36202354", "title": "", "text": "Pharmaceutical Public-Private Partnerships in theUnited States and Europe: Moving from theBench to the BedsideBoth to address unmetmedical needs and to improve industrycompetitiveness, regulators in both the UnitedStates and the European Union have taken boldsteps to translate academic research from theuniversity lab to the patient. A pharmaceuticalpublic-private partnership (PPPP), which is alegally binding contract between a privatepharmaceutical enterprise and a public researchuniversity (or a private university doing researchfunded with public funds), can be a significanttool to ensure a more efficient payoff in thehighly regulated world of pharmaceuticals. Inparticular, a properly framed binding contract,coupled with respect for positive social norms,can move the parties away from an inefficientprisoners’ dilemma Nash Equilibrium to thePareto Optimal Frontier. When coupled withappropriate attention to the difficult task ofcoordinating the actions of interdependent", "metadata": {}}
+{"_id": "36211049", "title": "", "text": "Chronic stress and psychological well-being:evidence from Thailand on householdcrowding.This paper examines the effect of oneform of chronic stress--household crowding--onpsychological well-being, as measured bymultiple inverse indicators of psychologicalwell-being. We rely on data from a large (n =2017) random sample of households in Bangkok,Thailand, a context that has a higher level andbroader range of crowding than typically found inthe United States. Objective household crowdingis found to be detrimental to psychologicalwell-being, controlling for a number ofbackground characteristics. The effect ofobjective crowding is mediated by subjectivecrowding, which has strong, consistent and directdetrimental effects on well-being. There is noevidence of a gender effect. Extended familyhouseholds are not uncommon in Bangkok, butthe effects of objective and subjective crowdingare similar in both two- and three-generationhouseholds, as well as in one- and", "metadata": {}}
+{"_id": "36212758", "title": "", "text": "Age- and sex-specific genomic profiles innon-small cell lung cancer.CONTEXT Geneexpression profiling may be useful in examiningdifferences underlying age- and sex-specificoutcomes in non-small cell lung cancer (NSCLC).OBJECTIVE To describe clinically relevantdifferences in the underlying biology of NSCLCbased on patient age and sex. DESIGN,SETTING, AND PATIENTS Retrospective analysisof 787 patients with predominantly early stageNSCLC performed at Duke University, Durham,North Carolina, from July 2008 to June 2009.Lung tumor samples with correspondingmicroarray and clinical data were used. Allpatients were divided into subgroups based onage (< 70 vs > or = 70 years old) or sex. Geneexpression signatures representing oncogenicpathway activation and tumorbiology/microenvironment status were applied tothese samples to obtain patterns ofactivation/deregulation. MAIN OUTCOMEMEASURES Patterns of oncogenic and molecular", "metadata": {}}
+{"_id": "36216395", "title": "", "text": "Amelioration of colitis by genetically engineeredmurine regulatory T cells redirected byantigen-specific chimeric receptor.BACKGROUND& AIMS The therapeutic application of regulatoryT cells (Tregs) for the treatment of inflammatorydiseases is limited by the scarcity ofantigen-specific Tregs. A preferred approach toendow effector T cells (Teff) with a desiredspecificity uses chimeric immune receptors withantibody-type specificity. Accordingly, employingsuch chimeric immune receptors to redirectTregs to sites of inflammation may be a usefultherapeutic approach to alleviate a broad scopeof diseases in which an uncontrolledinflammatory response plays a major role.METHODS To enable application of the approachin clinical setting, which requires the geneticmodification of the patient's own Tregs, wedescribe here a novel protocol that allows theefficient retroviral transduction and2,4,6-trinitrophenol-specific expansion of murinenaturally occurring regulatory T cells (nTregs),", "metadata": {}}
+{"_id": "36233757", "title": "", "text": "Purification and activation properties ofUreD-UreF-urease apoprotein complexes.In vivoassembly of the Klebsiella aerogenes ureasenickel metallocenter requires the presence ofUreD, UreF, and UreG accessory proteins and isfurther facilitated by UreE. Prior studies hadshown that urease apoprotein exists in anuncomplexed form as well as in a series ofUreD-urease (I.-S. Park, M.B. Carr, and R.P.Hausinger, Proc. Natl. Acad. Sci. USA91:3233-3237, 1994) andUreD-UreF-UreG-urease (I.-S. Park and R.P.Hausinger, J. Bacteriol. 177:1947-1951, 1995)apoprotein complexes. This study demonstratesthe existence of a distinct series of complexesconsisting of UreD, UreF, and urease apoprotein.These novel complexes exhibited activationproperties that were distinct from urease andUreD-urease apoprotein complexes. Unlike thepreviously described species, theUreD-UreF-urease apoprotein complexes wereresistant to inactivation by NiCl2. The", "metadata": {}}
+{"_id": "36242796", "title": "", "text": "Coordinate regulation of the IL-4, IL-13, and IL-5cytokine cluster in Th2 clones revealed by allelicexpression patterns.The cytokines IL-4, IL-13,and IL-5 are markers for the Th2 subset ofeffector T cells and are often expressed together.These cytokine genes are organized within 140kb of orthologous DNA in both mouse andhuman. Using IL-4-expressing CD4+ T cellclones derived from F1 mice, we identified allelicpolymorphisms for each of these cytokines andassessed the parental identity of the cytokinemRNAs. Both monoallelic and biallelic expressionoccurred for each gene and for an additionalgene, IL-3, that lies with GM-CSF over 450 kbtelomeric on the same chromosome. Whencoexpressed in T cell clones, IL-4 was expressedfrom the same allele as IL-13 or IL-5 in 81% ofinstances. In contrast, there was only 52%concordance of these three cytokines at theallelic level among clones that expressed IL-3.Independent expression of the cytokine allelesoccurs commonly in T cells, but the clustered", "metadata": {}}
+{"_id": "36271512", "title": "", "text": "T-cell activation.INTRODUCTION • • CELLULARAND MOLECULAR REQUIREMENTS FOR T-CELLACTIVATION . The T-Cell Antigen ReceptorComplex . . . .. . . . ..... . . . . . . . . . . . . . . . ....... . . . T-Cell Activation by Antibodies andLeetins . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OtherCell Surface Structures (Accessory Molecules)Involved in Antigen Recognition and Activation . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . MinimalRequirements/or T-Cell Activation . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . CONSEQUE\u0000CES o\u0000, T-CELLAC::IV A TION ; . ExpressIOn of ActIVatIOnAnllgens . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . Mechanisms of Signal Transmission viathe TCR Complex . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . The Mode of Control ofGene Expression during T-Cell Activation . . . . . .", "metadata": {}}
+{"_id": "36288526", "title": "", "text": "Effect of hydroxyethyl starch on bleeding aftercardiopulmonary bypass: a meta-analysis ofrandomized trials.OBJECTIVE The effects ofhydroxyethyl starch on bleeding aftercardiopulmonary bypass were determined.METHODS A meta-analysis was performed ofpostoperative blood loss in randomized clinicaltrials of hydroxyethyl starch versus albumin forfluid management in adult cardiopulmonarybypass surgery. Impacts of hydroxyethyl starchmolecular weight and molar substitution wereassessed. Randomized trials directly comparingdifferent hydroxyethyl starch solutions were alsoincluded. RESULTS Eighteen trials with 970 totalpatients were included. Compared with albumin,hydroxyethyl starch increased postoperativeblood loss by 33.3% of a pooled SD (95%confidence interval, 18.2%-48.3%; P < .001).Risk of reoperation for bleeding was more thandoubled by hydroxyethyl starch (relative risk,2.24; 95% confidence interval, 1.14-4.40; P =.020). Hydroxyethyl starch increased transfusion", "metadata": {}}
+{"_id": "36310858", "title": "", "text": "Downstream of Mutant KRAS, the TranscriptionRegulator YAP Is Essential for NeoplasticProgression to Pancreatic DuctalAdenocarcinomaPancreatic ductaladenocarcinoma (PDAC) is an aggressive cancerwith poor survival rates and frequently carriesoncogenic KRAS mutation. However, KRAS hasthus far not been a viable therapeutic target. Wefound that the abundance of YAP mRNA, whichencodes Yes-associated protein (YAP), a proteinregulated by the Hippo pathway during tissuedevelopment and homeostasis, was increased inhuman PDAC tissue compared with that innormal pancreatic epithelia. In geneticallyengineered KrasG12D andKrasG12D:Trp53R172H mouse models,pancreas-specific deletion of Yap halted theprogression of early neoplastic lesions to PDACwithout affecting normal pancreatic developmentand endocrine function. Although Yap wasdispensable for acinar to ductal metaplasia(ADM), an initial step in the progression to PDAC,", "metadata": {}}
+{"_id": "36345185", "title": "", "text": "Rho, Rac and Cdc42 regulate actin organizationand cell adhesion in macrophages.Rho familyproteins are known to regulate actin organizationin fibroblasts, but their functions in cells ofhaematopoietic origin have not been studied indetail. Bac1.2F5 cells are a colony-stimulatingfactor-1 (CSF-1)-dependent murine macrophagecell line; CSF-1 stimulates their proliferation andmotility, and acts as a chemoattractant. CSF-1rapidly induced actin reorganization in Bac1cells: it stimulated the formation of filopodia,lamellipodia and membrane ruffles at the plasmamembrane, as well as the appearance of fineactin cables within the cell interior. Microinjectionof constitutively activated (V12)Rac1 stimulatedlamellipodium formation and membrane ruffling.The dominant inhibitory Rac mutant, N17Rac1,inhibited CSF-1-induced lamellipodiumformation, and also induced cell rounding.V12Cdc42 induced the formation of longfilopodia, while the dominant inhibitory mutantN17Cdc42 prevented CSF-1-induced formation of", "metadata": {}}
+{"_id": "36345578", "title": "", "text": "Visualizing the function and fate of neutrophils insterile injury and repairNeutrophils have beenimplicated as harmful cells in a variety ofinappropriate inflammatory conditions wherethey injure the host, leading to the death of theneutrophils and their subsequent phagocytosisby monocytes and macrophages. Here we showthat in a fully repairing sterile thermal hepaticinjury, neutrophils also penetrate the injury siteand perform the critical tasks of dismantlinginjured vessels and creating channels for newvascular regrowth. Upon completion of thesetasks, they neither die at the injury site nor arephagocytosed. Instead, many of theseneutrophils reenter the vasculature and have apreprogrammed journey that entails a sojourn inthe lungs to up-regulate CXCR4 (C-X-C motifchemokine receptor 4) before entering the bonemarrow, where they undergo apoptosis.", "metadata": {}}
+{"_id": "36355784", "title": "", "text": "The effect of mass screening on incidence andmortality of squamous and adenocarcinoma ofcervix uteri.OBJECTIVE To describe the efficacyof the Finnish mass screening program forcervical squamous carcinoma andadenocarcinoma, as reflected by changes ofincidence and mortality rate. METHODS Cervicalcancer incidence and mortality data wereobtained from the Finnish Cancer Registry. Datawere available from the year 1953, when theregistry was established. The nationwide massscreening program in Finland was started in themid-1960s. A centralized organizationadministers this program. Women age 30-60years are notified for screening every 5 years.RESULTS The mean incidence of cervicalcarcinoma in the early 1960s was 15.4 per 10(5)woman-years. In 1991, it was only 2.7 per 10(5)woman-years. The mortality rate has decreasedin the same proportion since the mass screeningprogram. In the early 1960s, the mortality was6.6 and in 1991 1.4 per 10(5) woman-years.", "metadata": {}}
+{"_id": "36357627", "title": "", "text": "Role of 5-HT in the regulation of thebrain-pituitary-adrenal axis: effects of 5-HT onadrenocortical cells.Serotonin (5-HT) plays apivotal role in the regulation of thebrain-pituitary-adrenal axis. In particular, 5-HThas been shown to control the activity ofhypothalamic CRF neurons and pituitarycorticotrope cells through activation of 5-HT1Aand (or) 5-HT(2A/2C) receptor subtypes. 5-HT,acting through 5-HT2 receptors, can also triggerthe renin-angiotensin system by stimulatingrenin secretion and consequently can enhancealdosterone production. At the adrenal level,5-HT produced locally stimulates the secretoryactivity of adrenocortical cells through aparacrine mode of communication. The presenceof 5-HT in the adrenal gland has beendemonstrated immunohistochemically andbiochemically in various species. In the frog, rat,and pig adrenal gland, 5-HT is synthesized bychromaffin cells, while in the mouse adrenalcortex, 5-HT is contained in nerve fibers. In man,", "metadata": {}}
+{"_id": "36386637", "title": "", "text": "Effect of interleukin-1 and tumor necrosisfactor/cachectin on glucose turnover in therat.We studied the effect of recombinant humaninterleukin-1 beta (IL-1) and recombinant humantumor necrosis factor alpha/cachectin (TNF) onglucose kinetics in healthy rats by means of aprimed constant infusion of D-(6-3H)glucose andD-[U-14C]glucose. During the isotope (6-hour)and monokine (4-hour) infusion, plasma levels ofglucagon and insulin were determined andcorrelated with changes in glucose metabolism.The rates of glucose appearance (Ra) anddisappearance (Rd) were elevated only with IL-1and were associated with an increase in glucagonand a concomitant decrease in the ratio of insulinto glucagon. Plasma glucose concentration wasincreased early after IL-1 administration andcoincided with the peak in the Ra. Theaugmentation of the metabolic clearance rate(MCR) and percent of flux oxidized by IL-1suggest that this monokine induces theutilization of glucose as a substrate. TNF", "metadata": {}}
+{"_id": "36398420", "title": "", "text": "Human and murine very small embryonic-likecells represent multipotent tissue progenitors, invitro and in vivo.The purpose of this study was todetermine the lineage progression of human andmurine very small embryonic-like (HuVSEL orMuVSEL) cells in vitro and in vivo. In vitro,HuVSEL and MuVSEL cells differentiated into cellsof all three embryonic germ layers. HuVSEL cellsproduced robust mineralized tissue of humanorigin compared with controls in calvarialdefects. Immunohistochemistry demonstratedthat the HuVSEL cells gave rise to neurons,adipocytes, chondrocytes, and osteoblasts withinthe calvarial defects. MuVSEL cells were also ableto differentiate into similar lineages. First roundserial transplants of MuVSEL cells into irradiatedosseous sites demonstrated that \u000060% of thecells maintained their VSEL cell phenotype whileother cells differentiated into multiple tissues at3 months. Secondary transplants did not identifydonor VSEL cells, suggesting limited self renewalbut did demonstrate VSEL cell derivatives in situ", "metadata": {}}
+{"_id": "36399107", "title": "", "text": "High frequency of p16 (CDKN2/MTS-1/INK4A)inactivation in head and neck squamous cellcarcinoma.The tumor suppressor gene p16(CDKN2/MTS-1/INK4A) can be inactivated bymultiple genetic mechanisms. We analyzed 29invasive primary head and neck squamous cellcarcinomas (HNSCC) for p16 inactivation withimmunohistochemistry utilizing a newmonoclonal antibody (mAb), DCS-50. p16staining of the primary lesions was correlatedwith genetic analysis including: (a) detailedmicrosatellite analysis of markers at the p16locus to detect homozygous deletion; (b)sequence analysis of p16; and (c) Southern blotanalysis to determine the methylation status ofthe 5' CpG island of p16. Twenty-four of 29(83%) head and neck squamous cell carcinomatumors displayed an absence of p16 nuclearstaining using immunohistochemistry. Of these24 tumors, we found that 16 (67%) harboredhomozygous deletions, 5 (21%) weremethylated, 1 displayed a rearrangement at the", "metadata": {}}
+{"_id": "36399109", "title": "", "text": "Genome-wide RNAi screen of Ca(2+) influxidentifies genes that regulate Ca(2+)release-activated Ca(2+) channel activity.Recentstudies by our group and others demonstrated arequired and conserved role of Stim instore-operated Ca(2+) influx and Ca(2+)release-activated Ca(2+) (CRAC) channelactivity. By using an unbiased genome-wide RNAinterference screen in Drosophila S2 cells, wenow identify 75 hits that strongly inhibitedCa(2+) influx upon store emptying bythapsigargin. Among these hits are 11 predictedtransmembrane proteins, including Stim, andone, olf186-F, that upon RNAinterference-mediated knockdown exhibited aprofound reduction of thapsigargin-evokedCa(2+) entry and CRAC current, and uponoverexpression a 3-fold augmentation of CRACcurrent. CRAC currents were further increased to8-fold higher than control and developed morerapidly when olf186-F was cotransfected withStim. olf186-F is a member of a highly conserved", "metadata": {}}
+{"_id": "36432234", "title": "", "text": "Wedelolactone induces growth of breast cancercells by stimulation of estrogen receptorsignalling.Wedelolactone, a plant coumestan,was shown to act as anti-cancer agent for breastand prostate carcinomas in vitro and in vivotargeting multiple cellular proteins includingandrogen receptors, 5-lipoxygenase andtopoisomerase IIα. It is cytotoxic to breast,prostate, pituitary and myeloma cancer cell linesin vitro at μM concentrations. In this study,however, a novel biological activity of nM dose ofwedelolactone was demonstrated. Wedelolactoneacts as agonist of estrogen receptors (ER) α andβ as demonstrated by transactivation of estrogenresponse element (ERE) in cells transientlyexpressing either ERα or ERβ and by moleculardocking of this coumestan into ligand bindingpocket of both ERα and ERβ. In breast cancercells, wedelolactone stimulates growth ofestrogen receptor-positive cells, expression ofestrogen-responsive genes and activates rapidnon-genomic estrogen signalling. All these", "metadata": {}}
+{"_id": "36444198", "title": "", "text": "Subpopulations of mouse blood monocytes differin maturation stage and inflammatoryresponse.Blood monocytes arewell-characterized precursors for macrophagesand dendritic cells. Subsets of human monocyteswith differential representation in various diseasestates are well known. In contrast, mousemonocyte subsets have been characterizedminimally. In this study we identify threesubpopulations of mouse monocytes that can bedistinguished by differential expression of Ly-6C,CD43, CD11c, MBR, and CD62L. The subsetsshare the characteristics of extensivephagocytosis, similar expression of M-CSFreceptor (CD115), and development intomacrophages upon M-CSF stimulation. Byeliminating blood monocytes withdichloromethylene-bisphosphonate-loadedliposomes and monitoring their repopulation, weshowed a developmental relationship betweenthe subsets. Monocytes were maximally depleted18 h after liposome application and subsequently", "metadata": {}}
+{"_id": "36450001", "title": "", "text": "Proteogenomics to discover the full codingcontent of genomes: a computationalperspective.Proteogenomics has emerged as afield at the junction of genomics and proteomics.It is a loose collection of technologies that allowthe search of tandem mass spectra againstgenomic databases to identify and characterizeprotein-coding genes. Proteogenomic peptidesprovide invaluable information for geneannotation, which is difficult or impossible toascertain using standard annotation methods.Examples include confirmation of translation,reading-frame determination, identification ofgene and exon boundaries, evidence forpost-translational processing, identification ofsplice-forms including alternative splicing, andalso, prediction of completely novel genes. Forproteogenomics to deliver on its promise,however, it must overcome a number oftechnological hurdles, including speed andaccuracy of peptide identification, constructionand search of specialized databases, correction", "metadata": {}}
+{"_id": "36464673", "title": "", "text": "The in vitro phosphorylation of p53 bycalcium-dependent protein kinaseC--characterization of a protein-kinase-C-bindingsite on p53.We show that, in vitro,Ca2+-dependent protein kinase C (PKC)phosphorylates recombinant murine p53 proteinon several residues contained within a conservedbasic region of 25 amino acids, located in theC-terminal part of the protein. Accordingly,synthetic p53-(357-381)-peptide isphosphorylated by PKC at multiple Ser and Thrresidues, including Ser360, Thr365, Ser370 andThr377. We also establish thatp53-(357-381)-peptide at micromolarconcentrations has the ability to stimulatesequence-specific DNA binding by p53. Thatstimulation is lost upon phosphorylation by PKC.To further characterise the mechanisms thatregulate PKC-dependent phosphorylation ofp53-(357-381)-peptide, the phosphorylation ofrecombinant p53 and p53-(357-381)-peptide byPKC were compared. The results suggest that", "metadata": {}}
+{"_id": "36480032", "title": "", "text": "Role of ocular pigment epithelial cells in immuneprivilegeThe ocular microenvironment is bothimmunosuppressive and anti-inflammatory innature. Pigment epithelial (PE) cells isolated fromthe eye possess the ability to suppress the T cellreceptor-dependent activation of T cells and theinduction of regulatory T cells in vitro. Thisproperty is dependent on the cells’ capacity toproduce cell-surface and soluble inhibitorymolecules, for example CD86 (B7-2),transforming growth factor (TGF)-β,thrombospondin-1, programmed cell death 1ligand 1 (PD-L1/B7-H1), and cytotoxic Tlymphocyte-associated antigen 2α. Culturedocular PE cells from the iris, ciliary body, andretina can individually suppress T-cell activationvia mechanisms that partially overlap. Moreover,PE-derived regulatory T cells acquire functionsthat play a role in establishing immuneregulation in the eye. Multiple strategies areemployed within the eye to controlimmune-mediated inflammation. This", "metadata": {}}
+{"_id": "36497180", "title": "", "text": "Drug-resistant Salmonella in the United States:an epidemiologic perspective.Salmonellosisposes a health problem of large proportions inthe United States. Annually, it accounts for morethan 40,000 reported cases, 500 deaths, andfinancial costs well in excess of $50 million.Antimicrobial resistance is increasing inSalmonella strains, a finding that has importantpublic health implications. Although the chain oftransmission of the bacteria is often complex,combined epidemiologic and laboratory studieswith the use of new methods in molecularbiology make it possible to traceantimicrobial-resistant salmonellae to theirprimary source--foods of animal origin. Thesestudies suggest that the antimicrobial drugs towhich food animals are exposed provide selectivepressure that leads to the appearance andpersistence of resistant strains.", "metadata": {}}
+{"_id": "36540079", "title": "", "text": "Glutamine-specific N-terminal amidase, acomponent of the N-end rulepathway.Deamidation of N-terminal Gln byNt(Q)-amidase, an N-terminal amidohydrolase,is a part of the N-end rule pathway of proteindegradation. We detected the activity ofNt(Q)-amidase, termed Ntaq1, in mouse tissues,purified Ntaq1 from bovine brains, identified itsgene, and began analyzing this enzyme. Ntaq1 ishighly conserved among animals, plants, andsome fungi, but its sequence is dissimilar tosequences of other amidases. An earlier mutantin the Drosophila Cg8253 gene that we showhere to encode Nt(Q)-amidase has defectivelong-term memory. Other studies identifiedprotein ligands of the uncharacterized humanC8orf32 protein that we show here to be theNtaq1 Nt(Q)-amidase. Remarkably,\"high-throughput\" studies have recently solvedthe crystal structure of C8orf32 (Ntaq1). Oursite-directed mutagenesis of Ntaq1 and itscrystal structure indicate that the active site and", "metadata": {}}
+{"_id": "36547290", "title": "", "text": "Brahma-related gene 1-dependent STAT3recruitment at IL-6-inducible genes.IL-6 is animmunoregulatory cytokine with multiplefunctions in hemopoiesis, proliferation, andtumorigenesis. IL-6 triggers phosphorylation,dimerization, and nuclear translocation of STAT3,which binds to target promoters and activatestranscription. Brahma-related gene 1 (BRG1),the enzymatic engine of the yeast-matingtype-switching and sucrose-nonfermentingchromatin-remodeling complex, is essential forrecruitment of STAT1 orSTAT1/STAT2-containing complexes to IFNtargets. We hypothesized that BRG1 might alsobe required for STAT3 recruitment. In this study,we show that induction of a subset of humanIL-6-responsive genes is BRG1 dependent. BRG1is constitutively present at these targets and isrequired for STAT3 recruitment, downstreamhistone modifications, and IL-6-inducedchromatin remodeling. IL-6-induced recruitmentof STAT3 to the IFN regulatory factor 1 promoter", "metadata": {}}
+{"_id": "36558211", "title": "", "text": "High and low fat consumers, their macronutrientintake and body mass index: further analysis ofthe National Diet and Nutrition Survey of BritishAdults.OBJECTIVES To explore the differentcharacteristics of high and low fat consumers, inparticular their macronutrient intake and bodymass index. DESIGN Reanalysis of data from theDietary and Nutritional Survey of British Adults.Comparisons were made between groups definedas high and low fat consumers on the basis of7-day weighed food records considered to bevalid for energy intake. Individuals wereclassified in two ways according to thepercentage energy from fat (FAT%) and theabsolute amount of fat consumed (FATg). Thecriteria for classification of the high FAT% being> 45% (high fat) and < or = 35% (low fat). Forthe FATg group the threshold for the high fatgroup was > 138 g/day (men) and > 102 g/day(women), and for the low fat group < 85 g/day(men) and < 70 g/day (women). SETTINGDietary data was collected from private", "metadata": {}}
+{"_id": "36606083", "title": "", "text": "Quantitative, genome-wide analysis of eukaryoticreplication initiation and termination.Manyfundamental aspects of DNA replication, such asthe exact locations where DNA synthesis isinitiated and terminated, how frequently originsare used, and how fork progression is influencedby transcription, are poorly understood. Via thedeep sequencing of Okazaki fragments, wecomprehensively document replication forkdirectionality throughout the S. cerevisiaegenome, which permits the systematic analysisof initiation, origin efficiency, fork progression,and termination. We show that leading-strandinitiation preferentially occurs within anucleosome-free region at replication origins.Using a strain in which late origins can beinduced to fire early, we show that replicationtermination is a largely passive phenomenon thatdoes not rely on cis-acting sequences orreplication fork pausing. The replication profile ispredominantly determined by the kinetics oforigin firing, allowing us to reconstruct", "metadata": {}}
+{"_id": "36618603", "title": "", "text": "The murine H19 gene is activated duringembryonic stem cell differentiation in vitro and atthe time of implantation in the developingembryo.The differentiation in vitro of murineembryonic stem cells to embryoid bodies mimicsevents that occur in vivo shortly before and afterembryonic implantation. We have used thissystem, together with differential cDNA cloning,to identify genes the expression of which isregulated during early embryogenesis. Here wedescribe the isolation of several such cDNAclones, one of which corresponds to the geneH19. This gene is activated in extraembryoniccell types at the time of implantation, suggestingthat it may play a role at this stage ofdevelopment, and is subsequently expressed inall of the cells of the mid-gestation embryo withthe striking exception of most of those of thedeveloping central and peripheral nervoussystems. After birth, expression of this geneceases or is dramatically reduced in all tissues.", "metadata": {}}
+{"_id": "36623997", "title": "", "text": "Localization of Sir2p: the nucleolus as acompartment for silent information regulators.Inwild-type budding yeast strains, the proteinsencoded by SIR3, SIR4 and RAP1 co-localize withtelomeric DNA in a limited number of foci ininterphase nuclei. Immunostaining of Sir2pshows that in addition to a punctate staining thatcoincides with Rap1 foci, Sir2p localizes to asubdomain of the nucleolus. The presence ofSir2p at both the spacer of the rDNA repeat andat telomeres is confirmed by formaldehydecross-linking and immunoprecipitation withanti-Sir2p antibodies. In strains lacking Sir4p,Sir3p becomes concentrated in the nucleolus, bya pathway requiring SIR2 and UTH4, a gene thatregulates life span in yeast. The unexpectednucleolar localization of Sir2p and Sir3pcorrelates with observed effects of sir mutationson rDNA stability and yeast longevity, defining anew site of action for silent informationregulatory factors.", "metadata": {}}
+{"_id": "36637129", "title": "", "text": "Optogenetics reveal delayed afferentsynaptogenesis on grafted human-inducedpluripotent stem cell-derived neuralprogenitors.Reprogramming of somatic cells intopluripotency stem cell state has opened newopportunities in cell replacement therapy anddisease modeling in a number of neurologicaldisorders. It still remains unknown, however, towhat degree the grafted human-inducedpluripotent stem cells (hiPSCs) differentiate intoa functional neuronal phenotype and if theyintegrate into the host circuitry. Here, wepresent a detailed characterization of thefunctional properties and synaptic integration ofhiPSC-derived neurons grafted in an in vitromodel of hyperexcitable epileptic tissue, namelyorganotypic hippocampal slice cultures (OHSCs),and in adult rats in vivo. The hiPSCs were firstdifferentiated into long-term self-renewingneuroepithelial stem (lt-NES) cells, which areknown to form primarily GABAergic neurons.When differentiated in OHSCs for 6 weeks,", "metadata": {}}
+{"_id": "36642096", "title": "", "text": "Anti-CD3 monoclonal antibody in new-onset type1 diabetes mellitus.BACKGROUND Type 1diabetes mellitus is a chronic autoimmunedisease caused by the pathogenic action of Tlymphocytes on insulin-producing beta cells.Previous clinical studies have shown thatcontinuous immune suppression temporarilyslows the loss of insulin production. Preclinicalstudies suggested that a monoclonal antibodyagainst CD3 could reverse hyperglycemia atpresentation and induce tolerance to recurrentdisease. METHODS We studied the effects of anonactivating humanized monoclonal antibodyagainst CD3--hOKT3gamma1(Ala-Ala)--on theloss of insulin production in patients with type 1diabetes mellitus. Within 6 weeks afterdiagnosis, 24 patients were randomly assignedto receive either a single 14-day course oftreatment with the monoclonal antibody or noantibody and were studied during the first yearof disease. RESULTS Treatment with themonoclonal antibody maintained or improved", "metadata": {}}
+{"_id": "36651210", "title": "", "text": "Establishment and in vitro differentiation of anew embryonic stem cell line from humanblastocyst.Embryonic stem cells have the abilityto remain undifferentiated and proliferateindefinitely in vitro while maintaining thepotential to differentiate into derivatives of allthree embryonic germ layers. These cells have,therefore, potential for in vitro differentiationstudies, gene function, and so on. The aim of thisstudy was to produce a human embryonic stemcell line. An inner cell mass of a humanblastocyst was separated and cultured on mouseembryonic fibroblasts in embryonic stem cellmedium with related additives. The establishedline was evaluated by morphology; passaging;freezing and thawing; alkaline phosphatase;Oct-4 expression; anti-surface markers includingTra-1-60 and Tra-1-81; and karyotype andspontaneous differentiation. Differentiatedcardiomyocytes and neurons were evaluated bytransmission electron microscopy andimmunocytochemistry. Here, we report the", "metadata": {}}
+{"_id": "36653415", "title": "", "text": "Lactate Metabolism in Human LungTumorsCancer cells consume glucose and secretelactate in culture. It is unknown whether lactatecontributes to energy metabolism in livingtumors. We previously reported that humannon-small-cell lung cancers (NSCLCs) oxidizeglucose in the tricarboxylic acid (TCA) cycle.Here, we show that lactate is also a TCA cyclecarbon source for NSCLC. In human NSCLC,evidence of lactate utilization was most apparentin tumors with high 18fluorodeoxyglucose uptakeand aggressive oncological behavior. Infusinghuman NSCLC patients with 13C-lactate revealedextensive labeling of TCA cycle metabolites. Inmice, deleting monocarboxylate transporter-1(MCT1) from tumor cells eliminatedlactate-dependent metabolite labeling,confirming tumor-cell-autonomous lactateuptake. Strikingly, directly comparing lactate andglucose metabolism in vivo indicated thatlactate's contribution to the TCA cyclepredominates. The data indicate that tumors,", "metadata": {}}
+{"_id": "36654066", "title": "", "text": "Increased lipid peroxidation as a mechanism ofmethionine-induced atherosclerosis inrabbits.Methionine is converted by thetransmethylation/transsulfuration pathway tohomocysteine which may exert atherogeniceffects by several mechanisms, including lipidperoxidation. Therefore, the excessive dietarymethionine may induce the development ofatherosclerosis. To test this hypothesis, plasmaand aortic thiobarbituric acid reactive substances(TBARS), as well as activities of aortic anderythrocyte superoxide dismutase (SOD),catalase and selenium-dependent glutathioneperoxidase (GPX) were measured in rabbits fed adiet enriched with 0.3% methionine for 6 or 9months. Histological examinations of aortas alsowere performed. Feeding rabbits amethionine-enriched diet for 6 or 9 monthsresulted in significant increases in plasma andaortic TBARS levels and aortic antioxidantenzyme activities. However, a decrease inplasma antioxidant activity (AOA) was observed.", "metadata": {}}
+{"_id": "36708463", "title": "", "text": "Sex differences in sex chromosome geneexpression in mouse brain.A major question iswhether genes encoded on the sex chromosomesact directly in non-gonadal tissues to cause sexdifferences in development or function, orwhether all sex differences in somatic tissues areinduced by gonadal secretions. As part of thisquestion we asked whether mouse X-Yhomologous gene pairs are expressed in brain ina sex-specific fashion. Using RT-PCR andnorthern blot analysis, we assessed mRNAexpression in brain of eight Y-linked genes aswell as their X-linked homologues, at three ages:13.5 days post coitum, the day of birth (P1) andadult. Transcripts of six Y genes were expressedat one or more ages: Usp9y, Ube1y, Smcy,Eif2s3y, Uty and Dby. Their expression alsooccurred in XY female brain, and therefore doesnot require testicular secretions. Six X-linkedhomologues (Usp9x, Ube1x, Smcx, Eif2s3x, Utxand Dbx) were also expressed in brain, and inadulthood all of these transcripts were expressed", "metadata": {}}
+{"_id": "36713289", "title": "", "text": "Genome architecture, rearrangements andgenomic disorders.An increasing number ofhuman diseases are recognized to result fromrecurrent DNA rearrangements involvingunstable genomic regions. These are termedgenomic disorders, in which the clinicalphenotype is a consequence of abnormal dosageof gene(s) located within the rearranged genomicfragments. Both inter- and intrachromosomalrearrangements are facilitated by the presence ofregion-specific low-copy repeats (LCRs) andresult from nonallelic homologous recombination(NAHR) between paralogous genomic segments.LCRs usually span approximately 10-400 kb ofgenomic DNA, share >or= 97% sequenceidentity, and provide the substrates forhomologous recombination, thus predisposingthe region to rearrangements. Moreover, it hasbeen suggested that higher order genomicarchitecture involving LCRs plays a significantrole in karyotypic evolution accompanyingprimate speciation.", "metadata": {}}
+{"_id": "36721932", "title": "", "text": "painDETECT: a new screening questionnaire toidentify neuropathic components in patients withback pain.OBJECTIVE Nociceptive andneuropathic components both contribute to pain.Since these components require different painmanagement strategies, correct pain diagnosisbefore and during treatment is highly desirable.As low back pain (LBP) patients constitute animportant subgroup of chronic pain patients, weaddressed the following issues: (i) to establish asimple, validated screening tool to detectneuropathic pain (NeP) components in chronicLBP patients, (ii) to determine the prevalence ofneuropathic pain components in LBP in alarge-scale survey, and (iii) to determinewhether LBP patients with an NeP componentsuffer from worse, or different, co-morbidities.METHODS In co-operation with the GermanResearch Network on Neuropathic Pain wedeveloped and validated the painDETECTquestionnaire (PD-Q) in a prospective,multicentre study and subsequently applied it to", "metadata": {}}
+{"_id": "36749390", "title": "", "text": "Scoring of dual fluorescein and ICG inflammatoryangiographic signs for the grading of posteriorsegment inflammation (dual fluorescein and ICGangiographic scoring system for uveitis)PurposeTo propose a semiquantitative dual fluoresceinangiography (FA) and indocyanine greenangiography (ICGA) scoring system for uveitisthat would assist in the follow-up of diseaseprogression and monitoring response totreatment. Methods The scoring system wasbased on the FA scoring systems, thestandardized ICGA protocol, and schematicinterpretation of ICGA findings in posterioruveitis that have been previously published. Weassigned scores to the fluorescein and ICGangiographic signs that represent ongoinginflammatory process in the posterior segment.We rated each angiographic sign according to theimpact it has on our appreciation of activeintraocular inflammation. In order to permitdirect comparison between FA and ICGA, wemultiplied the total ICGA score by a coefficient of", "metadata": {}}
+{"_id": "36799998", "title": "", "text": "Improving outcomes of acute kidney injury:report of an initiativeAcute kidney injury (AKI) isa complex disorder comprising several etiologicalfactors and occurring in multiple settings. Thedisorder has a variety of clinical manifestationsthat range from minimal elevation in serumcreatinine level to anuric renal failure. Wedescribe the formation of a multidisciplinarycollaborative network focused on AKI. This AcuteKidney Injury Network has proposed uniformstandards for diagnosing and classifying AKI.These proposed standards will need to bevalidated in future studies, a process that will befacilitated by the Acute Kidney Injury Network,which offers a forum that encourages acquisitionof knowledge to improve patient outcomes.", "metadata": {}}
+{"_id": "36816310", "title": "", "text": "A Screen for Endocytic MotifsSorting signals forcargo selection into coated vesicles are usually inthe form of short linear motifs. Three motifs forclathrin-mediated endocytosis have beenidentified: YXXPhi, [D/E]XXXL[L/I] and FXNPXY.To search for new endocytic motifs, we made alibrary of CD8 chimeras with random sequencesin their cytoplasmic tails, and used a novelfluorescence-activated cell sorting (FACS)-basedassay to select for endocytosed constructs. Outof the five tails that were most efficientlyinternalized, only one was found to contain aconventional motif. Two contain dileucine-likesequences that appear to be variations on the[D/E]XXXL[L/I] motif. Another contains a novelinternalization signal, YXXXPhiN, which is able tofunction in cells expressing a mutant mu2 thatcannot bind YXXPhi, indicating that it is not avariation on the YXXPhi motif. Similar sequencesare present in endogenous proteins, including afunctional YXXXPhiN (in addition to a classicalYXXPhi) in cytotoxic T-lymphocyte-associated", "metadata": {}}
+{"_id": "36830715", "title": "", "text": "Microtubule stabilization reduces scarring andcauses axon regeneration after spinal cordinjury.Hypertrophic scarring and poor intrinsicaxon growth capacity constitute major obstaclesfor spinal cord repair. These processes are tightlyregulated by microtubule dynamics. Here,moderate microtubule stabilization decreasedscar formation after spinal cord injury in rodentsthrough various cellular mechanisms, includingdampening of transforming growth factor-βsignaling. It prevented accumulation ofchondroitin sulfate proteoglycans and renderedthe lesion site permissive for axon regenerationof growth-competent sensory neurons.Microtubule stabilization also promoted growth ofcentral nervous system axons of theRaphe-spinal tract and led to functionalimprovement. Thus, microtubule stabilizationreduces fibrotic scarring and enhances thecapacity of axons to grow.", "metadata": {}}
+{"_id": "36831892", "title": "", "text": "Histone tails: Directing the chromatin responseto DNA damage.Considerable energeticinvestment is devoted to altering large stretchesof chromatin adjacent to DNA double strandbreaks (DSBs). Immediately ensuing DSBformation, a myriad of histone modifications areelicited to create a platform for inducible andmodular assembly of DNA repair proteincomplexes in the vicinity of the DNA lesion. Thiscomplex signaling network is critical to repairDNA damage and communicate with cellularprocesses that occur in cis and in trans to thegenomic lesion. Failure to properly execute DNAdamage inducible chromatin changes isassociated with developmental abnormalities,immunodeficiency, and malignancy in humansand in genetically engineered mouse models.This review will discuss current knowledge ofDNA damage responsive histone changes thatoccur in mammalian cells, highlighting theirinvolvement in the maintenance of genomeintegrity.", "metadata": {}}
+{"_id": "36838958", "title": "", "text": "Sestrin2 inhibits uncoupling protein 1 expressionthrough suppressing reactive oxygenspecies.Uncoupling protein 1 (Ucp1), which islocalized in the mitochondrial inner membrane ofmammalian brown adipose tissue (BAT),generates heat by uncoupling oxidativephosphorylation. Upon cold exposure ornutritional abundance, sympathetic neuronsstimulate BAT to express Ucp1 to induce energydissipation and thermogenesis. Accordingly,increased Ucp1 expression reduces obesity inmice and is correlated with leanness in humans.Despite this significance, there is currently alimited understanding of how Ucp1 expression isphysiologically regulated at the molecular level.Here, we describe the involvement of Sestrin2and reactive oxygen species (ROS) in regulationof Ucp1 expression. Transgenic overexpressionof Sestrin2 in adipose tissues inhibited both basaland cold-induced Ucp1 expression ininterscapular BAT, culminating in decreasedthermogenesis and increased fat accumulation.", "metadata": {}}
+{"_id": "36855703", "title": "", "text": "The non-catalytic function of XPG protein duringdual incision in human nucleotide excisionrepair.XPG is a member of the FEN-1structure-specific endonuclease family. It has3'-junction cutting activity on bubble substratesand makes the 3'-incision in the human dualincision (excision nuclease) repair system. Toinvestigate the precise role of XPG in nucleotideexcision repair, we mutagenized two amino acidresidues thought to be involved in DNA bindingand catalysis, overproduced the mutant proteinsusing a baculovirus/insect cell system, andpurified and characterized the mutant proteins.The mutation D77A had a modest effect onjunction cutting and excision activity and gaverise to uncoupled 5'-incision by mammaliancell-free extracts. The D812A mutationcompletely abolished the junction cutting and3'-incision activities of XPG, but the excisionnuclease reconstituted with XPG (D812A) carriedout normal 5'-incision at the 23rd-24thphosphodiester bonds 5' to a (6-4) photoproduct", "metadata": {}}
+{"_id": "36860856", "title": "", "text": "A 40-Hz auditory potential recorded from thehuman scalp.Computer techniques readilyextract from the brainwaves an orderly sequenceof brain potentials locked in time to soundstimuli. The potentials that appear 8 to 80 msecafter the stimulus resemble 3 or 4 cycles of a40-Hz sine wave; we show here that thesewaves combined to form a single, stable,composite wave when the sounds are repeatedat rates around 40 per sec. This phenomenon,the 40-Hz event-related potential (ERP), displaysseveral properties of theoretical and practicalinterest. First, it reportedly disappears withsurgical anesthesia, and it resembles similarphenomena in the visual and olfactory system,facts which suggest that adequate processing ofsensory information may require cyclical brainevents in the 30- to 50-Hz range. Second,latency and amplitude measurements on the40-Hz ERP indicate it may contain usefulinformation on the number and basilarmembrane location of the auditory nerve fibers a", "metadata": {}}
+{"_id": "36889513", "title": "", "text": "Bile acids: natural ligands for an orphan nuclearreceptor.Bile acids regulate the transcription ofgenes that control cholesterol homeostasisthrough molecular mechanisms that are poorlyunderstood. Physiological concentrations of freeand conjugated chenodeoxycholic acid,lithocholic acid, and deoxycholic acid activatedthe farnesoid X receptor (FXR; NR1H4), anorphan nuclear receptor. As ligands, these bileacids and their conjugates modulated interactionof FXR with a peptide derived from steroidreceptor coactivator 1. These results provideevidence for a nuclear bile acid signalingpathway that may regulate cholesterolhomeostasis.", "metadata": {}}
+{"_id": "36904081", "title": "", "text": "The yeast ribosomal protein L32 and its gene.Theyeast ribosomal protein gene RPL32 ofSaccharomyces cerevisiae is of particular interestfor two reasons: 1) it is adjacent to anotherribosomal protein gene, RP29, whose divergenttranscription may be driven from the samecontrol sequences, and 2) it appears that thesplicing of its transcript is regulated by theproduct of the gene, ribosomal protein in L32.RPL32 has been analyzed in detail. It is essentialfor cell growth. Its sequence predicts L32 to be aprotein of 105 amino acids, somewhat basic nearthe NH2 terminus, rather acidic near the COOHterminus, and homologous to ribosomal proteinL30 of mammals. The reading frame has beenconfirmed by partial NH2-terminal analysis ofL32. The nucleotide sequence also predicts anintron of 230 nucleotides, which begins with theunusual sequence GTCAGT and ends 40nucleotides downstream of the consensussequence TAC-TAAC. The intron has beenconfirmed by determination of the sequence of a", "metadata": {}}
+{"_id": "36921186", "title": "", "text": "Derivation conditions impact X-inactivationstatus in female human induced pluripotent stemcells.Female human induced pluripotent stem cell(hiPSC) lines exhibit variability in X-inactivationstatus. The majority of hiPSC lines maintain onetranscriptionally active X (Xa) and one inactive X(Xi) chromosome from donor cells. However, atlow frequency, hiPSC lines with two Xas areproduced, suggesting that epigenetic alterationsof the Xi occur sporadically duringreprogramming. We show here thatX-inactivation status in female hiPSC linesdepends on derivation conditions. hiPSC linesgenerated by the Kyoto method (retroviral orepisomal reprogramming), which uses leukemiainhibitory factor (LIF)-expressing SNL feeders,frequently had two Xas. Early passage Xa/XihiPSC lines generated on non-SNL feeders wereconverted into Xa/Xa hiPSC lines after severalpassages on SNL feeders, and supplementationwith recombinant LIF caused reactivation ofsome of X-linked genes. Thus, feeders are a", "metadata": {}}
+{"_id": "36950726", "title": "", "text": "Loss of 5-hydroxymethylcytosine and ten-eleventranslocation 2 protein expression in malignantmelanoma.Several research groups haverecently reported on markedly reduced levels of5-hydroxymethylcytosine (5hmC) in humanbreast, liver, lung, pancreatic, colon, prostate,brain, and myeloid cancers. We studied benigncompound nevi (BCN, n=17), dysplasticcompound nevi (DCN, n=15), superficialspreading melanomas [SSM, stratified in <1 mm(n=19) and >4 mm (n=18) Breslow tumorthickness], and cutaneous metastatic disease(CMD, n=24). Immunohistochemistry includedspecific antibodies against 5hmC,5-methylcytosine (5mC), and ten-eleventranslocation 2 protein (TET2).Immunohistological scoring showed significantly(P<0.0001) higher median 5hmC levels in BCNand DCN than in thin SSM, thick SSM, and CMD.5mC immunoreactivity did not differ significantly(P=0.15) between nevi and melanoma. Theintensity of TET2 expression was predominantly", "metadata": {}}
+{"_id": "36960449", "title": "", "text": "Estimation of the dietary requirement for vitaminD in healthy adults.BACKGROUND Knowledgegaps have contributed to considerable variationamong international dietary recommendationsfor vitamin D.   OBJECTIVE We aimed toestablish the distribution of dietary vitamin Drequired to maintain serum 25-hydroxyvitamin D[25(OH)D] concentrations above severalproposed cutoffs (ie, 25, 37.5, 50, and 80nmol/L) during wintertime after adjustment forthe effect of summer sunshine exposure anddiet. DESIGN A randomized, placebo-controlled,double-blind 22-wk intervention study wasconducted in men and women aged 20-40 y (n =238) by using different supplemental doses (0,5, 10, and 15 microg/d) of vitamin D(3)throughout the winter. Serum 25(OH)Dconcentrations were measured by usingenzyme-linked immunoassay at baseline(October 2006) and endpoint (March 2007).RESULTS There were clear dose-relatedincrements (P < 0.0001) in serum 25(OH)D with", "metadata": {}}
+{"_id": "36962270", "title": "", "text": "Rapid purification of homodimer and heterodimerHIV-1 reverse transcriptase by metal chelateaffinity chromatography.We have modified anEscherichia coli vector expressing 66-kDa HIV-1reverse transcriptase (p66) so that itsimultaneously expresses this and the pol-codedprotease. The twin expression cassette yieldshigh quantities of both reverse transcriptase andprotease; however, under these conditions, 50%of the over-expressed p66 reverse transcriptaseis processed, resulting in accumulation of largequantities of p66/p51 enzyme. Furthermore,addition of a poly(histidine) affinity label at theamino terminus of thereverse-transcriptase-coding sequence (His-p66)permits a simple, rapid purification of milligramquantities of either p66 or p66/p51 enzyme froma crude lysate by metal chelate affinitychromatography. Purified His-p66 andHis-p66/His-p51 reverse transcriptase exhibitboth reverse transcriptase and RNase H activity.Purification by metal chelate chromatography of", "metadata": {}}
+{"_id": "36991551", "title": "", "text": "Polyphenols of Cocoa: Inhibition of Mammalian15-LipoxygenaseAbstract Some cocoas andchocolates are rich in ()epicatechin and itsrelated oligomers, the procyanidins. Fractions ofthese compounds, isolated from the seeds ofTheobroma cacao, caused dosedependentinhibition of isolated rabbit 15-lipoxygenase-1with the larger oligomers being more active; thedecamer fraction revealed an IC 50 of 0.8 M.Among the monomeric flavanols,epigallocatechin gallate (IC 50 = 4 M) andepicatechin gallate (5 M) were more potent than()epicatechin (IC50 = 60 M). ()Epicatechin andprocyanidin nonamer also inhibited the formationof 15-hydroxyeicosatetraenoic acid fromarachidonic acid in rabbit smooth muscle cellstransfected with human 15-lipoxygenase-1. Incontrast, inhibition of the lipoxygenase pathwayin J774A.1 cells transfected with porcineleukocytetype 12- lipoxygenase (anotherrepresentative of the 12/15- lipoxygenasefamily) was only observed upon sonication of the", "metadata": {}}
+{"_id": "37029185", "title": "", "text": "Quality of life in patients with advanced heartfailure.Although evaluation of the treatment ofcongestive heart failure is usually based onobjective clinical outcomes, patientself-assessment is increasingly recognized as animportant component of evaluation. A study wasdesigned to measure the quality of life of 134patients with symptoms of advanced heartfailure who were being evaluated for possibleheart transplantation. The patients' quality of lifewas assessed using a mix of subjective andobjective measures, including functional status,physical symptoms, emotional state, andpsychosocial adaptation. There was no significantrelationship between patients' cardiac ejectionfraction and any quality-of-life measures;however, the results of a 6-minute walking test,New York Heart Association classification, andself-reported functional status were allsignificantly correlated with psychosocialadjustment. Self-reported functional status,depression, and hostility accounted for 43% of", "metadata": {}}
+{"_id": "37037012", "title": "", "text": "Regional vascular resistance during exercise:role of cardiac afferents and exercisetraining.This study was designed to determinewhether cardiac vagal afferents exert aninhibitory influence on increases in regionalvascular resistance during exercise and todetermine whether endurance exercise trainingenhances the inhibitory influence of cardiac vagalafferents. We measured changes in regionalvascular resistance in 12 rabbits at rest andduring running at 12.6 m/min, 20% grade,before and after reversible denervation of cardiacafferents (intrapericardial procainamide HCl,2%). In addition, these procedures wererepeated in five of these rabbits following an8-wk endurance exercise training program.Because intrapericardial injections ofprocainamide anesthetize both the efferent aswell as the afferent innervation to the heart, itwas necessary to determine the effects ofblocking the efferent innervation on theregulation of regional vascular resistance during", "metadata": {}}
+{"_id": "37065914", "title": "", "text": "Serum Soluble Corin is Decreased inStroke.BACKGROUND AND PURPOSE Solublecorin was decreased in coronary heart disease.Given the connections between cardiacdysfunction and stroke, circulating corin mightbe a candidate marker of stroke risk. However,the association between circulating corin andstroke has not yet been studied in humans. Here,we aimed to examine the association in patientswtith stroke and community-based healthycontrols. METHODS Four hundred eighty-onepatients with ischemic stroke, 116 patients withhemorrhagic stroke, and 2498 healthy controlswere studied. Serum soluble corin and someconventional risk factors of stroke wereexamined. Because circulating corin wasreported to be varied between men and women,the association between serum soluble corin andstroke was evaluated in men and women,respectively. RESULTS Patients with ischemicand hemorrhagic stroke had a significantly lowerlevel of serum soluble corin than healthy controls", "metadata": {}}
+{"_id": "37118634", "title": "", "text": "Topical application of chlorhexidine to neonatalumbilical cords for prevention of omphalitis andneonatal mortality in a rural district of Pakistan:a community-based, cluster-randomisedtrial.BACKGROUND Umbilical cord infection(omphalitis) is a risk factor for neonatal sepsisand mortality in low-resource settings wherehome deliveries are common. We aimed toassess the effect of umbilical-cord cleansing with4% chlorhexidine (CHX) solution, with or withouthandwashing with antiseptic soap, on theincidence of omphalitis and neonatal mortality.METHODS We did a two-by-two factorial,cluster-randomised trial in Dadu, a rural area ofSindh province, Pakistan. Clusters were definedas the population covered by a functionaltraditional birth attendant (TBA), and wererandomly allocated to one of four groups (groupsA to D) with a computer-generated randomnumber sequence. Implementation and datacollection teams were masked to allocation.Liveborn infants delivered by participating TBAs", "metadata": {}}
+{"_id": "37138639", "title": "", "text": "The IKK complex, a central regulator ofNF-kappaB activation.The IKK kinase complex isthe core element of the NF-kappaB cascade. It isessentially made of two kinases (IKKalpha andIKKbeta) and a regulatory subunit,NEMO/IKKgamma. Additional components mayexist, transiently or permanently, but theircharacterization is still unsure. In addition, it hasbeen shown that two separate NF-kappaBpathways exist, depending on the activatingsignal and the cell type, the canonical(depending on IKKbeta and NEMO) and thenoncanonical pathway (depending solely onIKKalpha). The main question, which is still onlypartially answered, is to understand how anNF-kappaB activating signal leads to theactivation of the kinase subunits, allowing themto phosphorylate their targets and eventuallyinduce nuclear translocation of the NF-kappaBdimers. I will review here the genetic,biochemical, and structural data accumulatedduring the last 10 yr regarding the function of", "metadata": {}}
+{"_id": "37156349", "title": "", "text": "Cognitive predictors of young children'sreadiness for powered mobility.Independentmobility in early childhood has been associatedwith the development of various cognitive andpsychosocial skills. However, children withphysical disabilities are not always able to moveindependently and may be at risk for delays inthese areas. Early provision of powered mobilitycan offer young children an opportunity forindependent mobility. Despite this, there is littleinformation to help determine when a youngchild has the cognitive skills necessary to operatea powered wheelchair safely. This currentresearch aims to identify these skills. A cognitiveassessment battery and a wheelchair mobilitytraining and assessment program weredeveloped. Twenty-six children with physicaldisabilities between the ages of 20 and 36months were evaluated on the cognitiveassessment and participated in the wheelchairtraining and assessment program. A stepwiseregression analysis was used to determine which", "metadata": {}}
+{"_id": "37164306", "title": "", "text": "Knockdown of the co-chaperone Hop promotesextranuclear accumulation of Stat3 in mouseembryonic stem cells.A key event in themechanism of mouse embryonic stem cell(mESC) pluripotency is phosphorylation,dimerisation and translocation to the nucleus ofthe signal transducer and activator oftranscription3, Stat3. We used RNAi to suppressthe levels of the co-chaperone Hsp70/Hsp90organising protein (Hop) in an mESC line. Hopknockdown caused 68% depletion in Stat3 mRNAlevels, decreased soluble pYStat3 levels, and ledto an extranuclear accumulation of Stat3. Themajor binding partner of Hop, Hsp90,co-localised with a small non-nuclear fraction ofStat3 in mESCs, and both Stat3 and Hopco-precipitated with Hsp90. Hop knockdown didnot affect Nanog and Oct4 protein levels;however, Nanog mRNA levels were decreased.We found that in the absence of Hop, mESCs losttheir pluripotent ability to form embryoid bodieswith a basement membrane. These data suggest", "metadata": {}}
+{"_id": "37182501", "title": "", "text": "B-cell self-tolerance in humans.Two mechanismsaccount for generation of the human antibodyrepertoire; V(D)J recombination during the earlystages of B-cell development in the bone marrowand somatic mutation of immunoglobulin genesin mature B cells responding to antigen in theperiphery. V(D)J recombination producesdiversity by random joining of gene segmentsand somatic mutation by introducing randompoint mutations. Both are required to attain thedegree of antigen receptor diversification that isnecessary for immune protection: defects ineither mechanism are associated with increasedsusceptibility to infection. However, thedownside of producing enormous randomdiversity in the antibody repertoire is thegeneration of autoantibodies. To preventautoimmunity B cells expressing autoantibodiesare regulated by strict mechanisms that eithermodify the specificity of autoantibodies or thefate of cells expressing such antibodies.Abnormalities in B-cell self-tolerance are", "metadata": {}}
+{"_id": "37204802", "title": "", "text": "JMJD6 Promotes Colon Carcinogenesis throughNegative Regulation of p53 byHydroxylationJumonji domain-containing 6(JMJD6) is a member of the Jumonji Cdomain-containing family of proteins. Comparedto other members of the family, the cellularactivity of JMJD6 is still not clearly defined andits biological function is still largely unexplored.Here we report that JMJD6 is physicallyassociated with the tumor suppressor p53. Wedemonstrated that JMJD6 acts as anα-ketoglutarate- and Fe(II)-dependent lysylhydroxylase to catalyze p53 hydroxylation. Wefound that p53 indeed exists as a hydroxylatedprotein in vivo and that the hydroxylation occursmainly on lysine 382 of p53. We showed thatJMJD6 antagonizes p53 acetylation, promotesthe association of p53 with its negative regulatorMDMX, and represses transcriptional activity ofp53. Depletion of JMJD6 enhances p53transcriptional activity, arrests cells in the G1phase, promotes cell apoptosis, and sensitizes", "metadata": {}}
+{"_id": "37205685", "title": "", "text": "Spread of chloroquine resistance in Plasmodiumfalciparum.Malaria resistant to chloroquine hasnow been confirmed in more than 40 countries.The drug was introduced in 1934, but was not inlarge-scale use until the early 1950s. Anecdotalreports suggest that resistance emerged as earlyas 1957 both in Colombia and along the thenCambodia-Thailand border area. But by 1960,resistance in these areas was confirmed - andmay represent two separate events. Resistancespread rapidly, with a new focus of resistanceconfirmed in East Africa by 1977. Chloroquineresistance represents a severe problem both forprophylaxis and treatment of malaria. In thisaricle, David Payne traces the spread ofresistance and discusses some of its implications.", "metadata": {}}
+{"_id": "37205759", "title": "", "text": "Obesity occurring in apolipoprotein E-knockoutmice has mild effects on fertility.TheApolipoprotein (Apo) family is implicated in lipidmetabolism. There are five types of Apo: Apoa,Apob, Apoc, Apod, and Apoe. Apoe has beendemonstrated to play a central role in lipoproteinmetabolism and to be essential for efficientreceptor-mediated plasma clearance ofchylomicron remnants and VLDL remnantparticles by the liver. Apoe-deficient (Apoe(-/-))mice develop atherosclerotic plaquesspontaneously, followed by obesity. In thisstudy, we investigated whether lipid depositioncaused by Apoe knockout affects reproduction infemale mice. The results demonstrated thatApoe(-/-) mice were severelyhypercholesterolemic, with their cholesterolmetabolism disordered, and lipid accumulating inthe ovaries causing the ovaries to be heaviercompared with the WT counterparts. In addition,estrogen and progesterone decreasedsignificantly at D 100. Quantitative PCR analysis", "metadata": {}}
+{"_id": "37207226", "title": "", "text": "Lipid metabolism and toxicity in the heart.Theheart has both the greatest caloric needs and themost robust oxidation of fatty acids (FAs). Underpathological conditions such as obesity and type2 diabetes, cardiac uptake and oxidation are notbalanced and hearts accumulate lipid potentiallyleading to cardiac lipotoxicity. We will first reviewthe pathways utilized by the heart to acquire FAsfrom the circulation and to store triglycerideintracellularly. Then we will describe mousemodels in which excess lipid accumulation causesheart dysfunction and experiments performed toalleviate this toxicity. Finally, the knownrelationships between heart lipid metabolism anddysfunction in humans will be summarized.", "metadata": {}}
+{"_id": "37248570", "title": "", "text": "Malaria eradication back on the table.After alapse of almost 40 years, malaria eradication isback on the global health agenda. Inspired bythe Gates Malaria Forum in October 2007,1,2 keyorganizations are starting to debate the pros andcons of redefining eradication as an explicit goalof malaria control efforts. Attempts to eliminatemalaria in southern Africa3 and Pacific Islandstates,4 and WHO’s Global Malaria Programmeagenda and field manual for malariaelimination,5,6 foreshadow this movementtowards another global attempt at eradication.When marking 60 years of WHO’s commitmentto fighting malaria, we must ask what has beenachieved, but also what can we learn from thepast. We now know so much more about thebiology of parasite-host responses, thedeterminants of endemicity and transmissiondynamics, the social, economic and culturalimplications of malaria at household, communityand national levels, and the demands made uponhealth systems in endemic countries. We do not", "metadata": {}}
+{"_id": "37248765", "title": "", "text": "CI-994 (N-acetyl-dinaline) in combination withconventional anti-cancer agents is effectiveagainst acute myeloid leukemia in vitro and invivo.N-acetyl-dinaline (CI-994) is aninvestigational anti-cancer drug which inhibitshistone deacetylases. We evaluated theinteraction between CI-994 and conventionalchemotherapeutics used in acute myeloidleukemia (AML) in a rat model for AML andBrown Norway rat acute myelocytic leukemia(BNML). In vitro, CI-994 in combination withcytarabine (ara-C), daunorubicin andmitoxantrone, resulted in moderate synergism.In vivo, higher dosages of CI-994 inducedcomplete remissions. CI-994/ara-C was veryactive against BNML. The combinations ofCI-994/daunorubicin and CI-994/mitoxantronewere also active against BNML. This studydemonstrates favorable in vitro and in vivointeractions between CI-994 and conventionalanti-cancer agents used for the treatment ofAML.", "metadata": {}}
+{"_id": "37249641", "title": "", "text": "CTCF and Cohesin in Genome Folding andTranscriptional Gene Regulation.Genomefunction, replication, integrity, and propagationrely on the dynamic structural organization ofchromosomes during the cell cycle. Genomefolding in interphase provides regulatorysegmentation for appropriate transcriptionalcontrol, facilitates ordered genome replication,and contributes to genome integrity by limitingillegitimate recombination. Here, we reviewrecent high-resolution chromosome conformationcapture and functional studies that haveinformed models of the spatial and regulatorycompartmentalization of mammalian genomes,and discuss mechanistic models for how CTCFand cohesin control the functional architecture ofmammalian chromosomes.", "metadata": {}}
+{"_id": "37256966", "title": "", "text": "Melatonin synthesized by T lymphocytes as aligand of the retinoic acid-related orphanreceptor.Melatonin modulates a wide array ofphysiological events with pleiotropic effects onthe immune system. While the relevance ofspecific melatonin membrane receptors has beenwell established for several biological functions,retinoic acid-related orphan receptor alpha(RORα) has been suggested as a mediator ofnuclear melatonin signalling by results obtainedfrom pharmacological approaches. However, amelatonin-mediated downstream effect cannotbe ruled out, and further evidence is needed tosupport a direct interaction between melatoninand RORα. Here, we show that RORα is mainlylocated in human Jurkat T-cell nucleus, and it isco-immunoprecipitated with melatonin.Moreover, immunocytochemistry studiesconfirmed the co-localization of melatonin andRORα. Melatonin promoted a time-dependentdecrease in nuclear RORα levels, suggesting arole in the RORα transcriptional activity.", "metadata": {}}
+{"_id": "37269418", "title": "", "text": "Age- and infection intensity-dependent cytokineand antibody production in human trichuriasis:the importance of IgE.The cytokine and antibodyresponse to Trichuris trichiura infection wasdetermined for 96 persons living in an areawhere the parasite is highly endemic andinfection exhibits a convex age intensity profile.In response to stimulation with T. trichiuraantigen, a small proportion of the study groupproduced interleukin (IL)-4 (7%), IL-9 (5%), andIL-13 (17%). A larger proportion produced IL-10(97%), tumor necrosis factor (TNF)-alpha(93%), and interferon (IFN)-gamma (32%). Thelevels of TNF-alpha (P =.016) and IFN-gamma (P=.012) significantly increased with age,suggesting a switch to a more chronic infectionphenotype. The predominant parasite-specificantibodies produced were IgG1, IgG4, IgA, andIgE. Unlike the IgG subclasses and IgA,parasite-specific IgE correlated negatively withinfection intensity, as defined by egg output (P=.008), and positively with host age (P =.010).", "metadata": {}}
+{"_id": "37296667", "title": "", "text": "The cryoprotective effect of trehalosesupplementation on boar spermatozoa quality.Inorder to improve boar sperm quality duringfrozen-thawed process, the influence of thepresence of trehalose on success ofcryopreservation of boar sperm wereinvestigated. We evaluated freeze-thawingtolerance of boar spermatozoa in a base coolingextender with the addition of different trehaloseconcentrations (0, 25, 50, 100 and 200mmol/l),and tried to determine the optimumconcentration of trehalose. We chose spermmotility, acrosome integrity, membrane integrityand cryocapacitation as parameters to evaluatecryopreservation capacity of boar spermatozoa.We obtained the best results for 100mmol/ltrehalose-supplemented extenders, with valuesof 49.89% for motility, 66.52% for acrosomeintegrity and 44.61% for membrane integrity,while freeze-thawing tolerance was diminishedsignificantly for 200mmol/l of trehalose. Beforeand after capacitation, the CTC score for semen", "metadata": {}}
+{"_id": "37297740", "title": "", "text": "Roads to polyploidy: the megakaryocyteexample.Polyploidy, recognized by multiplecopies of the haploid chromosome number, hasbeen described in plants, insects, and inmammalian cells such as, the plateletprecursors, the megakaryocytes. Several ofthese cell types reach high ploidy via a differentcell cycle. Megakaryocytes undergo anendomitotic cell cycle, which consists of an Sphase interrupted by a gap, during which thecells enter mitosis but skip anaphase B andcytokinesis. Here, we review the mechanismsthat lead to this cell cycle and to polyploidy inmegakaryocytes, while also comparing them tothose described for other systems in which highploidy is achieved. Overall, polyploidy isassociated with an orchestrated change inexpression of several genes, of which, some maybe a result of high ploidy and hence adeterminant of a new cell physiology, whileothers are inducers of polyploidization. Futurestudies will aim to further explore these two", "metadata": {}}
+{"_id": "37311371", "title": "", "text": "Central memory and effector memory T cellsubsets: function, generation, andmaintenance.The memory T cell pool functionsas a dynamic repository of antigen-experienced Tlymphocytes that accumulate over the lifetime ofthe individual. Recent studies indicate thatmemory T lymphocytes contain distinctpopulations of central memory (TCM) andeffector memory (TEM) cells characterized bydistinct homing capacity and effector function.This review addresses the heterogeneity of TCMand TEM, their differentiation stages, and thecurrent models for their generation andmaintenance in humans and mice.", "metadata": {}}
+{"_id": "37328025", "title": "", "text": "The Werner and Bloom syndrome proteins helpresolve replication blockage by converting(regressed) holliday junctions to functionalreplication forks.Cells cope with blockage ofreplication fork progression in a manner thatallows DNA synthesis to be completed andgenomic instability minimized. Models forresolution of blocked replication involve forkregression to form Holliday junction structures.The human RecQ helicases WRN and BLM(deficient in Werner and Bloom syndromes,respectively) are critical for maintaining genomicstability and thought to function in accurateresolution of replication blockage. Consistentwith this notion, WRN and BLM localize to sites ofblocked replication after certain DNA-damagingtreatments and exhibit enhanced activity onreplication and recombination intermediates.Here we examine the actions of WRN and BLM ona special Holliday junction substrate reflective ofa regressed replication fork. Our resultsdemonstrate that, in reactions requiring ATP", "metadata": {}}
+{"_id": "37336085", "title": "", "text": "Do Montelukast Sodium and N-AcetylcysteineHave a Nephroprotective Effect on UnilateralUreteral Obstruction? A Placebo Controlled Trialin a Rat Model.PURPOSE We assessed thenephroprotective effects of montelukast sodiumand N-acetylcysteine on secondary renal damagedue to unilateral ureteral obstruction in a ratmodel. MATERIALS AND METHODS In this study30 Wistar albino male rats were randomized into3 groups, including placebo, N-acetylcysteineand montelukast sodium. Three rats served asthe control group. The left ureter of the rats wassutured with 4-zero polyglactin sutures.Medications were given 3 days before obstructionand continued for 15 days. Dimercaptosuccinicacid renal scintigraphy was performed beforeobstruction and on day 15. Rats were sacrificedon day 15 and histopathological examinationswere done. We biochemically assessed oxidativestress markers (myeloperoxidase andmalondialdehyde), sulfhydryl and total nitrite forlipid peroxidation, oxidative protein damage and", "metadata": {}}
+{"_id": "37362689", "title": "", "text": "Oxidative phosphorylation: synthesis ofmitochondrially encoded proteins and assemblyof individual structural subunits into functionalholoenzyme complexes.The bulk of ATPconsumed by various cellular processes in highereukaryotes is normally produced by fivemultimeric protein complexes (I-V) embeddedwithin the inner mitochondrial membrane, in aprocess known as oxidative phosphorylation(OXPHOS). Maintenance of energy homeostasisunder most physiological conditions is thereforecontingent upon the ability of OXPHOS to meetcellular changes in bioenergetic demand, with achronic failure to do so being a frequent cause ofhuman disease. With the exception of ComplexII, the structural subunits of OXPHOS complexesare encoded by both the nuclear and themitochondrial genomes. The physical separationof the two genomes necessitates that theexpression of the 13 mitochondrially encodedpolypeptides be co-ordinated with that ofrelevant nuclear-encoded partners in order to", "metadata": {}}
+{"_id": "37405449", "title": "", "text": "Familial gastroesophageal reflux anddevelopment of Barrett's esophagus.The familyof an elderly man with Barrett's esophagus wasexamined for gastroesophageal reflux anddevelopment of Barrett's esophagus. All fiveliving children have gastroesophageal reflux oresophagitis, or both, and three have unequivocalBarrett's esophagus. Two third-generationdescendents have gastroesophageal reflux. Thispattern suggests autosomal dominanttransmission of the gastroesophageal reflux trait.The family also has a high prevalence of cancer,which may represent the cancer familysyndrome.", "metadata": {}}
+{"_id": "37424881", "title": "", "text": "The effect of folate fortification on folicacid-based homocysteine-lowering interventionand stroke risk: a meta-analysis.OBJECTIVEFolate and vitamin B12 are two vital regulators inthe metabolic process of homocysteine, which isa risk factor of atherothrombotic events. Lowfolate intake or low plasma folate concentrationis associated with increased stroke risk. Previousrandomized controlled trials presenteddiscordant findings in the effect of folic acidsupplementation-based homocysteine loweringon stroke risk. The aim of the present review wasto perform a meta-analysis of relevantrandomized controlled trials to check the howdifferent folate fortification status might affectthe effects of folic acid supplementation inlowering homocysteine and reducing stroke risk.DESIGN Relevant randomized controlled trialswere identified through formal literature search.Homocysteine reduction was compared insubgroups stratified by folate fortification status.Relative risks with 95 % confidence intervals", "metadata": {}}
+{"_id": "37437064", "title": "", "text": "On the origin and impact of mesenchymal stemcell heterogeneity: new insights and emergingtools for single cell analysis.Mesenchymal stemcells (MSCs) display substantial cell-to-cellvariation. This heterogeneity manifests amongdonors, among tissue sources, and within cellpopulations. Such pervasive variabilitycomplicates the use of MSCs in regenerativeapplications and may limit their therapeuticefficacy. Most conventional assays measure MSCproperties in bulk and, as a consequence, maskthis cell-to-cell variation. Recent studies haveidentified extensive variability amongst andwithin clonal MSC populations, in dimensionsincluding functional differentiation capacity,molecular state (e.g. epigenetic, transcriptomic,and proteomic status), and biophysicalproperties. While the origins of these variationsremain to be elucidated, potential mechanismsinclude in vivo micro-anatomical heterogeneity,epigenetic bistability, and transcriptionalfluctuations. Emerging tools for single cell", "metadata": {}}
+{"_id": "37438296", "title": "", "text": "Altered microRNA expression in bovine skeletalmuscle with age.Age-dependent decline inskeletal muscle function leads to severalinherited and acquired muscular disorders inelderly individuals. The levels of microRNAs(miRNAs) could be altered during musclemaintenance and repair. We therefore performeda comprehensive investigation for miRNAs fromfive different periods of bovine skeletal muscledevelopment using next-generation small RNAsequencing. In total, 511 miRNAs, including oneputatively novel miRNA, were identified.Thirty-six miRNAs were differentially expressedbetween prenatal and postnatal stages of muscledevelopment including several myomiRs (miR-1,miR-206 and let-7 families). Compared withmiRNA expression between different muscletissues, 14 miRNAs were up-regulated and 22miRNAs were down-regulated in the muscle ofpostnatal stage. In addition, a novel miRNA waspredicted and submitted to the miRBasedatabase as bta-mir-10020. A dual luciferase", "metadata": {}}
+{"_id": "37444589", "title": "", "text": "Apoptosis occurs predominantly in bystandercells and not in productively infected cells of HIV-and SIV-infected lymph nodesAlthough 13 yearshave passed since identification of humanimmunodeficiency virus-1 (HIV-1) as the causeof AIDS, we do not yet know how HIV kills itsprimary target, the T cell that carries the CD4antigen. We and others have shown an increasein the percentage of apoptotic cells amongcirculating CD4+ (and CD8+) T cells ofHIV-seropositive individuals and an increase infrequency of apoptosis with disease progression.However, it is not known if this apoptosis occursin infected or uninfected T cells. We show here,using in situ labelling of lymph nodes fromHIV-infected children and SIV-infectedmacaques, that apoptosis occurs predominantlyin bystander cells and not in the productivelyinfected cells themselves. These data haveimplications for pathogenesis and therapy,namely, arguing that rational drug therapy mayinvolve combination agents targeting viral", "metadata": {}}
+{"_id": "37450671", "title": "", "text": "Neuronal origin of a cerebral amyloid:neurofibrillary tangles of Alzheimer's diseasecontain the same protein as the amyloid ofplaque cores and blood vessels.The proteincomponent of Alzheimer's disease amyloid[neurofibrillary tangles (NFT), amyloid plaquecore and congophilic angiopathy] is anaggregated polypeptide with a subunit mass of 4kd (the A4 monomer). Based on the degree ofN-terminal heterogeneity, the amyloid is firstdeposited in the neuron, and later in theextracellular space. Using antisera raised againstsynthetic peptides, we show that the N terminusof A4 (residues 1-11) contains an epitope forneurofibrillary tangles, and the inner region ofthe molecule (residues 11-23) contains anepitope for plaque cores and vascular amyloid.The non-protein component of the amyloid(aluminum silicate) may form the basis for thedeposition or amplification (possibleself-replication) of the aggregated amyloidprotein. The amyloid of Alzheimer's disease is", "metadata": {}}
+{"_id": "37480103", "title": "", "text": "Pregnancy characteristics and maternal risk ofbreast cancer.CONTEXT During pregnancy,serum levels of estrogen, progesterone, andother hormones are markedly higher than duringother periods of life. Pregnancy hormonesprimarily are produced in the placenta, and signsof placental impairment may serve as indirectmarkers of hormone exposures duringpregnancy. During pregnancy, these markershave been inconsistently associated withsubsequent risk of breast cancer in the mother.OBJECTIVE To examine associations betweenindirect markers of hormonal exposures, such asplacental weight and other pregnancycharacteristics, and maternal risk of developingbreast cancer. DESIGN AND SETTINGPopulation-based cohort study using data fromthe Swedish Birth Register, the Swedish CancerRegister, the Swedish Cause of Death Register,and the Swedish Register of Population andPopulation Changes. PARTICIPANTS Womenincluded in the Sweden Birth Register who", "metadata": {}}
+{"_id": "37488367", "title": "", "text": "Attention-deficit hyperactivity disorder: acategory or a continuum? Genetic analysis of alarge-scale twin study.OBJECTIVE To investigateheritability and continuum versus categoricalapproaches to attention-deficit hyperactivitydisorder (ADHD), using a large-scale twinsample. METHOD A cohort of 1,938 families withtwins and siblings aged 4 to 12 years, recruitedfrom the Australian National Health and MedicalResearch Council Twin Registry, was assessed forADHD using a DSM-III-R-based maternal ratingscale. Probandwise concordance rates andcorrelations in monozygotic and dizygotic twinsand siblings were calculated, and heritability wasexamined using the De Fries and Fulkerregression technique. RESULTS There was anarrow (additive) heritability of 0.75 to 0.91which was robust across familial relationships(twin, sibling, and twin-sibling) and acrossdefinitions of ADHD as part of a continuum or asa disorder with various symptom cutoffs. Therewas no evidence for nonadditive genetic variation", "metadata": {}}
+{"_id": "37549932", "title": "", "text": "Antiapoptotic BCL-2 is required for maintenanceof a model leukemia.Resistance to apoptosis,often achieved by the overexpression ofantiapoptotic proteins, is common and perhapsrequired in the genesis of cancer. However, itremains uncertain whether apoptotic defects areessential for tumor maintenance. To test this, wegenerated mice expressing a conditional BCL-2gene and constitutive c-myc that developlymphoblastic leukemia. Eliminating BCL-2yielded rapid loss of leukemic cells andsignificantly prolonged survival, formallyvalidating BCL-2 as a rational target for cancertherapy. Loss of this single molecule resulted incell death, despite or perhaps attributable to thepresence of other oncogenic events. Thissuggests a generalizable model in whichaberrations inherent to cancer generate tonicdeath signals that would otherwise kill the cell ifnot opposed by a requisite apoptotic defect(s).", "metadata": {}}
+{"_id": "37562370", "title": "", "text": "Cellular and histopathological changes in theinfrapatellar fat pad in the monoiodoacetatemodel of osteoarthritis pain.OBJECTIVE Theinfrapatellar fat pad (IPFP) has been identified asa source of anterior knee pain. Fibrosis andmarked inflammatory infiltrate in the IPFP ofpatients with arthritis of the knee and reductionin pain post knee replacement in patientsfollowing resection of the IPFP have beenobserved. We have investigated changes in theIPFP of rats undergoing the monoiodoacetate(MIA) model of degenerative joint disease, amodel that exhibits some histopathologicalsimilarities to osteoarthritis (OA). METHODS Ratswere injected intra-articularly with MIA and thedevelopment of weight bearing asymmetry wasfollowed for 21 days as compared tovehicle-injected animals. In addition, IPFPs wereremoved from both ipsilateral and contralateraljoints. Both inflammatory infiltrate andhistopathological changes were analysed.RESULTS MIA injection caused marked weight", "metadata": {}}
+{"_id": "37578311", "title": "", "text": "Angiogenesis therapy: amidst the hype, theneglected potential for serious sideeffects.Although essentially unknown as atherapeutic concept as recently as a decade ago,it is difficult now to open a cardiology journal,attend a cardiology meeting, or scan anewspaper without being caught up in theexcitement generated by the thought thatangiogenesis therapy may soon have a majorimpact on the treatment of patients withatherosclerotic lesions obstructing arteries thatsupply the myocardium or legs. Potenttherapeutic interventions, however, are rarelyfree of at least the potential for causing harmfuleffects. Angiogenesis therapy is no exception.Despite this and despite the fact that the onlyreasonably powered, randomized, double-blindclinical studies to date have failed todemonstrate primary end-point efficacy,1thoughtful consideration of the serious sideeffects that might accompany any therapeuticbenefit has been largely missing from scientific", "metadata": {}}
+{"_id": "37583120", "title": "", "text": "Body mass index and magnetic resonancemarkers of brain integrity in adults.OBJECTIVEObesity and being overweight during adulthoodhave been consistently linked to increased riskfor development of dementia later in life,especially Alzheimer's disease. They have alsobeen associated with cognitive dysfunction andbrain structural alterations in otherwise healthyadults. Although proton magnetic resonancespectroscopy may distinguish between neuronaland glial components of the brain and may pointto neurobiological mechanisms underlying brainatrophy and cognitive changes, no spectroscopicstudies have yet assessed the relationshipsbetween adiposity and brain metabolites.METHODS We have utilized magnetic resonanceimaging and proton magnetic resonancespectroscopic imaging data from 50 healthymiddle-aged participants (mean age, 41.7 +/-8.5 years; 17 women), who were scanned ascontrol subjects for another study. RESULTSAfter adjustment for age and sex, greater body", "metadata": {}}
+{"_id": "37592824", "title": "", "text": "Characteristics of medial temporal lobe epilepsy:II. Interictal and ictal scalpelectroencephalography, neuropsychologicaltesting, neuroimaging, surgical results, andpathology.Sixty-seven patients with temporallobe epilepsy without circumscribed, potentiallyepileptogenic lesions, who were studied withintracranial electrodes and who became seizurefree following temporal lobectomy wereretrospectively evaluated with regard topreoperative scalp electroencephalographic(EEG) findings, neuropsychological test results,neuroimaging findings, results of surgery, andpathology of resected tissue. Interictal scalp EEGshowed paroxysmal abnormalities duringprolonged monitoring in 64 patients (96%).These were localized in the anterior temporalregion in 60 (94%) of these 64 patients. Bilateralindependent paroxysmal activity occurred in42% of the patients and was preponderant overthe side of seizure origin in half. Ictal EEGchanges were rarely detected at the time of", "metadata": {}}
+{"_id": "37608303", "title": "", "text": "OPA1-dependent cristae modulation is essentialfor cellular adaptation to metabolicdemand.Cristae, the organized invaginations ofthe mitochondrial inner membrane, respondstructurally to the energetic demands of the cell.The mechanism by which these dynamic changesare regulated and the consequences thereof arelargely unknown. Optic atrophy 1 (OPA1) is themitochondrial GTPase responsible for innermembrane fusion and maintenance of cristaestructure. Here, we report that OPA1 respondsdynamically to changes in energetic conditions toregulate cristae structure. This cristae regulationis independent of OPA1's role in mitochondrialfusion, since an OPA1 mutant that can stilloligomerize but has no fusion activity was able tomaintain cristae structure. Importantly, OPA1was required for resistance to starvation-inducedcell death, for mitochondrial respiration, forgrowth in galactose media and for maintenanceof ATP synthase assembly, independently of itsfusion activity. We identified mitochondrial solute", "metadata": {}}
+{"_id": "37619697", "title": "", "text": "Phenylpropanolamine and the risk ofhemorrhagic stroke.BACKGROUNDPhenylpropanolamine is commonly found inappetite suppressants and cough or coldremedies. Case reports have linked the use ofproducts containing phenylpropanolamine tohemorrhagic stroke, often after the first use ofthese products. To study the association, wedesigned a case-control study. METHODS Menand women 18 to 49 years of age were recruitedfrom 43 U.S. hospitals. Eligibility criteria includedthe occurrence of a subarachnoid or intracerebralhemorrhage within 30 days before enrollmentand the absence of a previously diagnosed brainlesion. Random-digit dialing identified twomatched control subjects per patient. RESULTSThere were 702 patients and 1376 controlsubjects. For women, the adjusted odds ratiowas 16.58 (95 percent confidence interval, 1.51to 182.21; P=0.02) for the association betweenthe use of appetite suppressants containingphenylpropanolamine and the risk of a", "metadata": {}}
+{"_id": "37628989", "title": "", "text": "The safety of intravenous fluorescein for confocallaser endomicroscopy in the gastrointestinaltract.BACKGROUND Confocal laserendomicroscopy (CLE) is rapidly emerging as avaluable tool for gastrointestinal endoscopicimaging. Fluorescent contrast agents are used tooptimize imaging with CLE, and intravenousfluorescein is the most widely used contrastagent. Fluorescein is FDA-cleared for diagnosticangiography of the retina. For these indications,the safety profile of fluorescein has beenwell-documented; however, to date, fluoresceinis not cleared for use with CLE. AIMS To estimatethe rate of serious and total adverse eventsattributable to intravenous fluorescein whenused for gastrointestinal CLE. METHODS Weperformed a cross sectional survey of 16International Academic Medical Centres withactive research protocols in CLE that involvedintravenous fluorescein. Centres using i.v.fluorescein for CLE who were actively monitoredfor adverse events were included. RESULTS", "metadata": {}}
+{"_id": "37641175", "title": "", "text": "Metabolic DNA as the origin of spontaneouslyreleased DNA?A DNA fraction is spontaneouslyreleased from living, but not dead or dying,human, other mammalian, avian, amphibian,plant, and prokaryote cells. The spontaneouslyreleased DNA fraction has been shown to be (a)present in both actively dividing and nondividing,differentiated cell populations; (b) labile; (c)associated with DNA-dependent RNA or DNApolymerase; (d) associated with an RNA fraction;and to have (e) a lower molecular weight thanthe typical genetic DNA fraction; and (f) Alurepeat sequences in increased proportionscompared to a unique gene in plasma/serum. Onthe other hand, early autoradiographic andbiochemical and quantitative cytochemical andcytophysical studies on DNA permitted theidentification of a DNA fraction which was (1)present in both actively dividing and nondividing,differentiated cell populations; (2) labile; and (3)had a lower molecular weight than the typicalgenetic DNA fraction. This DNA fraction was", "metadata": {}}
+{"_id": "37643601", "title": "", "text": "The flavivirus precursor membrane-envelopeprotein complex: structure and maturation.Manyviruses go through a maturation step in the finalstages of assembly before being transmitted toanother host. The maturation process offlaviviruses is directed by the proteolyticcleavage of the precursor membrane protein(prM), turning inert virus into infectious particles.We have determined the 2.2 angstrom resolutioncrystal structure of a recombinant protein inwhich the dengue virus prM is linked to theenvelope glycoprotein E. The structurerepresents the prM-E heterodimer and fits wellinto the cryo-electron microscopy density ofimmature virus at neutral pH. The pr peptidebeta-barrel structure covers the fusion loop in E,preventing fusion with host cell membranes. Thestructure provides a basis for identifying thestages of its pH-directed conformationalmetamorphosis during maturation, ending withrelease of pr when budding from the host.", "metadata": {}}
+{"_id": "37673301", "title": "", "text": "Peptide and non-peptide G-protein coupledreceptors (GPCRs) in skeletal muscle.G-proteincoupled receptors (GPCRs) represent a largeclass of cell surface receptors that mediate amultitude of functions. Over the years, a numberof GPCRs and ancillary proteins have been shownto be expressed in skeletal muscle. Unlike thecase with other muscle tissues like cardiac andvascular smooth muscle cells, there has beenlittle attempt at systematically analyzing GPCRsin skeletal muscle. Here we have compiled all theGPCRs that are expressed in skeletal muscle. Inaddition, we review the known function of thesereceptors in both skeletal muscle tissue and incultured skeletal muscle cells.", "metadata": {}}
+{"_id": "37677954", "title": "", "text": "Characterization of complete genome and smallRNA profile of pagoda yellow mosaic associatedvirus, a novel badnavirus in China.A newbadnavirus was discovered from pagoda treesshowing yellow mosaic symptoms on the leavesby high throughput sequencing of small RNAs.The complete genome of this virus wasdetermined to comprise 7424 nucleotides, andthe virus shared 40.4-45.1% identity with that ofother badnaviruses. The genome encodes fiveopen reading frames (ORFs) on the plus strand,which includes three conserved badnaviral ORFs.These results suggest that this virus is a newmember of the genus Badnavirus in the familyCaulimoviridae. The virus is tentatively namedpagoda yellow mosaic associated virus (PYMAV).Phylogenetic analysis suggested that this virustogether with gooseberry vein banding virus(GVBV) and grapevine vein-clearing virus(GVCV) forms a separate group that is distincttwo other well characterized badnaviral groups.Additionally, the viral derived small RNA (vsRNA)", "metadata": {}}
+{"_id": "37686718", "title": "", "text": "Experimental approaches for the treatment ofmalignant gliomas.Malignant gliomas, whichinclude glioblastomas and anaplasticastrocytomas, are the most common primarytumors of the brain. Over the past 30 years, thestandard treatment for these tumors has evolvedto include maximal safe surgical resection,radiation therapy and temozolomidechemotherapy. While the median survival ofpatients with glioblastomas has improved from 6months to 14.6 months, these tumors continueto be lethal for the vast majority of patients.There has, however, been recent substantialprogress in our mechanistic understanding oftumor development and growth. The translationof these genetic, epigenetic and biochemicalfindings into therapies that have been tested inclinical trials is the subject of this review.", "metadata": {}}
+{"_id": "37699461", "title": "", "text": "Reversal of hyperglycemia in mice by usinghuman expandable insulin-producing cellsdifferentiated from fetal liver progenitorcells.Beta-cell replacement is considered to bethe most promising approach for treatment oftype 1 diabetes. Its application on a large scale ishindered by a shortage of cells fortransplantation. Activation of insulin expression,storage, and regulated secretion instem/progenitor cells offers novel ways toovercome this shortage. We explored whetherfetal human progenitor liver cells (FH) could beinduced to differentiate into insulin-producingcells after expression of the pancreatic duodenalhomeobox 1 (Pdx1) gene, which is a keyregulator of pancreatic development and insulinexpression in beta cells. FH cells possess aconsiderable replication capacity, and this wasfurther extended by introduction of the gene forthe catalytic subunit of human telomerase.Immortalized FH cells expressing Pdx1 activatedmultiple beta-cell genes, produced and stored", "metadata": {}}
+{"_id": "37722384", "title": "", "text": "A review of the methods for human iPSCderivation.The ability to reprogram somatic cellsto induced pluripotent stem cells (iPSCs) offersan opportunity to generate pluripotentpatient-specific cell lines that can help modelhuman diseases. These iPSC lines could also bepowerful tools for drug discovery and thedevelopment of cellular transplantationtherapies. Many methods exist for generatingiPSC lines but those best suited for use instudying human diseases and developingtherapies must be of adequate efficiency toproduce iPSCs from samples that may be oflimited abundance, capable of reprogrammingcells from both skin fibroblasts and blood, andfootprint-free. Several reprogrammingtechniques meet these criteria and can beutilized to derive iPSCs in projects with bothbasic scientific and therapeutic goals. Combiningthese reprogramming methods with smallmolecule modulators of signaling pathways canlead to successful generation of iPSCs from even", "metadata": {}}
+{"_id": "37727521", "title": "", "text": "EB virus-encoded RNAs are recognized by RIG-Iand activate signaling to induce type IIFN.Epstein-Barr virus (EBV)-encoded smallRNAs (EBERs) are nonpolyadenylated,untranslated RNAs, exist most abundantly inlatently EBV-infected cells, and are expected toshow secondary structures with many shortstem-loops. Retinoic acid-inducible gene I(RIG-I) is a cytosolic protein that detects viraldouble-stranded RNA (dsRNA) inside the cell andinitiates signaling pathways leading to theinduction of protective cellular genes, includingtype I interferons (IFNs). We investigatedwhether EBERs were recognized by RIG-I asdsRNA. Transfection of RIG-I plasmid inducedIFNs and IFN-stimulated genes (ISGs) inEBV-positive Burkitt's lymphoma (BL) cells, butnot in their EBV-negative counterparts orEBER-knockout EBV-infected BL cells.Transfection of EBER plasmid or invitro-synthesized EBERs induced expression oftype I IFNs and ISGs in RIG-I-expressing,", "metadata": {}}
+{"_id": "37731372", "title": "", "text": "Pregnancy in dialysis patients: a review ofoutcomes, complications, andmanagement.Although uncommon, pregnancyoccurs in women on chronic dialysis. In 1980 theincidence of pregnancy in women on dialysis was0.9%. Studies from 1992 to 2003 indicate thatpregnancy occurred in 1-7% of women onchronic dialysis. Half of the infants born towomen on chronic dialysis survive. Ofimportance is that \"intensive dialysis\" of 16-24hr/week is associated with improved infantsurvival. In this article, the incidence, duration,fetal and maternal complications, and outcomesof pregnancy in women on chronic dialysis arereviewed. The management of anemia,hypertension, electrolytes, bone minerals, andacid-base parameters in the pregnant dialysispatient is also summarized. Recommendationsregarding the dialysis prescription for thepregnant woman on hemodialysis (HD) orperitoneal dialysis (PD) are also made. Thecomplex and precarious condition of the", "metadata": {}}
+{"_id": "37762357", "title": "", "text": "Potent immunosuppressive activities ofcytomegalovirus-encodedinterleukin-10.Cytomegalovirus (CMV) has highlyevolved mechanisms for avoiding detection bythe host immune system. Recently, in thegenomes of human and primate CMV, a novelgene comprising segments of noncontiguousopen reading frames was identified and found tohave limited predicted homology to endogenouscellular interleukin-10 (IL-10). Here weinvestigate the biological activities of the CMVIL-10-like gene product and show it to possesspotent immunosuppressive properties. Bothpurified bacterium-derived recombinant CMVIL-10 and CMV IL-10 expressed in supernatantsof human cells were found to inhibit proliferationof mitogen-stimulated peripheral bloodmononuclear cells (PBMCs), with specific activitycomparable to that of recombinant human IL-10.In addition, CMV IL-10 expressed from humancells inhibited cytokine synthesis, as treatment ofstimulated PBMCs and monocytes with CMV", "metadata": {}}
+{"_id": "37768883", "title": "", "text": "Evidence for the presence of urease apoproteincomplexes containing UreD, UreF, and UreG incells that are competent for in vivo enzymeactivation.In vivo activation of Klebsiellaaerogenes urease, a nickel-containing enzyme,requires the presence of functional UreD, UreF,and UreG accessory proteins and is furtherfacilitated by UreE. These accessory proteins areproposed to be involved in metallocenterassembly (M. H. Lee, S. B. Mulrooney, M. J.Renner, Y. Markowicz, and R. P. Hausinger, J.Bacteriol. 174:4324-4330, 1992). A series ofthree UreD-urease apoprotein complexes arepresent in cells that express ureD at high levels,and these complexes are thought to be essentialfor in vivo activation of the enzyme (I.-S. Park,M. B. Carr, and R. P. Hausinger, Proc. Natl. Acad.Sci. USA 91:3233-3237, 1994). In this study, wedescribe the effect of accessory gene deletionson urease complex formation. The ureE, ureF,and ureG gene products were found not to berequired for formation of the UreD-urease", "metadata": {}}
+{"_id": "37822406", "title": "", "text": "Human somatic cell nuclear transfer using adultcells.Derivation of patient-specific humanpluripotent stem cells via somatic cell nucleartransfer (SCNT) has the potential for applicationsin a range of therapeutic contexts. However,successful SCNT with human cells has provedchallenging to achieve, and thus far has onlybeen reported with fetal or infant somatic cells.In this study, we describe the application of arecently developed methodology for thegeneration of human ESCs via SCNT usingdermal fibroblasts from 35- and 75-year-oldmales. Our study therefore demonstrates theapplicability of SCNT for adult human cells andsupports further investigation of SCNT as astrategy for regenerative medicine.", "metadata": {}}
+{"_id": "37895688", "title": "", "text": "\"Natural\" killer cells in the mouse. I. Cytotoxiccells with specificity for mouse Moloney leukemiacells. Specificity and distribution according togenotype.In the spleens of young, adult micethere exist naturally occurring killer lymphocyteswith specificity for mouse Moloney leukemiacells. The lytic activity was directed againstsyngeneic or allogeneic Moloney leukemia cellsto a similar extent, but was primarily expressedwhen tested against in vitro grown leukemiacells. Two leukemias of non-Moloney origin wereresistant and so was the mastocytoma line P815.Although killer activity varied between differentstrains of mice, the specificity of lysis was thesame as indicated by competition experimentsusing unlabeled Moloney or other tumor cells asinhibitors in the cytotoxic assays. Capacity tocompete and sensitivy to lysis by the killer cellswere found to be highly positively correlated.Analysis of the kinetics of the cytotoxic assayrevealed a rapid induction of lysis within one tofour hours, arguing against any conventional in", "metadata": {}}
+{"_id": "37912677", "title": "", "text": "Dose-response study on thyrotoxic patientsundergoing positron emission tomography andradioiodine therapyWith the acknowledgedproblems associated with assessment offunctioning thyroid mass and hence radiationdose, our policy had been to give 75 MBqiodine-131 at 6-monthly intervals to patientswith Graves' disease until they becameeuthyroid. Since positron emission tomography(PET) has been available at this hospital, theradiation dose to the thyroid has been calculatedwith an accuracy of \u000020%, the thyroid massbeing determined from an iodine-124 PET scan.A dose-response study has been carried out on65 patients who have received single orcumulative radiation doses of <80 Gy. Theresults show that patients who receive a lowradiation dose (<20 Gy) at their first treatmenthave a high probability of remaining toxic at 12months. In contrast, patients who receive higherradiation doses (>40 Gy) at their first treatmenthave a high probability of control. The probability", "metadata": {}}
+{"_id": "37916361", "title": "", "text": "Increased serum soluble corin in mid pregnancyis associated with hypertensive disorders ofpregnancy.OBJECTIVE The study of soluble corinin the circulation before hypertensive disordersof pregnancy (HDP) has been limited. Here weaimed to study serum soluble corin in midpregnancy in patients with HDP and their age-and gestational weeks-matched controls.METHODS Sixty-eight pairs of cases of HDP andcontrols were studied. Blood samples wereobtained in mid pregnancy between 16 and 20gestational weeks. Serum soluble corin wasexamined by enzyme-linked immunosorbentassay methods. The relationship between serumsoluble corin and HDP was examined usingconditional logistic regression models. RESULTSSerum soluble corin in mid pregnancy wasincreased in cases with HDP compared withcontrols (median [interquartile range]: 1968[1644-2332] pg/mL vs. 1700 [1446-2056]pg/mL, p=0.002). Participants were categorizedinto quartiles of serum soluble corin distributed", "metadata": {}}
+{"_id": "37949139", "title": "", "text": "The in vitro effect of dandelions antioxidants onmicrosomal lipid peroxidation.Dandelions havelong been used in herbal medicine for theircholeretic, diuretic, antiinflammatory,appetite-stimulating and laxative properties. Anantioxidant property can be supposed as a basisof their-therapeutic effects. To understand themechanism of the drug's action, the effects ofnatural extracts on a microsomal fraction of ratliver were examined. The extracts diminished theenzymatically induced-lipid peroxidation andreduced the cytochrome c with and withoutNADPH in a concentration dependent manner.", "metadata": {}}
+{"_id": "37964706", "title": "", "text": "Local Ca2+ influx through Ca2+release-activated Ca2+ (CRAC) channelsstimulates production of an intracellularmessenger and an intercellular pro-inflammatorysignal.Ca2+ entry through store-operated Ca2+channels drives the production of thepro-inflammatory molecule leukotriene C4(LTC4) from mast cells through a pathwayinvolving Ca2+-dependent protein kinase C,mitogen-activated protein kinases ERK1/2,phospholipase A2, and 5-lipoxygenase. Here weexamine whether local Ca2+ influx throughstore-operated Ca2+ release-activated Ca2+(CRAC) channels in the plasma membranestimulates this signaling pathway. Manipulatingthe amplitude and spatial extent of Ca2+ entryby altering chemical and electrical gradients forCa2+ influx or changing the Ca2+ buffering ofthe cytoplasm all impacted on protein kinase Cand ERK activation, generation of arachidonicacid and LTC4 secretion, with little change in thebulk cytoplasmic Ca2+ rise. Similar bulk", "metadata": {}}
+{"_id": "37969403", "title": "", "text": "Cytokine production patterns andlymphoproliferative responses in volunteersorally immunized with attenuated vaccine strainsof Salmonella typhi.New recombinant strains ofattenuated Salmonella typhi used as live oralvaccines elicit potent immune responses. Thisstudy examined the patterns of cytokineproduction and proliferation to specific S. typhiantigens in subjects orally immunized withattenuated S. typhi vaccines CVD 906, CVD 908,and CVD 908 expressing the circumsporozoiteprotein of Plasmodium falciparum. Afterimmunization, sensitized lymphocytes werefound in subjects' blood that exhibitedsignificantly increased proliferative responsesand interferon-gamma production to purified S.typhi flagella when compared withpreimmunization levels. Significant negativecorrelations were observed betweeninterleukin-4 production and bothinterferon-gamma production and proliferation toS. typhi flagella. These results demonstrate that", "metadata": {}}
+{"_id": "38009906", "title": "", "text": "Molecular interplay of the noncoding RNA ANRILand methylated histone H3 lysine 27 bypolycomb CBX7 in transcriptional silencing ofINK4a.Expression of the INK4b/ARF/INK4atumor suppressor locus in normal and cancerouscell growth is controlled by methylation ofhistone H3 at lysine 27 (H3K27me) as directedby the Polycomb group proteins. The antisensenoncoding RNA ANRIL of the INK4b/ARF/INK4alocus is also important for expression of theprotein-coding genes in cis, but its mechanismhas remained elusive. Here we report thatchromobox 7 (CBX7) within the polycombrepressive complex 1 binds to ANRIL, and bothCBX7 and ANRIL are found at elevated levels inprostate cancer tissues. In concert withH3K27me recognition, binding to RNAcontributes to CBX7 function, and disruption ofeither interaction impacts the ability of CBX7 torepress the INK4b/ARF/INK4a locus and controlsenescence. Structure-guided analysis revealsthe molecular interplay between noncoding RNA", "metadata": {}}
+{"_id": "38023457", "title": "", "text": "Tumor necrosis factor alpha mediates apoptosisof brown adipocytes and defective brownadipocyte function in obesity.Severe quantitativeand qualitative brown adipocyte defects arecommon in obesity. To investigate whetheraberrant expression of tumor necrosis factoralpha (TNF-alpha) in obesity is involved infunctional brown fat atrophy, we have studiedgenetically obese (ob/ob) mice with targeted nullmutations in the genes encoding the two TNFreceptors. The absence of both TNF receptors orp55 receptor alone resulted in a significantreduction in brown adipocyte apoptosis and anincrease in beta(3)-adrenoreceptor anduncoupling protein-1 expression in obese mice.Increased numbers of multilocular functionallyactive brown adipocytes, and improvedthermoregulation was also observed in obeseanimals lacking TNF-alpha function. Theseresults indicate that TNF-alpha plays animportant role in multiple aspects of brownadipose tissue biology and mediates the", "metadata": {}}
+{"_id": "38025907", "title": "", "text": "Engineered FGF19 eliminates bile acid toxicityand lipotoxicity leading to resolution ofsteatohepatitis and fibrosis in miceNonalcoholicfatty liver disease (NAFLD) is an increasinglyprevalent chronic liver disease for which noapproved therapies are available. Despiteintensive research, the cellular mechanisms thatmediate NAFLD pathogenesis and progressionare poorly understood. Although obesity,diabetes, insulin resistance, and relatedmetabolic syndrome, all consequences of aWestern diet lifestyle, are well-recognized riskfactors for NAFLD development, dysregulatedbile acid metabolism is emerging as a novelmechanism contributing to NAFLD pathogenesis.Notably, NAFLD patients exhibit a deficiency infibroblast growth factor 19 (FGF19), anendocrine hormone in the gut-liver axis thatcontrols de novo bile acid synthesis, lipogenesis,and energy homeostasis. Using a mouse modelthat reproduces the clinical progression of humanNAFLD, including the development of simple", "metadata": {}}
+{"_id": "38028419", "title": "", "text": "Leptin deficiency contributes to the pathogenesisof alcoholic fatty liver disease in mice.Whiteadipose tissue (WAT) secretes adipokines, whichcritically regulate lipid metabolism. The presentstudy investigated the effects of alcohol onadipokines and the mechanistic link betweenadipokine dysregulation and alcoholic fatty liverdisease. Mice were fed alcohol for 2, 4, or 8weeks to document changes in adipokines overtime. Alcohol exposure reduced WAT mass andbody weight in association with hepatic lipidaccumulation. The plasma adiponectinconcentration was increased at 2 weeks, butdeclined to normal at 4 and 8 weeks. Alcoholexposure suppressed leptin gene expression inWAT and reduced the plasma leptinconcentration at all times measured. There is ahighly positive correlation between plasma leptinconcentration and WAT mass or body weight. Todetermine whether leptin deficiency mediatesalcohol-induced hepatic lipid dyshomeostasis,mice were fed alcohol for 8 weeks with or", "metadata": {}}
+{"_id": "38037690", "title": "", "text": "Three-dimensional chemical imaging of skinusing stimulated Raman scatteringmicroscopyAbstract. Stimulated Ramanscattering (SRS) microscopy is used to generatestructural and chemical three-dimensionalimages of native skin. We employed SRSmicroscopy to investigate the microanatomicalfeatures of skin and penetration of topicallyapplied materials. Image depth stacks arecollected at distinct wavelengths correspondingto vibrational modes of proteins, lipids, andwater in the skin. We observed that corneocytesin stratum corneum are grouped together inclusters, 100 to 250 μm in diameter, separatedby 10- to 25-μm-wide microanatomical skin-foldscalled canyons. These canyons occasionallyextend down to depths comparable to that of thedermal–epidermal junction below the flat surfaceregions in porcine and human skin. SRS imagingshows the distribution of chemical species withincell clusters and canyons. Water ispredominately located within the cell clusters,", "metadata": {}}
+{"_id": "38040186", "title": "", "text": "Familial amyloidosis: a study of 52 NorthAmerican-born patients examined during a30-year period.Between 1961 and 1990, 52patients with biopsy-proven familial amyloidosisborn in North America were examined at theMayo Clinic. At the time of diagnosis of familialamyloidosis, 83% of these patients hadperipheral neuropathy, 33% had autonomicneuropathy, and 27% had cardiomyopathy.Renal disease was noted in fewer than 10%, andliver involvement was rare. The median age atdiagnosis was 64 years. The sensitivity of variousdiagnostic biopsies was similar to that forprimary amyloidosis: deposits of amyloid werefound in 77 and 78% of the subcutaneous fataspirates or rectal biopsy specimens,respectively, and in 41% of specimens of bonemarrow. The median duration of survival of 5.8years for patients with inherited amyloidosis wassuperior to that for patients with primaryamyloidosis. When patients were stratified byorgan involvement, the survival of patients with", "metadata": {}}
+{"_id": "38043606", "title": "", "text": "Mycobacterium tuberculosis and the environmentwithin the phagosome.Once across the barrier ofthe epithelium, macrophages constitute theprimary defense against microbial invasion. Formost microbes, the acidic, hydrolyticallycompetent environment of the phagolysosome issufficient to kill them. Despite our understandingof the trafficking events that regulatephagosome maturation, our appreciation of thelumenal environment within the phagosome isonly now becoming elucidated through real-timefunctional assays. The assays quantify pHchange, phagosome/lysosome fusion,proteolysis, lipolysis, and beta-galactosidaseactivity. This information is particularly importantfor understanding pathogens that successfullyparasitize the endosomal/lysosomal continuum.Mycobacterium tuberculosis infects macrophagesthrough arresting the normal maturation processof the phagosome, retaining its vacuole at pH 6.4with many of the characteristics of an earlyendosome. Current studies are focusing on the", "metadata": {}}
+{"_id": "38076716", "title": "", "text": "High density DNA methylation array with singleCpG site resolution.We have developed a newgeneration of genome-wide DNA methylationBeadChip which allows high-throughputmethylation profiling of the human genome. Thenew high density BeadChip can assay over 480KCpG sites and analyze twelve samples in parallel.The innovative content includes coverage of 99%of RefSeq genes with multiple probes per gene,96% of CpG islands from the UCSC database,CpG island shores and additional contentselected from whole-genome bisulfite sequencingdata and input from DNA methylation experts.The well-characterized Infinium® Assay is usedfor analysis of CpG methylation usingbisulfite-converted genomic DNA. We applied thistechnology to analyze DNA methylation innormal and tumor DNA samples and comparedresults with whole-genome bisulfite sequencing(WGBS) data obtained for the same samples.Highly comparable DNA methylation profileswere generated by the array and sequencing", "metadata": {}}
+{"_id": "38127792", "title": "", "text": "Acentrosomal Microtubule Assembly in Mitosis:The Where, When, and How.In mitosis the cellassembles the bipolar spindle, a microtubule(MT)-based apparatus that segregates theduplicated chromosomes into two daughter cells.Most animal cells enter mitosis with duplicatedcentrosomes that provide an active source ofdynamic MTs. However, it is now established thatspindle assembly relies on the nucleation ofacentrosomal MTs occurring around thechromosomes after nuclear envelope breakdown,and on pre-existing microtubules. Wherechromosome-dependent MT nucleation occurs,when MT amplification takes place and how thetwo pathways function are still key questionsthat generate some controversies. We reconcilethe data and present an integrated modelaccounting for acentrosomal microtubuleassembly in the dividing cell.", "metadata": {}}
+{"_id": "38131471", "title": "", "text": "Molecular mechanisms of mammalian DNA repairand the DNA damage checkpoints.DNA damageis a relatively common event in the life of a celland may lead to mutation, cancer, and cellular ororganismic death. Damage to DNA inducesseveral cellular responses that enable the celleither to eliminate or cope with the damage or toactivate a programmed cell death process,presumably to eliminate cells with potentiallycatastrophic mutations. These DNA damageresponse reactions include: (a) removal of DNAdamage and restoration of the continuity of theDNA duplex; (b) activation of a DNA damagecheckpoint, which arrests cell cycle progressionso as to allow for repair and prevention of thetransmission of damaged or incompletelyreplicated chromosomes; (c) transcriptionalresponse, which causes changes in thetranscription profile that may be beneficial to thecell; and (d) apoptosis, which eliminates heavilydamaged or seriously deregulated cells. DNArepair mechanisms include direct repair, base", "metadata": {}}
+{"_id": "38143689", "title": "", "text": "Characterization of serotonin 5-HT2C receptorsignaling to extracellular signal-regulated kinases1 and 2.Serotonin 5-HT2C receptors(5-HT(2C)Rs) are almost exclusively expressedin the CNS, and implicated in disorders such asobesity, depression, and schizophrenia. Thepresent study investigated the mechanismsgoverning the coupling of the 5-HT(2C)R to theextracellular signal-regulated kinases (ERKs)1/2, using a Chinese hamster ovary (CHO) cellline stably expressing the receptor at levelscomparable to those found in the brain. Usingthe non-RNA-edited isoform of the 5-HT(2C)R,constitutive ERK1/2 phosphorylation wasobserved and found to be modulated by full,partial and inverse agonists. Interestingly,agonist-directed trafficking of receptor stimuluswas also observed when comparing effects onphosphoinositide accumulation and intracellularCa2+ elevation to ERK1/2 phosphorylation,whereby the agonists,[+/-]-2,5-dimethoxy-4-iodoamphetamine (DOI)", "metadata": {}}
+{"_id": "38180456", "title": "", "text": "Short-term medical service trips: a systematicreview of the evidence.Short-term medicalservice trips (MSTs) aim to address unmet healthcare needs of low- and middle-income countries.The lack of critically reviewed empirical evidenceof activities and outcomes is a concern.Developing evidence-based recommendations forhealth care delivery requires systematic researchreview. I focused on MST publications withempirical results. Searches in May 2013identified 67 studies published since 1993, only6% of the published articles on the topic in thepast 20 years. Nearly 80% reported on surgicaltrips. Although the MST field is growing, itsmedical literature lags behind, with nearly all ofthe scholarly publications lacking significant datacollection. By incorporating data collection intoservice trips, groups can validate practices andprovide information about areas needingimprovement.", "metadata": {}}
+{"_id": "38211681", "title": "", "text": "Comparison of Beck Depression Inventories -IAand -II in psychiatric outpatients.The amended(revised) Beck Depression Inventory (BDI-IA;Beck & Steer, 1993b) and the Beck DepressionInventory-II (BDI-II; Beck, Steer, & Brown,1996) were self-administered to 140 psychiatricoutpatients with various psychiatric disorders.The coefficient alphas of the BDI-IA and theBDI-II were, respectively, .89 and .91. The meanrating for Sadness on the BDI-IA was higher thanit was on the BDI-II, but the mean ratings forPast Failure, Self-Dislike, Change in SleepingPattern, and Change in Appetite were higher onthe BDI-II than they were on the BDI-IA. Themean BDI-II total score was approximately 2points higher than it was for the BDI-IA, and theoutpatients also endorsed approximately onemore symptom on the BDI-II than they did onthe BDI-IA. The correlations of BDI-IA andBDI-II total scores with sex, ethnicity, age, thediagnosis of a mood disorder, and the BeckAnxiety Inventory (Beck & Steer, 1993a) were", "metadata": {}}
+{"_id": "38243984", "title": "", "text": "Tumor engraftment in nude mice and enrichmentin stroma- related gene pathways predict poorsurvival and resistance to gemcitabine inpatients with pancreatic cancer.PURPOSE Thegoal of this study was to evaluate prospectivelythe engraftment rate, factors influencingengraftment, and predictability of clinicaloutcome of low-passage xenografts frompatients with resectable pancreatic ductaladenocarcinoma (PDA) and to establish a bank ofPDA xenografts. EXPERIMENTAL DESIGNPatients with resectable PDA scheduled forresection at the Johns Hopkins Hospital wereeligible. Representative pieces of tumor wereimplanted in nude mice. The status of the SMAD4gene and content of tumor-generating cells weredetermined by immunohistochemistry. Geneexpression was carried out by using a U133 Plus2.0 array. Patients were followed for progressionand survival. RESULTS A total of 94 patients withPDA were resected, 69 tumors implanted in nudemice, and 42 (61%) engrafted. Engrafted", "metadata": {}}
+{"_id": "38252314", "title": "", "text": "The MCM8-MCM9 complex promotes RAD51recruitment at DNA damage sites to facilitatehomologous recombination.The minichromosomemaintenance protein homologs MCM8 and MCM9have previously been implicated in DNAreplication elongation and prereplication complex(pre-RC) formation, respectively. We found thatMCM8 and MCM9 physically associate with eachother and that MCM8 is required for the stabilityof MCM9 protein in mammalian cells. Depletionof MCM8 or MCM9 in human cancer cells or theloss of function MCM9 mutation in mouse embryofibroblasts sensitizes cells to the DNA interstrandcross-linking (ICL) agent cisplatin. Consistentwith a role in the repair of ICLs by homologousrecombination (HR), knockdown of MCM8 orMCM9 significantly reduces HR repair efficiency.Chromatin immunoprecipitation analysis usinghuman DR-GFP cells or Xenopus egg extractdemonstrated that MCM8 and MCM9 proteins arerapidly recruited to DNA damage sites andpromote RAD51 recruitment. Thus, these two", "metadata": {}}
+{"_id": "38296571", "title": "", "text": "The 5TMM series: a useful in vivo mouse modelof human multiple myeloma.The presentinvention provides a combination sink anddishwashing apparatus having a sink sharing acommon side wall with a cabinet which defines aclosed space. The cabinet has a wire basket forholding and washing a plurality of dishes withinthe cabinet. The common side wall is a part ofthe cabinet that defines the closed space and ispositioned to form one side of the sink. Thecommon side wall can be opened to allow thewire basket to slide from within the cabinet andinto the sink, for loading and unloading thedishes. Within the cabinet, the invention containsa pump powered by a motor, the pump sprayingwater through a rotatably mounted spray armonto the dishes to wash them, as with traditionaldishwashing machines. The invention preferablyincludes a garbage disposal which is alsopowered by the motor. In an alternativeembodiment, this invention can include twocabinets as described above, each located on", "metadata": {}}
+{"_id": "38300781", "title": "", "text": "Ionic protein-lipid interaction at the plasmamembrane: what can the chargedo?Phospholipids are the major components ofcell membranes, but they have functional rolesbeyond forming lipid bilayers. In particular,acidic phospholipids form microdomains in theplasma membrane and can ionically interact withproteins via polybasic sequences, which can havefunctional consequences for the protein. The listof proteins regulated by ionic protein-lipidinteraction has been quickly expanding, and nowincludes membrane proteins, cytoplasmic solubleproteins, and viral proteins. Here we review howacidic phospholipids in the plasma membraneregulate protein structure and function via ionicinteractions, and how Ca(2+) regulates ionicprotein-lipid interactions via direct and indirectmechanisms.", "metadata": {}}
+{"_id": "38355793", "title": "", "text": "A20 is overexpressed in glioma cells and mayserve as a potential therapeutictarget.OBJECTIVE A20 is a TNF-inducible primaryresponse gene, which has been found to haveantiapoptotic function in several cancer cells.This study investigates A20 expression in humanglioma tissues and four glioma cell lines, and itseffect on tumorigenesis of glioma cells and amouse tumor model. METHODS Human gliomatissue samples and cells were subject to reversetranscription-PCR (RT-PCR), western blotting andimmunohistochemistry. Glioma cells was testedby flow cytometry. A xenograft tumor model inmice was utilized to examine the knock-downeffect of specific A20 siRNAs on tumorigenesis.RESULTS A20 was overexpressed in clinicalglioma tissue samples (63.9%) and correlatedwith clinical staging. All four human glioma celllines expressed A20, among which U87 displayedthe strongest expression signals. Inhibiting A20expression by siRNAs in vitro reduced the growthrates of glioma cells and resulted in G1/S arrest", "metadata": {}}
+{"_id": "38369817", "title": "", "text": "Prevalence and size of directly detected patentforamen ovale in migraine withaura.BACKGROUND Transcranial contrastDoppler studies have shown an increasedprevalence of right-to-left shunts in patients withmigraine with aura compared with controls. Theanatomy and size of these right-to-left shuntshave never been directly assessed. METHODS Ina cross-sectional case-control study, the authorsperformed transesophageal contrastechocardiography in 93 consecutive patients withmigraine with aura and 93 healthy controls.RESULTS A patent foramen ovale was present in44 (47% [95% CI 37 to 58%]) patients withmigraine with aura and 16 (17% [95% CI 10 to26%]) control subjects (OR 4.56 [95% CI 1.97to 10.57]; p < 0.001). A small shunt was equallyprevalent in migraineurs (10% [95% CI 5 to18%]) and controls (10% [95% CI 5 to 18%]),but a moderate-sized or large shunt was foundmore often in the migraine group (38% [95% CI28 to 48%] vs 8% [95% CI 2 to 13%] in", "metadata": {}}
+{"_id": "38376189", "title": "", "text": "A Live Attenuated Chimeric West Nile VirusVaccine, rWN/DEN4&Dgr;30, Is Well Toleratedand Immunogenic in Flavivirus-Naive Older AdultVolunteersWest Nile virus (WNV) is a majorcause of mosquito-borne illness in the UnitedStates. Human disease ranges from mild febrileillness to severe fatal neurologic infection. Adultsaged >60 years are more susceptible toneuroinvasive disease accompanied by a highmortality rate or long-lasting neurologicsequelae. A chimeric live attenuated West Nilevirus vaccine, rWN/DEN4&Dgr;30, was shown tobe safe and immunogenic in healthy adults aged18–50 years. This study evaluatedrWN/DEN4&Dgr;30 in flavivirus-naive adultsaged 50–65 years and found it to be safe andimmunogenic. Outbreaks of WNV infection tendto be unpredictable, and a safe and effectivevaccine will be an important public health tool.", "metadata": {}}
+{"_id": "38380061", "title": "", "text": "Localization and requirement for Myosin II at thedorsal-ventral compartment boundary of theDrosophila wing.As organisms develop, theirtissues can become separated into distinct cellpopulations through the establishment ofcompartment boundaries. Compartmentboundaries have been discovered in a widevariety of tissues, but in many cases themolecular mechanisms that separate cells remainpoorly understood. In the Drosophila wing, astripe of Notch activation maintains thedorsal-ventral compartment boundary, through aprocess that depends on the actin cytoskeleton.Here, we show that the dorsal-ventral boundaryexhibits a distinct accumulation of Myosin II, andthat this accumulation is regulated downstreamof Notch signaling. Conversely, thedorsal-ventral boundary is depleted for the Par-3homologue Bazooka. We further show thatmutations in the Myosin heavy chain subunitencoded by zipper can impair dorsal-ventralcompartmentalization without affecting", "metadata": {}}
+{"_id": "38401028", "title": "", "text": "The cause of hepatic accumulation of fructose1-phosphate on fructose loading.1. The changesin the metabolite content in freeze-clampedlivers of fed rats occurring on perfusion with10mm-d-fructose have been examined. 2. Themost striking effects of fructose were anaccumulation of fructose 1-phosphate, as alreadyknown, up to 8.7mumol/g of liver within 10min,a loss of total adenine nucleotides (up to 35%after 40min) with a decrease in the ATP contentto 23% within 10min, a sevenfold rise in theconcentration of IMP to 1.1mumol/g and aneightfold rise of alpha-glycerophosphate to1.1mumol/g. 3. There was a transient decreasein P(i) from 4.2 to 1.7mumol/g. Within 40min theP(i) content recovered to the normal value,probably because of an uptake of P(i) from theperfusion medium. 4. The degradation of theadenine nucleotides beyond the stage of AMP canbe accounted for by the decrease of ATP andP(i). As ATP inhibits 5-nucleotidase, and as P(i)inhibits AMP deaminase any AMP arising in the", "metadata": {}}
+{"_id": "38410121", "title": "", "text": "Reported side effects to chloroquine, chloroquineplus proguanil, and mefloquine aschemoprophylaxis against malaria in Danishtravelers.BACKGROUND The aim of the studywas to provide data on the relative frequency ofreported symptoms in travelers usingchloroquine, chloroquine plus proguanil, andmefloquine. METHOD The study was an open,nonrandomized study recording self-reportedevents in travelers recruited consecutively fromtwo travel clinics in Copenhagen, Denmark. Themain outcome measures were the relativeproportion of travelers reporting particularsymptoms in the three prophylaxis groups,compliance, hospitalization and prematuretermination of the travel. RESULTS From May1996 to April 1998 5, 446 travelers wereincluded and 4,158 questionnaires (76.3%)returned. Compliance was significantly better inmefloquine users with 83.3% of short termtravelers compared to 76.3% in chloroquine plusproguanil users. Also, 84.8%, 59.3% and 69.5%", "metadata": {}}
+{"_id": "38477436", "title": "", "text": "Ubiquitinylation of the cytosolic domain of a typeI membrane protein is not required to initiate itsdislocation from the endoplasmicreticulum.Human cytomegalovirus US2 and US11target newly synthesized class I majorhistocompatibility complex (MHC) heavy chainsfor rapid degradation by the proteasome througha process termed dislocation. The presence ofUS2 induces the formation of class I MHC heavychain conjugates of increased molecular weightthat are recognized by a conformation-specificmonoclonal antibody, W6/32, suggesting thatthese class I MHC molecules retain their propertertiary structure. These conjugates are properlyfolded glycosylated heavy chains modified byattachment of an estimated one, two, and threeubiquitin molecules. The folded ubiquitinatedclass I MHC heavy chains are not observed incontrol cells or in cells transfected with US11,suggesting that US2 targets class I MHC heavychains for dislocation in a manner distinct fromthat used by US11. This is further supported by", "metadata": {}}
+{"_id": "38485364", "title": "", "text": "The adaptor protein Tks5/Fish is required forpodosome formation and function, and for theprotease-driven invasion of cancercells.Tks5/Fish is a scaffolding protein with fiveSH3 domains and one PX domain. InSrc-transformed cells, Tks5/Fish localizes topodosomes, discrete protrusions of the ventralmembrane. We generated Src-transformed cellswith reduced Tks5/Fish levels. They no longerformed podosomes, did not degrade gelatin, andwere poorly invasive. We detected Tks5/Fishexpression in podosomes in invasive cancer cells,as well as in human breast cancer and melanomasamples. Tks5/Fish expression was also requiredfor protease-driven matrigel invasion in humancancer cells. Finally, coexpression of Tks5/Fishand Src in epithelial cells resulted in theappearance of podosomes. Thus, Tks5/Fishappears to be required for podosome formation,for degradation of the extracellular matrix, andfor invasion of some cancer cells.", "metadata": {}}
+{"_id": "38493521", "title": "", "text": "Corticosteroid injections for shoulderpain.BACKGROUND While many treatments,including corticosteroid injections in and aroundthe shoulder, are advocated to be of benefit forshoulder pain, few are of proven efficacy. Thisreview of corticosteroid injections for shoulderpain is one in a series of reviews of varyinginterventions for shoulder disorders. OBJECTIVESTo determine the efficacy and safety ofcorticosteroid injections in the treatment ofadults with shoulder pain. SEARCH STRATEGYMEDLINE, EMBASE, CINAHL, Central and ScienceCitation Index were searched up to and includingJune 2002. SELECTION CRITERIA Randomisedand pseudo-randomised trials in all languages ofcorticosteroid injections compared to placebo oranother intervention, or of varying types anddosages of steroid injection in adults withshoulder pain. Specific exclusions were durationof shoulder pain less than three weeks,rheumatoid arthritis, polymyalgia rheumaticaand fracture. DATA COLLECTION AND ANALYSIS", "metadata": {}}
+{"_id": "38502066", "title": "", "text": "IL-2 receptor signaling is essential for thedevelopment of Klrg1+ terminally differentiatedT regulatory cells.Thymic-derived natural Tregulatory cells (Tregs) are characterized byfunctional and phenotypic heterogeneity.Recently, a small fraction of peripheral Tregs hasbeen shown to express Klrg1, but it remainsunclear as to what extent Klrg1 defines a uniqueTreg subset. In this study, we show thatKlrg1(+) Tregs represent a terminallydifferentiated Treg subset derived from Klrg1(-)Tregs. This subset is a recent Ag-responsive andhighly activated short-lived Treg population thatexpresses enhanced levels of Treg suppressivemolecules and that preferentially resides withinmucosal tissues. The development of Klrg1(+)Tregs also requires extensive IL-2R signaling.This activity represents a distinct function forIL-2, independent from its contribution to Treghomeostasis and competitive fitness. These andother properties are analogous to terminallydifferentiated short-lived CD8(+) T effector cells.", "metadata": {}}
+{"_id": "38528892", "title": "", "text": "The aurora B kinase promotes inner and outerkinetochore interactions in budding yeast.Thekinetochore is the macromolecular proteincomplex that mediates chromosome segregation.The Dsn1 component is crucial for kinetochoreassembly and is phosphorylated by the Aurora Bkinase. We found that Aurora B phosphorylationof Dsn1 promotes the interaction between outerand inner kinetochore proteins in budding yeast.", "metadata": {}}
+{"_id": "38533515", "title": "", "text": "AMP-activated/SNF1 protein kinases: conservedguardians of cellular energyTheSNF1/AMP-activated protein kinase (AMPK)family maintains the balance between ATPproduction and consumption in all eukaryoticcells. The kinases are heterotrimers thatcomprise a catalytic subunit and regulatorysubunits that sense cellular energy levels. Whenenergy status is compromised, the systemactivates catabolic pathways and switches offprotein, carbohydrate and lipid biosynthesis, aswell as cell growth and proliferation.Surprisingly, recent results indicate that theAMPK system is also important in functions thatgo beyond the regulation of energy homeostasis,such as the maintenance of cell polarity inepithelial cells.", "metadata": {}}
+{"_id": "38551172", "title": "", "text": "Mammographic density, plasma vitamin D levelsand risk of breast cancer in postmenopausalwomen.Mammographic density is a strong riskfactor for breast cancer, but the underlyingbiology for this association is unknown. Studiessuggest that vitamin D may reduce breast cancerrisk and dietary vitamin D intake has beenassociated with reduced breast density. Weconducted a case-control study nested within theNurses' Health Study cohort consisting of 463and 497 postmenopausal cases and controls,respectively. We examined the associationbetween mammographic density and plasmalevels of 25-hydroxyvitamin D [25(OH)D] and1,25-dihydroxyvitamin D [1,25(OH)(2)D]. Weassessed whether plasma vitamin D metabolitesmodify the association between breast densityand breast cancer. Percent mammographicdensity was measured from digitized filmmammograms. Generalized linear models wereused to determine mean percent breast densityper quartile of vitamin D metabolite. Logistic", "metadata": {}}
+{"_id": "38587347", "title": "", "text": "Finding the right niche: B-cell migration in theearly phases of T-dependent antibodyresponses.Humoral immune responses dependon B cells encountering antigen, interacting withhelper T cells, proliferating and differentiatinginto low-affinity plasma cells or, after organizinginto a germinal center (GC), high-affinity plasmacells and memory B cells. Remarkably, each ofthese events occurs in association with distinctstromal cells in separate subcompartments of thelymphoid tissue. B cells must migrate from nicheto niche in a rapid and highly regulated mannerto successfully mount a response. Thechemokine, CXCL13, plays a central role inguiding B cells to follicles whereas T-zonechemokines guide activated B cells to the T zone.Sphingosine-1-phosphate (S1P) promotes cellegress from the tissue, as well as marginal-zoneB-cell positioning in the spleen. Recent studieshave identified a role for the orphan receptor,EBV-induced molecule 2 (EBI2; GPR183), inguiding activated B cells to inter and outer", "metadata": {}}
+{"_id": "38623601", "title": "", "text": "Arginine Starvation Impairs MitochondrialRespiratory Function in ASS1-Deficient BreastCancer CellsAutophagy is the principal catabolicresponse to nutrient starvation and is necessaryto clear dysfunctional or damaged organelles,but excessive autophagy can be cytotoxic orcytostatic and contributes to cell death.Depending on the abundance of enzymesinvolved in molecule biosynthesis, cells can bedependent on uptake of exogenous nutrients toprovide these molecules. Argininosuccinatesynthetase 1 (ASS1) is a key enzyme in argininebiosynthesis, and its abundance is reduced inmany solid tumors, making them sensitive toexternal arginine depletion. We demonstratedthat prolonged arginine starvation by exposureto ADI-PEG20 (pegylated arginine deiminase)induced autophagy-dependent death ofASS1-deficient breast cancer cells, becausethese cells are arginine auxotrophs (dependenton uptake of extracellular arginine). Indeed,these breast cancer cells died in culture when", "metadata": {}}
+{"_id": "38630735", "title": "", "text": "A prospective natural-history study of coronaryatherosclerosis.BACKGROUND Atheroscleroticplaques that lead to acute coronary syndromesoften occur at sites of angiographically mildcoronary-artery stenosis. Lesion-related riskfactors for such events are poorly understood.METHODS In a prospective study, 697 patientswith acute coronary syndromes underwentthree-vessel coronary angiography andgray-scale and radiofrequency intravascularultrasonographic imaging after percutaneouscoronary intervention. Subsequent majoradverse cardiovascular events (death fromcardiac causes, cardiac arrest, myocardialinfarction, or rehospitalization due to unstable orprogressive angina) were adjudicated to berelated to either originally treated (culprit)lesions or untreated (nonculprit) lesions. Themedian follow-up period was 3.4 years. RESULTSThe 3-year cumulative rate of major adversecardiovascular events was 20.4%. Events wereadjudicated to be related to culprit lesions in", "metadata": {}}
+{"_id": "38664102", "title": "", "text": "What do medical schools teach about women'shealth and gender differences?PURPOSE Toexamine the curricula of U.S. medical schools toassess the inclusion of women's health andgender-specific information and identifyinstitutional characteristics associated with thiscontent. METHOD Using data from theAssociation of American Medical Colleges'Curriculum Management and Information Tool(CurrMIT), in November 2003 to February 2004the authors performed a curriculum search ofschools that entered course/clerkships inCurrMIT to identify interdisciplinary women'shealth or gender-specific courses/clerkships. Asubset of schools that entered comprehensiveinformation in CurrMIT was searched for aspecified list of women's health topics and orgender-specific content on any topic. Statisticalanalyses were performed to assess therelationship between frequency of topics andschool characteristics. RESULTS The authorsidentified 95 schools that entered related", "metadata": {}}
+{"_id": "38675228", "title": "", "text": "A molecular framework for plantregeneration.Plants and some animals have aprofound capacity to regenerate organs fromadult tissues. Molecular mechanisms forregeneration have, however, been largelyunexplored. Here we investigate a localregeneration response in Arabidopsis roots.Laser-induced wounding disrupts the flow ofauxin-a cell-fate-instructive plant hormone-inroot tips, and we demonstrate that resultingcell-fate changes require the PLETHORA,SHORTROOT, and SCARECROW transcriptionfactors. These transcription factors regulate theexpression and polar position of PIN auxinefflux-facilitating membrane proteins toreconstitute auxin transport in renewed root tips.Thus, a regeneration mechanism usingembryonic root stem-cell patterning factors firstresponds to and subsequently stabilizes a newhormone distribution.", "metadata": {}}
+{"_id": "38712515", "title": "", "text": "Cocoa flavonols and procyanidins promotetransforming growth factor-beta1 homeostasis inperipheral blood mononuclear cells.Evidencesuggests that certain flavan-3-ols andprocyanidins (FP) can have a positive influenceon cardiovascular health. It has been previouslyreported that FP isolated from cocoa canpotentially modulate the level and production ofseveral signaling molecules associated withimmune function and inflammation, includingseveral cytokines and eicosanoids. In the presentstudy, we examined whether FP fractionsmonomers through decamers modulate secretionof the cytokine transforming growth factor(TGF)-beta(1) from resting human peripheralblood mononuclear cells (PBMC). A total of 13healthy subjects were studied and groupedaccording to their baseline production ofTGF-beta(1). When cells from individuals withlow baseline levels of TGF-beta(1) (n = 7) werestimulated by individual FP fractions (25microg/ml), TGF-beta(1) release was enhanced", "metadata": {}}
+{"_id": "38727075", "title": "", "text": "BMP receptor IA is required in mammalian neuralcrest cells for development of the cardiac outflowtract and ventricular myocardium.The neuralcrest is a multipotent, migratory cell populationarising from the border of the neural and surfaceectoderm. In mouse, the initial migratory neuralcrest cells occur at the five-somite stage. Bonemorphogenetic proteins (BMPs), particularlyBMP2 and BMP4, have been implicated asregulators of neural crest cell induction,maintenance, migration, differentiation andsurvival. Mouse has three known BMP2/4 type Ireceptors, of which Bmpr1a is expressed in theneural tube sufficiently early to be involved inneural crest development from the outset;however, earlier roles in other domains obscureits requirement in the neural crest. We haveablated Bmpr1a specifically in the neural crest,beginning at the five-somite stage. We find thatmost aspects of neural crest development occurnormally; suggesting that BMPRIA isunnecessary for many aspects of early neural", "metadata": {}}
+{"_id": "38735355", "title": "", "text": "Early intermittent noninvasive ventilation foracute chest syndrome in adults with sickle celldisease: a pilot studyAlveolar hypoxia andhypoxic vasoconstriction lead to trapping ofsickle cells within the pulmonary vasculature.Improving alveolar ventilation and oxygenationmay improve the outcome of acute chestsyndrome (ACS). Prospective randomizedsingle-center open study from November 1998 toFebruary 2002 to test whether noninvasiveventilation (NIV) was more effective than oxygenalone in improving oxygenation on day 3 inadults with ACS and to evaluate the effects onpain, transfusion requirements, and length ofstay. Seventy-one consecutive ACS episodes in67 patients were randomly allocated to oxygen(n = 36) or NIV (n = 35) for 3 days in a medicalstep-down unit. Baseline respiratory rate andpain score were higher in the NIV group. NIVpromptly lowered the respiratory rate, raised $${\\text{Pa}}_{{\\text{O}_{2}}} $$ , anddecreased alveolar–arterial oxygen gradient $$", "metadata": {}}
+{"_id": "38745690", "title": "", "text": "Serum Exosome MicroRNA as aMinimally-Invasive Early Biomarker ofAMLRelapse remains the major cause ofmortality for patients with Acute MyeloidLeukemia (AML). Improved tracking of minimalresidual disease (MRD) holds the promise oftimely treatment adjustments to preemptrelapse. Current surveillance techniques detectcirculating blasts that coincide with advanceddisease and poorly reflect MRD during earlyrelapse. Here, we investigate exosomes as aminimally invasive platform for a microRNA(miRNA) biomarker. We identify a set of miRNAenriched in AML exosomes and track levels ofcirculating exosome miRNA that distinguishleukemic xenografts from both non-engraftedand human CD34+ controls. We developbiostatistical models that reveal circulatingexosomal miRNA at low marrow tumor burdenand before circulating blasts can be detected.Remarkably, both leukemic blasts and marrowstroma contribute to serum exosome miRNA. We", "metadata": {}}
+{"_id": "38747567", "title": "", "text": "Human cytomegalovirus encodes an MHC classI-like molecule (UL142) that functions to inhibitNK cell lysis.Clinical and low passage strains ofhuman CMV (HCMV) encode an additional MHCclass I-related molecule UL142, in addition to thepreviously described UL18. The UL142 openreading frame is encoded within the ULb' regionwhich is missing from a number of common highpassage laboratory strains. Cells expressingUL142 following transfection, and fibroblastsinfected with a recombinantadenovirus-expressing UL142, were used toscreen both polyclonal NK cells and NK cellclones, in a completely autologous system.Analysis of 100 NK cell clones derived from fivedonors, revealed 23 clones that were inhibited byfibroblasts expressing UL142 alone.Small-interfering RNA-mediated knockdown ofUL142 mRNA expression in HCMV-infected cellsresulted in increased sensitivity to lysis. Fromthese data we conclude that UL142 is a novelHCMV-encoded MHC class I-related molecule", "metadata": {}}
+{"_id": "38751591", "title": "", "text": "Identification of the conserved serine/threonineresidues important for gibberellin-sensitivity ofArabidopsis RGL2 protein.The DELLA proteinsGAI, RGA, RGL1 and RGL2 in Arabidopsis areplant growth repressors, repressing diversedevelopmental processes. Studies have shownthat gibberellin (GA) attenuates the repressivefunction of DELLA proteins by triggering theirdegradation via the proteasome pathway.However, it is not known if GA-induced proteindegradation is the only pathway for regulatingthe bioactivity of DELLA proteins. We show herethat tobacco BY2 cells represent a suitablesystem for studying GA signaling. RGL2 exists ina phosphorylated form in BY2 cells. RGL2undergoes GA-induced degradation, and thisprocess is blocked by proteasome inhibitors andserine/threonine phosphatase inhibitors;however, serine/threonine kinase inhibitors hadno detectable effect, suggesting thatdephosphorylation of serine/threonine isprobably a prerequisite for degradation of RGL2", "metadata": {}}
+{"_id": "38752049", "title": "", "text": "A chart review of cyproheptadine forstimulant-induced weight loss.Youths withattention deficit hyperactivity disorder oftenexperience weight loss on stimulants, which maylimit optimal dosing and compliance.Cyproheptadine has been shown in medicalsamples to stimulate weight gain. We conducteda retrospective chart review of 28 consecutivepediatric psychiatry outpatients prescribedcyproheptadine for weight loss or insomnia whileon stimulants. Of these, 4 patients never tookcyproheptadine consistently, and 3 discontinuedit within the first 7 days due to intolerable sideeffects. Data were analyzed for 21 other patients(age range 4-15 years) who continued with 4-8mg of cyproheptadine nightly (mean final dose =4.9 mg/day) for at least 14 days (mean duration= 104.7 days). Most had lost weight on stimulantalone (mean weight loss was 2.1 kg, meanweight velocity was -19.3 g/day). All 21 gainedweight taking concomitant cyproheptadine, witha mean gain of 2.2 kg (paired t = 6.87, p <", "metadata": {}}
+{"_id": "38784540", "title": "", "text": "Life course breast cancer risk factors and adultbreast density (United Kingdom)Objective Todetermine whether risk factors in childhood andearly adulthood affect later mammographicbreast density. Methods: Subjects were 628women who attended a medical examination atthe University of Glasgow Student Health Service(1948–1968), responded to a questionnaire(2001) and had a screening mammogram inScotland (1989–2002). Mammograms (medianage of 59years) were classified using a sixcategory classification (SCC) of breast densitypercent. Logistic regression was used todetermine associations between risk factors andhaving a high-risk mammogram (≥25 dense).Results: In multi-variable analyses, high-riskmammograms were associated with parity(adjusted odds ratio (OR) per child: 0.77 (95confidence interval (CI) 0.61–0.99)), age at firstbirth, OR per year: 1.05 (0.99–1.11), smoking atuniversity, OR smokers versus non-smokers:0.58 (0.36–0.92) and body mass index (BMI)", "metadata": {}}
+{"_id": "38793927", "title": "", "text": "Osteoclast nuclei of myeloma patients showchromosome translocations specific for themyeloma cell clone: a new type of cancer-hostpartnership?A major clinical manifestation ofbone cancers is bone destruction. It is widelyaccepted that this destruction is not caused bythe malignant cells themselves, but byosteoclasts, multinucleated cells of monocyticorigin that are considered to be the only cellsable to degrade bone. The present studydemonstrates that bone-resorbing osteoclastsfrom myeloma patients contain nuclei withtranslocated chromosomes of myeloma B-cellclone origin, in addition to nuclei without thesetranslocations, by using combined FISH andimmunohistochemistry on bone sections. Thesenuclei of malignant origin are transcriptionallyactive and appear fully integrated amongst theother nuclei. The contribution of malignant nucleito the osteoclast population analysed in thisstudy was greater than 30%.Osteoclast-myeloma clone hybrids contained", "metadata": {}}
+{"_id": "38794814", "title": "", "text": "Frequency modulation entrains slow neuraloscillations and optimizes human listeningbehavior.The human ability to continuously trackdynamic environmental stimuli, in particularspeech, is proposed to profit from \"entrainment\"of endogenous neural oscillations, which involvesphase reorganization such that \"optimal\" phasecomes into line with temporally expected criticalevents, resulting in improved processing. Thecurrent experiment goes beyond previous workin this domain by addressing two thus farunanswered questions. First, how general isneural entrainment to environmental rhythms:Can neural oscillations be entrained by temporaldynamics of ongoing rhythmic stimuli withoutabrupt onsets? Second, does neural entrainmentoptimize performance of the perceptual system:Does human auditory perception benefit fromneural phase reorganization? In a humanelectroencephalography study, listeners detectedshort gaps distributed uniformly with respect tothe phase angle of a 3-Hz frequency-modulated", "metadata": {}}
+{"_id": "38799797", "title": "", "text": "Interventions by pharmacists in out-patientpharmaceutical care.Interventions by thepharmacists have always been considered as avaluable input by the health care community inthe patient care process by reducing themedication errors, rationalizing the therapy andreducing the cost of therapy. The primaryobjective of this study was to determine thenumber and types of medication errorsintervened by the dispensing pharmacists at OPDpharmacy in the Khoula Hospital during 2009retrospectively. The interventions filed by thepharmacists and assistant pharmacists in OPDpharmacy were collected. Then they werecategorized and analyzed after a detailed review.The results show that 72.3% of the interventionswere minor of which 40.5% were about changemedication order. Comparatively more numbersof prescriptions were intervened in femalepatients than male patients. 98.2% of theinterventions were accepted by the prescribersreflecting the awareness of the doctors about the", "metadata": {}}
+{"_id": "38805486", "title": "", "text": "Biochemical studies on Mycobacteriumtuberculosis UreG and comparative modelingreveal structural and functional conservationamong the bacterial UreG family.Nickel is afundamental micronutrient for cellular life, but itis toxic in soluble form at nonphysiologicalconcentrations. Such potentially contradictoryfeatures required living organisms to developefficient systems for nickel utilization andhomeostasis. This is the case for incorporation ofnickel into the active site of urease, a multistep,tightly regulated process, requiring the interplayof various accessory proteins. The understandingof this activation mechanism may find medicalapplications against ureolytic bacteria, amongwhich Mycobacterium tuberculosis is a deadlypathogen for humans. The topic of this study isUreG, an essential chaperone in the in vivoactivation of urease upon insertion of Ni2+ intothe active site. The protein was examined usingboth experimental and computationalapproaches. In particular, the soluble M.", "metadata": {}}
+{"_id": "38808600", "title": "", "text": "(99m)Tc-HisoDGR as a Potential SPECT Probe forOrthotopic Glioma Detection via Targeting ofIntegrin α5β1.Integrins, a large family of celladhesion receptors, have been shown to play animportant role for glioma proliferation andinvasion. Several integrin receptors, includingαvβ3, αvβ5, and α5β1, have generated clinicalinterest for glioma diagnosis and antitumortherapy. Integrin α5β1 has been highlighted as aprognostic and diagnostic marker in glioma, andits expression is correlated with a worseprognosis in high-grade glioma. However, unlikeextensively studied integrins αvβ3 and αvβ5,very few integrin α5β1-specific radiotracers havebeen reported. Developing α5β1-specificradiotracers may provide alternative diagnosisand evaluation options in addition to well-studiedαvβ3/αvβ5-specific tracers, and they may addnew documents for profiling tumor progression.Here, a novel integrin α5β1-specific probe(99m)Tc-HisoDGR was fabricated for SPECT(single-photon emission computed tomography)", "metadata": {}}
+{"_id": "38811597", "title": "", "text": "Effect of cyclic AMP-dependent proteinphosphorylating conditions on the pH-dependentactivity of tyrosine hydroxylase from beef and ratstriata.Tyrosine hydroxylase (TH, EC 1.14.16.2)from beef brain striata was purified 23-fold froman extract of an acetone powder. If this enzymepreparation is treated with a cyclicAMP[-dependent protein phosphorylationsystem, there is a change in the pH dependenceof the enzyme activity. The pH optimum atsaturating tetrahydrobiopterin (BH4)concentration is shifted from below pH 6 to aboutpH 6.7. At pH 7, activation is expressed mainlyas an increase in Vmax, whereas at pH 6,activation is expressed mainly as a decrease inKm for the pterin cofactor. Further, even withthe control enzyme the Km for pterin cofactordeclines precipitously as the pH is increased from6 toward neutrality. Similar data were obtainedwith G-25 Sephadex-treated rat striatal TH.Experiments in which rat striatal synaptosomeswere used demonstrated that the in situ", "metadata": {}}
+{"_id": "38830961", "title": "", "text": "Interaction of TNF with TNF receptor type 2promotes expansion and function of mouseCD4+CD25+ T regulatory cells.Although TNF is amajor proinflammatory cytokine, increasingevidence indicates that TNF also hasimmunosuppressive feedback effects. We havedemonstrated in this study that, in both restingand activated states, mouse peripheralCD4(+)CD25(+) T regulatory cells (Tregs)expressed remarkably higher surface levels ofTNFR2 than CD4(+)CD25(-) T effector cells(Teffs). In cocultures of Tregs and Teffs,inhibition of proliferation of Teffs by Tregs wasinitially transiently abrogated by exposure toTNF, but longer exposure to TNF restoredsuppressive effects. Cytokine production by Teffsremained continually suppressed by Tregs. Theprofound anergy of Tregs in response to TCRstimulation was overcome by TNF, whichexpanded the Treg population. Furthermore, insynergy with IL-2, TNF expanded Tregs evenmore markedly up-regulated expression of CD25", "metadata": {}}
+{"_id": "38844612", "title": "", "text": "The basics of epithelial-mesenchymaltransition.The origins of the mesenchymal cellsparticipating in tissue repair and pathologicalprocesses, notably tissue fibrosis, tumorinvasiveness, and metastasis, are poorlyunderstood. However, emerging evidencesuggests that epithelial-mesenchymal transitions(EMTs) represent one important source of thesecells. As we discuss here, processes similar tothe EMTs associated with embryo implantation,embryogenesis, and organ development areappropriated and subverted by chronicallyinflamed tissues and neoplasias. Theidentification of the signaling pathways that leadto activation of EMT programs during thesedisease processes is providing new insights intothe plasticity of cellular phenotypes and possibletherapeutic interventions.", "metadata": {}}
+{"_id": "38873881", "title": "", "text": "Child maltreatment, other trauma exposure, andposttraumatic symptomatology among childrenwith oppositional defiant and attention deficithyperactivity disorders.Consecutive childpsychiatric outpatient admissions with disruptivebehavior or adjustment disorders were assessedby validated instruments for trauma exposureand posttraumatic stress disorder (PTSD)symptoms and other psychopathology. Fourreliably diagnosed groups were defined in aretrospective case-control design: AttentionDeficit Hyperactivity Disorder (ADHD),Oppositional Defiant Disorder (ODD), comorbidADHD-ODD, and adjustment disorder controls.ODD and (although to a lesser extent) ADHDwere associated with a history of physical orsexual maltreatment. PTSD symptoms weremost severe if (a) ADHD and maltreatmentco-occurred or (b) ODD and accident/illnesstrauma co-occurred. The association betweenODD and PTSD Criterion D(hyperarousal/hypervigilance) symptoms", "metadata": {}}
+{"_id": "38882175", "title": "", "text": "Exercise-induced asthma screening of eliteathletes: field versus laboratory exercisechallenge.PURPOSE The purpose of this studywas to compare a laboratory based exercisechallenge (LBC) to a field based exercisechallenge (FBC) for pulmonary function test(PFT) exercise-induced asthma (EIA) screeningof elite athletes. METHODS Twenty-three elitecold weather athletes (14 men, 9 women) PFTpositive for EIA (FBC screened) served assubjects. Twenty-three gender and sportmatched controls (nonasthmatics) wererandomly selected to establish PFT referencevalues for normal elite athletes. Before FBC,athletes completed a medical historyquestionnaire for EIA symptoms. FBC evaluationsconsisted of baseline spirometry, actual orsimulated competition, and 5, 10, and 15 minpostexercise spirometry. PFT positive athleteswere evaluated in the laboratory using anexercise challenge simulating race intensity(ambient conditions: 21 degrees C, 60% relative", "metadata": {}}
+{"_id": "38886345", "title": "", "text": "Use of a targeted oncolytic poxvirus, JX-594, inpatients with refractory primary or metastaticliver cancer: a phase I trial.BACKGROUNDJX-594 is a targeted oncolytic poxvirus designedto selectively replicate in and destroy cancer cellswith cell-cycle abnormalities and epidermalgrowth factor receptor (EGFR)-ras pathwayactivation. Direct oncolysis plusgranulocyte-macrophage colony-stimulatingfactor (GM-CSF) expression also stimulatesshutdown of tumour vasculature and antitumoralimmunity. We aimed to assess intratumoralinjection of JX-594 in patients with refractoryprimary or metastatic liver cancer. METHODSBetween Jan 4, 2006, and July 4, 2007, 14patients with histologically confirmed refractoryprimary or metastatic liver tumours (up to 10.9cm total diameter) that were amenable toimage-guided intratumoral injections wereenrolled into this non-comparative, open-label,phase I dose-escalation trial (standard 3x3design; two to six patients for each dose with", "metadata": {}}
+{"_id": "38899659", "title": "", "text": "PTH Signaling in Osteoprogenitors Is Essentialfor B-Lymphocyte Differentiation andMobilization.Cells of the osteoblast lineageprovide critical support for B lymphopoiesis inthe bone marrow (BM). Parathyroid hormone(PTH) signaling in osteoblastic cells through itsreceptor (PPR) is an important regulator ofhematopoietic stem cells; however, its role inregulation of B lymphopoiesis is not clear. Herewe demonstrate that deletion of PPR inosteoprogenitors results in a significant loss oftrabecular and cortical bone. PPR signaling inosteoprogenitors, but not in mature osteoblastsor osteocytes, is critical for B-cell precursordifferentiation via IL-7 production. Interestingly,despite a severe reduction in B-cell progenitorsin BM, mature B-lymphocytes were increased3.5-fold in the BM of mice lacking PPR inosteoprogenitors. This retention of matureIgD(+) B cells in the BM was associated withincreased expression of vascular cell adhesionmolecule 1 (VCAM1) by PPR-deficient", "metadata": {}}
+{"_id": "38919140", "title": "", "text": "Snail coordinately regulates downstreampathways to control multiple aspects ofmammalian neural precursor development.TheSnail transcription factor plays a key role inregulating diverse developmental processes butis not thought to play a role in mammalianneural precursors. Here, we have examinedradial glial precursor cells of the embryonicmurine cortex and demonstrate that Snailregulates their survival, self-renewal, anddifferentiation into intermediate progenitors andneurons via two distinct and separable targetpathways. First, Snail promotes cell survival byantagonizing a p53-dependent death pathwaybecause coincident p53 knockdown rescuessurvival deficits caused by Snail knockdown.Second, we show that the cell cycle phosphataseCdc25b is regulated by Snail in radial precursorsand that Cdc25b coexpression is sufficient torescue the decreased radial precursorproliferation and differentiation observed uponSnail knockdown. Thus, Snail acts via p53 and", "metadata": {}}
+{"_id": "38944245", "title": "", "text": "Endothelial KLF2 links local arterial shear stresslevels to the expression of vasculartone-regulating genes.Lung Krüppel-like factor(LKLF/KLF2) is an endothelial transcription factorthat is crucially involved in murinevasculogenesis and is specifically regulated byflow in vitro. We now show a relation to localflow variations in the adult human vasculature:decreased LKLF expression was noted at theaorta bifurcations to the iliac and carotidarteries, coinciding with neointima formation.The direct involvement of shear stress in the invivo expression of LKLF was determinedindependently by in situ hybridization and lasermicrobeam microdissection/reversetranscriptase-polymerase chain reaction in amurine carotid artery collar model, in which a 4-to 30-fold induction of LKLF occurred at thehigh-shear sites. Dissection of the biomechanicsof LKLF regulation in vitro demonstrated thatsteady flow and pulsatile flow induced basal LKLFexpression 15- and 36-fold at shear stresses", "metadata": {}}
+{"_id": "39048693", "title": "", "text": "Synapsin I Cre transgene expression in malemice produces germline recombination inprogeny.The cre/LoxP system can produceconditional loss of gene function in specific celltypes such as neurons. A transgenic mouse line,utilized by multiple studies, used the Synapsin Ipromoter to drive expression of cre (SynCre) toachieve neuronal-specific cre expression. Hereinwe describe that cre expression can also beobserved in SynCre mice within the testes afterbeing bred into a floxed transgenic mouse line.Cre transcript was expressed in testes resultingin recombination of the floxed substrate intestes. In the majority of cases, progeny of maleSynCre mice inherited a germline recombinedfloxed allele, while this was never observed inprogeny from female mice carrying the SynCreallele. This observation should alert investigatorsto a potential confound using these mice andenables male germ cell \"deletor\" strategies.", "metadata": {}}
+{"_id": "39059143", "title": "", "text": "Hospital mortality, length of stay, andpreventable complications among critically illpatients before and after tele-ICU reengineeringof critical care processes.CONTEXT Theassociation of an adult tele-intensive care unit(ICU) intervention with hospital mortality, lengthof stay, best practice adherence, andpreventable complications for an academicmedical center has not been reported.OBJECTIVE To quantify the association of atele-ICU intervention with hospital mortality,length of stay, and complications that arepreventable by adherence to best practices.DESIGN, SETTING, AND PATIENTS Prospectivestepped-wedge clinical practice study of 6290adults admitted to any of 7 ICUs (3 medical, 3surgical, and 1 mixed cardiovascular) on 2campuses of an 834-bed academic medicalcenter that was performed from April 26, 2005,through September 30, 2007. Electronicallysupported and monitored processes for bestpractice adherence, care plan creation, and", "metadata": {}}
+{"_id": "39084565", "title": "", "text": "CD11b+ monocytes abrogate Th17 CD4+ Tcell-mediated experimental autoimmunemyocarditis.Experimental autoimmunemyocarditis (EAM) represents a Th17 Tcell-mediated mouse model of postinflammatoryheart disease. In BALB/c wild-type mice, EAM isa self-limiting disease, peaking 21 days afteralpha-myosin H chain peptide (MyHC-alpha)/CFAimmunization and largely resolving thereafter. InIFN-gammaR(-/-) mice, however, EAM isexacerbated and shows a chronic progressivedisease course. We found that this progressivedisease course paralleled persistently elevatedIL-17 release from T cells infiltrating the heartsof IFN-gammaR(-/-) mice 30 days afterimmunization. In fact, IL-17 promoted therecruitment of CD11b(+) monocytes, the majorheart-infiltrating cells in EAM. In turn, CD11b(+)monocytes suppressed MyHC-alpha-specific Th17T cell responses IFN-gamma-dependently invitro. In vivo, injection ofIFN-gammaR(+/+)CD11b(+), but not", "metadata": {}}
+{"_id": "39128592", "title": "", "text": "The cytokine RANKL produced by positivelyselected thymocytes fosters medullary thymicepithelial cells that express autoimmuneregulator.The thymic medulla provides amicroenvironment where medullary thymicepithelial cells (mTECs) express autoimmuneregulator and diverse tissue-restricted genes,contributing to launching self-tolerance. Positiveselection is essential for thymic medullaformation via a previously unknown mechanism.Here we show that the cytokine RANK ligand(RANKL) was produced by positively selectedthymocytes and regulated the cellularity of mTECby interacting with RANK and osteoprotegerin.Forced expression of RANKL restored thymicmedulla in mice lacking positive selection,whereas RANKL perturbation impaired medullaformation. These results indicate that RANKLproduced by positively selected thymocytes isresponsible for fostering thymic medullaformation, thereby establishing central tolerance.", "metadata": {}}
+{"_id": "39164524", "title": "", "text": "Fibrosis and adipogenesis originate from acommon mesenchymal progenitor in skeletalmuscle.Accumulation of adipocytes and collagentype-I-producing cells (fibrosis) is observed inmuscular dystrophies. The origin of these cellshad been largely unknown, but recently weidentified mesenchymal progenitors positive forplatelet-derived growth factor receptor alpha(PDGFRα) as the origin of adipocytes in skeletalmuscle. However, the origin of muscle fibrosisremains largely unknown. In this study, clonalanalyses show that PDGFRα(+) cells alsodifferentiate into collagen type-I-producing cells.In fact, PDGFRα(+) cells accumulated in fibroticareas of the diaphragm in the mdx mouse, amodel of Duchenne muscular dystrophy.Furthermore, mRNA of fibrosis markers wasexpressed exclusively in the PDGFRα(+) cellfraction in the mdx diaphragm. Importantly,TGF-β isoforms, known as potent profibroticcytokines, induced expression of markers offibrosis in PDGFRα(+) cells but not in myogenic", "metadata": {}}
+{"_id": "39174007", "title": "", "text": "The pecking order of free radicals andantioxidants: lipid peroxidation,alpha-tocopherol, and ascorbate.Free radicalsvary widely in their thermodynamic properties,ranging from very oxidizing to very reducing.These thermodynamic properties can be used topredict a pecking order, or hierarchy, for freeradical reactions. Using one-electron reductionpotentials, the predicted pecking order is inagreement with experimentally observed freeradical electron (hydrogen atom) transferreactions. These potentials are also in agreementwith experimental data that suggest that vitaminE, the primary lipid soluble small moleculeantioxidant, and vitamin C, the terminal watersoluble small molecule antioxidant, cooperate toprotect lipids and lipid structures againstperoxidation. Although vitamin E is located inmembranes and vitamin C is located in aqueousphases, vitamin C is able to recycle vitamin E;i.e., vitamin C repairs the tocopheroxyl(chromanoxyl) radical of vitamin E, thereby", "metadata": {}}
+{"_id": "39187170", "title": "", "text": "Mitochondrial respiration in subcutaneous andvisceral adipose tissue from patients with morbidobesity.Adipose tissue exerts importantendocrine and metabolic functions in health anddisease. Yet the bioenergetics of this tissue is notcharacterized in humans and possible regionaldifferences are not elucidated. Using highresolution respirometry, mitochondrialrespiration was quantified in human abdominalsubcutaneous and intra-abdominal visceral(omentum majus) adipose tissue from biopsiesobtained in 20 obese patients undergoingbariatric surgery. Mitochondrial DNA (mtDNA)and genomic DNA (gDNA) were determined bythe PCR technique for estimation ofmitochondrial density. Adipose tissue sampleswere permeabilized and respirometricmeasurements were performed in duplicate at 37degrees C. Substrates (glutamate (G) + malate(M) + octanoyl carnitine (O) + succinate (S))were added sequentially to provide electrons tocomplex I + II. ADP ((D)) for state 3 respiration", "metadata": {}}
+{"_id": "39225849", "title": "", "text": "Endogenous gamma-H2AX-ATM-Chk2 checkpointactivation in Bloom's syndrome helicase deficientcells is related to DNA replication arrestedforks.The Bloom syndrome helicase (BLM) iscritical for genomic stability. A defect in BLMactivity results in the cancer-predisposing Bloomsyndrome (BS). Here, we report thatBLM-deficient cell lines and primary fibroblastsdisplay an endogenously activated DNAdouble-strand break checkpoint response withprominent levels of phosphorylated histone H2AX(gamma-H2AX), Chk2 (p(T68)Chk2), and ATM(p(S1981)ATM) colocalizing in nuclear foci.Interestingly, the mitotic fraction ofgamma-H2AX foci did not seem to be higher inBLM-deficient cells, indicating that these lesionsform transiently during interphase. Pulse labelingwith iododeoxyuridine and immunofluorescencemicroscopy showed the colocalization ofgamma-H2AX, ATM, and Chk2 together withreplication foci. Those foci costained for Rad51,indicating homologous recombination at these", "metadata": {}}
+{"_id": "39264456", "title": "", "text": "Impact of TNF-alpha and IL-6 levels ondevelopment of cachexia in newly diagnosedNSCLC patients.OBJECTIVES We investigated therole of cytokines tumor necrosis factor-alpha(TNF-alpha) and interleukin-6 (IL-6) in cachexiadevelopment in newly diagnosed nonsmall celllung cancer (NSCLC) patients. METHODS : Weevaluated 44 (M/F:41/3) NSCLC patients and 12(M/F:10/2) age matched healthy smokers.NSCLC cases with a weight loss of > or =10%consisted the cachectic group (n:23, M/F:21/2)and the ones with <10% weight loss consistedthe noncachectic group (n:21, M/F:19/2).RESULTS Body mass index (BMI) of cachecticswas significantly lower than that of noncachectics(21.0 +/- 2.9 versus 24.5 +/- 3.6, P = 0.02) andcontrols (21.0 +/- 2.9 versus 25.5 +/- 2.6, P =0.01). Serum TNF-alpha level did not differbetween cachectic and noncachectics (37.3 +/-39.1 and 51.6 +/- 84.2 pg/mL, respectively).However, it was significantly higher in NSCLCpatients compared with controls (44.1 +/- 64.3", "metadata": {}}
+{"_id": "39281140", "title": "", "text": "Treatment of antidepressant-associated sexualdysfunction with sildenafil: a randomizedcontrolled trial.CONTEXT Sexual dysfunction is acommon adverse effect of antidepressants thatfrequently results in treatment noncompliance.OBJECTIVE To assess the efficacy of sildenafilcitrate in men with sexual dysfunction associatedwith the use of selective and nonselectiveserotonin reuptake inhibitor (SRI)antidepressants. DESIGN, SETTING, ANDPATIENTS Prospective, parallel-group,randomized, double-blind, placebo-controlledtrial conducted between November 1, 2000, andJanuary 1, 2001, at 3 US university medicalcenters among 90 male outpatients (mean [SD]age, 45 [8] years) with major depression inremission and sexual dysfunction associated withSRI antidepressant treatment. INTERVENTIONPatients were randomly assigned to takesildenafil (n = 45) or placebo (n = 45) at aflexible dose starting at 50 mg and adjustable to100 mg before sexual activity for 6 weeks. MAIN", "metadata": {}}
+{"_id": "39281166", "title": "", "text": "Noncoding transcription at enhancers: generalprinciples and functional models.Mammaliangenomes are extensively transcribed outside theborders of protein-coding genes. Genome-widestudies recently demonstrated that cis-regulatorygenomic elements implicated in transcriptionalcontrol, such as enhancers and locus-controlregions, represent major sites of extragenicnoncoding transcription. Enhancer-templatedtranscripts provide a quantitatively smallcontribution to the total amount of cellularnonribosomal RNA; nevertheless, the possibilitythat enhancer transcription and the resultingenhancer RNAs may, in some cases, havefunctional roles, rather than represent meretranscriptional noise at accessible genomicregions, is supported by an increasing amount ofexperimental data. In this article we review thecurrent knowledge on enhancer transcription andits functional implications.", "metadata": {}}
+{"_id": "39285547", "title": "", "text": "Microarray analysis of pneumococcal geneexpression during invasive disease.Streptococcuspneumoniae is a leading cause of invasivebacterial disease. This is the first study toexamine the expression of S. pneumoniae genesin vivo by using whole-genome microarraysavailable from The Institute for GenomicResearch. Total RNA was collected frompneumococci isolated from infected blood,infected cerebrospinal fluid, and bacteriaattached to a pharyngeal epithelial cell line invitro. Microarray analysis of pneumococcal genesexpressed in these models identified bodysite-specific patterns of expression for virulencefactors, transporters, transcription factors,translation-associated proteins, metabolism, andgenes with unknown function. Contributions tovirulence predicted for several unknown geneswith enhanced expression in vivo were confirmedby insertion duplication mutagenesis andchallenge of mice with the mutants. Finally, wecross-referenced our results with previous", "metadata": {}}
+{"_id": "39291138", "title": "", "text": "Integration of Smad and MAPK pathways: a linkand a linker revisited.Cells develop by readingmixed signals. Nowhere is this clearer than in thehighly dynamic processes that propelembryogenesis, when critical cell-fate decisionsare made swiftly in response to well-orchestratedgrowthfactor combinations. Learning how diversesignaling pathways are integrated is thereforeessential for understanding physiology. Thisrequires the identification, in tangible molecularterms, of key nodes for pathway integration thatoperate in vivo. A report in this issue, on theintegration of Smad and Ras/MAPK pathwaysduring neural induction (Pera et al. 2003),provides timely insights into the relevance of onesuch node. Pera et al. (2003) report that FGF8and IGF2—two growth factors that activate theRas/MAPK pathway— favor neural differentiationand mesoderm dorsalization in Xenopus byinhibiting BMP (Bone Morphogenetic Protein)signaling. Mesoderm is formed from ectoderm inresponse to Nodal-related signals from the", "metadata": {}}
+{"_id": "39300105", "title": "", "text": "A brief analysis of clinical pharmacy interventionsundertaken in an Australian teachinghospital.Selected clinical pharmacy interventionsundertaken during a 30-day data capture periodwere analysed, seeking to gain a greaterunderstanding of the nature of the drug-relatedproblems involved. Pharmacists were asked torecord only interventions that were of potentiallymajor significance. A total of 67 interventionswere submitted for analysis. In 28 cases (41.7%of the initial total) the intervention reports wereexcluded from further analysis after initialreview. For the remaining 39 interventions, 20patients (51%) were under the care of a medicalunit, and cardiovascular/antithrombotic agentsaccounted for 17 reports (43.5%). The majorityof interventions were implemented at the time ofinpatient medication order review by the clinicalpharmacist (n=25, 64%). The most commoncategory of drug-related problem addressed inthe interventions related to the prescription ofinappropriately high doses of the correct drug for", "metadata": {}}
+{"_id": "39304380", "title": "", "text": "Lethal complications oftyphoid-cholera-vaccination. (Case report andreview of the literature).Simultaneous parenteralvaccination against typhoid and cholera lead todeath through either anaphylactic shock orendotoxic shock in a 36-year-old male. Atautopsy the charactertic features of shock as wellas chronic interstitial myocarditis were noted.Moreover, fresh histiocytic and lymphocyticnodules were found in the liver, heart andmeninges. A review of the literature dealing withlethal complications following parenteral tyhoidvaccinations shows an increased risk indebilitated persons (emaciation, stress, cold).Most of the fatalities occurred in persons whohad previous disturbances of the cardiovascularsystem, as in the case reviewed here. Cardiacfailure, Landry's paralysis, renal failure anddisturbances of skin, joints and intestines mayalso follow typhoid vaccinations. However, theselatter complications are usually not lethal. Thepatients presented here had many of the", "metadata": {}}
+{"_id": "39326723", "title": "", "text": "Functional genomics and proteomics approachesto study the ERBB network in cancer.Substantialprogress in functional genomic and proteomictechnologies has opened new perspectives inbiomedical research. The sequence of the humangenome has been mostly determined and openednew visions on its complexity and regulation.New technologies, like RNAi and protein arrays,allow gathering knowledge beyond single geneanalysis. Increasingly, biological processes arestudied with systems biological approaches,where qualitative and quantitative data of thecomponents are utilized to model the respectiveprocesses, to predict effects of perturbations,and to then refine these models afterexperimental testing. Here, we describe thepotential of applying functional genomics andproteomics, taking the ERBB family ofgrowth-factor receptors as an example to studythe signaling network and its impact on cancer.", "metadata": {}}
+{"_id": "39334724", "title": "", "text": "Evaluation of spatial filters to create smoothedmaps of health data.Spatial filters have beenused as an easy and intuitive way to createsmoothed disease maps. Birth weight data fromNew York State for 1994 and 1995 are used tocompare the traditional filter type of fixedgeographical size with a filter size of constant ornearly constant population size. The latter aremore appropriate for mapping disease ingeographic areas with widely varying populationdensity, such as New York State. Issues such asthe choice of population size for the filter, thescale of smoothing, the ability to detect truespatial variation and the ability to smooth overrandom spatial noise are evaluated anddiscussed.", "metadata": {}}
+{"_id": "39368721", "title": "", "text": "Glucose tolerance and blood pressure: long termfollow up in middle aged men.OBJECTIVE toinvestigate the role of glucose tolerance in thedevelopment of hypertension. DESIGNRetrospective analysis of the results of a healthcheck up in a group of clinically healthy middleaged men in the late 1960s (median year 1968).The subjects were invited to enter into a primaryprevention trial for cardiovascular disease in1974, when they underwent clinical examinationfor risk factors. The trial was completed in 1979,when the men were re-examined. Follow up wasin 1986. SETTING Institute of OccupationalHealth, Helsinki, Finland and second departmentof medicine, University of Helsinki. SUBJECTS Inall, 3490 men born during 1919-34 participatedin a health check up in the late 1960s. In 1974,1815 of these men who were clinically healthywere entered into a primary prevention trial forcardiovascular disease. On clinical examination1222 of the men were considered at high risk ofcardiovascular disease. Of these, 612 received", "metadata": {}}
+{"_id": "39381118", "title": "", "text": "At the gates of death.Apoptosis that proceeds viathe mitochondrial pathway involvesmitochondrial outer membrane permeabilization(MOMP), responsible for the release ofcytochrome c and other proteins of themitochondrial intermembrane space. Thisessential step is controlled and mediated byproteins of the Bcl-2 family. The proapoptoticproteins Bax and Bak are required for MOMP,while the antiapoptotic Bcl-2 proteins, includingBcl-2, Bcl-xL, Mcl-1, and others, prevent MOMP.Different proapoptotic BH3-only proteins act tointerfere with the function of the antiapoptoticBcl-2 members and/or activate Bax and Bak.Here, we discuss an emerging view, proposed byCerto et al. in this issue of Cancer Cell, on howthese interactions result in MOMP and apoptosis.", "metadata": {}}
+{"_id": "39389082", "title": "", "text": "Structure of human RNase H1 complexed with anRNA/DNA hybrid: insight into HIV reversetranscription.We report here crystal structures ofhuman RNase H1 complexed with an RNA/DNAsubstrate. Unlike B. halodurans RNase H1,human RNase H1 has a basic protrusion, whichforms a DNA-binding channel and together withthe conserved phosphate-binding pocket confersspecificity for the B form and 2'-deoxy DNA. TheRNA strand is recognized by four consecutive2'-OH groups and cleaved by a two-metal ionmechanism. Although RNase H1 is overallpositively charged, the substrate interface isneutral to acidic in character, which likelycontributes to the catalytic specificity. Positionsof the scissile phosphate and two catalytic metalions are interdependent and highly coupled.Modeling of HIV reverse transcriptase (RT) withRNA/DNA in its RNase H active site suggests thatthe substrate cannot simultaneously occupy thepolymerase active site and must undergo aconformational change to toggle between the", "metadata": {}}
+{"_id": "39390206", "title": "", "text": "A diffusion tensor magnetic resonance imagingstudy of brain tissue from patients withmigraine.OBJECTIVE To measure in vivo, usingdiffusion tensor magnetic resonance imaging(DT-MRI) the extent of pathological damage ofnormal appearing brain tissue (NABT) frompatients with migraine. METHODS Dual echo andDT-MRI scans of the brain were acquired from 34patients with migraine and 17 sex and agematched healthy volunteers. Mean diffusivity(MD) and fractional anisotropy (FA) histogramsof the NABT were obtained from all subjects andthe histograms' peak heights and average NABTMD and FA measured. When present, averageMD and FA values of T2 visible lesions were alsomeasured. RESULTS In comparison with healthyvolunteers, patients with migraine had lower MDhistogram peak height (p=0.02) of the NABT. Nodifferences were found in FA histogram derivedmetrics between migraine patients and healthysubjects. No difference was found for any MDand FA histogram derived metrics between", "metadata": {}}
+{"_id": "39391953", "title": "", "text": "Determination of chloramphenicol residues inmilk by enzyme-linked immunosorbent assay:improvement by biotin-streptavidin-amplifiedsystem.A sensitive biotin-streptavidin amplifiedenzyme-linked immunosorbent assay (BA-ELISA)method was developed for the determination ofchloramphenicol residues in milk. Thebiotin-streptavidin system was applied toenhance the sensitivity. After optimization, thedetection limit of the method was found to be0.042 +/- 0.006 ng mL(-1), which is 8-fold moresensitive than the traditional competitive ELISAusing the same antibody and coating antigen.The amplification mechanism of thebiotin-streptavidin system and the major factorsaffecting the sensitivity of detection arediscussed. This method was successfully appliedto determine the chloramphenicol residues inmilk samples with a simple and rapid extractionprocedure, and good recoveries(85.66-109.67%) were obtained. The resultindicated that the biotin-streptavidin system may", "metadata": {}}
+{"_id": "39424916", "title": "", "text": "Wedelolactone exhibits anti-fibrotic effects onhuman hepatic stellate cell lineLX-2.Wedelolactone is a major coumarin ofEclipta prostrata, which is used for preventingliver damage. However the effects ofwedelolactone on hepatic fibrosis remainedunexplored. The purpose of this study was todemonstrate the anti-fibrotic effects ofwedelolactone on activated human hepaticstellate cell (HSC) line LX-2 and the possibleunderlying mechanisms by means of MTT assay,Hoechst staining, as well as real-timequantitative PCR and western blot. The resultsshowed that wedelolactone reduced the cellularviability of LX-2 in a time and dose-dependentmanner. After treatment of wedelolactone, theexpressions of collagen I and α-smooth muscleactin, two biomarkers of LX-2 activation, wereremarkably decreased. The apoptosis of LX-2cells was induced by wedelolactone accompaniedwith the decreasing expression of anti-apoptoticBcl-2 and increasing expression of pro-apoptotic", "metadata": {}}
+{"_id": "39426225", "title": "", "text": "Adipose stem cells originate from perivascularcells.Recent research has shown that adiposetissues contain abundant MSCs (mesenchymalstem cells). The origin and location of theadipose stem cells, however, remain unknown,presenting an obstacle to the further purificationand study of these cells. In the present study, weaimed at investigating the origins of adiposestem cells. α-SMA (α-smooth muscle actin) isone of the markers of pericytes. We harvestedASCs (adipose stromal cells) from α-SMA-GFP(green fluorescent protein) transgenic mice andsorted them into GFP-positive and GFP-negativecells by FACS. Multilineage differentiation testswere applied to examine the pluripotent ability ofthe α-SMA-GFP-positive and -negative cells.Immunofluorescent staining for α-SMA andPDGF-Rβ (platelet-derived growth factor receptorβ) were applied to identify theα-SMA-GFP-positive cells. Thenα-SMA-GFP-positive cells were loaded on acollagen-fibronectin gel with endothelial cells to", "metadata": {}}
+{"_id": "39443128", "title": "", "text": "Interferon alpha and zidovudine therapy in adultT-cell leukaemia lymphoma: response andoutcome in 15 patients.Adult T-cell leukaemialymphoma (ATLL) is an aggressive diseasecaused by the human T-lymphotropic virus 1(HTLV-I) with a short survival. Responses tointerferon alpha (IFN-alpha) and zidovudine(AZT) have been documented but not withlong-term follow-up. We treated 15 ATLLpatients with IFN and AZT. Eleven patients hadacute ATLL, two had lymphoma and twosmouldering ATLL, with progression. The mainfeatures were: organomegaly (14), skin lesions(10), high white blood cell (WBC) count (11) andhypercalcaemia (9). Eleven patients hadpreviously received chemotherapy and one hadreceived an autograft. At the time of the study,seven patients had progressive disease and eightwere in partial or complete clinical remission.Responses (PR) lasting 2+ to 44+ months wereseen in 67%; 26% did not respond (NR) and onepatient was not evaluable. Hypercalcaemia", "metadata": {}}
+{"_id": "39462488", "title": "", "text": "Replisome stalling and stabilization at CGGrepeats, which are responsible for chromosomalfragilityExpanded CGG repeats causechromosomal fragility and hereditaryneurological disorders in humans. Replicationforks stall at CGG repeats in a length-dependentmanner in primate cells and in yeast.Saccharomyces cerevisiae proteins Tof1 andMrc1 facilitate replication fork progressionthrough CGG repeats. Remarkably, thefork-stabilizing role of Mrc1 does not involve itscheckpoint function. Thus, chromosomal fragilitymight occur when forks stalled at expanded CGGrepeats escape the S-phase checkpoint.", "metadata": {}}
+{"_id": "39465575", "title": "", "text": "Direct reprogramming of fibroblasts into neuralstem cells by defined factors.Recent studies haveshown that defined sets of transcription factorscan directly reprogram differentiated somaticcells to a different differentiated cell type withoutpassing through a pluripotent state, but therestricted proliferative and lineage potential ofthe resulting cells limits the scope of theirpotential applications. Here we show that acombination of transcription factors(Brn4/Pou3f4, Sox2, Klf4, c-Myc, plus E47/Tcf3)induces mouse fibroblasts to directly acquire aneural stem cell identity-which we term asinduced neural stem cells (iNSCs). Directreprogramming of fibroblasts into iNSCs is agradual process in which the donortranscriptional program is silenced over time.iNSCs exhibit cell morphology, gene expression,epigenetic features, differentiation potential, andself-renewing capacity, as well as in vitro and invivo functionality similar to those of wild-typeNSCs. We conclude that differentiated cells can", "metadata": {}}
+{"_id": "39481265", "title": "", "text": "Epigenetics in lung fibrosis: from pathobiology totreatment perspective.PURPOSE OF REVIEWIdiopathic pulmonary fibrosis (IPF) is a fataldisease with limited treatment options andextensive gene expression changes identified inthe lung parenchyma. Multiple lines of evidencesuggest that epigenetic factors contribute todysregulation of gene expression in IPF lung.Most importantly, risk factors that predispose toIPF - age, sex, cigarette smoke, and geneticvariants - all influence epigenetic marks. Thisreview summarizes recent findings of associationof DNA methylation and histone modificationswith the presence of disease andfibroproliferation. RECENT FINDINGS In additionto targeted studies focused on specific gene loci,genome-wide profiles of DNA methylationdemonstrate widespread DNA methylationchanges in IPF lung tissue and a substantialeffect of these methylation changes on geneexpression. Genetic loci that have been recentlyassociated with IPF also contain differentially", "metadata": {}}
+{"_id": "39506601", "title": "", "text": "Novel roles for KLF1 in erythropoiesis revealedby mRNA-seq.KLF1 (formerly known as EKLF)regulates the development of erythroid cells frombi-potent progenitor cells via the transcriptionalactivation of a diverse set of genes. Mice lackingKlf1 die in utero prior to E15 from severe anemiadue to the inadequate expression of genescontrolling hemoglobin production, cellmembrane and cytoskeletal integrity, and thecell cycle. We have recently described the fullrepertoire of KLF1 binding sites in vivo byperforming KLF1 ChIP-seq in primary erythroidtissue (E14.5 fetal liver). Here we describe theKLF1-dependent erythroid transcriptome bycomparing mRNA-seq from Klf1(+/+) andKlf1(-/-) erythroid tissue. This has revealednovel target genes not previously obtainable bytraditional microarray technology, and providednovel insights into the function of KLF1 as atranscriptional activator. We define acis-regulatory module bound by KLF1, GATA1,TAL1, and EP300 that coordinates a core set of", "metadata": {}}
+{"_id": "39532074", "title": "", "text": "Self-assembling peptides optimize thepost-traumatic milieu and synergisticallyenhance the effects of neural stem cell therapyafter cervical spinal cord injury.INTRODUCTIONThe hostile environment after spinal cord injury(SCI) can compromise effects of regenerativetherapies. We hypothesized that optimizing thepost-traumatic environment with QL6self-assembling peptides (SAPs) before neuralprecursor cell (NPC) transplantation wouldimprove cell survival, differentiation andfunctional recovery. METHODS A total of 90Wistar rats received a clip-compression SCI atC7. Within each of two study arms, animals wererandomized into 5 groups (NPC, SAP, NPC+SAP,vehicle, and sham). SAPs and NPCs wereinjected into the spinal cord 1day and 14dayspost-injury, respectively. Animals receivedgrowth factors over 7days and wereimmunosuppressed. Rats were sacrificed at4weeks and sections of the cervical spinal cordprepared for immunohistochemistry (first study", "metadata": {}}
+{"_id": "39539647", "title": "", "text": "A direct role for IFN-gamma in regulation of Th1cell development.IL-12 has been identified as amajor cytokine influencing the differentiation ofCD4 cells to a Th1 phenotype, whereas a role forIFN-gamma is controversial. We investigated theinterrelationship between IL-12 and IFN-gammain promoting Th1 responses using naive CD4cells reactive with pigeon cytochrome c from TCRtransgenics and memory CD4 cells derived by invivo priming with KLH. Without exogenous rIL-12or rIFN-gamma, primary and memory effectorsinduced by Ag or anti-CD3 and anti-CD28secreted variable levels of IL-2 and IFN-gamma.The level of IFN-gamma secreted by effectorscorrelated with endogenous IFN-gammaproduced in primary cultures, andanti-IFN-gamma largely inhibited thedevelopment of effectors producing IFN-gamma.With optimal TCR stimulation and costimulation,endogenous IFN-gamma, without IL-12, wassufficient to elicit Th1 cells via an autocrinemechanism, whereas with suboptimal", "metadata": {}}
+{"_id": "39545358", "title": "", "text": "Neuregulin 1 promotes excitatory synapsedevelopment and function in GABAergicinterneurons.Neuregulin 1 (NRG1) and itsreceptor ErbB4 are both susceptibility genes ofschizophrenia. However, little is known about theunderlying mechanisms of their malfunction.Although ErbB4 is enriched in GABAergicinterneurons, the role of NRG1 in excitatorysynapse formation in these neurons remainspoorly understood. We showed that NRG1increased both the number and size of PSD-95puncta and the frequency and amplitude ofminiature EPSCs (mEPSCs) in GABAergicinterneurons, indicating that NRG1 stimulatesthe formation of new synapses and strengthensexisting synapses. In contrast, NRG1 treatmenthad no effect on either the number or size ofexcitatory synapses in glutamatergic neurons,suggesting its synaptogenic effect is specific toGABAergic interneurons. Ecto-ErbB4 treatmentdiminished both the number and size ofexcitatory synapses, suggesting that endogenous", "metadata": {}}
+{"_id": "39550665", "title": "", "text": "Tolerance rather than immunity protects fromHelicobacter pylori-induced gastricpreneoplasia.BACKGROUND & AIMS Chronicinfection with the bacterial pathogenHelicobacter pylori causes gastric disorders,ranging from chronic gastritis to gastricadenocarcinoma. Only a subset of infectedpersons will develop overt disease; most remainsasymptomatic despite lifelong colonization. Thisstudy aims to elucidate the differentialsusceptibility to H pylori that is found both acrossand within populations. METHODS We haveestablished a C57BL/6 mouse model of H pyloriinfection with a strain that is capable ofdelivering the virulence factorcytotoxin-associated gene A (CagA) into hostcells through the activity of a Cag-pathogenicityisland-encoded type IV secretion system.RESULTS Mice infected at 5-6 weeks of age withCagA(+)H pylori rapidly develop gastritis, gastricatrophy, epithelial hyperplasia, and metaplasia ina type IV secretion system-dependent manner.", "metadata": {}}
+{"_id": "39558597", "title": "", "text": "Impaired mitochondrial fatty acid oxidation andinsulin resistance in aging: novel protective roleof glutathione.Aging is associated with impairedfasted oxidation of nonesterified fatty acids(NEFA) suggesting a mitochondrial defect. Agingis also associated with deficiency of glutathione(GSH), an important mitochondrial antioxidant,and with insulin resistance. This study testedwhether GSH deficiency in aging contributes toimpaired mitochondrial NEFA oxidation andinsulin resistance, and whether GSH restorationreverses these defects. Three studies wereconducted: (i) in 82-week-old C57BL/6 mice, theeffect of naturally occurring GSH deficiency andits restoration on mitochondrial (13) C1-palmitate oxidation and glucose metabolism wascompared with 22-week-old C57BL/6 mice; (ii) in20-week C57BL/6 mice, the effect of GSHdepletion on mitochondrial oxidation of (13) C1-palmitate and glucose metabolism was studied;(iii) the effect of GSH deficiency and itsrestoration on fasted NEFA oxidation and insulin", "metadata": {}}
+{"_id": "39559521", "title": "", "text": "Control of central and peripheral tolerance byAire.The negative selection of self-reactivethymocytes depends on the expression oftissue-specific antigens by medullary thymicepithelial cells. The autoimmune regulator (Aire)protein plays an important role in turning onthese antigens, and the absence of even oneAire-induced tissue-specific antigen in thethymus can lead to autoimmunity in theantigen-expressing target organ. Recently, Aireprotein has been detected in peripheral lymphoidorgans, suggesting that peripheral Aire plays acomplementary role here. In these peripheralsites, Aire was found to regulate the expressionof a group of tissue-specific antigens that isdistinct from those expressed in the thymus.Furthermore, transgenic antigen expression inextrathymic Aire-expressing cells (eTACs) canmediate deletional tolerance, but theimmunological relevance of Aire-dependent,endogenous tissue-specific antigens remains tobe determined.", "metadata": {}}
+{"_id": "39571812", "title": "", "text": "Congenital Hypogonadotropic Hypogonadism: ATrait Shared by Several ComplexNeurodevelopmental Disorders.Reproductivefunction depends on the activity of thegonadotropic axis, which is controlled by ahypothalamic neural network whose mainfunction is to regulate the secretion ofgonadotropin-releasing hormone (GnRH). Thisendocrine network is not mature at birth, andseveral phases of activation-inactivation of thegonadotropic axis are necessary for its normaldevelopment. The postnatal maturation of theGnRH network lies under the control of aneurodevelopmental program that starts in fetallife and ends at puberty. There are many clinicalsituations in which this program is interrupted,leading to congenital hypogonadotropichypogonadism (CHH) and an absence of puberty.For many years, attention has mainly beenfocused on the genetics of isolated CHH. Morerecently, the emergence of new genomicstechniques has led to the description of genetic", "metadata": {}}
+{"_id": "39580129", "title": "", "text": "Elevated expression of miR-24-3p is a potentiallyadverse prognostic factor in colorectaladenocarcinoma.OBJECTIVES Several miRNAsare aberrantly expressed in cancer. miR-24-3p isinvolved in cancer-related cellular processes,including cell cycle control, cell growth,proliferation, and apoptosis. In this study, weexamined the potential diagnostic and prognosticsignificance of miR-24-3p expression incolorectal adenocarcinoma. DESIGN ANDMETHODS Total RNA was isolated from 182colorectal adenocarcinoma specimens and 86paired non-cancerous colorectal mucosae. Afterpolyadenylation of 2μg total RNA and reversetranscription into first-strand cDNA using anoligo-dT-adapter primer, miR-24-3p expressionwas quantified using an in-house-developedreverse-transcription real-time quantitative PCRmethod, based on the SYBR Green chemistry.SNORD43 (RNU43) was used as a referencegene. RESULTS miR-24-3p levels do notsignificantly differ between colorectal", "metadata": {}}
+{"_id": "39593548", "title": "", "text": "Reforming the health sector in developingcountries: the central role of policyanalysis.Policy analysis is an establisheddiscipline in the industrialized world, yet itsapplication to developing countries has beenlimited. The health sector in particular appears tohave been neglected. This is surprising becausethere is a well recognized crisis in healthsystems, and prescriptions abound of whathealth policy reforms countries should introduce.However, little attention has been paid to howcountries should carry out reforms, much lesswho is likely to favour or resist such policies. Thispaper argues that much health policy wronglyfocuses attention on the content of reform, andneglects the actors involved in policy reform (atthe international, national sub-national levels),the processes contingent on developing andimplementing change and the context withinwhich policy is developed. Focus on policycontent diverts attention from understanding theprocesses which explain why desired policy", "metadata": {}}
+{"_id": "39637840", "title": "", "text": "The processing of Holliday junctions by BLM andWRN helicases is regulated by p53.BLM, WRN,and p53 are involved in the homologous DNArecombination pathway. The DNAstructure-specific helicases, BLM and WRN,unwind Holliday junctions (HJ), an activity thatcould suppress inappropriate homologousrecombination during DNA replication. Here, weshow that purified, recombinant p53 binds toBLM and WRN helicases and attenuates theirability to unwind synthetic HJ in vitro. The p53248W mutant reduces abilities of both to bind HJand inhibit helicase activities, whereas the p53273H mutant loses these abilities. Moreover,full-length p53 and a C-terminal polypeptide(residues 373-383) inhibit the BLM and WRNhelicase activities, but phosphorylation atSer(376) or Ser(378) completely abolishes thisinhibition. Following blockage of DNA replication,Ser(15) phospho-p53, BLM, and RAD51colocalize in nuclear foci at sites likely to containDNA replication intermediates in cells. Our", "metadata": {}}
+{"_id": "39652608", "title": "", "text": "Trim and fill: A simple funnel-plot-based methodof testing and adjusting for publication bias inmeta-analysis.We study recently developednonparametric methods for estimating thenumber of missing studies that might exist in ameta-analysis and the effect that these studiesmight have had on its outcome. These are simplerank-based data augmentation techniques, whichformalize the use of funnel plots. We show thatthey provide effective and relatively powerfultests for evaluating the existence of suchpublication bias. After adjusting for missingstudies, we find that the point estimate of theoverall effect size is approximately correct andcoverage of the effect size confidence intervals issubstantially improved, in many cases recoveringthe nominal confidence levels entirely. Weillustrate the trim and fill method on existingmeta-analyses of studies in clinical trials andpsychometrics.", "metadata": {}}
+{"_id": "39661951", "title": "", "text": "Familial Barrett's esophagus associated withadenocarcinoma.A family with six cases ofBarrett's esophagus over three generations isdescribed. The Barrett's esophagus affected onlymales, and there were three associatedadenocarcinomas. The mechanism of inheritanceis compatible with an autosomal dominantpattern with nearly complete penetrance. Othercase reports in the literature are compared withthis familial case of Barrett's esophagus withassociated adenocarcinomas.", "metadata": {}}
+{"_id": "39668245", "title": "", "text": "Development of an insect model for the in vivopathogenicity testing of yeasts.Conventional invivo assays to determine the relativepathogenicity of yeast isolates rely upon the useof a range of mammalian species. The purpose ofthe work presented here was to investigate thepossibility of using an insect (Galleria mellonella)as a model system for in vivo pathogenicitytesting. The haemolymph of G. mellonella larvaewas inoculated with PBS containing differentconcentrations of stationary phase yeasts of thegenus Candida by injection at the last pro-leg.Larvae were incubated at 30 degrees C andmonitored over 72 hours. Results indicate that G.mellonella can be killed by the pathogenic yeastCandida albicans and by a range of otherCandida species but not to a significant extent bythe yeast Saccharomyces cerevisiae. The killkinetics for larvae inoculated with clinical andlaboratory isolates of C. albicans indicate theformer class of isolates to be more pathogenic.Differences in the relative pathogenicity of a", "metadata": {}}
+{"_id": "39728826", "title": "", "text": "Use of TLS parameters to model anisotropicdisplacements in macromolecular refinement.Anessential step in macromolecular refinement isthe selection of model parameters which give asgood a description of the experimental data aspossible while retaining a realisticdata-to-parameter ratio. This is particularly trueof the choice of atomic displacement parameters,where the move from individual isotropic toindividual anisotropic refinement involves asixfold increase in the number of requireddisplacement parameters. The number ofrefinement parameters can be reduced by usingcollective variables rather than independentatomic variables and one of the simplestexamples of this is the TLS parameterization fordescribing the translation, libration andscrew-rotation displacements of a pseudo-rigidbody. This article describes the implementationof the TLS parameterization in themacromolecular refinement program REFMAC.Derivatives of the residual with respect to the", "metadata": {}}
+{"_id": "39729277", "title": "", "text": "Sequence features surrounding the translationinitiation sites assigned on the genome sequenceof Synechocystis sp. strain PCC6803 byamino-terminal protein sequencing.Tocharacterize the sequence features surroundingthe translation initiation sites on the genome ofSynechocystis sp. strain 6803, the total proteinsextracted from the cell were resolved bytwo-dimensional electrophoresis, and theamino-terminal sequences of the relativelyabundant protein spots were determined. Bycomparison of the determined amino-terminalsequences with the nucleotide sequence of theentire genome, the translation initiation sites of atotal of 72 proteins were successfully assignedon the genome. The sequence features emergedfrom the nucleotide sequences at andsurrounding the translation initiation sites wereas follows: (1) In addition to the three initiationcodons, ATG, GTG, and TTG, evidence wasobtained that ATT was also used as a rareinitiation codon; (2) the core sequences (GAGG,", "metadata": {}}
+{"_id": "39758684", "title": "", "text": "Deregulated DNA polymerase beta induceschromosome instability and tumorigenesis.Toreach the biological alterations that characterizecancer, the genome of tumor cells must acquireincreased mutability resulting from a malfunctionof a network of genome stability systems, e.g.,cell cycle arrest, DNA repair, and high accuracyof DNA synthesis during DNA replication.Numeric chromosomal imbalance, referred to asaneuploidy, is the most prevalent geneticchanges recorded among many types of solidtumors. We report here that ectopic expressionin cells of DNA polymerase beta, an error-proneenzyme frequently over-regulated in humantumors, induces aneuploidy, an abnormallocalization of the centrosome-associatedgamma-tubulin protein during mitosis, adeficient mitotic checkpoint, and promotestumorigenesis in nude immunodeficient mice.Thus, we find that alteration of polymerase betaexpression appears to induce major geneticchanges associated with a malignant phenotype.", "metadata": {}}
+{"_id": "39763465", "title": "", "text": "Combinatorial signaling by Sonic hedgehog andWnt family members induces myogenic bHLHgene expression in the somite.We havedemonstrated previously that a combination ofsignals from the neural tube and the floorplate/notochord complex synergistically inducethe expression of myogenic bHLH genes andmyogenic differentiation markers in unspecifiedsomites. In this study we demonstrate that Sonichedgehog (Shh), which is expressed in the floorplate/notochord, and a subset of Wnt familymembers (Wnt-1, Wnt-3, and Wnt-4), which areexpressed in dorsal regions of the neural tube,mimic the muscle inducing activity of thesetissues. In combination, Shh and either Wnt-1 orWnt-3 are sufficient to induce myogenesis insomitic tissue in vitro. Therefore, we proposethat myotome formation in vivo may be directedby the combinatorial activity of Shh secreted byventral midline tissues (floor plate andnotochord) and Wnt ligands secreted by thedorsal neural tube.", "metadata": {}}
+{"_id": "39776978", "title": "", "text": "Advances in osteoclast biology: old findings andnew insights from mouse modelsThemaintenance of adequate bone mass isdependent upon the controlled and timelyremoval of old, damaged bone. This complexprocess is performed by the highly specialized,multinucleated osteoclast. Over the past 15years, a detailed picture has emerged describingthe origins, differentiation pathways andactivation stages that contribute to normalosteoclast function. This information hasprimarily been obtained by the development andskeletal analysis of genetically modified mousemodels. Mice harboring mutations in specificgenetic loci exhibit bone defects as a direct resultof aberrations in normal osteoclast recruitment,formation or function. These findings include theidentification of the RANK–RANKL–OPG systemas a primary mediator of osteoclastogenesis, thecharacterization of ion transport and cellularattachment mechanisms and the recognition thatmatrix-degrading enzymes are essential", "metadata": {}}
+{"_id": "39801095", "title": "", "text": "DNA methylation in embryonic stemcells.Embryonic stem cells (ESCs) arepluripotent, self-renewing cells. These cells canbe used in applications such as cell therapy, drugdevelopment, disease modeling, and the study ofcellular differentiation. Investigating theinterplay of epigenetics, genetics, and geneexpression in control of pluripotence anddifferentiation could give important insights onhow these cells function. One of the best knownepigenetic factors is DNA methylation, which is amajor mechanism for regulation of geneexpression. This phenomenon is mostly seen inimprinted genes and X-chromosome inactivationwhere DNA methylation of promoter regionsleads to repression of gene expression.Differential DNA methylation ofpluripotence-associated genes such as Nanogand Oct4/Pou5f1 has been observed betweenpluripotent and differentiated cells. It is clearthat tight regulation of DNA methylation isnecessary for normal development. As more", "metadata": {}}
+{"_id": "39851630", "title": "", "text": "Reserves, functional, immunoregulatory, andcytogenetic properties of bone marrowmesenchymal stem cells in patients withmyelodysplastic syndromes.Defectivehematopoiesis supporting capacity of bonemarrow (BM) stroma has been implicated in thepathophysiology of myelodysplastic syndromes(MDS). The aim of this study is to explorewhether the BM stroma progenitors, namely themesenchymal stem cells (MSCs), are primarilyaffected in MDS by evaluating the reserves, thefunctional properties, as well as the cytogeneticcharacteristics, in comparison to BMhematopoietic cells, in patients with de novoMDS (n = 13). The number, differentiationpotential towardadipocytes/chondrocytes/osteoblasts andimmunosuppressive function in terms ofinhibition of mitogen-induced T-cell proliferationdid not differ significantly between patient andnormal (n = 20) MSCs. Patient MSCs did notshow any aberrations in the production of", "metadata": {}}
+{"_id": "39859981", "title": "", "text": "Symmetric signalling within asymmetric dimersof the Staphylococcus aureus receptor histidinekinase AgrC.Virulence in Staphylococcus aureusis largely under control of the accessory generegulator (agr) quorum-sensing system. TheAgrC receptor histidine kinase detects itsautoinducing peptide (AIP) ligand and generatesan intracellular signal resulting in secretion ofvirulence factors. Although agr is a well-studiedquorum-sensing system, little is known about themechanism of AgrC activation. Byco-immunoprecipitation analysis andintermolecular complementation of receptormutants, we showed that AgrC formsligand-independent dimers that undergotrans-autophosphorylation upon interaction withAIP. Remarkably, addition of specific AIPs toAgrC mutant dimers with only one functionalsensor domain caused symmetric activation ofeither kinase domain despite the sensorasymmetry. Furthermore, mutant dimersinvolving one constitutive protomer", "metadata": {}}
+{"_id": "39863735", "title": "", "text": "Attachment of the ubiquitin-related proteinUrm1p to the antioxidant protein Ahp1p.Urm1pis a ubiquitin-related protein that serves as aposttranslational modification of other proteins.Urm1p conjugation has been implicated in thebudding process and in nutrient sensing. Here,we have identified the first in vivo target for theurmylation pathway as the antioxidant proteinAhp1p. The attachment of Urm1p to Ahp1prequires the E1 for the urmylation pathway,Uba4p. Loss of the urmylation pathwaycomponents results in sensitivity to athiol-specific oxidant, as does loss of Ahp1p,implying that urmylation has a role in anoxidative-stress response. Moreover, treatmentof cells with thiol-specific oxidants affects theabundance of Ahp1p-Urm1p conjugates. Theseresults suggest that the conjugation of Urm1p toAhp1p could regulate the function of Ahp1p inantioxidant stress response in Saccharomycescerevisiae.", "metadata": {}}
+{"_id": "39892135", "title": "", "text": "Sulfasalazine in the treatment ofspondylarthropathy. A randomized, multicenter,double-blind, placebo-controlledstudy.OBJECTIVE To assess the efficacy andtolerability of sulfasalazine (SSZ) in thetreatment of spondylarthropathy. METHODS Weconducted a 6-month randomized,placebo-controlled, double-blind, multicenterstudy of patients with spondylarthropathy whosedisease had remained active despite treatmentwith nonsteroidal antiinflammatory drugs.Patients were treated with SSZ (3 gm/day) orplacebo. The primary efficacy variables were thephysician's and patient's overall assessments,pain, and morning stiffness. End points wereanalyzed in the intent-to-treat and completerpatient populations; the time course of effectwas analyzed in the completer patientpopulation. RESULTS Of the 351 patientsenrolled, 263 (75%) completed the 6-monthtreatment period. The withdrawal rates were 35(20%) and 53 (30%) in the placebo and SSZ", "metadata": {}}
+{"_id": "39903312", "title": "", "text": "A randomized trial of aspirin to prevent colorectaladenomas in patients with previous colorectalcancer.BACKGROUND Experimental studies inanimals and observational studies in humanssuggest that regular aspirin use may decreasethe risk of colorectal adenomas, the precursorsto most colorectal cancers. METHODS Weconducted a randomized, double-blind trial todetermine the effect of aspirin on the incidenceof colorectal adenomas. We randomly assigned635 patients with previous colorectal cancer toreceive either 325 mg of aspirin per day orplacebo. We determined the proportion ofpatients with adenomas, the number of recurrentadenomas, and the time to the development ofadenoma between randomization andsubsequent colonoscopic examinations. Relativerisks were adjusted for age, sex, cancer stage,the number of colonoscopic examinations, andthe time to a first colonoscopy. The study wasterminated early by an independent data andsafety monitoring board when statistically", "metadata": {}}
+{"_id": "39929509", "title": "", "text": "The Wilms tumour suppressor protein WT1(+KTS isoform) binds alpha-actinin 1 mRNA viaits zinc-finger domain.Mutations in WT1 areassociated with developmental syndromes thataffect the urogenital system and neoplasms,including Wilms tumour, acute myeloid leukemia,and breast and prostate cancers. The WT1protein belongs to the early growth responsefamily of zinc-finger transcription factors.Uniquely to WT1, an evolutionarily conservedalternative splice event inserts the tripeptideKTS, between zinc fingers 3 and 4. Whereas-KTS isoforms bind DNA and activate or represstranscription, +KTS isoforms bind DNA lessefficiently and interact with splice factors andRNA in vitro and in vivo. Although candidate DNAtargets have been found, physiological mRNAtargets are yet to be defined. We examined thedistribution of WT1 in ribonucleoprotein (RNP)complexes in nuclear extract prepared from M15cells, a mouse mesonephric fetal kidney cell line.WT1 cofractionated with the splice factor PSF in", "metadata": {}}
+{"_id": "39970500", "title": "", "text": "How safe are psychiatric medications after avoluntary overdose?PURPOSE This studyassessed psychiatric medications and theirpotential lethality in a representative sample ofsuicide attempts. MATERIALS AND METHODSDuring 1996-98, 563 suicide attempts werestudied in a general hospital in Madrid (Spain).Medication overdose was used in 456 suicideattempts (81%). The ratio between dose takenand maximum prescription dose recommendedwas used to evaluate the medication toxicity.RESULTS Benzodiazepines were the drugs mostoften used in self-poisoning (65% of overdoses),followed by new antidepressants (11%), tricyclicantidepressants (TCAs) (10%), andantipsychotics (8%). An overdose with any of thethree latter psychiatric medications wassignificantly more frequent in patients prescribedthose medications. The overdoses for TCA werepotentially lethal in 47% of the cases. However,all patients who overdosed on psychiatricmedications recovered well and were discharged", "metadata": {}}
+{"_id": "39984099", "title": "", "text": "Health benefits, costs, and cost-effectiveness ofearlier eligibility for adult antiretroviral therapyand expanded treatment coverage: a combinedanalysis of 12 mathematicalmodels.BACKGROUND New WHO guidelinesrecommend ART initiation for HIV-positivepersons with CD4 cell counts ≤500 cells/µL, ahigher threshold than was previouslyrecommended. Country decision makers mustconsider whether to further expand ARTeligibility accordingly. METHODS We usedmultiple independent mathematical models infour settings-South Africa, Zambia, India, andVietnam-to evaluate the potential health impact,costs, and cost-effectiveness of different adultART eligibility criteria under scenarios of currentand expanded treatment coverage, with resultsprojected over 20 years. Analyses consideredextending eligibility to include individuals withCD4 ≤500 cells/µL or all HIV-positive adults,compared to the previous recommendation ofinitiation with CD4 ≤350 cells/µL. We assessed", "metadata": {}}
+{"_id": "39985001", "title": "", "text": "Chronic daily headache: long-term prognosisfollowing inpatient treatment with repetitive IVDHE.We retrospectively studied the long-term(2-year) outcome of 50 consecutive patientsadmitted to our inpatient headache programbecause of chronic daily headache (CDH)associated with the overuse of analgesics,ergotamine, or both. They had been detoxified,given repetitive intravenous dihydroergotamine(IV DHE) and prophylactic medications as part ofthe program, and had become headache-free onthis regimen. At the time of admission, 37 of the50 patients had transformed migraine (TM), 12had new daily persistent headache (NDPH), and1 had chronic tension-type headache; 29 of thepatients with TM, 7 of those with NDPH, and thesingle patient with chronic tension-typeheadache had coexistent migraine. Substancesabused, alone or in combination, included:caffeine in 39 patients (av. 441 mg/d),acetaminophen in 32 (av. 2187 mg/d), aspirin in24 (av. 1807 mg/d), ibuprofen in 9 (av. 1156", "metadata": {}}
+{"_id": "40005757", "title": "", "text": "Survival in a case of massive paraquatingestion.Serious exposure to the herbicideparaquat usually results in death, either due togastrointestinal caustic lesions, shock, and acuterespiratory distress syndrome or related to theprogressive development of pulmonary fibrosisassociated with refractory hypoxemia. We reporta case of suicidal paraquat ingestion in a59-year-old man. Most of the indicators of poorprognosis were encountered in this patient.Treatment consisted of early digestivedecontamination and hemodialysis, followed byantioxidant therapy, including the administrationof deferoxamine (100 mg/kg in 24 h) and acontinuous infusion of acetylcysteine (300mg/kg/d during 3 weeks). The patient onlydeveloped a nonoliguric acute renal failure, amild alteration of liver tests, and an impairmentof CO transfer factor without any respiratorycomplaint. Renal and hepatic disturbancescompletely resolved within 1 month, whereas COtransfer factor remained altered 14 months later.", "metadata": {}}
+{"_id": "40044800", "title": "", "text": "Cyclic GMP-AMP synthase is a cytosolic DNAsensor that activates the type I interferonpathway.The presence of DNA in the cytoplasmof mammalian cells is a danger signal thattriggers host immune responses such as theproduction of type I interferons. Cytosolic DNAinduces interferons through the production ofcyclic guanosine monophosphate-adenosinemonophosphate (cyclic GMP-AMP, or cGAMP),which binds to and activates the adaptor proteinSTING. Through biochemical fractionation andquantitative mass spectrometry, we identified acGAMP synthase (cGAS), which belongs to thenucleotidyltransferase family. Overexpression ofcGAS activated the transcription factor IRF3 andinduced interferon-β in a STING-dependentmanner. Knockdown of cGAS inhibited IRF3activation and interferon-β induction by DNAtransfection or DNA virus infection. cGAS boundto DNA in the cytoplasm and catalyzed cGAMPsynthesis. These results indicate that cGAS is acytosolic DNA sensor that induces interferons by", "metadata": {}}
+{"_id": "40078758", "title": "", "text": "Eating pathology, emotion regulation, andemotional overeating in obese adults with BingeEating Disorder.OBJECTIVE The purpose of thecurrent study was to examine the relationshipamong emotional regulation, emotionalovereating, and general eating pathology in atreatment seeking sample of adults with BingeEating Disorder (BED). METHOD The sample wascomposed of 326 adults (248 women, 78 men)who were obese and met DSM-IV-TR criteria forBED. Prior to treatment, participants completedthe Difficulties in Emotion Regulation Scale(DERS), Emotional Overeating Questionnaire(EOQ), Beck Depression Inventory (BDI), andEating Disorder Examination-Questionnaire(EDE-Q) as part of a larger assessment battery.RESULTS A series of hierarchical regressionanalyses indicated that difficulties with emotionregulation accounted for unique variance in bothemotional overeating and general eatingpathology above and beyond sex and negativeaffect. DISCUSSION Emotion regulation may", "metadata": {}}
+{"_id": "40087494", "title": "", "text": "Monoallelic expression and methylation ofimprinted genes in human and mouse embryonicgerm cell lineages.Imprinting is an epigeneticmodification leading to monoallelic expression ofsome genes, and disrupted imprinting is believedto be a barrier to human stem celltransplantation, based on studies that suggestthat epigenetic marks are unstable in mouseembryonic germ (EG) and embryonic stem (ES)cells. However, stem cell imprinting has notpreviously been examined directly in humans.We found that three imprinted genes, TSSC5,H19, and SNRPN, show monoallelic expression inin vitro differentiated human EG-derived cells,and a fourth gene, IGF2, shows partially relaxedimprinting at a ratio from 4:1 to 5:1, comparableto that found in normal somatic cells. In addition,we found normal methylation of an imprintingcontrol region (ICR) that regulates H19 and IGF2imprinting, suggesting that imprinting may notbe a significant epigenetic barrier to human EGcell transplantation. Finally, we were able to", "metadata": {}}
+{"_id": "40090058", "title": "", "text": "Functional in vivo interactions between JNK1 andJNK2 isoforms in obesity and insulinresistance.The c-Jun N-terminal kinases (JNKs)are key regulators of inflammation and interferewith insulin action in cultured cells and wholeanimals. Obesity increases total JNK activity, andJNK1, but not JNK2, deficiency results in reducedadiposity and improved insulin sensitivity.Interestingly, a higher-than-normal level of JNKactivation is observed in Jnk2(-/-) mice,particularly in the liver, indicating an interactionbetween the isoforms that might have maskedthe metabolic activity of JNK2 in isolated mutantmice. To address the role of the JNK2 isoform inmetabolic homeostasis, we intercrossedJnk1(-/-) and Jnk2(-/-) mice and examined bodyweight and glucose metabolism in the resultingmutant allele combinations. Among all of theviable genotypes examined, we observed onlyreduced body weight and increased insulinsensitivity in Jnk1(-/-) and Jnk1(+/-)Jnk2(-/-)mice. These two groups of mice also exhibited", "metadata": {}}
+{"_id": "40094786", "title": "", "text": "The immunological synapse of CTL contains asecretory domain and membranebridges.Cytotoxic T lymphocytes (CTL) rapidlydestroy their targets. Here we show thatalthough target cell death occurs within 5 min ofCTL-target cell contact, an immunologicalsynapse similar to that seen in CD4 cells rapidlyforms in CTL, with a ring of adhesion proteinssurrounding an inner signaling molecule domain.Lytic granule secretion occurs in a separatedomain within the adhesion ring, maintainingsignaling protein organization during exocytosis.Live and fixed cell studies show target cellplasma membrane markers are transferred tothe CTL as the cells separate. Electronmicroscopy reveals continuities formingmembrane bridges between the CTL and targetcell membranes, suggesting a possiblemechanism for this transfer.", "metadata": {}}
+{"_id": "40096222", "title": "", "text": "Compromised intestinal epithelial barrier inducesadaptive immune compensation that protectsfrom colitis.Mice lacking junctional adhesionmolecule A (JAM-A, encoded by F11r) exhibitenhanced intestinal epithelial permeability,bacterial translocation, and elevated coloniclymphocyte numbers, yet do not develop colitis.To investigate the contribution of adaptiveimmune compensation in response to increasedintestinal epithelial permeability, we examinedthe susceptibility of F11r(-/-)Rag1(-/-) mice toacute colitis. Although negligible contributions ofadaptive immunity in F11r(+/+)Rag1(-/-) micewere observed, F11r(-/-)Rag1(-/-) miceexhibited increased microflora-dependent colitis.Elimination of T cell subsets and cytokineanalyses revealed a protective role forTGF-β-producing CD4(+) T cells in F11r(-/-)mice. Additionally, loss of JAM-A resulted inelevated mucosal and serum IgA that wasdependent upon CD4(+) T cells and TGF-β.Absence of IgA in F11r(+/+)Igha(-/-) mice did", "metadata": {}}
+{"_id": "40127292", "title": "", "text": "Apoptosis and chemoresistance in transgeniccancer modelsMultidrug resistance remains anunresolved problem in clinical oncology. Over adecade ago genes encoding cellular efflux pumpswere shown to confer resistance to a broadspectrum of biochemically unrelated anticancerdrugs even before the compounds reached theirintracellular targets. More recently it has becomeapparent that many drugs induce a commonapoptotic program, such that mutations in thisprogram can also produce multidrug resistance.However, a thorough evaluation of thecontribution of apoptotic defects to this\"postdamage\" drug resistant phenotype istechnically complicated, and this has led touncertainty about the overall significance ofapoptosis in therapy-induced cell death. Forexample, correlative analyses using patientspecimens are limited by unknown backgroundmutations in the biopsy material, and assaysusing cancer cell lines can be biased byunphysiological conditions. We sought to", "metadata": {}}
+{"_id": "40145839", "title": "", "text": "NC-100717: a versatile RGD peptide scaffold forangiogenesis imaging.Targeting the molecularpathways associated with angiogenesis offersgreat potential in detecting disease pathologyusing in vivo imaging technologies. Initiation ofangiogenesis requires activation and migration ofendothelial cells in order for neovascularizationto proceed. Endothelial cells associate with theextracellular matrix through specific interactionswith a variety of cell adhesion receptors knownas integrins. Peptides containing the tripeptidesequence RGD are known to bind with highaffinity to the alphavbeta3 and alphavbeta5integrins associated with angiogenesis. Wepresent herein the synthesis and in vitro bindingaffinity of the RGD-containing peptideNC-100717 and a range of molecular probesderived from this intermediate.", "metadata": {}}
+{"_id": "40156901", "title": "", "text": "Dose-dependent effect of statins on theincidence of acute kidney injury after cardiacsurgery.BACKGROUND Acute kidney injury (AKI)after cardiac surgery is associated with increasedmorbidity and mortality. METHODS We assessedwhether statin treatment is associated with alower incidence of postoperative AKI in 2,104consecutive patients who underwent coronaryartery bypass graft or valve surgery at theMinneapolis Veterans Administration MedicalCenter. Acute kidney injury was defined asabsolute increase greater than 0.3 mg/dL orrelative increase greater than 50% in serumcreatinine from baseline, within 48 hours aftersurgery or requiring postoperative hemodialysisper AKI network. Propensity scores were utilizedto adjust for the differences between the statinand the no-statin treatment groups. All statinswere converted to equivalent-dose simvastatinand divided at the median to construct high-dose(≥40 mg) and low-dose (<40 mg) statin groups.RESULTS Of the 2,104 patients, 1,435 (68%)", "metadata": {}}
+{"_id": "40164383", "title": "", "text": "Comparison of allogeneic vs autologous bonemarrow–derived mesenchymal stem cellsdelivered by transendocardial injection inpatients with ischemic cardiomyopathy: thePOSEIDON randomized trial.CONTEXTMesenchymal stem cells (MSCs) are underevaluation as a therapy for ischemiccardiomyopathy (ICM). Both autologous andallogeneic MSC therapies are possible; however,their safety and efficacy have not beencompared. OBJECTIVE To test whether allogeneicMSCs are as safe and effective as autologousMSCs in patients with left ventricular (LV)dysfunction due to ICM. DESIGN, SETTING, ANDPATIENTS A phase 1/2 randomized comparison(POSEIDON study) in a US tertiary-care referralhospital of allogeneic and autologous MSCs in 30patients with LV dysfunction due to ICM betweenApril 2, 2010, and September 14, 2011, with13-month follow-up. INTERVENTION Twentymillion, 100 million, or 200 million cells (5patients in each cell type per dose level) were", "metadata": {}}
+{"_id": "40212412", "title": "", "text": "Periosteal bone formation--a neglecteddeterminant of bone strength.Life forms thathave low body mass can hunt for food on theundersurface of branches or along shear clifffaces quite unperturbed by gravity. For largeranimals, the hunt for dinner and the struggle toavoid becoming someone else's meal requirerapid movement against gravity. This need ismet by the lever function of long bones,three-dimensional masterpieces of biomechanicalengineering that, by their material compositionand structural design, achieve the contradictoryproperties of stiffness and flexibility, strengthand lightness.1 Material stiffness results from theencrusting of the triple-helical structure ofcollagen type I with hydroxyapatite crystals,which confers . . .", "metadata": {}}
+{"_id": "40232172", "title": "", "text": "Triglyceride depletion of brown adipose tissueenables analysis of mitochondrial respiratoryfunction in permeabilized biopsies.The researchon mitochondrial functions in adipocytes hasincreasingly evidenced that mitochondria playsan important role in the onset and/or progressionof obesity and related pathologies. Mitochondrialfunction in brown adipose tissue (BAT) has beenclassically assessed by measuring either thelevels/activity of mitochondrial enzymes, or therespiration in isolated mitochondria. Isolation ofmitochondria is not advantageous because itdemands significant time and amount of tissueand, as tissue homogenates, disruptsbiochemical and physical connections ofmitochondria within the cell. Here, we describeda new and efficient protocol to analyze themitochondrial respiratory states in BAT biopsiesthat relies on intracellular triglyceride depletionfollowed by tissue permeabilization. In additionto minimizing tissue requirements to \u000017 mgwet weight, the proposed protocol enabled", "metadata": {}}
+{"_id": "40234452", "title": "", "text": "HES-1 preserves purified hematopoietic stemcells ex vivo and accumulates side populationcells in vivo.Mouse long-term hematopoieticreconstituting cells exist in the c-Kit+Sca-1+Lin-(KSL) cell population; among them, CD34(low/-)cells represent the most highly purifiedpopulation of hematopoietic stem cells in theadult bone marrow. Here, we demonstrate thatretrovirus-mediated transduction ofCD34(low/-)c-Kit+Sca-1+Lin- (34-KSL) cellswith the HES-1 gene, which encodes a basichelix-loop-helix transcription factor functioningdownstream of the Notch receptor, and is a keymolecule for the growth phase of neural stemcells in the embryo, preserves the long-termreconstituting activity of these cells in vitro. Wealso show that cells derived from theHES-1-transduced 34-KSL population produceprogenies characterized by negative Hoechst dyestaining, which defines the side population, andby CD34(low/-) profile in the bone marrow KSLpopulation in each recipient mouse at ratios 3.5-", "metadata": {}}
+{"_id": "40254495", "title": "", "text": "Measuring Absolute RNA Copy Numbers at HighTemporal Resolution Reveals TranscriptomeKinetics in Development.Transcript regulation isessential for cell function, and misregulation canlead to disease. Despite technologies to surveythe transcriptome, we lack a comprehensiveunderstanding of transcript kinetics, which limitsquantitative biology. This is an acute challenge inembryonic development, where rapid changes ingene expression dictate cell fate decisions. Byultra-high-frequency sampling of Xenopusembryos and absolute normalization of sequencereads, we present smooth gene expressiontrajectories in absolute transcript numbers.During a developmental period approximatingthe first 8 weeks of human gestation, transcriptkinetics vary by eight orders of magnitude.Ordering genes by expression dynamics, we findthat \"temporal synexpression\" predicts commongene function. Remarkably, a single parameter,the characteristic timescale, can classifytranscript kinetics globally and distinguish genes", "metadata": {}}
+{"_id": "40312663", "title": "", "text": "Inflammasome activation by adenylate cyclasetoxin directs Th17 responses and protectionagainst Bordetellapertussis.Inflammasome-mediated IL-1betaproduction is central to the innate immunedefects that give rise to certainautoinflammatory diseases and may also beassociated with the generation ofIL-17-producing CD4(+) T (Th17) cells thatmediate autoimmunity. However, the role of theinflammasome in driving adaptive immunity toinfection has not been addressed. In this article,we demonstrate that inflammasome-mediatedIL-1beta plays a critical role in promotingAg-specific Th17 cells and in generatingprotective immunity against Bordetella pertussisinfection. Using a murine respiratory challengemodel, we demonstrated that the course of B.pertussis infection was significantly exacerbatedin IL-1R type I-defective (IL-1RI(-/-)) mice. Wefound that adenylate cyclase toxin (CyaA), a keyvirulence factor secreted by B. pertussis, induced", "metadata": {}}
+{"_id": "40323148", "title": "", "text": "Infection and apoptosis as a combinedinflammatory trigger.While inflammatoryphagocytosis of microbial pathogens andnon-inflammatory phagocytosis of apoptotic cellshave each been studied extensively, theconsequences of innate immune recognition ofhost cells undergoing apoptosis as a direct resultof infection are unclear. In this situation, theinnate immune system is confronted with mixedsignals, those from apoptotic cells and thosefrom the infecting pathogen. Nuclear receptoractivation has been implicated downstream ofapoptotic cell recognition while Toll-like receptorsare the prototypical inflammatory receptorsengaged during infection. When the two signalscombine, a new set of events takes placebeginning with transrepression of a subset ofinflammatory-response genes and ending withthe induction of a T helper-17 adaptive immuneresponse. This response is best suited forclearing the infecting pathogen and repairing thedamage that occurred to the host tissue during", "metadata": {}}
+{"_id": "40323454", "title": "", "text": "Chronic lymphocytic leukemia witht(14;19)(q32;q13) is characterized by atypicalmorphologic and immunophenotypic featuresand distinctive genetic features.Thet(14;19)(q32;q13) involving the IGH@ and BCL3loci is an infrequent cytogenetic abnormalitydetected in B-cell malignancies. We describe theclinicopathologic, cytogenetic, and moleculargenetic characteristics of 14 cases of chroniclymphocytic leukemia/small lymphocyticlymphoma (CLL/SLL) with t(14;19)(q32;q13). Allpatients (10 men and 4 women) hadlymphocytosis; 10 had lymphadenopathy. Bloodand bone marrow lymphocytes werepredominantly small, but cytologically andimmunophenotypically atypical. In all cases,t(14;19) was found in the neoplastic stem line; itwas the sole abnormality in 4. Ten cases showedadditional cytogenetic abnormalities, includingtrisomy 12 in 9 and complex karyotypes in 7.Fluorescence in situ hybridization demonstratedIGH@/BCL3 fusion gene in all cases. In all cases,", "metadata": {}}
+{"_id": "40343416", "title": "", "text": "Risk factors for the development of gallstonerecurrence following medical dissolution. TheBritish-Italian Gallstone Study Group.OBJECTIVETo assess risk factors for gallstone recurrencefollowing non-surgical treatment. DESIGN Aprospective follow-up of a multicentre cohort ofpost-dissolution gallstone patients. SETTING Sixgastroenterology units in the UK and Italy.PARTICIPANTS One hundred and sixty-threepatients with confirmed gallstone dissolutionfollowing non-surgical therapy (bile acids orlithotripsy plus bile acids), followed up byultrasound scan and clinical assessment at6-monthly intervals for up to 6 years (median,25 months; range, 6-70 months). OUTCOMEMEASURES Subject-related variables (sex, age,height, weight, body mass index),gallstone-related variables (number, diameter,presence of symptoms, months to completestone clearance), treatment modalities (bile acidtherapy, extracorporeal shock wave lithotripsy)and follow-up related variables (weight change,", "metadata": {}}
+{"_id": "40349336", "title": "", "text": "Deletion of the developmentally essential geneATR in adult mice leads to age-relatedphenotypes and stem cell loss.Developmentalabnormalities, cancer, and premature aging eachhave been linked to defects in the DNA damageresponse (DDR). Mutations in the ATR checkpointregulator cause developmental defects in mice(pregastrulation lethality) and humans (Seckelsyndrome). Here we show that eliminating ATRin adult mice leads to defects in tissuehomeostasis and the rapid appearance ofage-related phenotypes, such as hair graying,alopecia, kyphosis, osteoporosis, thymicinvolution, fibrosis, and other abnormalities.Histological and genetic analyses indicate thatATR deletion causes acute cellular loss in tissuesin which continuous cell proliferation is requiredfor maintenance. Importantly, thymic involution,alopecia, and hair graying in ATR knockout micewere associated with dramatic reductions intissue-specific stem and progenitor cells andexhaustion of tissue renewal and homeostatic", "metadata": {}}
+{"_id": "40365566", "title": "", "text": "Conventional and monocyte-derived CD11b(+)dendritic cells initiate and maintain T helper 2cell-mediated immunity to house dust miteallergen.Dendritic cells (DCs) are crucial formounting allergic airway inflammation, but it isunclear which subset of DCs performs this task.By using CD64 and MAR-1 staining, we reliablyseparated CD11b(+) monocyte-derived DCs(moDCs) from conventional DCs (cDCs) andstudied antigen uptake, migration, andpresentation assays of lung and lymph node (LN)DCs in response to inhaled house dust mite(HDM). Mainly CD11b(+) cDCs but not CD103(+)cDCs induced T helper 2 (Th2) cell immunity inHDM-specific T cells in vitro and asthma in vivo.Studies in Flt3l(-/-) mice, lacking all cDCs,revealed that moDCs were also sufficient toinduce Th2 cell-mediated immunity but onlywhen high-dose HDM was given. The mainfunction of moDCs was the production ofproinflammatory chemokines and allergenpresentation in the lung during challenge. Thus,", "metadata": {}}
+{"_id": "40367499", "title": "", "text": "Interplay between the dividing cell and itsneighbors regulates adherens junction formationduring cytokinesis in epithelial tissue.Howadherens junctions (AJs) are formed upon celldivision is largely unexplored. Here, we foundthat AJ formation is coordinated with cytokinesisand relies on an interplay between the dividingcell and its neighbors. During contraction of thecytokinetic ring, the neighboring cells locallyaccumulate Myosin II and produce the corticaltension necessary to set the initial geometry ofthe daughter cell interface. However, theneighboring cell membranes impede AJformation. Upon midbody formation andconcomitantly to neighboring cell withdrawal,Arp2/3-dependent actin polymerization orientedby the midbody maintains AJ geometry andregulates AJ final length and the epithelial cellarrangement upon division. We propose thatcytokinesis in epithelia is a multicellular process,whereby the cooperative actions of the dividingcell and its neighbors define a two-tiered", "metadata": {}}
+{"_id": "40382183", "title": "", "text": "Cancer stem cells in solid tumours: accumulatingevidence and unresolved questionsSolid tumoursare an enormous cancer burden and a majortherapeutic challenge. The cancer stem cell(CSC) hypothesis provides an attractive cellularmechanism to account for the therapeuticrefractoriness and dormant behaviour exhibitedby many of these tumours. There is increasingevidence that diverse solid tumours arehierarchically organized and sustained by adistinct subpopulation of CSCs. Direct evidencefor the CSC hypothesis has recently emergedfrom mouse models of epithelial tumorigenesis,although alternative models of heterogeneityalso seem to apply. The clinical relevance ofCSCs remains a fundamental issue butpreliminary findings indicate that specifictargeting may be possible.", "metadata": {}}
+{"_id": "40383969", "title": "", "text": "The structure of the follistatin:activin complexreveals antagonism of both type I and type IIreceptor binding.TGF-beta ligands stimulatediverse cellular differentiation and growthresponses by signaling through type I and IIreceptors. Ligand antagonists, such as follistatin,block signaling and are essential regulators ofphysiological responses. Here we report thestructure of activin A, a TGF-beta ligand, boundto the high-affinity antagonist follistatin. Twofollistatin molecules encircle activin, neutralizingthe ligand by burying one-third of its residuesand its receptor binding sites. Previous studieshave suggested that type I receptor bindingwould not be blocked by follistatin, but thecrystal structure reveals that the follistatinN-terminal domain has an unexpected fold thatmimics a universal type I receptor motif andoccupies this receptor binding site. The formationof follistatin:BMP:type I receptor complexes canbe explained by the stoichiometric and geometricarrangement of the activin:follistatin complex.", "metadata": {}}
+{"_id": "40412980", "title": "", "text": "The activity of siRNA in mammalian cells isrelated to structural target accessibility: acomparison with antisense oligonucleotides.Thebiological activity of siRNA seems to beinfluenced by local characteristics of the targetRNA, including local RNA folding. Here, weinvestigated quantitatively the relationshipbetween local target accessibility and the extentof inhibition of the target gene by siRNA. Targetaccessibility was assessed by a computationalapproach that had been shown earlier to beconsistent with experimental probing of targetRNA. Two sites of ICAM-1 mRNA predicted toserve as accessible motifs and one site predictedto adopt an inaccessible structure were chosen totest siRNA constructs for suppression of ICAM-1gene expression in ECV304 cells. The localtarget-dependent effectiveness of siRNA wascompared with antisense oligonucleotides(asON). The concentration dependency ofsiRNA-mediated suppression indicates a>1000-fold difference between active siRNAs", "metadata": {}}
+{"_id": "40429879", "title": "", "text": "Rapid accumulation of mutations duringseed-to-seed propagation ofmismatch-repair-defective Arabidopsis.Duringthe many cell divisions that precede formation ofplant gametes, their apical-meristem and floralantecedents are continually exposed toendogenous and environmental mutagenicthreats. Although some deleterious recessivemutations may be eliminated during growth ofhaploid gametophytes and functionally haploidearly embryos (\"haplosufficiencyquality-checking\"), the multiplicity of plantgenome-maintenance systems suggestsaggressive quality control during prior diploidgrowth. To test in Arabidopsis a hypothesis thatprior mismatch repair (MMR) is paramount indefense of plant genetic fidelity, we propagatedin parallel 36 MMR-defective (Atmsh2-1) and 36wild-type lines. The Atmsh2-1 lines rapidlyaccumulated a wide variety of mutations:fifth-generation (G5) plants showedabnormalities in morphology and development,", "metadata": {}}
+{"_id": "40447899", "title": "", "text": "Archaeal chromatin and transcription.Archaeacontain a variety of sequence-independent DNAbinding proteins consistent with the evolution ofseveral different, sometimes overlapping andexchangeable solutions to the problem ofgenome compaction. Some of these proteinsundergo residue-specific post-translational lysineacetylation or methylation, hinting at analoguesof the histone modifications that regulateeukaryotic chromatin structure and transcription.Archaeal transcription initiation most closelyresembles the eukaryotic RNA polymerase II(RNAPII) system, but Archaea do not appear tohave homologues of the multisubunit complexesthat remodel eukaryotic chromatin and activateRNAPII initiation. In contrast, they havesequence-specific regulators that repress andperhaps activate archaeal transcription bymechanisms superficially similar to the bacterialparadigm of regulating promoter binding byRNAP. Repressors compete with archaealTATA-box binding protein (TBP) and TFB for the", "metadata": {}}
+{"_id": "40473317", "title": "", "text": "Temporal segregation of 4-1BB versusCD28-mediated costimulation: 4-1BB ligandinfluences T cell numbers late in the primaryresponse and regulates the size of the T cellmemory response following influenza infection.Inthis report, we demonstrate that CD28(-/-) miceare severely impaired in the initial expansion ofD(b)/NP366-374-specific CD8 T cells in responseto influenza virus infection, whereas 4-1BBligand (4-1BBL)(-/-) mice show no defect inprimary T cell expansion to influenza virus. Incontrast, 4-1BBL(-/-) mice show a decrease inD(b)/NP366-374-specific T cells late in theprimary response. Upon secondary challengewith influenza virus, 4-1BBL(-/-) mice show adecrease in the number ofD(b)/NP366-374-specific T cells compared towild-type mice such that the level of the CD8 Tcell expansion during the in vivo secondaryresponse is reduced to the level of a primaryresponse, with concomitant reduction of CTLeffector function. In contrast, Ab responses, as", "metadata": {}}
+{"_id": "40476126", "title": "", "text": "Functional role of high-affinity anandamidetransport, as revealed by selectiveinhibition.Anandamide, an endogenous ligand forcentral cannabinoid receptors, is released fromneurons on depolarization and rapidlyinactivated. Anandamide inactivation is notcompletely understood, but it may occur bytransport into cells or by enzymatic hydrolysis.The compoundN-(4-hydroxyphenyl)arachidonylamide (AM404)was shown to inhibit high-affinity anandamideaccumulation in rat neurons and astrocytes invitro, an indication that this accumulationresulted from carrier-mediated transport.Although AM404 did not activate cannabinoidreceptors or inhibit anandamide hydrolysis, itenhanced receptor-mediated anandamideresponses in vitro and in vivo. The data indicatethat carrier-mediated transport may be essentialfor termination of the biological effects ofanandamide, and may represent a potential drugtarget.", "metadata": {}}
+{"_id": "40500438", "title": "", "text": "Silibinin inhibits the invasion of IL-6-stimulatedcolon cancer cells via selective JNK/AP-1/MMP-2modulation in vitro.Silibinin is a flavonoid withantihepatotoxic properties and pleiotropicanticancer capabilities. This study investigatedsilibinin inhibition of cell invasion bydown-regulating matrix metalloproteinase-2(MMP-2) expression, via attenuation of activatorprotein-1 (AP-1) in IL-6-stimulated LoVo coloncancer cells. Western blot data showed that theexpression of MMP-2 protein was reduced 1.6- or1.7-fold over the control by treatment withsilibinin or JNK inhibitor in the models. Similarresults were revealed in zymography andconfocal microscopy. Pretreatment with silibininalso abolished the binding activity of AP-1 andMMP-2 promoter activity via AP-1 binding, asobserved by EMSA and luciferase assay. Finally,a [(3)H]-thymidine incorporation proliferationassay and cell migration assay demonstratedthat silibinin inhibited IL-6-stimulated LoVo cellproliferation and invasion. Taken together, these", "metadata": {}}
+{"_id": "40500723", "title": "", "text": "Immigration cohorts and residentialovercrowding in southern CaliforniaTo whatdegree do immigrants reduce their high rates ofresidential overcrowding with increasing lengthof residence in the United States? This questionis addressed through the application of a “doublecohort” method that nests birth cohorts withinimmigration cohorts. This method enablesduration of immigration effects to be separatedfrom aging effects as cohorts pass through lifecourse phases, when family sizes may begrowing or shrinking. The analysis finds thatcohort trends differ sharply from thecross-sectional pattern observed at a single pointin time. Cohorts’ growth in income is found tocontribute substantially to the decline inovercrowding over time. Cohort trends amongHispanic immigrants, however, diverge fromthose among others, indicating much lessdecrease in overcrowding and even increasesover certain age spans.", "metadata": {}}
+{"_id": "40558887", "title": "", "text": "Expression of green fluorescent protein in theureteric bud of transgenic mice: a new tool forthe analysis of ureteric bud morphogenesis.Thegrowth and branching of the ureteric bud is acomplex process that is ultimately responsiblefor the organization of the collecting duct systemas well as the number of nephrons in themetanephric kidney. While the genes involved inthe regulation of this process have begun to beelucidated, our understanding of the cellular andmolecular basis of ureteric bud morphogenesisremains rudimentary. Furthermore, the timingand sequence of branching and elongation thatgives rise to the collecting system of the kidneycan only be inferred from retrospective stainingor microdissection of fixed preparations. To aid inthe investigation of these issues, we developedstrains of transgenic mice in which a greenfluorescent protein (GFP) is expressed in theureteric bud under the control of the Hoxb7promoter. In these mice, GFP is expressed inevery branch of the ureteric bud throughout", "metadata": {}}
+{"_id": "40584205", "title": "", "text": "Biological properties of herpes simplex virus 2replication-defective mutant strains in a murinenasal infection model.We used a mouse nasalmodel of herpes simplex virus 2 (HSV-2)infection to examine the biological properties ofHSV-2 wild-type (wt), TK-negative, andreplication-defective strains in vivo. Nasal septatissue is the major site of wt viral replication postintranasal (i.n.) inoculation. The HSV-2 strain186 syn(+)-1 wt virus caused lethal encephalitisat doses of 10(4) PFU and above per nostril, andat lower doses no neurons in the trigeminalganglia were positive for the latency-associatedtranscript, indicating a lack of latent infection.The 186DeltaKpn TK-negative mutant virusreplicated in nasal septa tissue but showedlow-level replication in trigeminal ganglia at onlyone timepoint. In situ hybridization of trigeminalganglia showed that the number of LAT-positiveneurons was proportional to the inoculum dosefrom 10(3) to 10(6) PFU per nare. Thereplication-defective mutant virus 5BlacZ showed", "metadata": {}}
+{"_id": "40590358", "title": "", "text": "The sphingosine-1-phosphate receptor agonistFTY720 modulates dendritic cell trafficking invivo.The pro-drug FTY720 is undergoing phaseIII clinical trials for prevention of allograftrejection. After phosphorylation, FTY720 targetsthe G protein-coupled-sphingosine-1-phosphatereceptor 1 (S1PR1) on lymphocytes, therebyinhibiting their egress from lymphoid organs andtheir recirculation to inflammatory sites.Potential effects on dendritic cell (DC) traffickinghave not been evaluated. Here, we demonstratethe expression of all five S1PR subtypes(S1PR1-5) by murine DCs. Administration ofFTY720 to C57BL/10 mice markedly reducedcirculating T and B lymphocytes within 24 h, butnot blood-borne DCs, which were enhancedsignificantly for up to 96 h, while DCs in lymphnodes and spleen were reduced. Numbers ofadoptively transferred, fluorochrome-labeledsyngeneic or allogeneic DCs in blood wereincreased significantly in FTY720-treatedanimals, while donor-derived DCs and", "metadata": {}}
+{"_id": "40608679", "title": "", "text": "Sustained survivin expression from OX40costimulatory signals drives T cell clonalexpansion.Sustained signaling from the T cellreceptor (TCR) and costimulatory molecules isthought necessary for generating high numbersof effector T cells. Here, we show that Survivin iscontrolled in peripheral T cells by OX40cosignaling via sustained PI3k and PKBactivation. Survivin is induced by OX40independent of mitotic progression in late G1,and blocking Survivin suppresses S-phasetransition and division of T cells and leads toapoptosis. Moreover, Survivin expression alone issufficient to restore proliferation and toantagonize apoptosis in costimulation-deficient Tcells and can rescue T cell expansion in vivo.Survivin allows effector T cells to accumulate inlarge numbers, but Bcl-2 family proteins arerequired for T cell survival after the phase ofactive division. Thus, sustained Survivinexpression from costimulatory signalingmaintains T cell division over time and regulates", "metadata": {}}
+{"_id": "40631095", "title": "", "text": "The Combination of Exercise and RespiratoryTraining Improves Respiratory Muscle Function inPulmonary HypertensionIncreased dyspnea andreduced exercise capacity in pulmonary arterialhypertension (PAH) can be partly attributed toimpaired respiratory muscle function. Thisprospective study was designed to assess theimpact of exercise and respiratory training onrespiratory muscle strength and 6-min walkingdistance (6MWD) in PAH patients. Patients withinvasively confirmed PAH underwent 3 weeks ofin-hospital exercise and respiratory training,which was continued at home for another 12weeks. Medication remained constant during thestudy period. Blinded observers assessed efficacyparameters at baseline (I) and after 3 (II) and15 weeks (III). Respiratory muscle function wasassessed by twitch mouth pressure (TwPmo)during nonvolitional supramaximal magneticphrenic nerve stimulation. Seven PAH patients (4women; mean pulmonary artery pressure 45 ±11 mmHg, median WHO functional class 3.1 ±", "metadata": {}}
+{"_id": "40632104", "title": "", "text": "Dual role of the IL-12/IFN-gamma axis in thedevelopment of autoimmune myocarditis:induction by IL-12 and protection byIFN-gamma.IL-12 and IFN-gamma positivelyregulate each other and type 1 inflammatoryresponses, which are believed to cause tissuedamage in autoimmune diseases. Weinvestigated the role of the IL-12/IFN-gamma(Th1) axis in the development of autoimmunemyocarditis. IL-12p40-deficient mice on asusceptible background resisted myocarditis. Inthe absence of IL-12, autospecific CD4(+) T cellsproliferated poorly and showed increased Th2cytokine responses. However,IFN-gamma-deficient mice developed fatalautoimmune disease, and blockade of IL-4Rsignaling did not confer susceptibility tomyocarditis in IL-12p40-deficient mice,demonstrating that IL-12 triggers autoimmunityby a mechanism independent of the effectorcytokines IFN-gamma and IL-4. In conclusion,our results suggest that the IL-12/IFN-gamma", "metadata": {}}
+{"_id": "40655970", "title": "", "text": "Somatic and Germline Diversification of aPutative Immunoreceptor within One Phylum:Dscam in Arthropods.Arthropod Dscam, thehomologue of the human Down Syndrome celladhesion molecule, is a receptor used by thenervous and immune systems. Unlike invertebrates, evolutionary pressure has selectedand maintained a vast Dscam diversity ofisoforms, known to specifying neuronal identityduring the nervous system differentiation. Thischapter examines the different modes of Dscamdiversification in the context of arthropods'evolution and that of their immune system,where its role is controversial. In the singleDscam gene of insects and crustaceans, mutuallyexclusive alternative splicing affects threeclusters of duplicated exons encoding thevariable parts of the receptor. The Dscam geneproduces over 10,000 isoforms. In the morebasal arthropods such as centipedes, Dscamdiversity results from a combination of manygermline genes (over 80) with, in about half of", "metadata": {}}
+{"_id": "40666943", "title": "", "text": "Epidemiology, health-related quality of life andeconomic burden of binge eating disorder: asystematic literature reviewPURPOSE To performa systematic review on the epidemiology, thehealth-related quality of life (HRQoL) andeconomic burden of binge eating disorder (BED).METHODS A systematic literature search ofEnglish-language articles was conducted usingMedline, Embase, PsycINFO, PsycARTICLES,Academic Search Complete, CINAHL Plus,Business Source Premier and Cochrane Library.Literature search on epidemiology was limited tostudies published between 2009 and 2013. Costdata were inflated and converted to 2012 US$purchasing power parities. All of the includedstudies were assessed for quality. RESULTSForty-nine articles were included. Data onepidemiology were reported in 31, HRQoL burdenin 16, and economic burden in 7 studies.Diagnosis of BED was made using 4th Edition ofThe Diagnostic and Statistical Manual of MentalDisorders (DSM-IV) criteria in 46 studies.", "metadata": {}}
+{"_id": "40667066", "title": "", "text": "Subcellular steroid/nuclear receptordynamics.Steroid hormones, thyroid hormones,retinoic acids, and vitamin D bind to theirreceptors, which are now called steroid/nuclearreceptors, and liganded receptors translocateeither intracellularly or intranuclearly and formlarge protein complexes with cofactors to induceor repress gene transcription. Therefore,steroid/nuclear receptors are ligand-dependenttranscription factors. With the advent of greenfluorescent protein (GFP) and its color variants,the subcellular distribution of manysteroid/nuclear receptors has been found to bemuch more dynamic than previously thought,with some of the receptors shuttling between thecytoplasm and nucleus. Steroid/nuclearreceptors can be divided into three categoriesbased on their unliganded distribution: thosethat are primarily in the nucleus, those in thecytoplasm, and those with mixed cytoplasmicand nuclear distributions. However, in all cases,the addition of a ligand leads to almost complete", "metadata": {}}
+{"_id": "40667577", "title": "", "text": "EMT, the cytoskeleton, and cancer cellinvasionThe metastatic process, i.e. thedissemination of cancer cells throughout thebody to seed secondary tumors at distant sites,requires cancer cells to leave the primary tumorand to acquire migratory and invasivecapabilities. In a process ofepithelial-mesenchymal transition (EMT), besideschanging their adhesive repertoire, cancer cellsemploy developmental processes to gainmigratory and invasive properties that involve adramatic reorganization of the actin cytoskeletonand the concomitant formation of membraneprotrusions required for invasive growth. Themolecular processes underlying such cellularchanges are still only poorly understood, and thevarious migratory organelles, includinglamellipodia, filopodia, invadopodia andpodosomes, still require a better functional andmolecular characterization. Notably, directexperimental evidence linking the formation ofmigratory membrane protrusions and the", "metadata": {}}
+{"_id": "40710501", "title": "", "text": "Different response of human gliomatumor-initiating cells to epidermal growth factorreceptor kinase inhibitors.Because asubpopulation of cancer stem cells(tumor-initiating cells, TICs) is believed to beresponsible for the development, progression,and recurrence of many tumors, we evaluatedthe in vitro sensitivity of human glioma TICs toepidermal growth factor receptor (EGFR) kinaseinhibitors (erlotinib and gefitinib) and possiblemolecular determinants for their effects. Cellsisolated from seven glioblastomas (GBM 1-7) andgrown using neural stem cell permissiveconditions were characterized for in vivotumorigenicity, expression of tumor stem cellmarkers (CD133, nestin), and multilineagedifferentiation properties, confirming that thesecultures are enriched in TICs. TIC cultures werechallenged with increasing concentrations oferlotinib and gefitinib, and their survival wasevaluated after 1-4 days. In most cases, a time-and concentration-dependent cell death was", "metadata": {}}
+{"_id": "40721190", "title": "", "text": "Structural features of the interaction of the3'-untranslated region of mRNA containingexosomal RNA-specific motifs with YB-1, apotential mediator of mRNA sorting.We havepreviously shown that YB-1 is the only protein ofthe HEK293 cell cytoplasmic (S100) extract thatspecifically interacts with RNA hairpins eachcontaining one of the motifs ACCAGCCU (1),CAGUGAGC (2) and UAAUCCCA (3), which hadbeen identified as often found in exosomal RNAand proposed as potential cis-acting elementstargeting RNAs into exosomes. Here we exploredthe interactions of YB-1 with a fragment of the3'-untranslated region (UTR) of septin 14 mRNA(SEPT14 RNA), which contains all three motifs.We demonstrated the occurrence of YB-1 amongproteins pulled down from the HEK293 S100extract using biotinylated SEPT14 RNA. Withrecombinant YB-1, it was found that SEPT14 RNAcan bind up to 5 moles of protein per mole ofRNA in a cooperative manner, which was shownto be mainly facilitated by the presence of the", "metadata": {}}
+{"_id": "40735046", "title": "", "text": "Periodic screening for breast cancer: the HIPRandomized Controlled Trial. Health InsurancePlan.This paper summarizes the findings of thefirst breast cancer screening trial, which wasinitiated in December 1963 to explore theefficacy of screening. Women aged 40-64 yearswere selected from enrollees in the HealthInsurance Plan (HIP) of Greater New York andwere randomly assigned to study and controlgroups. Study group women were invited forscreening, an initial examination, and threeannual reexaminations. Screening consisted offilm mammography (cephalocaudal and lateralviews of each breast) and clinical examination ofbreasts. Breast cancer and mortality from breastcancer were examined by treatment group(study vs. control) and by entry-age subgroup.By the end of 18 years from entry, the studygroup had about a 25% lower breast cancermortality among women aged 40-49 and 50-59at time of entry than did the control group.However, to a large extent the difference among", "metadata": {}}
+{"_id": "40754510", "title": "", "text": "Staphylococcus aureus infections.Micrococcus,which, when limited in its extent and activity,causes acute suppurative inflammation(phlegmon), produces, when more extensive andintense in its action on the human system, themost virulent forms of septicaemia andpyaemia.1 In an elegant series of clinicalobservations and laboratory studies published in1880 and 1882, Ogston described staphylococcaldisease and its role in sepsis and abscessformation.1,2 More than 100 years later,Staphylococcus aureus remains a versatile anddangerous pathogen in humans. The frequenciesof both community-acquired andhospital-acquired staphylococcal infections haveincreased steadily, with little change in overallmortality. Treatment of these infections . . .", "metadata": {}}
+{"_id": "40760684", "title": "", "text": "Structural overview of the nuclear receptorsuperfamily: insights into physiology andtherapeutics.As ligand-regulated transcriptionfactors, the nuclear hormone receptors arenearly ideal drug targets, with internal pocketsthat bind to hydrophobic, drug-like moleculesand well-characterized ligand-inducedconformational changes that recruittranscriptional coregulators to promoterelements. Yet, due to the multitude of genesunder the control of a single receptor, the majorchallenge has been the identification of ligandswith gene-selective actions, impacting diseaseoutcomes through a narrow subset of targetgenes and not across their entiregene-regulatory repertoire. Here, we summarizethe concepts and work to date underlying thedevelopment of steroidal and nonsteroidalreceptor ligands, including the use of crystalstructures, high-throughput screens, and rationaldesign approaches for finding useful therapeuticmolecules. Difficulties in finding selective", "metadata": {}}
+{"_id": "40769868", "title": "", "text": "Differential assembly of inwardly rectifying K+channel subunits, Kir4.1 and Kir5.1, in brainastrocytes.The inwardly rectifying K+ channelsubunit Kir5.1 is expressed abundantly in thebrain, but its precise distribution and function arestill largely unknown. Because Kir5.1 isco-expressed with Kir4.1 in retinal glial Mullercells, we have compared the biochemical andimmunological properties of Kir5.1 and Kir4.1 inthe mouse brain. Immunoprecipitationexperiments suggested that brain expressed atleast two subsets of Kir channels, heteromericKir4.1/5.1 and homomeric Kir4.1.Immunolabeling using specific antibodies showedthat channels comprising Kir4.1 and Kir5.1subunits were assembled in a region-specificfashion. Heteromeric Kir4.1/5.1 was identified inthe neocortex and in the glomeruli of theolfactory bulb. Homomeric Kir4.1 was confined tothe hippocampus and the thalamus. HomomericKir5.1 was not identified. Kir4.1/5.1 and Kir4.1expression appeared to occur only in astrocytes,", "metadata": {}}
+{"_id": "40781557", "title": "", "text": "Low-grade serous ovarian cancer: a uniquedisease.Low-grade serous carcinomas representapproximately 10% of all serous ovariancarcinomas. A growing body of research hasdemonstrated several important differencesbetween the clinical and molecularcharacteristics of these tumors and those ofhigh-grade serous ovarian carcinomas. Patientswith low-grade serous ovarian tumors arediagnosed at a younger age, have a longeroverall survival, and have lower response ratesto conventional chemotherapy. In addition,low-grade serous ovarian carcinomas havepathologic and molecular characteristics distinctfrom high-grade serous carcinomas, yet similarto serous tumors of low malignant potential. Thissuggests a common pathogenesis and acontinuum of disease from serous tumors of lowmalignant potential to low-grade serouscarcinomas. Further study, focusing specificallyon low-grade serous carcinomas, is needed todetermine the role of other chemotherapeutic", "metadata": {}}
+{"_id": "40790033", "title": "", "text": "Renal outcomes with different fixed-dosecombination therapies in patients withhypertension at high risk for cardiovascularevents (ACCOMPLISH): a prespecified secondaryanalysis of a randomised controlledtrial.BACKGROUND The Avoiding CardiovascularEvents through Combination Therapy in PatientsLiving with Systolic Hypertension (ACCOMPLISH)trial showed that initial antihypertensive therapywith benazepril plus amlodipine was superior tobenazepril plus hydrochlorothiazide in reducingcardiovascular morbidity and mortality. Weassessed the effects of these drug combinationson progression of chronic kidney disease.METHODS ACCOMPLISH was a double-blind,randomised trial undertaken in five countries(USA, Sweden, Norway, Denmark, and Finland).11 506 patients with hypertension who were athigh risk for cardiovascular events wererandomly assigned via a central,telephone-based interactive voice responsesystem in a 1:1 ratio to receive benazepril (20", "metadata": {}}
+{"_id": "40817021", "title": "", "text": "Effects of exercise training on health status inpatients with chronic heart failure: HF-ACTIONrandomized controlled trial.CONTEXT Findingsfrom previous studies of the effects of exercisetraining on patient-reported health status havebeen inconsistent. OBJECTIVE To test the effectsof exercise training on health status amongpatients with heart failure. DESIGN, SETTING,AND PATIENTS Multicenter, randomizedcontrolled trial among 2331 medically stableoutpatients with heart failure with left ventricularejection fraction of 35% or less. Patients wererandomized from April 2003 through February2007. INTERVENTIONS Usual care plus aerobicexercise training (n = 1172), consisting of 36supervised sessions followed by home-basedtraining, vs usual care alone (n = 1159).Randomization was stratified by heart failureetiology, which was a covariate in all models.MAIN OUTCOME MEASURES Kansas CityCardiomyopathy Questionnaire (KCCQ) overallsummary scale and key subscales at baseline,", "metadata": {}}
+{"_id": "40867854", "title": "", "text": "Acute respiratory failure in patients with severecommunity-acquired pneumonia: a prospectiverandomized evaluation of noninvasiveventilation.In uncontrolled studies, noninvasivepositive pressure ventilation (NPPV) was founduseful in avoiding endotracheal intubation inpatients with acute respiratory failure (ARF)caused by severe community-acquiredpneumonia (CAP). We conducted a prospective,randomized study comparing standard treatmentplus NPPV delivered through a face mask tostandard treatment alone in patients with severeCAP and ARF. Patients fitting the AmericanThoracic Society criteria for severe CAP wereincluded in presence of ARF (refractoryhypoxemia and/or hypercapnia with acidosis).Exclusion criteria were: severe hemodynamicinstability, requirement for emergentcardiopulmonary resuscitation, home mechanicalventilation or oxygen long-termsupplementation, concomitant severe diseasewith a low expectation of life, inability to", "metadata": {}}
+{"_id": "40900242", "title": "", "text": "Smallest angiosperm genomes found inlentibulariaceae, with chromosomes of bacterialsize.Nuclear holoploid genome sizes (C-values)have been estimated to vary about 800-fold inangiosperms, with the smallest established1C-value of 157 Mbp recorded in Arabidopsisthaliana. In the highly specialized carnivorousfamily Lentibulariaceae now three taxa havebeen found that exhibit significantly lowervalues: Genlisea margaretae with 63 Mbp, G.aurea with 64 Mbp, and Utricularia gibba with 88Mbp. The smallest mitotic anaphase chromatidsin G. aurea have 2.1 Mbp and are thus ofbacterial size (NB: E. coli has ca. 4 Mbp). SeveralUtricularia species range somewhat lower than A.thaliana or are similar in genome size. Thehighest 1C-value known from species ofLentibulariaceae was found in Genlisea hispidulawith 1510 Mbp, and results in about 24-foldvariation for Genlisea and the Lentibulariaceae.Taking into account these new measurements,genome size variation in angiosperms is now", "metadata": {}}
+{"_id": "40900567", "title": "", "text": "Parasite multiplication potential and the severityof Falciparum malaria.The multiplication ratesand invasiveness of Plasmodium falciparumparasites isolated from adult Thai patientshospitalized with uncomplicated malaria (n=34)were compared with those from persons withsevere malaria (n=42). To simulate severemalaria and control for host effects, the in vitrocultures were adjusted to 1% parasitemia andused the same red blood cell donor. P.falciparum isolates from persons with severemalaria had initial cycle multiplication rates invitro that were 3-fold higher than those fromuncomplicated malaria (median [95% confidenceinterval], 8.3 [7. 1-10.5] vs. 2.8 [1.7-3.9];P=.001). Parasites causing severe malariaexhibited unrestricted red blood cell invasion,whereas those from uncomplicated malaria wererestricted to a geometric mean of 40 (31%-53%)of red blood cells. P. falciparum parasites causingsevere malaria were less selective and multipliedmore at high parasitemias than those causing", "metadata": {}}
+{"_id": "40901687", "title": "", "text": "PHD3-dependent hydroxylation of HCLK2promotes the DNA damage response.The DNAdamage response (DDR) is a complex regulatorynetwork that is critical for maintaining genomeintegrity. Posttranslational modifications arewidely used to ensure strict spatiotemporalcontrol of signal flow, but how the DDR respondsto environmental cues, such as changes inambient oxygen tension, remains poorlyunderstood. We found that an essentialcomponent of the ATR/CHK1 signaling pathway,the human homolog of the Caenorhabditiselegans biological clock protein CLK-2 (HCLK2),associated with and was hydroxylated by prolylhydroxylase domain protein 3 (PHD3). HCLK2hydroxylation was necessary for its interactionwith ATR and the subsequent activation ofATR/CHK1/p53. Inhibiting PHD3, either with thepan-hydroxylase inhibitor dimethyloxaloylglycine(DMOG) or through hypoxia, preventedactivation of the ATR/CHK1/p53 pathway anddecreased apoptosis induced by DNA damage.", "metadata": {}}
+{"_id": "40905302", "title": "", "text": "Economic implications of nighttime attendingintensivist coverage in a medical intensive careunit.OBJECTIVE Our objective was to assess thecost implications of changing the intensive careunit staffing model from on-demand presence tomandatory 24-hr in-house critical care specialistpresence. DESIGN A pre-post comparison wasundertaken among the prospectively assessedcohorts of patients admitted to our medicalintensive care unit 1 yr before and 1 yr after thechange. Our data were stratified by AcutePhysiology and Chronic Health Evaluation IIIquartile and whether a patient was admittedduring the day or at night. Costs were modeledusing a generalized linear model with log-linkand γ-distributed errors. SETTING A largeacademic center in the Midwest. PATIENTS Allpatients admitted to the adult medical intensivecare unit on or after January 1, 2005 anddischarged on or before December 31, 2006.Patients receiving care under both staffingmodels were excluded. INTERVENTION Changing", "metadata": {}}
+{"_id": "40913091", "title": "", "text": "GENOTYPING OF THALASSEMIA IN MICROCYTICHYPOCHROMIC ANEMIA PATIENTS FROMSOUTHWEST REGION OF IRANObjective: Toevaluate the frequency of α -gene, s-gene, andhemoglobin variant numbers in subjects withMicrocytic hypochromic anemia. Methodology: Intotal out of 850, 340 subjects with microcytichypochromic anemia [MCV<80fl; MCH<27pg]from Southwest part of Iran, were studied inResearch Center of Thalassemia andHemoglobinopathies (RCTH) which is the onlycenter working on hematology and oncology inSouthwest (Khuzestan) region of Iran. Theseinclude 325 individuals: 171 withBeta-thalassemia trait, 88 withAlpha-thalassemia trait, 13 with thalassemiamajor, 11 with hemoglobin variants (HbS, HbC,and HbD Punjab ) and 42 with iron-deficiencyanemia. The rest 15 patients diagnosed with nodefinite etiology. Results: Genotyping for -α 3.7 ,-α 4.2 , – α PA , - α 5NT and - - MED was donewith gap-PCR. The overall frequency of - α 3.7", "metadata": {}}
+{"_id": "40935722", "title": "", "text": "Systemic biomarkers in exacerbations of COPD:the evolving clinical challenge.BACKGROUNDExacerbations of COPD (ECOPD) remain a majorcause of mortality and morbidity. Despiteadvances in the understanding of theirpathophysiology, their assessment reliesprimarily on clinical presentation, which can bevariable and difficult to predict. A large numberof biomarkers already have been assessed in thiscontext, and some appear to be promising.METHODS An online search for articles publisheduntil December 2010 was conducted using threeterms for ECOPD, five terms for biomarkers, andfive terms for the sampling method. Biomarkerswere evaluated for their potential role in theestablishment and confirmation of the diagnosisof ECOPD, the evaluation of etiology andseverity, the prediction of prognosis, and theguidance of treatment decisions. RESULTSSeveral systemic biomarkers have beenmeasured in the context of ECOPD, and mosthave been found to increase at ECOPD onset and", "metadata": {}}
+{"_id": "40949706", "title": "", "text": "Preoperative Predictors of Weight Loss FollowingBariatric Surgery: Systematic ReviewObesityaffects 32% of adults in the USA. Surgerygenerates substantial weight loss, but 20–30%fails to achieve successful weight loss. Ourobjective was to identify preoperativepsychosocial factors associated with weight lossfollowing bariatric surgery. We performed aliterature search of PubMed® and the CochraneDatabase of Reviews of Effectiveness between1988 and April 2010. Articles were screened forbariatric surgery and weight loss if they includeda preoperative predictor of weight loss: bodymass index (BMI), preoperative weight loss,eating disorders, or psychiatricdisorder/substance abuse. One thousand seventitles were reviewed, 534 articles screened, and115 included in the review. Factors that may bepositively associated with weight loss aftersurgery include mandatory preoperative weightloss (7 of 14 studies with positive association).Factors that may be negatively associated with", "metadata": {}}
+{"_id": "40963697", "title": "", "text": "The tumor necrosis factor receptor stalk regionsdefine responsiveness to soluble versusmembrane-bound ligand.The family of tumornecrosis factor receptors (TNFRs) and theirligands form a regulatory signaling network thatcontrols immune responses. Various members ofthis receptor family respond differently to thesoluble and membrane-bound forms of theirrespective ligands. However, the determiningfactors and underlying molecular mechanisms ofthis diversity are not yet understood. Using anestablished system of chimeric TNFRs and novelligand variants mimicking the bioactivity ofmembrane-bound TNF (mTNF), we demonstratethat the membrane-proximal extracellular stalkregions of TNFR1 and TNFR2 are crucial incontrolling responsiveness to soluble TNF (sTNF).We show that the stalk region of TNFR2, incontrast to the corresponding part of TNFR1,efficiently inhibits both the receptor'senrichment/clustering in particular cellmembrane regions and ligand-independent", "metadata": {}}
+{"_id": "40971746", "title": "", "text": "A bird's-eye view of sex chromosome dosagecompensation.Intensive study of a fewgenetically tractable species with XX/XY sexchromosomes has produced generalizationsabout the process of sex chromosome dosagecompensation that do not fare well when appliedto ZZ/ZW sex chromosome systems, such asthose in birds. The inherent sexual imbalance indose of sex chromosome genes has led to theevolution of sex-chromosome-wide mechanismsfor balancing gene dosage between the sexesand relative to autosomal genes. Recentadvances in our knowledge of avian genomeshave led to a reexamination of sex-specificdosage compensation (SSDC) in birds, which isless effective than in known XX/XY systems.Insights about the mechanisms of SSDC in birdsalso suggest similarities to and differences fromthose in XX/XY species. Birds are thus offeringnew opportunities for studying dosagecompensation in a ZZ/ZW system, which shouldshed light on the evolution of SSDC more", "metadata": {}}
+{"_id": "40987633", "title": "", "text": "The role of CHMP2BIntron5 in autophagy andfrontotemporal dementia.Charged multivesicularbody protein 2B (CHMP2B) - a component of theendosomal complex required for transport-III(ESCRT-III) - is responsible for the vitalmembrane deformation functions in autophagyand endolysosomal trafficking. A dominantmutation in CHMP2B (CHMP2BIntron5) isassociated with a subset of heritablefrontotemporal dementia - frontotemporaldementia linked to chromosome 3 (FTD-3).ESCRT-III recruits Vps4, an AAA-ATPase thatabscises the membrane during various cellularprocesses including autophagy and intraluminalvesicle formation. CHMP2BIntron5 results in aC-terminus truncation removing an importantVps4 binding site as well as eliminating thenormal autoinhibitory resting state of CHMP2B.CHMP2B is expressed in most cell types butseems to be especially vital for proper neuronalfunction. CHMP2BIntron5-mediated phenotypesinclude misregulation of transmembrane", "metadata": {}}
+{"_id": "40996863", "title": "", "text": "Restless legs syndrome andattention-deficit/hyperactivity disorder: a reviewof the literature.STUDY OBJECTIVE To reviewevidence on the association between restlesslegs syndrome (RLS) andattention-deficit/hyperactivity disorder (ADHD),to discuss the hypothetical mechanismsunderlying this association, and to consider thepotential interest for common pharmacologictreatments of RLS and ADHD when co-occurring.METHOD A PubMed search. RESULTS In clinicalsamples, up to 44% of subjects with ADHD havebeen found to have RLS or RLS symptoms, andup to 26% of subjects with RLS have been foundto have ADHD or ADHD symptoms. Severalmechanisms may explain this association. Sleepdisruption associated with RLS might lead toinattentiveness, moodiness, and paradoxicaloveractivity. Diurnal manifestations of RLS, suchas restlessness and inattention, might mimicADHD symptoms. Alternatively, RLS might becomorbid with idiopathic ADHD. Subjects with", "metadata": {}}
+{"_id": "41022628", "title": "", "text": "Impact of the KU80 pathway on NHEJ-inducedgenome rearrangements in mammaliancells.Using a substrate measuring deletion orinversion of an I-SceI-excised fragment and bothaccurate and inaccurate rejoining, wedetermined the impact of non-homologousend-joining (NHEJ) on mammalian chromosomerearrangements. Deletion is 2- to 8-fold moreefficient than inversion, independent of the DNAends structure. KU80 controls accurate rejoining,whereas in absence of KU mutagenic rejoining,particularly microhomology-mediated repair,occurs efficiently. In cells bearing both the NHEJand a homologous recombination (HR) substratecontaining a third I-SceI site, we show that NHEJis at least 3.3-fold more efficient than HR, andtranslocation of the I-SceI fragment from theNHEJ substrate locus into the HR-I-SceI site canoccur, but 50- to 100-fold less frequently thandeletion. Deletions and translocations show bothaccurate and inaccurate rejoining, suggestingthat they correspond to a mix of KU-dependent", "metadata": {}}
+{"_id": "41024260", "title": "", "text": "The multi-zinc finger protein ZNF217 contactsDNA through a two-finger domain.Classical C2H2zinc finger proteins are among the mostabundant transcription factors found ineukaryotes, and the mechanisms through whichthey recognize their target genes have beenextensively investigated. In general, a tandemarray of three fingers separated by characteristicTGERP links is required for sequence-specificDNA recognition. Nevertheless, a significantnumber of zinc finger proteins do not contain ahallmark three-finger array of this type, raisingthe question of whether and how they contactDNA. We have examined the multi-finger proteinZNF217, which contains eight classical zincfingers. ZNF217 is implicated as an oncogeneand in repressing the E-cadherin gene. We showthat two of its zinc fingers, 6 and 7, can mediatecontacts with DNA. We examine its putativerecognition site in the E-cadherin promoter anddemonstrate that this is a suboptimal site. NMRanalysis and mutagenesis is used to define the", "metadata": {}}
+{"_id": "41074251", "title": "", "text": "Knowledge, attitudes, risk perception, andcancer screening behaviors among cancersurvivors.BACKGROUND Knowledge, attitudes,and risk perception in relation to second primarycancer (SPC) screening and their impact onscreening practices in cancer survivors arelargely unknown. METHODS A total of 326 cancersurvivors who had completed primary treatmentfor cancer >1 year previously were recruitedfrom 6 oncology care outpatient clinics in theRepublic of Korea. Survivors' knowledge,attitudes, perceived risk, and screening practiceswere assessed along with sociodemographic,behavioral, and clinical characteristics.Multivariate logistic regression was used toexamine behavioral factors associated with thecompletion of all appropriate SPC screeningaccording to national guidelines. RESULTSApproximately 37.7% of survivors hadundergone all appropriate SPC screening tests.Survivors were found to have a high perceivedrisk of SPC, high perceived benefits of screening,", "metadata": {}}
+{"_id": "41087952", "title": "", "text": "Ria1p (Ynl163c), a protein similar to elongationfactors 2, is involved in the biogenesis of the 60Ssubunit of the ribosome in SaccharomycescerevisiaeRIA1 (YNL163c) is a quasi-essentialgene that encodes a protein with strongsimilarities to elongation factors 2. SmallC-terminal deletions in the protein lead to asevere growth defect. In the case of a 22-residueC-terminal deletion this can be suppressed byintragenic mutations in the RIA1 gene ordominant extragenic mutations in TIF6, which isthought to be involved in the biogenesis of the60S subunit of the ribosome. The dominant TIF6alleles can also suppress the phenotypeassociated with a complete deletion of the RIA1gene. Depletion of Ria1p has a dramatic effect onthe polysome profile: there is a severe reductionin the level of the 80S monosomes, an imbalancein the 40S/60S ratio, and halfmers appear.Dissociation of the monosomes and polysomes inthe Ria1p depletion mutant revealed a specificreduction in the amount of 60S subunits.", "metadata": {}}
+{"_id": "41120293", "title": "", "text": "The Intestinal Immune System in Obesity andInsulin Resistance.Obesity and insulin resistanceare associated with chronic inflammation inmetabolic tissues such as adipose tissue and theliver. Recently, growing evidence has implicatedthe intestinal immune system as an importantcontributor to metabolic disease. Obesitypredisposes to altered intestinal immunity and isassociated with changes to the gut microbiota,intestinal barrier function, gut-residing innateand adaptive immune cells, and oral tolerance toluminal antigens. Accordingly, the gut immunesystem may represent a novel therapeutic targetfor systemic inflammation in insulin resistance.This review discusses the emerging field ofintestinal immunity in obesity-related insulinresistance and how it affects metabolic disease.", "metadata": {}}
+{"_id": "41131087", "title": "", "text": "Human placental lactogen and unconjugatedestriol concentrations in twin pregnancy:monitoring of fetal development in intrauterinegrowth retardation and single intrauterine fetaldeath.Human placental lactogen andunconjugated estriol concentrations in maternalserum were evaluated in 100 uneventful twinpregnancies, and these values were comparedwith those observed in 16 twin pregnanciesassociated with intrauterine growth retardationor single intrauterine fetal death. In pregnanciesassociated with intrauterine growth retardation(n = 8), human placental lactogen levels were atthe lower limit of normal range for singletonpregnancies, whereas estriol levels were normalin most cases. When one of the fetuses had diedbefore week 33 of pregnancy (n = 5), bothhuman placental lactogen and estriol levels werelow and they were almost at the levels insingleton pregnancy. When intrauterine fetaldeath occurred after week 36 of pregnancy (n =3), both hormone levels remained normal until", "metadata": {}}
+{"_id": "41133176", "title": "", "text": "Low antioxidant enzyme gene expression inpancreatic islets compared with various othermouse tissues.Using a sensitive Northern blothybridization technique, gene expression ofsuperoxide dismutase (SOD), catalase, andglutathione peroxidase was studied in pancreaticislets and for comparison in various other mousetissues (liver, kidney, brain, lung, skeletalmuscle, heart muscle, adrenal gland, andpituitary gland). Gene expression of theantioxidant enzymes was usually in the range of+/- 50% of that in the liver. Only in pancreaticislets gene expression was substantially lower.The levels of the cytoplasmic Cu/Zn SOD and themitochondrial Mn SOD gene expression were inthe range of 30-40% of those in the liver.Glutathione peroxidase gene expression was15%, and catalase gene expression was not atall detectable in pancreatic islets. These lowlevels of antioxidant enzyme gene expressionmay provide an explanation for the extraordinarysensitivity of pancreatic beta cells towards", "metadata": {}}
+{"_id": "41159361", "title": "", "text": "Cyclic nucleotide phosphodiesterase isozymesexpressed in mouse skeletal muscle.Tounderstand changes in cyclic nucleotidemetabolism in muscle disease states, theexpression of phosphodiesterase (PDE) isozymesin normal mouse leg muscle was examined. Foursubcellular fractions were generated bydifferential centrifugation at 10,000 x g and100,000 x g. cAMP PDE activity was foundpredominately in the soluble fractions, whilecGMP PDE activity was more evenly distributedamongst soluble and particulate fractions.Pharmacological inhibitors demonstrate thatPDE4 represents the major cAMP hydrolyzingactivity and PDE2 represents the major cGMPhydrolyzing activity in mouse leg muscle. PDE1 isexpressed at low levels, while PDE3 and PDE5are intermediate. Between 20 and 40% of totalPDE activity remained in the presence ofinhibitors for PDE1-PDE5, indicating that otherPDE families contribute to the total PDE pool.Reverse-transcription PCR with family-specific", "metadata": {}}
+{"_id": "41161366", "title": "", "text": "Exercise-induced asthma.The effect of exerciseon ventilatory function was studied in 7 patientswith asthma. Three showed appreciable decreasein forced expiratory volume in one second (FEV1) after exercise. The degree of hyperventilationproduced by exercise correlated with thepostexercise decrease in FEV 1. Voluntaryhyperventilation at rest produced a decrease inFEV 1 in all patients with asthma. Breathing 5.6per cent carbon dioxide during voluntaryhyperventilation instead of room air induced alarger ventilation and greater decrease in FEV1.Neither exercise nor voluntary hyperventilationhad any significant effect on the FEV 1 in normalsubjects and patients with chronic bronchitis.Both exercise·induced andhyperventilation-induced decrease in FEV 1 wereinhibited by prior administration of isoproterenolbut not by atropine. It is postulated thatexercise-induced asthma is probablyhyperventilation-induced asthma. Severalunderlying mechanisms by which airway", "metadata": {}}
+{"_id": "41165286", "title": "", "text": "An antimicrobial protein of the gut symbiontBacteroides fragilis with a MACPF domain of hostimmune proteins.Bacteroidales are the mostabundant Gram-negative bacteria of the humanintestinal microbiota comprising more than halfof the bacteria in many individuals. Some of thefactors that these bacteria use to establish andmaintain themselves in this ecosystem arebeginning to be identified. However, ecologicalcompetition, especially interference competitionwhere one organism directly harms another, islargely unexplored. To begin to understand therelevance of this ecological principle as it appliesto these abundant gut bacteria and factors thatmay promote such competition, we screenedBacteroides fragilis for the production ofantimicrobial molecules. We found that theproduction of extracellularly secretedantimicrobial molecules is widespread in thisspecies. The first identified molecule, describedin this manuscript, contains a membrane attackcomplex/perforin (MACPF) domain present in", "metadata": {}}
+{"_id": "41182002", "title": "", "text": "Directional perception of distributed soundsources.The perception of spatially distributedsound sources was investigated by conductingtwo listening experiments in anechoic conditionswith 13 loudspeakers evenly distributed in thefrontal horizontal plane emitting incoherent noisesignals. In the first experiment, widelydistributed sound sources with gaps in theirdistribution emitted pink noise. The resultsindicated that the exact loudspeaker distributioncould not be perceived accurately and that thewidth of the distribution was perceived to benarrower than it was in reality. Up to threespatially distributed loudspeakers that weresimultaneously emitting sound could beindividually perceived. In addition, the number ofloudspeakers that were indicated as emittingsound was smaller than the actual number. Inthe second experiment, a reference with 13loudspeakers and test cases with fewerloudspeakers were presented and their perceivedspatial difference was rated. The effect of the", "metadata": {}}
+{"_id": "41226276", "title": "", "text": "Adoptive T cell transfer for cancerimmunotherapy in the era of syntheticbiology.Adoptive T cell transfer for cancer andchronic infection is an emerging field that showspromise in recent trials. Synthetic-biology-basedengineering of T lymphocytes to expresshigh-affinity antigen receptors can overcomeimmune tolerance, which has been a majorlimitation of immunotherapy-based strategies.Advances in cell engineering and cultureapproaches to enable efficient gene transfer andex vivo cell expansion have facilitated broaderevaluation of this technology, moving adoptivetransfer from a \"boutique\" application to thecusp of a mainstream technology. The majorchallenge currently facing the field is to increasethe specificity of engineered T cells for tumors,because targeting shared antigens has thepotential to lead to on-target off-tumor toxicities,as observed in recent trials. As the field ofadoptive transfer technology matures, the majorengineering challenge is the development of", "metadata": {}}
+{"_id": "41233511", "title": "", "text": "Bruce treadmill test in children: normal values ina clinic population.The Bruce treadmill protocol issuitable for children as young as age 4 years.Maximal endurance time may be used as the solecriterion of exercise capacity, and normal valueswere established with 327 children having aninnocent heart murmur. Mean endurance time inboys increased from 10.4 minutes at age 4 to 5years, to 14.1 minutes at age 13 to 15 years.Mean endurance time in girls increased from 9.5minutes at age 4 to 5 years to 12.3 minutes atage 10 to 12 years. Mean maximal heart rateranged from 193 to 206 beats/min. Agedifferences in mean maximal and submaximalheart rates were small. There were negativecorrelations between endurance time and theratio of weight to height. There were negativecorrelations between heart rates at treadmillstages 1 to 3 and the endurance times. Thecorrelation coefficient of endurance time withmaximal oxygen uptake was 0.88, but for clinicalpurposes endurance time alone is a satisfactory", "metadata": {}}
+{"_id": "41239107", "title": "", "text": "Immunoproteasome and LMP2 polymorphism inaged and Alzheimer's disease brains.In thisstudy, we investigated the presence and role ofimmunoproteasome and its LMP2 subunitpolymorphism at codon 60 in Alzheimer's disease(AD). Immunoproteasome was present in brainareas such as hippocampus and cerebellum andlocalized in neurons, astrocytes and endothelialcells. A higher expression of immunoproteasomewas found in brain of AD patients than in brain ofnon-demented elderly, being its expression inyoung brain negligible or absent. Furthermore,AD affected regions showed a partial decrease inproteasome trypsin-like activity. The study ofLMP2 polymorphism (R/H) showed that it doesnot influence LMP2 expression (neither themRNA nor mature protein) in brain tissue.However, control brain areas of AD patientscarrying the RR genotype showed an increasedproteasome activity in comparison with RHcarriers. To test whether this effect of thegenotype might be related to AD onset we", "metadata": {}}
+{"_id": "41256402", "title": "", "text": "The centrosome and its mode of inheritance: thereduction of the centrosome duringgametogenesis and its restoration duringfertilization.Neither the restoration of thecentrosome during fertilization nor its reductionduring gametogenesis is fully understood, butboth are pivotal events in development. Duringeach somatic cell cycle, the chromosomes,cytoplasm, and centrosomes duplicate ininterphase, and all three split in two during eachcell division. While it has long been recognizedthat both the sperm and the egg contribute equalhaploid genomes during fertilization and that thevast majority of the cytoplasm is contributed bythe egg, the relative contributions of thecentrosome by each gamete are still in question.This article explores centrosome inheritancepatterns and considers nine integral andsecondarily derived activities of the centrosome.Boveri once hypothesized that \"The ripe eggpossesses all of the elements necessary fordevelopment save an active division-center. The", "metadata": {}}
+{"_id": "41264017", "title": "", "text": "Aggregation of vascular risk factors and risk ofincident Alzheimer disease.BACKGROUND Theprevalence of Alzheimer disease (AD) isincreasing in the elderly, and vascular riskfactors may increase its risk. OBJECTIVE Toexplore the association of the aggregation ofvascular risk factors with AD. METHODS Theauthors followed 1,138 individuals withoutdementia at baseline (mean age 76.2) for amean of 5.5 years. The presence of vascular riskfactors was related to incident possible andprobable AD. RESULTS Four risk factors(diabetes, hypertension, heart disease, andcurrent smoking) were associated with a higherrisk of AD (p < 0.10) when analyzed individually.The risk of AD increased with the number of riskfactors (diabetes + hypertension + heart disease+ current smoking). The adjusted hazards ratioof probable AD for the presence of three or morerisk factors was 3.4 (95% CI: 1.8, 6.3; p fortrend < 0.0001) compared with no risk factors.Diabetes and current smoking were the strongest", "metadata": {}}
+{"_id": "41293601", "title": "", "text": "Hotspot mutations in H3F3A and IDH1 definedistinct epigenetic and biological subgroups ofglioblastoma.Glioblastoma (GBM) is a braintumor that carries a dismal prognosis anddisplays considerable heterogeneity. We haverecently identified recurrent H3F3A mutationsaffecting two critical amino acids (K27 and G34)of histone H3.3 in one-third of pediatric GBM.Here, we show that each H3F3A mutation definesan epigenetic subgroup of GBM with a distinctglobal methylation pattern, and that they aremutually exclusive with IDH1 mutations, whichcharacterize a third mutation-defined subgroup.Three further epigenetic subgroups wereenriched for hallmark genetic events of adultGBM and/or established transcriptomicsignatures. We also demonstrate that the twoH3F3A mutations give rise to GBMs in separateanatomic compartments, with differentialregulation of transcription factors OLIG1, OLIG2,and FOXG1, possibly reflecting different cellularorigins.", "metadata": {}}
+{"_id": "41294031", "title": "", "text": "Glucocorticoid with cyclophosphamide forparaquat-induced lung fibrosis.BACKGROUNDParaquat is an effective and widely usedherbicide but is also a lethal poison. In manydeveloping countries paraquat is widely availableand inexpensive, making poisoning preventiondifficult. However most of the people whobecome poisoned from paraquat have taken it asa means of suicide. Standard treatment forparaquat poisoning both prevents furtherabsorption and reduces the load of paraquat inthe blood through haemoperfusion orhaemodialysis. The effectiveness of standardtreatments is extremely limited. The immunesystem plays an important role in exacerbatingparaquat-induced lung fibrosis.Immunosuppressive treatment usingglucocorticoid and cyclophosphamide incombination is being developed and studied.OBJECTIVES To assess the effects ofglucocorticoid with cyclophosphamide onmortality in patients with paraquat-induced lung", "metadata": {}}
+{"_id": "41298619", "title": "", "text": "Hydroxyethyl starch (HES) versus other fluidtherapies: effects on kidneyfunction.BACKGROUND Hydroxyethyl starches(HES) are synthetic colloids commonly used forfluid resuscitation, yet controversy exists abouttheir impact on kidney function. OBJECTIVES Toexamine the effects of HES on kidney functioncompared to other fluid resuscitation therapies indifferent patient populations. SEARCH STRATEGYWe searched the Cochrane Renal Group'sspecialised register, the Cochrane CentralRegister of Controlled Trials (CENTRAL, in TheCochrane Library), MEDLINE, EMBASE,MetaRegister and reference lists of articles.SELECTION CRITERIA Randomised controlledtrials (RCTs) and quasi-RCTs in which HES wascompared to an alternate fluid therapy for theprevention or treatment of effective intravascularvolume depletion. Primary outcomes were renalreplacement therapy (RRT), author-definedkidney failure and acute kidney injury (AKI) asdefined by the RIFLE criteria. Secondary", "metadata": {}}
+{"_id": "41310252", "title": "", "text": "Dietary fat and obesity: evidence fromepidemiology.The epidemiological evidence thata high-fat diet promotes the development ofobesity is considered suggestive but notdefinitive. The purpose of this paper is to providea review of various epidemiological methods thathave been used to address this issue as well asan updated summary of the existing evidence.Ecological studies describing dietary fat intakeand obesity at the population level provide mixedresults and are likely to be biased by bothconfounding and unknown data quality factorsthat differ systematically across the populationsstudied. Cross-sectional studies are generally inagreement that the concentration of fat in thediet is positively associated with relative weight.Prospective studies of diet in relation tosubsequent weight change give inconsistentresults. This may be due to behavioural factorssuch as dieting in response to weight gain; inaddition, this type of study rarely takes intoaccount the possible interaction between genetic", "metadata": {}}
+{"_id": "41314611", "title": "", "text": "Uncoupling of leading- and lagging-strand DNAreplication during lesion bypass invivo.Numerous agents attack DNA, forminglesions that impair normal replication.Specialized DNA polymerases transiently replacethe replicative polymerase and copy past lesions,thus generating mutations, the major initiatingcause of cancer. We monitored, in Escherichiacoli, the kinetics of replication of both strands ofDNA molecules containing a single replicationblock in either the leading or lagging strand.Despite a block in the leading strand,lagging-strand synthesis proceeded further,implying transient uncoupling of concurrentstrand synthesis. Replication through the lesionrequires specialized DNA polymerases and isachieved with similar kinetics and efficiencies inboth strands.", "metadata": {}}
+{"_id": "41325555", "title": "", "text": "Phosphoinositide 3-kinase signalling--which wayto target?Abstract Phosphoinositide 3-kinases(PI3Ks) are central to the control of cell growth,proliferation and survival, and drive theprogression of tumours by activatingphosphoinositide-dependent kinase, proteinkinase B and the target of rapamycin. Otherdownstream effectors link PI3K to cell motilityand the control of cardiovascular parameters.Current knowledge indicates that PI3Ks mightqualify as drug targets for the treatment ofcancer, chronic inflammation, allergy andcardiovascular failure. However, PI3Ks alsomodulate vital processes such as metaboliccontrol and nutrient uptake. Here, mechanisticdata and mouse phenotypic analyses aresummarised, and the possible success oftherapeutic inhibition of distinct PI3K isoforms isdiscussed.", "metadata": {}}
+{"_id": "41329220", "title": "", "text": "Determination of the time course of capacitationin mouse spermatozoa using a chlortetracyclinefluorescence assay.The heads of mousespermatozoa obtained 5 min after release fromthe excised caudae epididymides showed acharacteristic fluorescence pattern in thepresence of the fluorophore chlortetracycline(CTC). There was uniform fluorescence over theentire head with about half the sperm populationshowing a brighter line of fluorescence across theequatorial segment; this fluorescence patternwas designated \"F\". After 90-min incubation inculture medium (CM) containing 2% (w/v)bovine serum albumin, most of the sperm headsshowed a dark band of nonfluorescence over theequatorial and postequatorial segment, while theanterior portion of the head showed brightfluorescence. This fluorescence pattern wasdesignated \"B.\" The time course for thedisappearance of pattern F matched the timecourse of the appearance of pattern B, with ahalf-time of 30 min. The transformation was", "metadata": {}}
+{"_id": "41329906", "title": "", "text": "[Detection of CRISPR and its relationship to drugresistance in Shigella].OBJECTIVE To detectclustered regularly interspaced short palindromicrepeats (CRISPR) in Shigella, and to analyze itsrelationship to drug resistance. METHODS Fourpairs of primers were used for the detection ofconvincing CRISPR structures CRISPR-S2 andCRISPR-S4, questionable CRISPR structuresCRISPR-S1 and CRISPR-S3 in 60 Shigella strains.All primers were designed using sequences inCRISPR database. CRISPR Finder was used toanalyze CRISPR and susceptibilities of Shigellastrains were tested by agar diffusion method.Furthermore, we analyzed the relationshipbetween drug resistance and CRISPR-S4.RESULTS The positive rate of convincing CRISPRstructures was 95%. The four CRISPR lociformed 12 spectral patterns (A-L), all of whichcontained convincing CRISPR structures excepttype K. We found one new repeat and 12 newspacers. The multi-drug resistance rate was 53.33% . We found no significant difference", "metadata": {}}
+{"_id": "41337677", "title": "", "text": "The helicase DDX41 senses intracellular DNAmediated by the adaptor STING in dendriticcellsThe recognition of pathogenic DNA isimportant to the initiation of antiviral responses.Here we report the identification of DDX41, amember of the DEXDc family of helicases, as anintracellular DNA sensor in myeloid dendritic cells(mDCs). Knockdown of DDX41 expression byshort hairpin RNA blocked the ability of mDCs tomount type I interferon and cytokine responsesto DNA and DNA viruses. Overexpression of bothDDX41 and the membrane-associated adaptorSTING together had a synergistic effect inpromoting Ifnb promoter activity. DDX41 boundboth DNA and STING and localized together withSTING in the cytosol. Knockdown of DDX41expression blocked activation of themitogen-activated protein kinase TBK1 and thetranscription factors NF-κB and IRF3 by B-formDNA. Our results suggest that DDX41 is anadditional DNA sensor that depends on STING tosense pathogenic DNA.", "metadata": {}}
+{"_id": "41340212", "title": "", "text": "Radiotherapy plus concomitant and adjuvanttemozolomide for glioblastoma.BACKGROUNDGlioblastoma, the most common primary braintumor in adults, is usually rapidly fatal. Thecurrent standard of care for newly diagnosedglioblastoma is surgical resection to the extentfeasible, followed by adjuvant radiotherapy. Inthis trial we compared radiotherapy alone withradiotherapy plus temozolomide, givenconcomitantly with and after radiotherapy, interms of efficacy and safety. METHODS Patientswith newly diagnosed, histologically confirmedglioblastoma were randomly assigned to receiveradiotherapy alone (fractionated focal irradiationin daily fractions of 2 Gy given 5 days per weekfor 6 weeks, for a total of 60 Gy) or radiotherapyplus continuous daily temozolomide (75 mg persquare meter of body-surface area per day, 7days per week from the first to the last day ofradiotherapy), followed by six cycles of adjuvanttemozolomide (150 to 200 mg per square meterfor 5 days during each 28-day cycle). The", "metadata": {}}
+{"_id": "41354899", "title": "", "text": "Drug interactions between oral contraceptivesand antibiotics.OBJECTIVE To evaluate theevidence on possible drug interactions betweenantibiotics and oral contraceptives (OCs) thatmay lead to OC failure. DATA SOURCES MEDLINEand Lexis/Nexis Medical Library searches for1966-1999 using the key word \"oralcontraceptives,\" cross-indexed with the terms\"antibiotics,\" \"adverse effects,\" and \"pregnancy,\"and MEDLINE search using the additional MeSHterm \"drug interactions. \" No languagerestrictions were used. METHODS OF STUDYSELECTION A total of 167 articles were retrievedfor analysis. Another 32 articles were identifiedby review of the references cited in thesepublications. Articles were selected based ontheir ability to provide information on therelationship between antibiotic therapy and OCefficacy in otherwise compliant users (defined aswomen with unplanned pregnancies whoreported compliance with their OC regimen).Additionally, studies that either directly", "metadata": {}}
+{"_id": "41380943", "title": "", "text": "Male Japanese quails with female brains do notshow male sexual behaviors.During embryonicdevelopment, gonadal steroid hormones(androgens and estrogens) are thought toorganize the sexual differentiation of the brain inthe heterogametic sexes of higher vertebrates(males in mammals, females in birds). Braindifferentiation of the homogametic sexes isthought to proceed by default, not requiring sexhormones for sex-specific organization. Ingallinaceous birds such as the Japanese quail,female brain organization is thought to developvia estrogen-dependent demasculinization of adefault male brain phenotype. We performedmale donor-to-female host (MF), female-to-male(FM), male-to-male (MM), and female-to-female(FF) isotopic, isochronic transplantation of theforebrain primordium in Japanese quail embryosbefore gonadal differentiation had occurred;brain chimeras had a forebrain (including thehypothalamus) originating exclusively fromdonor cells. MM, FF, and MF chimeras all showed", "metadata": {}}
+{"_id": "41403996", "title": "", "text": "DNA joint dependence of pol X family polymeraseaction in nonhomologous end joining.DNA doublestrand breaks (DSBs) can be rejoined directly bythe nonhomologous end-joining (NHEJ) pathwayof repair. Nucleases and polymerases arerequired to promote accurate NHEJ when theterminal bases of the DSB are damaged. Thesame enzymes also participate in impreciserejoining and joining of incompatible ends,important mutagenic events. Previous work hasshown that the Pol X family polymerase Pol4 isrequired for some but not all NHEJ events thatrequire gap filling in Saccharomyces cerevisiae.Here, we systematically analyzed DSB endconfigurations and found that gaps on bothstrands and overhang polarity are the principalfactors that determine whether a joint requiresPol4. DSBs with 3'-overhangs and a gap on eachstrand strongly depended on Pol4 for repair,DSBs with 5'-overhangs of the same sequencedid not. Pol4 was not required when3'-overhangs contained a gap on only one", "metadata": {}}
+{"_id": "41493639", "title": "", "text": "ABC of burns. Introduction.Burns are one of themost devastating conditions encountered inmedicine. The injury represents an assault on allaspects of the patient, from the physical to thepsychological. It affects all ages, from babies toelderly people, and is a problem in both thedeveloped and developing world. All of us haveexperienced the severe pain that even a smallburn can bring. However the pain and distresscaused by a large burn are not limited to theimmediate event. The visible physical and theinvisible psychological scars are long lasting andoften lead to chronic disability. Burn injuriesrepresent a diverse and varied challenge tomedical and paramedical staff. Correctmanagement requires a skilled multidisciplinaryapproach that addresses all the problems facinga burn patient. This series provides an overviewof the most important aspects of burn injuries forhospital and non-hospital healthcareworkers.workers. Figure 1    Top: Child with 70%full thickness burns, which required", "metadata": {}}
+{"_id": "41496215", "title": "", "text": "DNA methylation is a critical cell-intrinsicdeterminant of astrocyte differentiation in thefetal brain.Astrocyte differentiation, which occurslate in brain development, is largely dependenton the activation of a transcription factor, STAT3.We show that astrocytes, as judged by glialfibrillary acidic protein (GFAP) expression, neveremerge from neuroepithelial cells on embryonicday (E) 11.5 even when STAT3 is activated, incontrast to E14.5 neuroepithelial cells. A CpGdinucleotide within a STAT3 binding element inthe GFAP promoter is highly methylated in E11.5neuroepithelial cells, but is demethylated in cellsresponsive to the STAT3 activation signal toexpress GFAP. This CpG methylation leads toinaccessibility of STAT3 to the binding element.We suggest that methylation of a celltype-specific gene promoter is a pivotal event inregulating lineage specification in the developingbrain.", "metadata": {}}
+{"_id": "41548287", "title": "", "text": "DNMT1 Inhibition Reprograms Pancreatic CancerStem Cells via Upregulation of the miR-17-92Cluster.Pancreatic ductal adenocarcinoma(PDAC) and other carcinomas are hierarchicallyorganized, with cancer stem cells (CSC) residingat the top of the hierarchy, where they drivetumor progression, metastasis, andchemoresistance. As CSC and non-CSC share anidentical genetic background, we hypothesizethat differences in epigenetics account for thestriking functional differences between these twocell populations. Epigenetic mechanisms, such asDNA methylation, play an important role inmaintaining pluripotency and regulating thedifferentiation of stem cells, but the role of DNAmethylation in pancreatic CSC is obscure. In thisstudy, we investigated the genome-wide DNAmethylation profile of PDAC CSC, and wedetermined the importance of DNAmethyltransferases for CSC maintenance andtumorigenicity. Using high-throughputmethylation analysis, we discovered that sorted", "metadata": {}}
+{"_id": "41599676", "title": "", "text": "Mutation spectrum in the nephrin gene (NPHS1)in congenital nephrotic syndrome.Congenitalnephrotic syndrome, Finnish type (CNF orNPHS1), is an autosomal recessive diseasecharacterized by massive proteinuria anddevelopment of nephrotic syndrome shortly afterbirth. The disease is most common in Finland,but many patients have been identified in otherpopulations. The disease is caused by mutationsin the gene for nephrin which is a key componentof the glomerual ultrafilter, the podocyte slitdiaphragm. A total of 30 mutations have beenreported in the nephrin gene in patients withcongenital nephrotic syndrome worldwide. In theFinnish population, two main mutations havebeen found. These two nonsense mutationsaccount for over 94% of all mutations in Finland.Most mutations found in non-Finnish patients aremissense mutations, but they include alsononsense and splice site mutations, as well asdeletions and insertions. This mutation updatesummarizes the nature of all previously reported", "metadata": {}}
+{"_id": "41620295", "title": "", "text": "The HSA domain binds nuclear actin-relatedproteins to regulate chromatin-remodelingATPasesWe identify thehelicase-SANT–associated (HSA) domain as theprimary binding platform for nuclearactin-related proteins (ARPs) and actin.Individual HSA domains from chromatinremodelers (RSC, yeast SWI-SNF, humanSWI-SNF, SWR1 and INO80) or modifiers (NuA4)reconstitute their respective ARP–ARP orARP–actin modules. In RSC, the HSA domainresides on the catalytic ATPase subunit Sth1. TheSth1 HSA is essential in vivo, and its omissioncauses the specific loss of ARPs and a moderatereduction in ATPase activity. Genetic selectionsfor arp suppressors yielded specificgain-of-function mutations in two new domainsin Sth1, the post-HSA domain and protrusion 1,which are essential for RSC function in vivo butnot ARP association. Taken together, we definethe role of the HSA domain and provide evidencefor a regulatory relationship involving the", "metadata": {}}
+{"_id": "41644178", "title": "", "text": "Increased dendritic complexity and axonal lengthin cultured mouse cortical neuronsoverexpressing methyl-CpG-binding proteinMeCP2Rett syndrome is caused byloss-of-function mutations in the gene encodingthe methyl DNA-binding factor MeCP2. As brainmass and neuronal complexity tend to bediminished in Rett patients, we tested whetherMeCP2 directly influences the morphologicalcomplexity of developing neurons. Our resultsshow that cultured mouse neuronsoverexpressing MeCP2beta (MECP2A) developmore complex morphologies, having longeraxonal and dendritic processes, and an increasednumber of axonal and dendritic terminal endings.We then tested whether overexpressing amutant form of MeCP2beta lacking its carboxylterminus would elicit the same effects.Interestingly, while neurons overexpressing thismutant failed to enhance axonal and dendriticprocess elongation, the complexity of theiraxonal and dendritic processes remained", "metadata": {}}
+{"_id": "41646286", "title": "", "text": "Folate affects apoptosis in human trophoblasticcells.Effects of folate deficiency on the rate ofapoptosis in human cytotrophoblastic cells hasbeen investigated. Apoptosis was determined incytotrophoblastic cells after culture in 1. controlmedium, 2. folate-free medium and 3. folate-freemedium plus 10% fetal calf serum. Apoptosisrates in cells cultured in mediums 2 and 3 weresignificantly higher than those cultured in thecontrol medium (P<0.02 and P<0.03,respectively). In conclusion, humancytotrophoblastic cells show a significantlyincreased rate of apoptosis in vitro after culturein a folate-free medium. Possible explanationsfor the association between folate deficiency andpregnancy complications are suggested.", "metadata": {}}
+{"_id": "41650417", "title": "", "text": "Role of KRAS and EGFR as biomarkers ofresponse to erlotinib in National Cancer Instituteof Canada Clinical Trials Group StudyBR.21.PURPOSE To evaluate the effect of KRASand epidermal growth factor receptor (EGFR)genotype on the response to erlotinib treatmentin the BR.21, placebo-controlled trial. PATIENTSAND METHODS We analyzed 206 tumors forKRAS mutation, 204 tumors for EGFR mutation,and 159 tumors for EGFR gene copy byfluorescent in situ hybridization (FISH). Wereanalyzed EGFR deletion/mutation using twohighly sensitive techniques that detectabnormalities in samples with 5% to 10% tumorcellularity. KRAS mutation was analyzed bydirect sequencing. RESULTS Thirty patients(15%) had KRAS mutations, 34 (17%) had EGFRexon 19 deletion or exon 21 L858R mutations,and 61 (38%) had high EGFR gene copy (FISHpositive). Response rates were 10% for wild-typeand 5% for mutant KRAS (P = .69), 7% forwild-type and 27% for mutant EGFR (P = .03),", "metadata": {}}
+{"_id": "41707539", "title": "", "text": "Immune dysregulation in major depression: acritical review of existing evidence.It is now wellestablished that depression is associated withimmune dysregulation. It is not, however, knownwhether this immune dysregulation plays a rolein the pathophysiology of major depression orwhether it increases the susceptibility of thedepressed patient to immune-related disorders.This article presents a critical review of existingevidence for immune dysregulation in majordepression, including changes in leucocytetrafficking, lymphocyte function, and markers ofimmune activation. Possible mediators ofimmune dysregulation in major depression arebriefly discussed. Finally, the relationshipbetween major depression and several medicalconditions such as infection, allergy andautoimmune disorders, cardiovascular diseases,cancer and AIDS is critically reviewed.", "metadata": {}}
+{"_id": "41710132", "title": "", "text": "Regulation of E2Fs and senescence by PMLnuclear bodies.The tumor suppressor PML(promyelocytic leukemia protein) regulatescellular senescence and terminal differentiation,two processes that implicate a permanent exitfrom the cell cycle. Here, we show that themechanism by which PML induces a permanentcell cycle exit and activates p53 and senescenceinvolves a recruitment of E2F transcriptionfactors bound to their promoters and theretinoblastoma (Rb) proteins to PML nuclearbodies enriched in heterochromatin proteins andprotein phosphatase 1α. Blocking the functionsof the Rb protein family or adding back E2Fs toPML-expressing cells can rescue their defects inE2F-dependent gene expression and cellproliferation, inhibiting the senescent phenotype.In benign prostatic hyperplasia, a neoplasticdisease that displays features of senescence,PML was found to be up-regulated and formingnuclear bodies. In contrast, PML bodies wererarely visualized in prostate cancers. The newly", "metadata": {}}
+{"_id": "41735503", "title": "", "text": "The International Classification of HeadacheDisorders.A set of related medical disorders thatlack a proper classification system and diagnosticcriteria is like a society without laws. The resultis incoherence at best, chaos at worst. For thisreason, the International Classification ofHeadache Disorders (ICHD) is arguably thesingle most important breakthrough in headachemedicine over the last 50 years. The ICHDidentifies and categorizes more than a hundreddifferent kinds of headache in a logical,hierarchal system. Even more important, it hasprovided explicit diagnostic criteria for all of theheadache disorders listed. The ICHD quicklybecame universally accepted, and criticism of theclassification has been minor relative to thatdirected at other disease classification systems.Over the 20 years following publication of thefirst edition of the ICHD, headache research hasrapidly accelerated despite sparse allocation ofresources to that effort. In summary, the ICHDhas attained widespread acceptance at the", "metadata": {}}
+{"_id": "41774099", "title": "", "text": "Call to Develop a Standard Acquisition ChargeModel for Kidney Paired DonationWe propose aMedicare Demonstration Project to develop astandard acquisition charge for kidney paireddonation. A new payment strategy is requiredbecause Medicare and commercial insurancecompanies may not directly pay living donorcosts intended to lead to transplantation of abeneficiary of a different insurance provider.Until the 1970s, when organ procurementorganizations were empowered to serve asfinancial intermediaries to pay the upfrontrecovery expenses for deceased donor kidneysbefore knowing the identity of the recipient,there existed similar limitations in the recoveryand placement of deceased donor organs.Analogous to the recovery of deceased donorkidneys, kidney paired donation requires theevaluation of living donors before identifyingtheir recipient. Tissue typing, crossmatching andtransportation of living donors or their kidneysrepresent additional financial barriers. Finally,", "metadata": {}}
+{"_id": "41781905", "title": "", "text": "Oxidant stress promotes disease by activatingCaMKII.CaMKII is activated by oxidation ofmethionine residues residing in the regulatorydomain. Oxidized CaMKII (ox-CaMKII) is nowthought to participate in cardiovascular andpulmonary diseases and cancer. This invitedreview summarizes current evidence for the roleof ox-CaMKII in disease, considers criticalknowledge gaps and suggests new areas forinquiry.", "metadata": {}}
+{"_id": "41782935", "title": "", "text": "Genetic diagnosis and prognosis of Alzheimer'sdisease: challenges andopportunities.Alzheimer's disease (AD), the mostcommon form of dementia in western societies,is a pathologically and clinically heterogeneousdisease with a strong genetic component. Therecent advances in high-throughput genometechnologies allowing for the rapid analysis ofmillions of polymorphisms in thousands ofsubjects has significantly advanced ourunderstanding of the genomic underpinnings ofAD susceptibility. During the last 5 years,genome-wide association and whole-exome- andwhole-genome sequencing studies have mappedmore than 20 disease-associated loci, providinginsights into the molecular pathways involved inAD pathogenesis and hinting at potential noveltherapeutic targets. This review articlesummarizes the challenges and opportunities ofwhen using genomic information for thediagnosis and prognosis of AD.", "metadata": {}}
+{"_id": "41790911", "title": "", "text": "WNT5A regulates adipose tissue angiogenesis viaantiangiogenic VEGF-A165b in obesehumans.Experimental studies have suggestedthat Wingless-related integration site 5A(WNT5A) is a proinflammatory secreted proteinthat is associated with metabolic dysfunction inobesity. Impaired angiogenesis in fat depots hasbeen implicated in the development of adiposetissue capillary rarefaction, hypoxia,inflammation, and metabolic dysfunction. Wehave recently demonstrated that impairedadipose tissue angiogenesis is associated withoverexpression of antiangiogenic factorVEGF-A165b in human fat and the systemiccirculation. In the present study, we postulatedthat upregulation of WNT5A is associated withangiogenic dysfunction and examined its role inregulating VEGF-A165b expression in humanobesity. We biopsied subcutaneous and visceraladipose tissue from 38 obese individuals (bodymass index: 44 ± 7 kg/m2, age: 37 ± 11 yr)during planned bariatric surgery and", "metadata": {}}
+{"_id": "41811327", "title": "", "text": "At least 1400 base pairs of 5'-flanking DNA isrequired for the correct expression of the HOgene in yeast.Homothallic yeast cells undergo aspecific pattern of mating-type switchinginitiated by an endonuclease encoded by the HOgene. HO transcription is affected by cell type (a,alpha, and a/alpha), by cell age (mother ordaughter), and by the cell cycle. This paperinvestigates the sequences involved in HOtranscription by replacing genomic DNA withcopies mutated in vitro. A region between -1000and 1400 (called URS1) is necessary fortranscription in addition to a \"TATA\"-like regionat -90. The 900 bp of DNA separating URS1 fromthe \"TATA\" box is not necessary for transcriptionnor for a/alpha repression and some measure ofmother/daughter control, but it is necessary forcorrect cell cycle control.", "metadata": {}}
+{"_id": "41822527", "title": "", "text": "Inflammation and its role in neuroprotection,axonal regeneration and functional recovery afterspinal cord injury.Trauma to the central nervoussystem (CNS) triggers intraparenchymalinflammation and activation of systemicimmunity with the capacity to exacerbateneuropathology and stimulate mechanisms oftissue repair. Despite our incompleteunderstanding of the mechanisms that controlthese divergent functions, immune-basedtherapies are becoming a therapeutic focus. Thisreview will address the complexities andcontroversies of post-traumaticneuroinflammation, particularly in spinal cord. Inaddition, current therapies designed to targetneuroinflammatory cascades will be discussed.", "metadata": {}}
+{"_id": "41852733", "title": "", "text": "Order of intron removal influences multiple spliceoutcomes, including a two-exon skip, in aCOL5A1 acceptor-site mutation that results inabnormal pro-alpha1(V) N-propeptides andEhlers-Danlos syndrome type I.Ehlers-Danlossyndrome (EDS) type I (the classical variety) is adominantly inherited, genetically heterogeneousconnective-tissue disorder. Mutations in theCOL5A1 and COL5A2 genes, which encode type Vcollagen, have been identified in severalindividuals. Most mutations affect either thetriple-helical domain of the protein or theexpression of one COL5A1 allele. We identified anovel splice-acceptor mutation (IVS4-2A-->G) inthe N-propeptide-encoding region of COL5A1, inone patient with EDS type I. The outcome of thismutation was complex: In the major product,both exons 5 and 6 were skipped; other productsincluded a small amount in which only exon 5was skipped and an even smaller amount inwhich cryptic acceptor sites within exon 5 wereused. All products were in frame. Pro-alpha1(V)", "metadata": {}}
+{"_id": "41877386", "title": "", "text": "Kruppel-like factor KLF10 targets transforminggrowth factor-beta1 to regulate CD4(+)CD25(-)T cells and T regulatory cells.CD4(+)CD25(+)regulatory T cells (T regs) play a major role inthe maintenance of self-tolerance and immunesuppression, although the mechanismscontrolling T reg development and suppressorfunction remain incompletely understood.Herein, we provide evidence that Kruppel-likefactor 10 (KLF10/TIEG1) constitutes animportant regulator of T regulatory cellsuppressor function and CD4(+)CD25(-) T cellactivation through distinct mechanisms involvingtransforming growth factor (TGF)-beta1 andFoxp3. KLF10 overexpressing CD4(+)CD25(-) Tcells induced both TGF-beta1 and Foxp3expression, an effect associated with reducedT-Bet (Th1 marker) and Gata3 (Th2 marker)mRNA expression. Consistently, KLF10(-/-)CD4(+)CD25(-) T cells have enhanceddifferentiation along both Th1 and Th2 pathwaysand elaborate higher levels of Th1 and Th2", "metadata": {}}
+{"_id": "41900731", "title": "", "text": "Synchrotron radiation solution X-ray scatteringstudy of the pH dependence of the quaternarystructure of yeast pyruvate decarboxylase.ThepH dependence of the quaternary structure ofpyruvate decarboxylase from yeast was studiedin the range 6.2 less than pH less than 8.4.There is an equilibrium with a midpoint aroundpH 7.5 between tetramers and dimers, and thecatalytic activity of the enzyme depends on thevolume fraction of tetramer. This equilibriummay provide an additional regulating mechanismbesides substrate activation since accumulationof pyruvate would lead to a reduction in pH andhence an increase of the concentration of thecatalytically active tetramer. Radiation damageduring the X-ray scattering experiments resultsin a shift of this equilibrium and in the formationof octamers. These effects could becircumvented and analyzed using experimentaland data processing methods which can bereadily applied to other radiation-sensitivesystems. The low-resolution shapes of the", "metadata": {}}
+{"_id": "41911192", "title": "", "text": "Enhancement of anxiety-like responsiveness tothe cannabinoid CB(1) receptor agonist HU-210following chronic stress.The effect that chronicunpredictable stress had on the anxiety-likeresponse elicited by the cannabinoid receptoragonist HU-210[3-(1,1-dimethylheptyl)-(-)-11-hydroxy-delta8-tetrahydrocannabinol] in the elevated plusmaze was investigated here. Male Long-Evansrats were either unstressed or were subjected toa 21-day regimen of chronic unpredictablestress, and subsequently were subdivided intothree testing groups (vehicle, 10 and 50microg/kg of HU-210) and tested on the elevatedplus maze. Results demonstrated that inunstressed animals, a low dose of HU-210induced an anxiolytic response, whereas a highdose induced an anxiogenic response. Further, instressed animals both the low and the high dosesof HU-210 induced anxiogenic responses. Thesefindings suggest that chronic stress enhanceseither cannabinoid receptor responsivity or one", "metadata": {}}
+{"_id": "41913714", "title": "", "text": "Cardiac glycosides inhibit TNF-α/NF-κB signalingby blocking recruitment of TNFreceptor-associated death domain to the TNFreceptorDigitoxin and structurally related cardiacglycoside drugs potently block activation of theTNF-α/NF-κB signaling pathway. We havehypothesized that the mechanism might bediscovered by searching systematically forselective inhibitory action through the entirepathway. We report that the common action ofthese drugs is to block the TNF-α-dependentbinding of TNF receptor 1 to TNFreceptor-associated death domain. This drugaction can be observed with native cells, such asHeLa, and reconstituted systems prepared inHEK293 cells. All other antiinflammatory effectsof digitoxin on NF-κB and c-Jun N-terminalkinase pathways appear to follow from theblockade of this initial upstream signaling event.", "metadata": {}}
+{"_id": "41915616", "title": "", "text": "Zinc supplementation during lactation: effects onmaternal status and milk zinc concentrations.Theeffects of a zinc supplement on maternal zincstatus and milk zinc concentrations through > or= 7 mo of lactation were examined. Seventy-onelactating women received either a daily 15-mgzinc supplement (ZS, n = 40) or placebo (NZS, n= 31) started by 2 wk postpartum in adouble-blind, randomized design. Overall meanzinc intakes were 13.0 +/- 3.4 mg/d for the NZSgroup and 25.7 +/- 3.9 mg/d (includingsupplement) for the ZS group. Plasma zincconcentrations of the ZS group were significantlyhigher than those of the NZS group (P = 0.05).Milk zinc concentrations declined significantlyover the course of the study for all subjects butwere not affected by zinc supplementation. Themean dietary zinc intake observed in thenonsupplemented group was adequate tomaintain normal maternal zinc status and milkzinc concentrations through > or = 7 molactation. Similar controlled intervention trials in", "metadata": {}}
+{"_id": "41925568", "title": "", "text": "DMSO as a vehicle for central injections: testswith feeding elicited by norepinephrine injectedinto the paraventricular nucleus.Dimethylsulfoxide (DMSO) is becoming increasinglypopular as a vehicle in studies employing centralinjections. The aim of the present study was todetermine whether the vehicle required forsolubilization of substances for central injection[75% DMSO and 25% artificial CSF (aCSF)]would alter the well-characterized stimulatoryresponse to norepinephrine (NE) injected intothe paraventricular nucleus (PVN) on short-termfood intake. To evaluate its suitability, wecompared the effects of repeated unilateralinjections of NE dissolved in two differentvehicles (100% aCSF or 75% DMSO, 25%aCSF), in separate groups of animals every 48 hover a 30-day period. NE (40 nmol) stimulatedfood intake by approximately sevenfoldcompared to either vehicle alone, and thestimulatory effect was similar whether aCSF or75% DMSO was used as a vehicle. Furthermore,", "metadata": {}}
+{"_id": "41928290", "title": "", "text": "Dodecameric structure and ATPase activity of thehuman TIP48/TIP49 complex.TIP48 and TIP49are two related and highly conserved eukaryoticAAA(+) proteins with an essential biologicalfunction and a critical role in major pathwaysthat are closely linked to cancer. They are foundtogether as components of several highlyconserved chromatin-modifying complexes. Bothproteins show sequence homology to bacterialRuvB but the nature and mechanism of theirbiochemical role remain unknown. Recombinanthuman TIP48 and TIP49 were assembled into astable high molecular mass equimolar complexand tested for activity in vitro. TIP48/TIP49complex formation resulted in synergisticincrease in ATPase activity but ATP hydrolysiswas not stimulated in the presence ofsingle-stranded, double-stranded or four-wayjunction DNA and no DNA helicase or branchmigration activity could be detected. Complexeswith catalytic defects in either TIP48 or TIP49had no ATPase activity showing that both", "metadata": {}}
+{"_id": "41976370", "title": "", "text": "Associations between work-related factors andspecific disorders of the shoulder--a systematicreview of the literature.OBJECTIVE Our aim wasto provide a quantitative assessment of theexposure-response relationships betweenwork-related physical and psychosocial factorsand the occurrence of specific shoulder disordersin occupational populations. METHODS Asystematic review of the literature wasconducted on the associations between type ofwork, physical load factors, and psychosocialaspects at work, on the one hand, and theoccurrence of tendinitis of the biceps tendon,rotator cuff tears, subacromial impingementsyndrome (SIS), and suprascapular nervecompression, on the other hand. Associationsbetween work factors and shoulder disorderswere expressed in quantitative measures as oddsratio (OR) or relative risk (RR). RESULTS Theoccurrence of SIS was associated with forcerequirements >10% maximal voluntarycontraction (MVC), lifting >20 kg >10 times/day,", "metadata": {}}
+{"_id": "41982985", "title": "", "text": "Altered TCR signaling from geometricallyrepatterned immunological synapses.Theimmunological synapse is a specialized cell-celljunction that is defined by large-scale spatialpatterns of receptors and signaling molecules yetremains largely enigmatic in terms of formationand function. We used supported bilayermembranes and nanometer-scale structuresfabricated onto the underlying substrate toimpose geometric constraints on immunologicalsynapse formation. Analysis of the resultingalternatively patterned synapses revealed acausal relation between the radial position of Tcell receptors (TCRs) and signaling activity, withprolonged signaling from TCR microclusters thathad been mechanically trapped in the peripheralregions of the synapse. These results areconsistent with a model of the synapse in whichspatial translocation of TCRs represents a directmechanism of signal regulation.", "metadata": {}}
+{"_id": "42009630", "title": "", "text": "Molecular regulation of histone H3 trimethylationby COMPASS and the regulation of geneexpression.The Set1-containing complexCOMPASS, which is the yeast homolog of thehuman MLL complex, is required for mono-, di-,and trimethylation of lysine 4 of histone H3. Wehave performed a comparative global proteomicscreen to better define the role of COMPASS inhistone trimethylation. We report that bothCps60 and Cps40 components of COMPASS arerequired for proper histone H3 trimethylation,but not for proper regulation oftelomere-associated gene silencing. PurifiedCOMPASS lacking Cps60 can mono- anddimethylate but is not capable of trimethylatingH3(K4). Chromatin immunoprecipitation (ChIP)studies indicate that the loss subunits ofCOMPASS required for histone trimethylation donot affect the localization of Set1 to chromatinfor the genes tested. Collectively, our resultssuggest a molecular requirement for severalcomponents of COMPASS for proper histone H3", "metadata": {}}
+{"_id": "42035464", "title": "", "text": "Mitosis-specific anchoring of gamma tubulincomplexes by pericentrin controls spindleorganization and mitotic entry.Microtubulenucleation is the best known function ofcentrosomes. Centrosomal microtubulenucleation is mediated primarily by gammatubulin ring complexes (gamma TuRCs).However, little is known about the molecules thatanchor these complexes to centrosomes. In thisstudy, we show that the centrosomal coiled-coilprotein pericentrin anchors gamma TuRCs atspindle poles through an interaction with gammatubulin complex proteins 2 and 3 (GCP2/3).Pericentrin silencing by small interfering RNAs insomatic cells disrupted gamma tubulinlocalization and spindle organization in mitosisbut had no effect on gamma tubulin localizationor microtubule organization in interphase cells.Similarly, overexpression of the GCP2/3 bindingdomain of pericentrin disrupted the endogenouspericentrin-gamma TuRC interaction andperturbed astral microtubules and spindle", "metadata": {}}
+{"_id": "42065070", "title": "", "text": "High levels of viral replication contrast with onlytransient changes in CD4(+) and CD8(+) cellnumbers during the early phase of experimentalinfection with simian immunodeficiency virusSIVmnd-1 in Mandrillus sphinx.Early eventsduring human immunodeficiency virus infectionsare considered to reflect the capacity of the hostto control infection. We have studied early virusand host parameters during the early phase ofsimian immunodeficiency virus SIVmnd-1nonpathogenic infection in its natural host,Mandrillus sphinx. Four mandrills wereexperimentally infected with a primary SIVmnd-1strain derived from a naturally infected mandrill.Two noninfected control animals were monitoredin parallel. Blood and lymph nodes were collectedat three time points before infection, twice aweek during the first month, and at days 60,180, and 360 postinfection (p.i.). Anti-SIVmnd-1antibodies were detected starting from days 28to 32 p.i. Neither elevated temperature norincreased lymph node size were observed. The", "metadata": {}}
+{"_id": "42080024", "title": "", "text": "Vascular endothelial growth factor stimulatesbone repair by promoting angiogenesis and boneturnover.Several growth factors are expressed indistinct temporal and spatial patterns duringfracture repair. Of these, vascular endothelialgrowth factor, VEGF, is of particular interestbecause of its ability to induce neovascularization(angiogenesis). To determine whether VEGF isrequired for bone repair, we inhibited VEGFactivity during secondary bone healing via acartilage intermediate (endochondralossification) and during direct bone repair(intramembranous ossification) in a novel mousemodel. Treatment of mice with a soluble,neutralizing VEGF receptor decreasedangiogenesis, bone formation, and callusmineralization in femoral fractures. Inhibition ofVEGF also dramatically inhibited healing of atibial cortical bone defect, consistent with ourdiscovery of a direct autocrine role for VEGF inosteoblast differentiation. In separateexperiments, exogenous VEGF enhanced blood", "metadata": {}}
+{"_id": "42095718", "title": "", "text": "Psychiatric comorbidity in chronic dailyheadache.Clinical evidence suggests that chronicdaily headache (CDH) occurs in association withpsychopathologies: previous studies havefocused particularly on migraine. To evaluate thisassociation, we studied, using the DSM-IIIRcriteria, a population of 88 patients (18M, 70F)affected by CDH (mean duration 7.4 +/- 8.7years). We documented the presence of apsychiatric disorder in 90% of this population.The most frequent diagnosis was a comorbidityof anxiety and mood disorders. The comorbidityof psychiatric disorders and headache hasimportant implications as far as treatment isconcerned.", "metadata": {}}
+{"_id": "42106119", "title": "", "text": "An Expanded Oct4 Interaction Network:Implications for Stem Cell Biology, Development,and DiseaseThe transcription factor Oct4 is keyin embryonic stem cell identity andreprogramming. Insight into its partners shouldilluminate how the pluripotent state isestablished and regulated. Here, we identify aconsiderably expanded set of Oct4-bindingproteins in mouse embryonic stem cells. We findthat Oct4 associates with a varied set of proteinsincluding regulators of gene expression andmodulators of Oct4 function. Half of its partnersare transcriptionally regulated by Oct4 itself orother stem cell transcription factors, whereasone-third display a significant change inexpression upon cell differentiation. The majorityof Oct4-associated proteins studied to date showan early lethal phenotype when mutated. Afraction of the human orthologs is associatedwith inherited developmental disorders orcausative of cancer. The Oct4 interactomeprovides a resource for dissecting mechanisms of", "metadata": {}}
+{"_id": "42150015", "title": "", "text": "Reproductive and lifestyle determinants ofanti-Müllerian hormone in a largepopulation-based study.CONTEXT Anti-müllerianhormone (AMH) is an ovarian reserve markerthat is increasingly applied in clinical practice asa prognostic and diagnostic tool. Despiteincreased use of AMH in clinical practice,large-scale studies addressing the influence ofpossible determinants on AMH levels are scarce.OBJECTIVE We aimed to address the role ofreproductive and lifestyle determinants of AMH ina large population-based cohort of women.DESIGN In this cross-sectional study,age-specific AMH percentiles were calculatedusing general linear modeling with CG-LMS (Coleand Green, Lambda, Mu, and Sigma model, anestablished method to calculate growth curvesfor children). SETTING Women from the generalcommunity participating in the DoetinchemCohort study were assessed. PARTICIPANTS Twothousand three hundred twenty premenopausalwomen were included. MAIN OUTCOME", "metadata": {}}
+{"_id": "42185082", "title": "", "text": "Primary care and health insurance amongwomen released from New York City jails.Factorsassociated with primary care utilization andhealth insurance coverage were examinedamong 511 women leaving jail in New York Cityfrom 1997-2001. One year after release, roughlyhalf of the sample reported primary careutilization (47%) and health insurance coverage(56%). Neither outcome was more likely amongthose reporting diabetes, asthma, or depression.Primary care utilization was more likely amongthose reporting receipt of public benefits, healthinsurance coverage, moderate social support,avoidance of illegal activity, and HIVseropositivity. Health insurance coverage wasassociated with receipt of public benefits,hospitalization, primary care, and avoidingre-arrest. This study demonstrated that amajority of women leaving jail, including thosewith chronic diseases, lack primary care. Thesedata highlight the need to plan for continuity ofcare from corrections to the community and", "metadata": {}}
+{"_id": "42240424", "title": "", "text": "The effects of prion protein proteolysis anddisaggregation on the strain properties ofhamster scrapie.Native mammalian prions existin self-propagating strains that exhibit distinctiveclinical, pathological and biochemicalcharacteristics. Prion strain diversity isassociated with variations in PrP(Sc)conformation, but it remains unknown preciselywhich physical properties of the PrP(Sc)molecules are required to encipher mammalianprion strain phenotypes. In this study, wesubjected prion-infected brain homogenatesderived from three different hamster scrapiestrains to either (i) proteinase K digestion or (ii)sonication, and inoculated the modified samplesinto normal hamsters. The results show that thestrain-specific clinical features andneuropathological profiles of inoculated animalswere not affected by either treatment. Similarly,the strain-dependent biochemical characteristicsof the PrP(Sc) molecules (includingelectrophoretic mobility, glycoform composition,", "metadata": {}}
+{"_id": "42267740", "title": "", "text": "Methylation of histone H3 lysine-79 by Dot1pplays multiple roles in the response to UVdamage in Saccharomyces cerevisiae.Variousproteins have been found to play roles in boththe repair of UV damaged DNA andheterochromatin-mediated silencing in the yeastSaccharomyces cerevisiae. In particular, factorsthat are involved in the methylation of lysine-79of histone H3 by Dot1p have been implicated inboth processes, suggesting a bipartite functionfor this modification. We find that a dot1 nullmutation and a histone H3 point mutation atlysine-79 cause increased sensitivity to UVradiation, suggesting that lysine-79 methylationis important for efficient repair of UV damage.Epistasis analysis between dot1 and various UVrepair genes indicates that lysine-79 methylationplays overlapping roles within the nucleotideexcision, post-replication and recombinationrepair pathways, as well as RAD9-mediatedcheckpoint function. In contrast, epistasisanalysis with the H3 lysine-79 point mutation", "metadata": {}}
+{"_id": "42278130", "title": "", "text": "Unmet need for personal assistance withactivities of daily living among olderadults.PURPOSE This study examined theprevalence, correlates, and negativeconsequences of unmet need for personalassistance with activities of daily living (ADLs)among older adults. DESIGN AND METHODS Theauthors analyzed cross-sectional data from the1994 National Health Interview Survey'sSupplement on Aging. Data were weighted to berepresentative of the noninstitutionalizedpopulation aged 70 years and older. RESULTSOverall, 20.7% of those needing help to perform1 or more ADLs (an estimated 629,000 persons)reported receiving inadequate assistance; forindividual ADLs, the prevalence of unmet needranged from 10.2% (eating) to 20.1%(transferring). The likelihood of having 1 or moreunmet needs was associated with lowerhousehold income, multiple ADL difficulties, andliving alone. Nearly half of those with unmetneeds reported experiencing a negative", "metadata": {}}
+{"_id": "42279414", "title": "", "text": "Multi-stage chemical carcinogenesis in mouseskin: Fundamentals and applicationsFor morethan 60 years, the chemical induction of tumorsin mouse skin has been used to studymechanisms of epithelial carcinogenesis andevaluate modifying factors. In the traditionaltwo-stage skin carcinogenesis model, theinitiation phase is accomplished by theapplication of a sub-carcinogenic dose of acarcinogen. Subsequently, tumor development iselicited by repeated treatment with atumor-promoting agent. The initiation protocolcan be completed within 1–3 h depending on thenumber of mice used; whereas the promotionphase requires twice weekly treatments (1–2 h)and once weekly tumor palpation (1–2 h) for theduration of the study. Using the protocoldescribed here, a highly reproducible papillomaburden is expected within 10–20 weeks withprogression of a portion of the tumors tosquamous cell carcinomas within 20–50 weeks.In contrast to complete skin carcinogenesis, the", "metadata": {}}
+{"_id": "42291761", "title": "", "text": "Preventing deaths by drowning in children in theUnited Kingdom: have we made progress in 10years? Population based incidence study.Detailedinformation on drowning in children is notroutinely collected by offices of nationalstatistics. Few studies have been carried out inthe United Kingdom, and none has been done onBritish children abroad. In 1988-9, two of theauthors (AMK and JRS) combined informationfrom national statistical offices, police forces(Royal Life Saving Society), and from a presscutting service (Royal Society for Prevention ofAccidents) for a detailed analysis of deaths bydrowning in children.1, 2, 3 This analysis foundthat 149 children had drowned in the UnitedKingdom during 1998-9. It also identified asafety agenda, which focused on young childrenin garden ponds and pools and on older childrenswimming without supervision. Over the past 10years there have been initiatives on children'ssafety in water, particularly swimming. Weobtained similar information for 1998-9 to", "metadata": {}}
+{"_id": "42298280", "title": "", "text": "Hypoxic heterogeneity in human tumors: EF5binding, vasculature, necrosis, andproliferation.We evaluated the levels anddistribution of hypoxia in 31 human tumors usingfluorescent immunohistochemical detection ofbinding by the 2-nitroimidazole, EF5. Hypoxiawas found to be a heterogeneous property ofhuman tumors. Necrosis was usually foundadjacent to the highest level of binding in anindividual patient's tumor. However, hypoxiaoften occurred without necrosis. In the group oftumors studied, the most common relationshipbetween blood vessels (PECAM/CD31) and EF5staining was consistent with diffusion-limitedhypoxia; acute hypoxia occurred infrequently.Within a given patient's tumor, there was aninverse correlation between regions ofproliferation (Ki-67) and regions of hypoxia.Again, however, when these parameters wereexamined in a group of patients, the absence ofproliferation did not predict the presence ofhypoxia. The relationships between hypoxia and", "metadata": {}}
+{"_id": "42314147", "title": "", "text": "The Sp1-like protein BTEB3 inhibits transcriptionvia the basic transcription element box byinteracting with mSin3A and HDAC-1co-repressors and competing with Sp1.Sp1-likeproteins are characterized by three conservedC-terminal zinc finger motifs that bind GC-richsequences found in promoters of numerousgenes essential for mammalian cell homeostasis.These proteins behave as transcriptionalactivators or repressors. Although significantinformation has been reported on the molecularmechanisms by which Sp1-like activatorsfunction, relatively little is known aboutmechanisms for repressor proteins. Here wereport the functional characterization of BTEB3, aubiquitously expressed Sp1-like transcriptionalrepressor. GAL4 assays show that the N terminusof BTEB3 contains regions that can act as directrepressor domains. Immunoprecipitation assaysreveal that BTEB3 interacts with the co-repressormSin3A and the histone deacetylase proteinHDAC-1. Gel shift assays demonstrate that", "metadata": {}}
+{"_id": "42330403", "title": "", "text": "Perceptual limits in a simulated \"Cocktailparty\".Numerosity judgments of simultaneoustalkers were examined. Listeners were requiredto report the number of talkers heard when thisnumber varied (1 to 13). Spatial location oftalkers (1 or 6 locations), duration of talkervoices (0.8 s, 5.0 s, and 15.0 s), and genderarrangement of talkers also were manipulated infour experiments. In all experiments, theproportion of correct numerosity judgmentsmonotonically decreased as talker numbersincreased. Perceptual limits, defined as talkernumbers with proportion correct scores of 0.5,varied between 3 to 5 talkers, on average,depending on listening conditions, and weresignificantly higher for spatially separatedtalkers, for the longer voices, and for the mixedgender voices (Experiments 1, 2, and 3). Inaddition, Experiment 4 found that averagenumerosity response times increasedmonotonically over a range of one to fourtalkers. These results support the idea that,", "metadata": {}}
+{"_id": "42373087", "title": "", "text": "The MOS social support survey.This paperdescribes the development and evaluation of abrief, multidimensional, self-administered, socialsupport survey that was developed for patientsin the Medical Outcomes Study (MOS), atwo-year study of patients with chronicconditions. This survey was designed to becomprehensive in terms of recent thinking aboutthe various dimensions of social support. Inaddition, it was designed to be distinct fromother related measures. We present a summaryof the major conceptual issues considered whenchoosing items for the social support battery,describe the items, and present findings basedon data from 2987 patients (ages 18 and older).Multitrait scaling analyses supported thedimensionality of four functional support scales(emotional/informational, tangible, affectionate,and positive social interaction) and theconstruction of an overall functional socialsupport index. These support measures aredistinct from structural measures of social", "metadata": {}}
+{"_id": "42373943", "title": "", "text": "Can hematological parameters discriminatemalaria from nonmalarious acute febrile illness inthe tropics?BACKGROUND Malaria is consideredas the main differential diagnosis of acute febrileillness in the tropics, and alteration of varioushematological parameters has been observed inpatients with malaria. AIM To ascertain if certainhematological parameters increase theprobability of malaria in patients with acutefebrile illnesses. SETTINGS AND DESIGN Hospitalbased, prospective cohort study. METHODS ANDMATERIAL All consecutive in patients with feverof less than seven days in duration were includedin the study. Patients where localizing cause forfever could be determined were excluded.Hematological parameters (Hemoglobin, Red celldistribution width (RDW), Leukocyte count, andplatelet counts) were determined by usingautomated counter, and peripheral smearexamination for malarial parasite was taken asgold standard for the diagnosis of malaria.STATISTICAL ANALYSIS USED Diagnostic", "metadata": {}}
+{"_id": "42377686", "title": "", "text": "14q deletions are associated with trisomy 12,NOTCH1 mutations and unmutated IGHV genesin chronic lymphocytic leukemia and smalllymphocytic lymphoma.Deletions of the long armof chromosome 14 [del(14q)] are rare butrecurrently observed in mature B-cell neoplasms,particularly in chronic lymphocytic leukemia(CLL). To further characterize this aberration, westudied 81 cases with del(14q): 54 of CLL and 27of small lymphocytic lymphoma (SLL), thelargest reported series to date. Using karyotypeand fluorescence in situ hybridization (FISH), themost frequent additional abnormality wastrisomy 12 (tri12), observed in 28/79 (35%)cases, followed by del13q14 (12/79, 15%),delTP53 (11/80, 14%) delATM (5/79, 6%), anddel6q21 (3/76, 4%). IGHV genes wereunmutated in 41/53 (77%) patients, with a highfrequency of IGHV1-69 (21/52, 40%). NOTCH1gene was mutated in 14/45 (31%) patients.There was no significant difference in cytogeneticand molecular abnormalities between CLL and", "metadata": {}}
+{"_id": "42387637", "title": "", "text": "Rapid DNA methylation changes after exposureto traffic particles.RATIONALE Exposure toparticulate air pollution has been related toincreased hospitalization and death, particularlyfrom cardiovascular disease. Lower blood DNAmethylation content is found in processes relatedto cardiovascular outcomes, such as oxidativestress, aging, and atherosclerosis. OBJECTIVESWe evaluated whether particulate pollutionmodifies DNA methylation in heavily methylatedsequences with high representation throughoutthe human genome. METHODS We measuredDNA methylation of long interspersed nucleotideelement (LINE)-1 and Alu repetitive elements byquantitative polymerase chainreaction-pyrosequencing of 1,097 blood samplesfrom 718 elderly participants in the Boston areaNormative Aging Study. We usedcovariate-adjusted mixed models to account forwithin-subject correlation in repeated measures.We estimated the effects on DNA methylation ofambient particulate pollutants (black carbon,", "metadata": {}}
+{"_id": "42404093", "title": "", "text": "Incidence of adverse drug events and potentialadverse drug events. Implications for prevention.ADE Prevention Study Group.OBJECTIVES Toassess incidence and preventability of adversedrug events (ADEs) and potential ADEs. Toanalyze preventable events to developprevention strategies. DESIGN Prospectivecohort study. PARTICIPANTS All 4031 adultadmissions to a stratified random sample of 11medical and surgical units in two tertiary carehospitals over a 6-month period. Units includedtwo medical and three surgical intensive careunits and four medical and two surgical generalcare units. MAIN OUTCOME MEASURES Adversedrug events and potential ADEs. METHODSIncidents were detected by stimulated self-reportby nurses and pharmacists and by daily review ofall charts by nurse investigators. Incidents weresubsequently classified by two independentreviewers as to whether they represented ADEsor potential ADEs and as to severity andpreventability. RESULTS Over 6 months, 247", "metadata": {}}
+{"_id": "42421723", "title": "", "text": "Induction of galactokinase in Saccharomycescerevisiae: kinetics of induction and glucoseeffects.The induced synthesis of galactokinaseand the repressing effects of glucose on thissynthesis have been investigated in whole yeastcells rendered permeable by treatment withdimethyl sulfoxide. It was found that theinduction response of uninduced cells togalactose is clearly dependent on the nature ofthe carbon source upon which the culture wasgrown prior to exposure to galactose.Glucose-grown cells exhibited a long lag beforeinduction, whereas lactate-grown cells exhibitedinduced synthesis within 8 min. A concentrationof 0.5% galactose was found to be optimal forinduction. The addition of glucose to yeastcultures growing on galactose resulted in asevere transient repression of synthesis whichwas followed by a resumed rate of synthesischaracteristic of a weaker permanent cataboliterepression. Neither 2-deoxygalactose nor fucoseacted as gratuitous inducers of the pathway, nor", "metadata": {}}
+{"_id": "42441846", "title": "", "text": "Gene--nutrition interactions in coronary arterydisease: correlation between the MTHFR C677Tpolymorphism and folate and homocysteinestatus in a Korean population.INTRODUCTIONElevated plasma total homocysteine is a majorrisk for coronary artery disease (CAD).Methyltetrahydrofolate reductase (MTHFR) is amain regulatory enzyme in homocysteinemetabolism; a common C677T mutation in theMTHFR gene results in decreased enzymeactivity, and contributes to increasedhomocysteine levels and decreased folate levels.We investigated the frequency of MTHFR C677Talleles in a Korean population, determined thegenotype-specific threshold levels of folate orvitamin B12, and investigated the relationshipbetween the TT genotype and the risk of CAD.MATERIALS AND METHODS We enrolled a studypopulation of 163 CAD patients and 50 controlsubjects, and screened the MTHFR C677Tpolymorphism using real-time PCR with meltingpoint analysis. Levels of plasma homocysteine,", "metadata": {}}
+{"_id": "42465769", "title": "", "text": "Human bone marrow adipocytes blockgranulopoiesis through neuropilin-1-inducedgranulocyte colony-stimulating factorinhibition.Adipocytes are part of hematopoieticmicroenvironment, even though up to now inhumans, their role in hematopoiesis is stillquestioned. We have previously shown thataccumulation of fat cells in femoral bone marrow(BM) coincides with increased expression ofneuropilin-1 (NP-1), while it is weakly expressedin hematopoietic iliac crest BM. Starting from thisobservation, we postulated that adipocytes mightexert a negative effect on hematopoiesismediated through NP-1. To test this hypothesis,we set up BM adipocytes differentiated intofibroblast-like fat cells (FLFC), which share themajor characteristics of primitive unilocular fatcells, as an experimental model. As expected,FLFCs constitutively produced macrophagecolony stimulating factor and induced CD34(+)differentiation into macrophages independentlyof cell-to-cell contact. By contrast, granulopoiesis", "metadata": {}}
+{"_id": "42484543", "title": "", "text": "The transcriptome profile of human embryonicstem cells as defined by SAGE.Human embryonicstem (ES) cell lines that have the ability toself-renew and differentiate into specific celltypes have been established. The molecularmechanisms for self-renewal and differentiation,however, are poorly understood. We determinedthe transcriptome profiles for two proprietaryhuman ES cell lines (HES3 and HES4, ES CellInternational), and compared them with murineES cells and other human tissues. Human andmouse ES cells appear to share a number ofexpressed gene products although there arenumerous notable differences, including aninactive leukemia inhibitory factor pathway andthe high preponderance of several importantgenes like POU5F1 and SOX2 in human ES cells.We have established a list of genes comprised ofknown ES-specific genes and new candidatesthat can serve as markers for human ES cellsand may also contribute to the \"stemness\"phenotype. Of particular interest was the", "metadata": {}}
+{"_id": "42489926", "title": "", "text": "Small-molecule antagonists of p53-MDM2binding: research tools and potentialtherapeutics.p53 regulates a key pathway whichprotects normal tissues from tumor developmentthat may result from diverse forms of stress. Inthe absence of stress, growth suppressive andproapoptotic activity of p53 is inhibited by MDM2which binds p53 and negatively regulates itsactivity and stability. MDM2 antagonists couldactivate p53 and may offer a novel therapeuticapproach to cancer. Recently, we identified thefirst potent and selective low molecular weightinhibitors of MDM2-p53 binding, the Nutlins.These molecules activate the p53 pathway andsuppress tumor growth in vitro and in vivo. Theyrepresent valuable new tools for studying thep53 pathway and its defects in cancer. Nutlinsinduce p53-dependent apoptosis in humancancer cells but appear cytostatic to proliferatingnormal cells. Their potent activity againstosteosarcoma xenografts suggests that MDM2antagonists may have clinical utility in the", "metadata": {}}
+{"_id": "42520882", "title": "", "text": "Slipped (CTG)•(CAG) repeats can be correctlyrepaired, escape repair or undergo error-pronerepairExpansion of (CTG)•(CAG) repeats, thecause of 14 or more diseases, is presumed toarise through escaped repair of slipped DNAs.We report the fidelity of slipped-DNA repair usinghuman cell extracts and DNAs with slip-outs of(CAG)20 or (CTG)20. Three outcomes occurred:correct repair, escaped repair and error-pronerepair. The choice of repair path depended onnick location and slip-out composition (CAG orCTG). A new form of error-prone repair wasdetected whereby excess repeats wereincompletely excised, constituting a previouslyunknown path to generate expansions but notdeletions. Neuron-like cell extracts yielded eachof the three repair outcomes, supporting a rolefor these processes in (CTG)•(CAG) instability inpatient post-mitotic brain cells. Mismatch repair(MMR) and nucleotide excision repair (NER)proteins hMSH2, hMSH3, hMLH1, XPF, XPG orpolymerase β were not required—indicating that", "metadata": {}}
+{"_id": "42565477", "title": "", "text": "High Dub3 expression in mouse ESCs couples theG1/S checkpoint to pluripotency.The molecularmechanism underlying G1/S checkpoint bypassin mouse embryonic stem cells (ESCs) remainsunknown. DNA damage blocks S phase entry byinhibiting the CDK2 kinase through destruction ofits activator, the Cdc25A phosphatase. Weobserved high Cdc25A levels in G1 that persisteven after DNA damage in mouse ESCs. We alsofound higher expression of Dub3, adeubiquitylase that controls Cdc25A proteinabundance. Moreover, we demonstrate that theDub3 gene is a direct target of Esrrb, a keytranscription factor of the self-renewalmachinery. We show that Dub3 expression isstrongly downregulated during neural conversionand precedes Cdc25A destabilization, whileforced Dub3 expression in ESCs becomes lethalupon differentiation, concomitant to cell-cycleremodeling and lineage commitment. Finally,knockdown of either Dub3 or Cdc25A inducedspontaneous differentiation of ESCs. Altogether,", "metadata": {}}
+{"_id": "42601237", "title": "", "text": "Paracrine effects of direct intramyocardialimplantation of bone marrow derived cells toenhance neovascularization in chronic ischaemicmyocardium.OBJECTIVE To determine theoptimal bone marrow (BM) cell types, and theirpotential mechanisms of action forneovascularization in chronic ischaemicmyocardium. METHODS AND RESULTS Thefunctional effects, angiogenic potential andcytokine expression of direct intramyocardialimplantation of autologous BM CD31-positiveendothelial progenitor cells (EPC, n=9), BMmononuclear cells (MNCs, n=9), and saline(n=9) were compared in a swine model ofchronic ischaemic myocardium. Autologous BMcells were harvested and catheter-basedelectromechanical mapping-guided directintramyocardial injection was performed totarget ischaemic myocardium. After 12 weeks,injection of BM-MNC resulted in significantimprovements in left ventricular dP/dt(+21+/-8%, P=0.032), left ventricular pressure", "metadata": {}}
+{"_id": "42662816", "title": "", "text": "Endogenous miRNA sponge lincRNA-RoRregulates Oct4, Nanog, and Sox2 in humanembryonic stem cell self-renewal.The embryonicstem cell (ESC) transcriptional and epigeneticnetworks are controlled by a multilayerregulatory circuitry, including core transcriptionfactors (TFs), posttranscriptional modifiermicroRNAs (miRNAs), and some otherregulators. However, the role of large intergenicnoncoding RNAs (lincRNAs) in this regulatorycircuitry and their underlying mechanismremains undefined. Here, we demonstrate that alincRNA, linc-RoR, may function as a keycompeting endogenous RNA to link the networkof miRNAs and core TFs, e.g., Oct4, Sox2, andNanog. We show that linc-RoR sharesmiRNA-response elements with these core TFsand that linc-RoR prevents these core TFs frommiRNA-mediated suppression in self-renewinghuman ESC. We suggest that linc-RoR forms afeedback loop with core TFs and miRNAs toregulate ESC maintenance and differentiation.", "metadata": {}}
+{"_id": "42693833", "title": "", "text": "Foxp3(+) T cells regulate immunoglobulin aselection and facilitate diversification of bacterialspecies responsible for immunehomeostasis.Foxp3(+) T cells play a critical rolefor the maintenance of immune tolerance. Herewe show that in mice, Foxp3(+) T cellscontributed to diversification of gut microbiota,particularly of species belonging to Firmicutes.The control of indigenous bacteria by Foxp3(+) Tcells involved regulatory functions both outsideand inside germinal centers (GCs), consisting ofsuppression of inflammation and regulation ofimmunoglobulin A (IgA) selection in Peyer'spatches, respectively. Diversified and selectedIgAs contributed to maintenance of diversifiedand balanced microbiota, which in turn facilitatedthe expansion of Foxp3(+) T cells, induction ofGCs, and IgA responses in the gut through asymbiotic regulatory loop. Thus, the adaptiveimmune system, through cellular and molecularcomponents that are required for immunetolerance and through the diversification as well", "metadata": {}}
+{"_id": "42708716", "title": "", "text": "The isolation and characterization of a cDNAencoding phospholipid-specific inositolpolyphosphate 5-phosphatase.We report thecDNA cloning and characterization of a novelhuman inositol polyphosphate 5-phosphatase(5-phosphatase) that has substrate specificityunlike previously described members of thislarge gene family. All previously describedmembers hydrolyze water soluble inositolphosphates. This enzyme hydrolyzes only lipidsubstrates, phosphatidylinositol3,4,5-trisphosphate and phosphatidylinositol4,5-bisphosphate. The cDNA isolated comprises3110 base pairs and predicts a protein product of644 amino acids and M(r) = 70,023. Wedesignate this 5-phosphatase as type IV. It is ahighly basic protein (pI = 8.8) and has thegreatest affinity toward phosphatidylinositol3,4,5-trisphosphate of known 5-phosphatases.The K(m) is 0.65 micrometer, 1/10 that of SHIP(5.95 micrometer), another 5-phosphatase thathydrolyzes phosphatidylinositol", "metadata": {}}
+{"_id": "42731834", "title": "", "text": "Lack of Absent in Melanoma 2 (AIM2) expressionin tumor cells is closely associated with poorsurvival in colorectal cancer patients.Functionalstudies on colorectal cancer cells indicated aprotective role of the interferon-inducible dsDNAsensor Absent in Melanoma 2 (AIM2) in cancerprogression. Given that a high mutation rate andlack of AIM2 expression was previously detectedin a subset of colorectal cancers, we hereinvestigated the association of AIM2 expressionin tumor cells and patient prognosis (5-yearfollow-up). A tissue microarray analysis of 476matched tissue pairs (colorectal tumor andadjacent normal colon epithelium) wasperformed by two independent observers.Samples from 62 patients were excludedbecause of missing follow-up information or dueto neo-adjuvant therapy before tissue sampling.Out of the remaining 414 tissue pairs, 279(67.4%) displayed reduced AIM2 expression incancer cells when compared to epithelial cells oftheir normal counterpart. Thirty-eight patients", "metadata": {}}
+{"_id": "42782688", "title": "", "text": "VSL#3 probiotic upregulates intestinal mucosalalkaline sphingomyelinase and reducesinflammation.BACKGROUND Alkalinesphingomyelinase, an enzyme found exclusivelyin bile and the intestinal brush border,hydrolyzes sphingomyelin into ceramide,sphingosine and sphingosine-1-phosphate,thereby inducing epithelial apoptosis. Reducedlevels of alkaline sphingomyelinase have beenfound in premalignant and malignant intestinalepithelia and in ulcerative colitis tissue. Probioticbacteria can be a source of sphingomyelinase.OBJECTIVE To determine the effect of VSL#3probiotic therapy on mucosal levels of alkalinesphingomyelinase, both in a mouse model ofcolitis and in patients with ulcerative colitis.METHODS Interleukin-10 gene-deficient(IL10KO) and wild type control mice weretreated with VSL#3 (10(9) colony-forming unitsper day) for three weeks, after which alkalinesphingomyelinase activity was measured in ilealand colonic tissue. As well, 15 patients with", "metadata": {}}
+{"_id": "42787108", "title": "", "text": "Nodal/Activin signaling predicts humanpluripotent stem cell lines prone to differentiatetoward the hematopoieticlineage.Lineage-specific differentiation potentialvaries among different human pluripotent stemcell (hPSC) lines, becoming therefore highlydesirable to prospectively know which hPSC linesexhibit the highest differentiation potential for acertain lineage. We have compared thehematopoietic potential of 14 human embryonicstem cell (hESC)/induced pluripotent stem cell(iPSC) lines. The emergence of hemogenicprogenitors, primitive and mature blood cells,and colony-forming unit (CFU) potential wasanalyzed at different time points. Significantdifferences in the propensity to differentiatetoward blood were observed among hPSCs:some hPSCs exhibited good blood differentiationpotential, whereas others barely displayedblood-differentiation capacity. Correlation studiesrevealed that the CFU potential robustlycorrelates with hemogenic progenitors and", "metadata": {}}
+{"_id": "42800527", "title": "", "text": "Addition of a Gastrointestinal MicrobiomeModulator to Metformin Improves MetforminTolerance and Fasting GlucoseLevels.BACKGROUND Adverse effects ofmetformin are primarily related togastrointestinal (GI) intolerance that could limittitration to an efficacious dose or causediscontinuation of the medication. Because somemetformin side effects may be attributable toshifts in the GI microbiome, we tested whether aGI microbiome modulator (GIMM) used incombination with metformin would amelioratethe GI symptoms. METHODS A 2-periodcrossover study design was used with 2treatment sequences, either placebo in period 1followed by GIMM in period 2 or vice versa.Study periods lasted for 2 weeks, with a 2-weekwashout period between. During the first week,type 2 diabetes patients (T2D) who experiencedmetformin GI intolerance took 500 mgmetformin along with their assigned NM504(GIMM) or placebo treatment with breakfast and", "metadata": {}}
+{"_id": "42836872", "title": "", "text": "Diverse tumorigenic pathways in ovarian serouscarcinoma.This study was undertaken to analyzegenetic alterations in 108 sporadic serousovarian neoplasms to elucidate ovarian serouscarcinogenesis. Our results demonstrate thatK-ras mutations occur in approximately 50% ofserous borderline tumors (SBTs), non-invasivemicropapillary serous carcinomas (MPSCs), andinvasive micropapillary serous carcinomas, whichrepresent a morphological continuum of tumorprogression. Moreover, progressive increase inthe degree of allelic imbalance of chromosomes1p, 5q, 8p, 18q, 22q, and Xp was observedcomparing serous borderline tumors tononinvasive and invasive micropapillary serouscarcinomas. In contrast, high-grade(conventional serous carcinoma) tumorscontained wild-type K-ras in all 23 cases studiedand a high frequency of allelic imbalance even insmall (early) primary tumors similar to thatfound in advanced stage tumors. Based on thesefindings, we propose a dualistic model for", "metadata": {}}
+{"_id": "42855554", "title": "", "text": "Tissue-inherent fate of GPI revealed byGPI-anchored GFP transgenesis.To clarify thefate of glycosylphosphatidylinositol (GPI) inmammals, we developed GPI-anchored enhancedgreen fluorescent protein (EGFP-GPI) andtransgenic mice carrying this fusion construct.When it was introduced to culture cells, theEGFP-GPI protein was correctly sorted to plasmamembranes and microsomes depending on GPIbiosynthesis. Transgenic mice carrying EGFP-GPIwere found to show a broad transgeneexpression. Histologically, a prominent polarizedlocalization of EGFP-GPI protein was observed invarious epithelia, the nervous system and liverand secreted from some exocrine glands, as wellas non-polarized presence in non-epithelialtissues, demonstrating a tissue-inherent mannerof GPI sorting.", "metadata": {}}
+{"_id": "42865134", "title": "", "text": "Essential role for the SANT domain in thefunctioning of multiple chromatin remodelingenzymes.The SANT domain is a novel motiffound in a number of eukaryotic transcriptionalregulatory proteins that was identified based onits homology to the DNA binding domain ofc-myb. Here we show that the SANT domain isessential for the in vivo functions of yeast Swi3p,Ada2p, and Rsc8p, subunits of three distinctchromatin remodeling complexes. We also findthat the Ada2p SANT domain is essential forhistone acetyltransferase activity of native,Gcn5p-containing HAT complexes. Furthermore,kinetic analyses indicate that an intact SANTdomain is required for an Ada2p-dependentenhancement of histone tail binding andenzymatic catalysis by Gcn5p. Our results areconsistent with a general role for SANT domainsin functional interactions with histone N-terminaltails.", "metadata": {}}
+{"_id": "42873134", "title": "", "text": "Mechanisms of pancreatic beta-cell death in type1 and type 2 diabetes: many differences, fewsimilarities.Type 1 and type 2 diabetes arecharacterized by progressive beta-cell failure.Apoptosis is probably the main form of beta-celldeath in both forms of the disease. It has beensuggested that the mechanisms leading tonutrient- and cytokine-induced beta-cell death intype 2 and type 1 diabetes, respectively, sharethe activation of a final common pathwayinvolving interleukin (IL)-1beta, nuclear factor(NF)-kappaB, and Fas. We review herein thesimilarities and differences between themechanisms of beta-cell death in type 1 and type2 diabetes. In the insulitis lesion in type 1diabetes, invading immune cells producecytokines, such as IL-1beta, tumor necrosisfactor (TNF)-alpha, and interferon (IFN)-gamma.IL-1beta and/or TNF-alpha plus IFN-gammainduce beta-cell apoptosis via the activation ofbeta-cell gene networks under the control of thetranscription factors NF-kappaB and STAT-1.", "metadata": {}}
+{"_id": "42913391", "title": "", "text": "Health-related quality of life among children withacute lymphoblastic leukemia.BACKGROUND Theobjective was to quantify the health-relatedquality of life (HRQL) of children treated foracute lymphoblastic leukemia (ALL) and identifyspecific disabilities for remediation. PROCEDURETwo types of subjects were included: ALLpatients 5 plus years old in a multi-center clinicaltrial and general population control groups.Patients were assessed during all four majorphases of active treatment and approximately 2years after treatment. Health status and HRQLwere measured using HEALTH UTILITIESINDEX® (HUI®) Mark 2 (HUI2) and Mark 3(HUI3). HRQL scores were used to calculatequality-adjusted life years (QALYs). Excessdisability rates identified attributes forremediation. RESULTS HUI assessments (n =749) were collected during the five phases. MeanHRQL increased from induction through thepost-treatment phase (P < 0.001). There wereno significant demographic or treatment effects", "metadata": {}}
+{"_id": "42944505", "title": "", "text": "JUVENILE MORTALITY INCREASES WITH CLUTCHSIZE IN A NEOTROPICAL BIRDThe change inavian clutch size with latitude is a celebratedexample of geographic variation in a vertebratelife-history trait. Alternative hypotheses for thispattern invoke nest predation, limited food fornestlings, or post-fledging juvenile mortality asselection pressures leading to small clutch size oftropical birds. We manipulated the clutch size ofSpotted Antbirds (Hylophylax naevioides) incentral Panama to test these hypotheses. Weobserved that rates of nest predation were notinfluenced by parental activity at nests andparents could successfully feed nestlings inenlarged broods. Although larger broodsproduced the most fledged juveniles, theseindividuals were less likely to survive to dispersalthan were juveniles that fledged from smallerbroods. Consequently, nest productivity did notvary with clutch size. Post-fledging mortality wasnot related to nestling mass two to three daysprior to fledging. Rather, differences in the", "metadata": {}}
+{"_id": "42950029", "title": "", "text": "Diagnosis of rotator cuff tears.Rotator cuff tearsaccount for almost 50% of major shoulderinjuries but are sometimes difficult to diagnose.To aid diagnosis, we did a prospective study,comparing results of 23 clinical tests from 400patients with and without rotator cuff tears.Three simple tests were predictive for rotatorcuff tear: supraspinatus weakness, weakness inexternal rotation, and impingement. When allthree were positive, or if two tests were positiveand the patient was aged 60 or older, theindividual had a 98% chance of having a rotatorcuff tear; combined absence of these featuresexcluded this diagnosis.", "metadata": {}}
+{"_id": "43014661", "title": "", "text": "Increased susceptibility to UV-induced skincarcinogenesis in polymerase eta-deficientmice.Xeroderma pigmentosum variant (XPV)patients with mutations in the DNA polymeraseeta (pol eta) gene are hypersensitive to sunlightand have greatly increased susceptibility tosunlight-induced skin cancer. Consistent with theability of Pol eta to efficiently bypass UVlight-induced cyclobutane pyrimidine dimers,XPV cells lacking Pol eta have diminishedcapacity to replicate UV-damaged DNA and aresensitive to UV light-induced killing andmutagenesis. To better understand these andother Pol eta functions, we generated Poleta-deficient mice. Mice homozygous for a nullmutation in pol eta are viable, fertile, and do notshow any obvious spontaneous defects duringthe first year of life. However, fibroblasts derivedfrom these mutant mice are sensitive to killingby exposure to UV light, and all Pol eta-deficientmice develop skin tumors after UV irradiation, incontrast to the wild-type littermate controls that", "metadata": {}}
+{"_id": "43048059", "title": "", "text": "Hydrogen sulfide interacts with nitric oxide in theheart: possible involvement of nitroxyl.AIMS Thepresent study aims to investigate the interactionbetween nitric oxide (NO) and hydrogen sulfide(H(2)S), the two important gaseous mediators inrat hearts. METHODS AND RESULTS Intracellularcalcium in isolated cardiomyocytes wasmeasured with a spectrofluorometric methodusing Fura-2. Myocyte contractility wasmeasured with a video edge system. NaHS (50µM, an H(2)S donor) had no significant effect onthe resting calcium level, electrically induced (EI)calcium transients, and cell contractility inventricular myocytes. Stimulating endogenousNO production with l-arginine or exogenousapplication of NO donors [sodium nitroprusside(SNP) and2-(N,N-diethylamino)-diazenolate-2-oxide]decreased myocyte twitch amplitudesaccompanied by slower velocities of both cellcontraction and relaxation. Surprisingly, NaHSreversed the negative inotropic and lusitropic", "metadata": {}}
+{"_id": "43054703", "title": "", "text": "A novel mechanism of rapid nuclear neutrophilextracellular trap formation in response toStaphylococcus aureus.Neutrophil extracellulartraps (NETs) are webs of DNA covered withantimicrobial molecules that constitute a newlydescribed killing mechanism in innate immunedefense. Previous publications reported thatNETs take up to 3-4 h to form via anoxidant-dependent event that requires lyticdeath of neutrophils. In this study, we describeneutrophils responding uniquely toStaphylococcus aureus via a novel process ofNET formation that did not require neutrophillysis or even breach of the plasma membrane.The multilobular nucleus rapidly became roundedand condensed. During this process, weobserved the separation of the inner and outernuclear membranes and budding of vesicles, andthe separated membranes and vesicles werefilled with nuclear DNA. The vesicles wereextruded intact into the extracellular spacewhere they ruptured, and the chromatin was", "metadata": {}}
+{"_id": "43122426", "title": "", "text": "131-I radioiodine therapy for hyperthyroidism inpatients with Graves' disease, uninodular goitreand multinodular goitre.We studied 201consecutive patients who received a relativelyfixed dose of radioiodine for the treatment ofhyperthyroidism between the years 1981-6.Patients with Graves' disease (170) were initiallytreated with a mean (SE) dose of 369 (10) MBq131-I with a remission rate of 94% at 6 monthsand a cumulative relapse rate of 12% at oneyear and 21% at 5 years. The cumulativeincidence of hypothyroidism was 26% at 3months, 55% at 6 months, 61% at 1 year and66% at 5 years. Patients with a uninodular goitre(10) were initially treated with a mean (SE) doseof 438 (85) MBq 131-I with a remission rate of100% at 6 months, without relapse at 1 year butrelapsing in 17% at 5 years. The cumulativeincidence of hypothyroidism was 26% at 3months, 30% at 6 months, 40% at 1 year and40% at 5 years. Patients with a multinodulargoitre (21) were initially treated with a mean", "metadata": {}}
+{"_id": "43128141", "title": "", "text": "Enteral nutrition in the critically ill patient.Timingand route of nutrition provided to critically illpatients can affect their outcome. Early enteralnutrition has been shown to decrease specificallyinfectious morbidity in the critically ill patient.There is a small group of patients who aremalnourished on arrival to the intensive care unitand in these patients parenteral nutrition isbeneficial.", "metadata": {}}
+{"_id": "43156471", "title": "", "text": "Genomewide analysis of nucleosome densityhistone acetylation and HDAC function in fissionyeast.We have conducted a genomewideinvestigation into the enzymatic specificity,expression profiles, and binding locations of fourhistone deacetylases (HDACs), representing thethree different phylogenetic classes in fissionyeast (Schizosaccharomyces pombe). By directlycomparing nucleosome density, histoneacetylation patterns and HDAC binding in bothintergenic and coding regions with geneexpression profiles, we found that Sir2 (class III)and Hos2 (class I) have a role in preventinghistone loss; Clr6 (class I) is the principalenzyme in promoter-localized repression. Hos2has an unexpected role in promoting highexpression of growth-related genes bydeacetylating H4K16Ac in their open readingframes. Clr3 (class II) acts cooperatively withSir2 throughout the genome, including the silentregions: rDNA, centromeres, mat2/3 andtelomeres. The most significant acetylation sites", "metadata": {}}
+{"_id": "43165768", "title": "", "text": "In vitro antimicrobial activity of mangrove plantSonneratia alba.OBJECTIVE To investigate theantimicrobial property of mangrove plantSonneratia alba (S. alba). METHODS Theantimicrobial activity was evaluated using discdiffusion and microdilution methods against sixmicroorganisms. Soxhlet apparatus was used forextraction with a series of solvents, n-hexane,ethyl acetate and methanol in sequence ofincreasing polarity. RESULTS Methanol extractappeared to be the most effective extract whilen-hexane extract showed no activity. Theantimicrobial activities were observed against thegram positive bacteria Staphylococcus aureus (S.aureus) and Bacillus cereus (B. cereus), thegram negative Escherichia coli (E. coli) and theyeast Cryptococcus neoformans. Pseudomonasaeruginosa and Candida albicans appeared to benot sensitive to the concentrations tested sinceno inhibition zone was observed. E. coli (17.5mm) appeared to be the most sensitive strainfollowed by S. aureus (12.5 mm) and B. cereus", "metadata": {}}
+{"_id": "43192375", "title": "", "text": "Obesity induces a phenotypic switch in adiposetissue macrophage polarization.Adipose tissuemacrophages (ATMs) infiltrate adipose tissueduring obesity and contribute to insulinresistance. We hypothesized that macrophagesmigrating to adipose tissue upon high-fat feedingmay differ from those that reside there undernormal diet conditions. To this end, we found anovel F4/80(+)CD11c(+) population of ATMs inadipose tissue of obese mice that was not seenin lean mice. ATMs from lean mice expressedmany genes characteristic of M2 or \"alternativelyactivated\" macrophages, including Ym1, arginase1, and Il10. Diet-induced obesity decreasedexpression of these genes in ATMs whileincreasing expression of genes such as thoseencoding TNF-alpha and iNOS that arecharacteristic of M1 or \"classically activated\"macrophages. Interestingly, ATMs from obeseC-C motif chemokine receptor 2-KO (Ccr2-KO)mice express M2 markers at levels similar tothose from lean mice. The antiinflammatory", "metadata": {}}
+{"_id": "43220289", "title": "", "text": "Psychological Outcome 4 Years after RestrictiveBariatric SurgeryExtreme obesity is associatedwith severe psychiatric and somatic comorbidityand impairment of psychosocial functioning.Bariatric surgery is the most effective treatmentnot only with regard to weight loss but also withobesity-associated illnesses. Health-relatedpsychological and psychosocial variables havebeen increasingly considered as importantoutcome variables of bariatric surgery. However,the long-term impact of bariatric surgery onpsychological and psychosocial functioning islargely unclear. The aim of this study was toevaluate the relationship between the course ofweight and psychological variables includingdepression, anxiety, health-related quality of life(HRQOL), and self-esteem up to 4 years afterobesity surgery. By standardized questionnairesprior to (T1) and 1 year (T2), 2 years (T3), and 4years (T4) after surgery, 148 patients (47 males(31.8 %), 101 females (68.2 %), mean age 38.8± 10.2 years) were assessed. On average,", "metadata": {}}
+{"_id": "43224840", "title": "", "text": "Dynamics of Microvillus Extension and TetherFormation in Rolling Leukocytes.P-selectinglycoprotein ligand-1 (PSGL-1) binding toP-selectin mediates leukocyte rolling underconditions of flow. In human neutrophils, a typeof leukocyte belonging to the innate immunesystem, PSGL-1 molecules are located on theneutrophil's surface ruffles, called microvilli. Eachnewly formed P-selectin-PSGL-1 bond canbecome load bearing, imposing on its microvillusa pulling force that deforms the microvillus.Depending on the magnitude of the bond force, amicrovillus can be extended, or a thin membranecylinder (a tether) can be formed at the tip of themicrovillus. Here we propose a Kelvin-Voigtviscoelastic material as an improved model formicrovillus extension. Using a modified versionof our Event-Tracking Model of Adhesion (ETMA),we demonstrate how P-selectin-PSGL-1load-bearing bonds shape microvillusdeformation during neutrophil rolling at lowshear (wall shear rate of 50 s(-1), P-selectin site", "metadata": {}}
+{"_id": "43226130", "title": "", "text": "Female Gender and Reproductive FactorsAffecting Risk, Relapses and Progression inMultiple SclerosisMultiple sclerosis (MS), achronic inflammatory demyelina-ting anddegenerative disease of the central nervoussystem, is a frequent cause of neurologicaldisability in young adults. Female predominancehas increased over the last decades. Althoughfemale gender carries a higher risk of developingrelapsing remitting MS, being female and atchild-bearing age also appears to provide someprotection against cognitive decline and againstprogressive onset MS, an adverse predictivefactor when considering long-term disability inMS. The risk of MS in women has beenassociated with an earlier age at menarche. Inmost studies, parity did not impact MS risk.However, the recently published association ofhigher parity and offspring number with areduced risk of a first demyelinating eventsuggests a potential suppressive effect.Pregnancy in MS patients has been associated", "metadata": {}}
+{"_id": "43283375", "title": "", "text": "Spatial release from masking based on binauralprocessing for up to six maskers.Spatial Releasefrom Masking (SRM) was measured foridentification of a female target word spoken inthe presence of male masker words. Targetwords from a single loudspeaker located atmidline were presented when two, four, or sixmasker words were presented either from thesame source as the target or from spatiallyseparated masker sources. All masker wordswere presented from loudspeakers locatedsymmetrically around the centered target sourcein the front azimuth hemifield. Three maskingconditions were employed: speech-in-speechmasking (involving both informational andenergetic masking), speech-in-noise masking(involving energetic masking), and filteredspeech-in-filtered speech masking (involvinginformational masking). Psychophysical resultswere summarized as three-point psychometricfunctions relating proportion of correct wordidentification to target-to-masker ratio (in", "metadata": {}}
+{"_id": "43311750", "title": "", "text": "Nephrin mutations cause childhood- andadult-onset focal segmentalglomerulosclerosis.Mutations in the NPHS1 genecause congenital nephrotic syndrome of theFinnish type presenting before the first 3 monthsof life. Recently, NPHS1 mutations have alsobeen identified in childhood-onsetsteroid-resistant nephrotic syndrome and mildercourses of disease, but their role in adults withfocal segmental glomerulosclerosis remainsunknown. Here we developed an in silico scoringmatrix to evaluate the pathogenicity ofamino-acid substitutions using the biophysicaland biochemical difference between wild-typeand mutant amino acid, the evolutionaryconservation of the amino-acid residue inorthologs, and defined domains, with theaddition of contextual information. Mutationanalysis was performed in 97 patients from 89unrelated families, of which 52 presented withsteroid-resistant nephrotic syndrome after 18years of age. Compound heterozygous or", "metadata": {}}
+{"_id": "43329366", "title": "", "text": "Use of clomifene during early pregnancy and riskof hypospadias: population based case-controlstudy.Clomifene is widely used for inducingovulation.1 It is structurally related todiethylstilbestrol, which has been linked tovaginal and cervical clear cell adenocarcinoma inwomen exposed in utero. The adverse effect isless severe in sons, although links to testicularcancer and urogenital anomalies, such asepididymal cysts, have been reported.2 3 Arecent study also found an increased risk ofhypospadias in the sons of women exposed todiethylstilbestrol in utero.4 Clomifene has a halflife of about five days, but its metabolites havebeen found in blood samples on day 22 of themenstrual cycle and in faeces up to six weeksafter administration.5 The occurrence ofhypospadias may be increasing. Little is knownabout the risk of hypospadias in boys born towomen who have used clomifene to induceovulation. ### Methods and results  Ourcase-control study was done in the Danish", "metadata": {}}
+{"_id": "43334921", "title": "", "text": "Association of aspirin and NSAID use with risk ofcolorectal cancer according to geneticvariants.IMPORTANCE Use of aspirin and othernonsteroidal anti-inflammatory drugs (NSAIDs)is associated with lower risk of colorectal cancer.OBJECTIVE To identify common genetic markersthat may confer differential benefit from aspirinor NSAID chemoprevention, we tested gene ×environment interactions between regular use ofaspirin and/or NSAIDs and single-nucleotidepolymorphisms (SNPs) in relation to risk ofcolorectal cancer. DESIGN, SETTING, ANDPARTICIPANTS Case-control study using datafrom 5 case-control and 5 cohort studies initiatedbetween 1976 and 2003 across the UnitedStates, Canada, Australia, and Germany andincluding colorectal cancer cases (n=8634) andmatched controls (n=8553) ascertained between1976 and 2011. Participants were all of Europeandescent. EXPOSURES Genome-wide SNP dataand information on regular use of aspirin and/orNSAIDs and other risk factors. MAIN OUTCOMES", "metadata": {}}
+{"_id": "43378932", "title": "", "text": "Intravaginal ring eluting tenofovir disoproxilfumarate completely protects macaques frommultiple vaginal simian-HIV challenges.Topicalpreexposure prophylaxis interrupts HIVtransmission at the site of mucosal exposure.Intermittently dosed vaginal gels containing theHIV-1 reverse transcriptase inhibitor tenofovirprotected pigtailed macaques depending on thetiming of viral challenge relative to gelapplication. However, modest or no protectionwas observed in clinical trials. Intravaginal rings(IVRs) may improve efficacy by providinglong-term sustained drug delivery leading toconstant mucosal antiretroviral concentrationsand enhancing adherence. Although a few IVRshave entered the clinical pipeline, 100% efficacyin a repeated macaque vaginal challenge modelhas not been achieved. Here we describe areservoir IVR technology that delivers thetenofovir prodrug tenofovir disoproxil fumarate(TDF) continuously over 28 d. With four monthlyring changes in this repeated challenge model,", "metadata": {}}
+{"_id": "43385013", "title": "", "text": "Epithelial and mesenchymal subpopulationswithin normal basal breast cell lines exhibitdistinct stem cell/progenitor properties.It hasbeen proposed that epithelial-mesenchymaltransition (EMT) in mammary epithelial cells andbreast cancer cells generates stem cell features,and that the presence of EMT characteristics inclaudin-low breast tumors reveals their origin inbasal stem cells. It remains to be determined,however, whether EMT is an inherent property ofnormal basal stem cells, and if the presence of amesenchymal-like phenotype is required for themaintenance of all their stem cell properties. Weused nontumorigenic basal cell lines as models ofnormal stem cells/progenitors and demonstratethat these cell lines contain an epithelialsubpopulation (\"EpCAM+,\" epithelial celladhesion molecule positive[EpCAM(pos)]/CD49f(high)) that spontaneouslygenerates mesenchymal-like cells (\"Fibros,\"EpCAM(neg)/CD49f(med/low)) through EMT.Importantly, stem cell/progenitor properties such", "metadata": {}}
+{"_id": "43390777", "title": "", "text": "Involvement of members of the Rab family andrelated small GTPases in autophagosomeformation and maturationMacroautophagy, theprocess by which cytosolic components andorganelles are engulfed and degraded by adouble-membrane structure, could be viewed asa specialized, multistep membrane transportprocess. As such, it intersects with the exocyticand endocytic membrane trafficking pathways. Anumber of Rab GTPases which regulate secretoryand endocytic membrane traffic have beenshown to play either critical or accessory roles inautophagy. The biogenesis of thepre-autophagosomal isolation membrane (orphagophore) is dependent on the functionality ofRab1. A non-canonical, Atg5/Atg7-independentmode of autophagosome generation from thetrans-Golgi or endosome requires Rab9. OtherRabs, such as Rab5, Rab24, Rab33, and Rab7have all been shown to be required, or involvedat various stages of autophagosomal genesis andmaturation. Another small GTPase, RalB, was", "metadata": {}}
+{"_id": "43417006", "title": "", "text": "Comparative risk of new-onset diabetes mellitusfor antihypertensive drugs: A networkmeta-analysis.New-onset diabetes mellitus(NOD) refers to forms of diabetes mellitus thatdevelop during the therapeutic processes ofother diseases such as hypertension. This studyhas been conducted in a network meta-analysisto compare antihypertensive drugs by identifyingboth the advantages and disadvantages on NODby focusing on their respective effect rates. Oddratios and corresponding 95% confidenceintervals or credible intervals were calculatedwithin pairwise and network meta-analysis. Atotal of 38 articles with 224 140 patients wereincluded to evaluate the preventive effect ofhypertension drugs on NOD. From the networkmeta-analysis it was evident that bothangiotensin-converting enzyme inhibitor as wellas angiotensin receptor blocker treatments areassociated with a lower risk of developing NODcompared with placebo, with rankingprobabilities of 79.81% and 72.77%,", "metadata": {}}
+{"_id": "43419566", "title": "", "text": "Transformation of mammalian cells byconstitutively active MAP kinasekinase.Mitogen-activated protein (MAP) kinasekinase (MAPKK) activates MAP kinase in a signaltransduction pathway that mediates cellularresponses to growth and differentiation factors.Oncogenes such as ras, src, raf, and mos havebeen proposed to transform cells by prolongingthe activated state of MAPKK and of componentsdownstream in the signaling pathway. To testthis hypothesis, constitutively active MAPKKmutants were designed that had basal activitiesup to 400 times greater than that of theunphosphorylated wild-type kinase. Expressionof these mutants in mammalian cells activatedAP-1-regulated transcription. The cells formedtransformed foci, grew efficiently in soft agar,and were highly tumorigenic in nude mice. Thesefindings indicate that constitutive activation ofMAPKK is sufficient to promote celltransformation.", "metadata": {}}
+{"_id": "43427621", "title": "", "text": "Psychological treatment of malignant vasovagalsyncope due to bloodphobia.A 17-year-old boywith frequent faints due to blood-injury phobiawas studied. During cardiovascular reflexinvestigation in our syncope unit, 50 seconds ofasystole were recorded. He was treated usingsystematic desensitization with muscular tensionand cognitive techniques by the PediatricPsychosocial Department and has notexperienced syncopal events again.", "metadata": {}}
+{"_id": "43483151", "title": "", "text": "QT and QTc dispersion are accurate predictors ofcardiac death in newly diagnosed non-insulindependent diabetes: cohort study.Patients withnon-insulin dependent diabetes mellitus have anexcess risk of dying from cardiovascular disease.One small study suggested that a prolonged QTinterval could predict cardiac death in patientswith diabetic nephropathy who have receivedinsulin treatment. The question now is whetherthe same is true in newly diagnosed diabetes inpatients who have no apparent complications. Inaddition, QT dispersion, a new but relatedelectrocardiographic variable, predicts cardiacdeath in patients who have chronic heart failure,peripheral vascular disease, or essentialhypertension.1–3 We investigated whether italso predicted cardiac death in diabetic patients.The study group of 182 patients with non-insulindependent diabetes mellitus (103 men; meanage 52.8 (SD 8.5) years) represented theDundee cohort of the United Kingdomprospective diabetes study, which was recruited", "metadata": {}}
+{"_id": "43534665", "title": "", "text": "Recombinant human IL-10 prevents the onset ofdiabetes in the nonobese diabetic mouse.Therole of IL-10 in the pathogenesis of autoimmunediabetes mellitus was assessed in the nonobesediabetic (NOD) mouse. In these studies theeffect of IL-10 was determined on threeparameters of diabetes: The development ofhyperglycemia, the development of insulitis, andthe production of insulin by beta cells. Initialexperiments investigated the effect ofanticytokine antibodies on the development ofdisease. These results indicated that monoclonalanti-IFN-gamma antibody greatly reduced theincidence of hyperglycemia in female NOD mice,while anti-IL-4, IL-5, and IL-10 were ineffective.In subsequent studies, daily subcutaneousadministration of IL-10, a known potent inhibitorof IFN-gamma production by TH1 T cells, to 9and 10-week-old NODs was shown to delay theonset of disease and significantly reduce theincidence of diabetes. Histopathology performedon pancreatic tissue demonstrated that", "metadata": {}}
+{"_id": "43557480", "title": "", "text": "Arterial hypertension and progression of chronickidney disease in children during 10-yearambulatory observation.The aim of this studywas the long-term retrospective analysis ofchronic kidney disease (CKD) progression inchildren, especially with regard to the presenceof hypertension (HTN). The average rate ofprogression of CKD was higher in patients withHTN than without HTN. Hypertension treatmentrequires multidrug schemes which need to beintensified with extended time of CKD duration.", "metadata": {}}
+{"_id": "43566999", "title": "", "text": "Exercise blood flow patterns within and amongrat muscles after training.This study wasdesigned to determine the influence of along-term, moderate-intensity treadmill trainingprogram on the distribution of blood flow withinand among muscles of rats during exercise. Onegroup (T) of male Sprague-Dawley rats trainedfor 1 h/day for 13-17 wk at 30 m/min on amotor-driven treadmill. A second group (UT) ofrats was conditioned for 10 min/day for 4 wk atthe same speed. Muscle succinatedehydrogenase activities were higher in T thanUT rats indicating a significant training effect.Blood flows (BFs) in 32 hindlimb muscles ormuscle parts and other selected organs weremeasured in the two groups with radiolabeledmicrospheres during preexercise and while therats ran for 30 s, 5 min, or 15 min at 30 m/minon the treadmill. The data indicate 1) there wereno differences in total hindlimb muscle BFbetween UT and T rats at any time; however, 2)T rats had higher preexercise heart rates and", "metadata": {}}
+{"_id": "43587663", "title": "", "text": "Serious infections after unrelated donortransplantation in 136 children: impact of stemcell source.How the infection risks compare afterumbilical cord blood (UCB) and bone marrow(BM) transplantation is not known. Therefore, wecompared serious infections in the 2 years afterpediatric myeloablative unrelated donortransplantation with unmanipulated BM (n = 52),T cell-depleted (TCD) BM (n = 24), or UCB (n =60) for the treatment of hematologicmalignancy. Overall, the cumulative incidence of1 or more serious infections was comparablebetween groups (BM, 81%; TCD, 83%; UCB,90%; P = .12). Furthermore, by taking allserious infections into account and usingmultivariate techniques with unmanipulated BMas the reference, there were also no significantdifferences between groups (TCD relative risk[RR], 1.6; P = .10; UCB RR, 1.0; P = .84).Within the time periods days 0 to 42, days 43 to100, and days 101 to 180, the only differencewas a greater risk of viral infections from days 0", "metadata": {}}
+{"_id": "43602749", "title": "", "text": "The NBS1–Treacle complex controls ribosomalRNA transcription in response to DNAdamageChromosome breakage elicits transientsilencing of ribosomal RNA synthesis, but themechanisms involved remained elusive. Here wediscover an in trans signalling mechanism thattriggers pan-nuclear silencing of rRNAtranscription in response to DNA damage. This isassociated with transient recruitment of theNijmegen breakage syndrome protein 1 (NBS1),a central regulator of DNA damage responses,into the nucleoli. We further identify TCOF1 (alsoknown as Treacle), a nucleolar factor implicatedin ribosome biogenesis and mutated in TreacherCollins syndrome, as an interaction partner ofNBS1, and demonstrate that NBS1 translocationand accumulation in the nucleoli is Treacledependent. Finally, we provide evidence thatTreacle-mediated NBS1 recruitment into thenucleoli regulates rRNA silencing in trans in thepresence of distant chromosome breaks.", "metadata": {}}
+{"_id": "43619625", "title": "", "text": "Inflammatory T cells rapidly inducedifferentiation of human bone marrow stromalcells into mature osteoblasts.Activated T cellssecrete multiple osteoclastogenic cytokineswhich play a major role in the bone destructionassociated with rheumatoid arthritis. While therole of T cells in osteoclastogenesis has receivedmuch attention recently, the effect of T cells onosteoblast formation and activity is poorlydefined. In this study, we investigated thehypothesis that in chronic inflammation activatedT cells contribute to enhanced bone turnover bypromoting osteoblastic differentiation. We showthat T cells produce soluble factors that inducealkaline phosphatase activity in bone marrowstromal cells and elevated expression of mRNAfor Runx2 and osteocalcin. This data indicate thatT cell derived factors have the capacity tostimulate the differentiation of bone marrowstromal cells into the osteoblast phenotype.RANKL mRNA was undetectable under anyconditions in highly purified bone marrow", "metadata": {}}
+{"_id": "43629704", "title": "", "text": "Prevention of coronary heart disease withpravastatin in men with hypercholesterolemia.West of Scotland Coronary Prevention StudyGroup.BACKGROUND Lowering the bloodcholesterol level may reduce the risk of coronaryheart disease. This double-blind study wasdesigned to determine whether theadministration of pravastatin to men withhypercholesterolemia and no history ofmyocardial infarction reduced the combinedincidence of nonfatal myocardial infarction anddeath from coronary heart disease. METHODSWe randomly assigned 6595 men, 45 to 64 yearsof age, with a mean (+/- SD) plasma cholesterollevel of 272 +/- 23 mg per deciliter (7.0 +/- 0.6mmol per liter) to receive pravastatin (40 mgeach evening) or placebo. The average follow-upperiod was 4.9 years. Medical records,electrocardiographic recordings, and the nationaldeath registry were used to determine theclinical end points. RESULTS Pravastatin loweredplasma cholesterol levels by 20 percent and", "metadata": {}}
+{"_id": "43647194", "title": "", "text": "Validation of a migraine-specific questionnairefor use in family studies.The availability of validmigraine-specific questionnaires is importantwhen large numbers of migraine patients have tobe analysed. The Finnish Migraine-SpecificQuestionnaire has been validated in two stages.In the first, a clinical diagnosis of migraine wasreached, using International Headache Societycriteria, in 100 consecutive patients. Migrainewas then diagnosed independently on the basisof responses to the Finnish Migraine-SpecificQuestionnaire. In the second stage, responses to100 questionnaires returned consecutively in afamily study in progress were analysed, andrespondents were contacted by telephone forinterview and diagnosis of migraine. Contactproved impossible in six cases. The sensitivity ofthe questionnaire for migraine was 0.99 (167 outof 168; validation stages 1 and 2 combined) andspecificity was 0.96 (25 out of 26 cases;validation stage 2). It also proved possible todifferentiate between migraine with and without", "metadata": {}}
+{"_id": "43661837", "title": "", "text": "Defining early lineage specification of humanembryonic stem cells by the orchestratedbalance of canonical Wnt/beta-catenin,Activin/Nodal and BMP signaling.The canonicalWnt/beta-catenin signaling has remarkablydiverse roles in embryonic development, stemcell self-renewal and cancer progression. Here,we show that stabilized expression ofbeta-catenin perturbed human embryonic stem(hES)-cell self-renewal, such that up to 80% ofthe hES cells developed into the primitive streak(PS)/mesoderm progenitors, reminiscent of earlymammalian embryogenesis. The formation of thePS/mesoderm progenitors essentially dependedon the cooperative action of beta-catenintogether with Activin/Nodal and BMP signalingpathways. Intriguingly, blockade of BMPsignaling completely abolished mesodermgeneration, and induced a cell fate changetowards the anterior PS progenitors. ThePI3-kinase/Akt, but not MAPK, signaling pathwayhad a crucial role in the anterior PS specification,", "metadata": {}}
+{"_id": "43700577", "title": "", "text": "Sphingosine can pre- and post-condition heartand utilizes a different mechanism fromsphingosine 1-phosphate.Consistent withprevious reports, sphingosine at a highconcentration (5 microM) was cardiotoxic asevidenced by increased infarct size in responseto ischemia/reperfusion in an ex vivo rat heart.Sphingosine 1-phosphate (S1P) at 5 microM wascardioprotective. However, at a physiologicconcentration (0.4 microM) sphingosine as wellas S1P was effective in protecting the heart fromischemia/reperfusion injury both when perfusedprior to 40 min of ischemia (preconditioning) orwhen added to reperfusion media followingischemia (postconditioning). Protection bysphingosine and S1P was evidenced with bothpre- and post-conditioning by a >75% recoveryof left ventricular developed pressure duringreperfusion and a decrease in infarct size from45% of the risk area to less than 8%. WhenVPC23019, an S1P(1and3)G-protein coupledreceptor antagonist, was added to the", "metadata": {}}
+{"_id": "43711341", "title": "", "text": "Coordination of p300-mediated chromatinremodeling and TRAP/mediator function throughcoactivator PGC-1alpha.Transcriptionalcoactivators showing physical and functionalinteractions with PPARgamma include the proteinacetyl transferase p300, the TRAP/Mediatorcomplex that interacts with the generaltranscription machinery, and the highly regulatedPGC-1alpha. We show that PGC-1alpha directlyinteracts with TRAP/Mediator, through thePPARgamma-interacting subunit TRAP220, andstimulates TRAP/Mediator-dependent function onDNA templates. Further, while ineffective byitself, PGC-1alpha stimulates p300-dependenthistone acetylation and transcription onchromatin templates in response to PPARgamma.These functions are mediated by largelyindependent PPARgamma, p300, and TRAP220interaction domains in PGC-1alpha, whereasp300 and TRAP220 show ligand-dependentinteractions with a common region ofPPARgamma. Apart from showing PGC-1alpha", "metadata": {}}
+{"_id": "43752562", "title": "", "text": "Phospholipid synthesis and lipid composition ofsubcellular membranes in the unicellulareukaryote Saccharomyces cerevisiae.Subcellularmembranes of Saccharomyces cerevisiae,including mitochondria, microsomes, plasmamembranes, secretory vesicles, vacuoles,nuclear membranes, peroxisomes, and lipidparticles, were isolated by improved proceduresand analyzed for their lipid composition and theircapacity to synthesize phospholipids and tocatalyze sterol delta 24-methylation. Themicrosomal fraction is heterogeneous in terms ofdensity and classical microsomal marker proteinsand also with respect to the distribution ofphospholipid-synthesizing enzymes. The specificactivity of phosphatidylserine synthase washighest in a microsomal subfraction which wasdistinct from heavier microsomes harboringphosphatidylinositol synthase and thephospholipid N-methyltransferases. Theexclusive location of phosphatidylserinedecarboxylase in mitochondria was confirmed.", "metadata": {}}
+{"_id": "43855756", "title": "", "text": "Use of health services by prison inmates:comparisons with the community.The futureorganisation of prison health care 1 recommendsthat the NHS and the Prison Service worktogether to plan and provide health care servicesfor prisoners. Whereas previously the PrisonService had this responsibility alone. The NHSwill therefore have to take stock of the currentlevel at which prison health care is demandedand provided. A key part of the information basefor joint planning therefore includes data oncurrent service utilisation. This paper comparesprimary care and inpatient health serviceutilisation data for UK prisoners with healthservices utilisation data for equivalentcommunity populations. In the community,primary care is provided principally by generalpractitioners and professions allied to medicine(mostly nurses). Residents in the communityhave access to the full range of NHS outpatientand inpatient facilities. Within prisons, primarycare is provided by medical officers (some of", "metadata": {}}
+{"_id": "43880096", "title": "", "text": "Regulation of p53 in response to DNAdamageActivation of p53 can occur in responseto a number of cellular stresses, including DNAdamage, hypoxia and nucleotide deprivation.Several forms of DNA damage have been shownto activate p53, including those generated byionising radiation (IR), radio-mimetic drugs,ultraviolet light (UV) and chemicals such asmethyl methane sulfonate (MMS). Under normalconditions, p53 levels are maintained at a lowstate by virtue of the extremely short-half life ofthe polypeptide. In addition to this, p53 normallyexists in an largely inactive state that isrelatively inefficient at binding to DNA andactivating transcription. Activation of p53 inresponse to DNA damage is associated with arapid increase in its levels and with an increasedability of p53 to bind DNA and mediatetranscriptional activation. This then leads to theactivation of a number of genes whose productstrigger cell-cycle arrest, apoptosis, or DNArepair. Recent work has suggested that this", "metadata": {}}
+{"_id": "43890638", "title": "", "text": "Hydrogen sulphide regulates intracellular pH invascular smooth muscle cells.We investigatedthe role of hydrogen sulphide (H(2)S) inintracellular pH (pH(i)) regulation in vascularsmooth muscle cells and its contribution onvasodilation. NaHS, a H(2)S donor, decreasedpH(i) in a concentration-dependent mannerranging from 10 microM to 1mM. Neitherinhibition of the Na(+)/H(+) exchanger with5-(N-ethyl-N-isopropyl) amiloride, (EIPA, 10microM), nor plasmalemmal Ca(2+)-ATPase withCdCl(2) (20nM) alters the effect of NaHS onpH(i). Blockade of the Cl(-)/HCO3- exchangerwith 4,4'-diisothiocyanatostilbene-2,2'-disulfonicacid (DIDS) significantly attenuated the pH(i)lowering effect of NaHS. Moreover, NaHSsignificantly increased the activity of Cl(-)/HCO3-exchanger when measured with NH(4)Clprepulse method. DIDS attenuated thevasorelaxation induced by NaHS whereas EIPAand CdCl(2) did not cause any change. Inconclusion, H(2)S induced intracellular", "metadata": {}}
+{"_id": "43990286", "title": "", "text": "Cell and biomolecule delivery for tissue repairand regeneration in the central nervoussystem.Tissue engineering frequently involvescells and scaffolds to replace damaged ordiseased tissue. It originated, in part, as ameans of effecting the delivery of biomoleculessuch as insulin or neurotrophic factors, giventhat cells are constitutive producers of suchtherapeutic agents. Thus cell delivery is intrinsicto tissue engineering. Controlled release ofbiomolecules is also an important tool forenabling cell delivery since the biomolecules canenable cell engraftment, modulate inflammatoryresponse or otherwise benefit the behavior of thedelivered cells. We describe advances in cell andbiomolecule delivery for tissue regeneration, withemphasis on the central nervous system (CNS).In the first section, the focus is on encapsulatedcell therapy. In the second section, the focus ison biomolecule delivery in polymericnano/microspheres and hydrogels for the nerveregeneration and endogenous cell stimulation. In", "metadata": {}}
+{"_id": "44030361", "title": "", "text": "The angiotensin II type 1 receptor blockerolmesartan preferentially improves nocturnalhypertension and proteinuria in chronic kidneydiseaseAccumulated evidence suggests that analtered ambulatory blood pressure (BP) profile,particularly elevated nighttime BP, reflects targetorgan injury and is a better predictor of furthercardiorenal risk than the clinic BP or daytime BPin hypertensive patients complicated by chronickidney disease (CKD). In this study, weexamined the beneficial effects of olmesartan, anangiotensin II type 1 receptor blocker (ARB), onambulatory BP profiles and renal function inhypertensive CKD patients. Forty-six patientswere randomly assigned to the olmesartanadd-on group (n=23) or the non-ARB group(n=23). At baseline and after the 16-weektreatment period, ambulatory BP monitoring wasperformed and renal function parametermeasurements were collected. Although thebaseline clinic BP levels and theafter-treatment/baseline (A/B) ratios of clinic BP", "metadata": {}}
+{"_id": "44048701", "title": "", "text": "Surgical vs nonsurgical treatment of adults withdisplaced fractures of the proximal humerus: thePROFHER randomized clinical trial.IMPORTANCEThe need for surgery for the majority of patientswith displaced proximal humeral fractures isunclear, but its use is increasing. OBJECTIVE Toevaluate the clinical effectiveness of surgical vsnonsurgical treatment for adults with displacedfractures of the proximal humerus involving thesurgical neck. DESIGN, SETTING, ANDPARTICIPANTS A pragmatic, multicenter,parallel-group, randomized clinical trial, theProximal Fracture of the Humerus Evaluation byRandomization (PROFHER) trial, recruited 250patients aged 16 years or older (mean age, 66years [range, 24-92 years]; 192 [77%] werefemale; and 249 [99.6%] were white) whopresented at the orthopedic departments of 32acute UK National Health Service hospitalsbetween September 2008 and April 2011 within3 weeks after sustaining a displaced fracture ofthe proximal humerus involving the surgical", "metadata": {}}
+{"_id": "44172171", "title": "", "text": "Kinetics and Fidelity of the Repair ofCas9-Induced Double-Strand DNA BreaksTheRNA-guided DNA endonuclease Cas9 is apowerful tool for genome editing. Little is knownabout the kinetics and fidelity of thedouble-strand break (DSB) repair process thatfollows a Cas9 cutting event in living cells. Here,we developed a strategy to measure the kineticsof DSB repair for single loci in human cells.Quantitative modeling of repaired DNA in timeseries after Cas9 activation reveals variable andoften slow repair rates, with half-life times up to\u000010 hr. Furthermore, repair of the DSBs tendsto be error prone. Both classical andmicrohomology-mediated end joining pathwayscontribute to the erroneous repair. Estimation oftheir individual rate constants indicates that thebalance between these two pathways changesover time and can be altered by additionalionizing radiation. Our approach providesquantitative insights into DSB repair kinetics andfidelity in single loci and indicates that", "metadata": {}}
+{"_id": "44264297", "title": "", "text": "Network meta-analysis for indirect treatmentcomparisons.I present methods for assessing therelative effectiveness of two treatments whenthey have not been compared directly in arandomized trial but have each been comparedto other treatments. These networkmeta-analysis techniques allow estimation ofboth heterogeneity in the effect of any giventreatment and inconsistency ('incoherence') inthe evidence from different pairs of treatments.A simple estimation procedure using linear mixedmodels is given and used in a meta-analysis oftreatments for acute myocardial infarction.", "metadata": {}}
+{"_id": "44265107", "title": "", "text": "Liver transplantation and opioiddependence.ContextChronic hepatitis C is theleading cause for liver transplantation in theUnited States. Intravenous drug use, the majorrisk factor, accounts for approximately 60% ofhepatitis C virus transmission. Information fromthe United Network of Organ Sharing (UNOS)does not address substance use among livertransplantation patients. ObjectiveTo identifyaddiction-related criteria for admission to theUNOS liver transplantation waiting list andposttransplantation problems experienced bypatients who are prescribed maintenancemethadone. Design, Setting, and ParticipantsMailsurvey of all 97 adult US liver transplantationprograms (belonging to UNOS) in March 2000with telephone follow-up conducted in May andJune 2000.Main Outcome MeasuresPrograms'acceptance and management of patients withpast or present substance use disorder.ResultsOf the 97 programs surveyed, 87 (90%)responded. All accept applicants with a history of", "metadata": {}}
+{"_id": "44366096", "title": "", "text": "RIG-I-mediated antiviral responses tosingle-stranded RNA bearing5'-phosphates.Double-stranded RNA (dsRNA)produced during viral replication is believed to bethe critical trigger for activation of antiviralimmunity mediated by the RNA helicase enzymesretinoic acid-inducible gene I (RIG-I) andmelanoma differentiation-associated gene 5(MDA5). We showed that influenza A virusinfection does not generate dsRNA and thatRIG-I is activated by viral genomicsingle-stranded RNA (ssRNA) bearing5'-phosphates. This is blocked by the influenzaprotein nonstructured protein 1 (NS1), which isfound in a complex with RIG-I in infected cells.These results identify RIG-I as a ssRNA sensorand potential target of viral immune evasion andsuggest that its ability to sense5'-phosphorylated RNA evolved in the innateimmune system as a means of discriminatingbetween self and nonself.", "metadata": {}}
+{"_id": "44384384", "title": "", "text": "In-hospital switching between adenosinediphosphate receptor inhibitors in patients withacute myocardial infarction treated withpercutaneous coronary intervention: Insightsinto contemporary practice from theTRANSLATE-ACS study.AIMS While randomizedclinical trials have compared clopidogrel withhigher potency adenosine diphosphate (ADP)receptor inhibitors among patients with acutemyocardial infarction, little is known about thefrequency, effectiveness and safety of switchingbetween ADP receptor inhibitors in routineclinical practice. METHODS AND RESULTS Westudied 11,999 myocardial infarction patientstreated with percutaneous coronary interventionat 230 hospitals from April 2010 to October 2012in the TRANSLATE-ACS study. Multivariable Coxregression was used to compare six-monthpost-discharge risks of major adversecardiovascular events (MACE: death, myocardialinfarction, stroke, or unplannedrevascularization) and Global Utilization of", "metadata": {}}
+{"_id": "44387884", "title": "", "text": "Platelet activation in type 2 diabetes mellitus.Theabnormal metabolic state that accompaniesdiabetes renders arteries susceptible toatherosclerosis, being capable of altering thefunctional properties of multiple cell types,including endothelium and platelets. Inparticular, an altered platelet metabolism andchanges in intraplatelet signaling pathways maycontribute to the pathogenesis ofatherothrombotic complications of diabetes. Avariety of mechanisms may be responsible forenhanced platelet aggregation. Among them,hyperglycemia may represent a causal factor forin vivo platelet activation, and may beresponsible for nonenzymatic glycation ofplatelet glycoproteins, causing changes in theirstructure and conformation, as well asalterations of membrane lipid dynamics.Furthermore, hyperglycemia-induced oxidativestress is responsible for enhanced peroxidationof arachidonic acid to form biologically activeisoprostanes, which represents an important", "metadata": {}}
+{"_id": "44408494", "title": "", "text": "Nicotinic receptor-mediated neuroprotection inneurodegenerative disease models.Multiple linesof evidence, from molecular and cellular toepidemiological, have implicated nicotinictransmission in the pathology of Alzheimer'sdisease (AD) and Parkinson's disease (PD). Thisreview article presents evidence for nicotinicacetylcholine receptor (nAChR)-mediatedprotection and the signal transduction involved inthis mechanism. The data is based mainly on ourstudies using rat-cultured primary neurons.Nicotine-induced protection was blocked by analpha7 nAChR antagonist, a phosphatidylinositol3-kinase (PI3K) inhibitor, and an Src inhibitor.Levels of phosphorylated Akt, an effector ofPI3K, Bcl-2 and Bcl-x were increased by nicotineadministration. From these experimental data,our hypothesis for the mechanism ofnAChR-mediated survival signal transduction isthat the alpha7 nAChR stimulates the Src family,which activates PI3K to phosphorylate Akt, whichsubsequently transmits the signal to up-regulate", "metadata": {}}
+{"_id": "44409062", "title": "", "text": "High-throughput parallel proteogenomics: abacterial case study.In recent years, a newparadigm for genome annotation has emerged,termed \"proteogenomics,\" that leverages peptideMS to annotate a genome. This is achieved bymapping peptides to a six-frame translation of agenome, including available splice databases,which may suggest refinements to gene models.Using this approach, it is possible to refine generegions such as exon boundaries, novel genes,gene boundaries, frame shifts, reverse strands,translated UTRs, and novel splice junctions. Oneof the challenges of proteogenomics is how bestto (1) tackle assigning confidence to anyresulting annotation and (2) apply these genemodel refinements, either through manualannotation or through an automated process viatraining gene prediction tools. This is not astraightforward process, as many geneprediction tools have their defined suitability forniche genomes (either eukaryotic or prokaryotic)trained on and refined with model organisms", "metadata": {}}
+{"_id": "44420873", "title": "", "text": "Keratinocyte-specific transglutaminase ofcultured human epidermal cells: relation tocross-linked envelope formation and terminaldifferentiation.The predominant form of thecross-linking enzyme, transglutaminase, incultured normal human epidermal keratinocytes,is found in cell particulate material and can besolubilized by nonionic detergent. It elutes as asingle peak upon either anion-exchange orgel-filtration chromatography. Monoclonalantibodies raised to the particulate enzymecross-react with one of two transglutaminases inthe cell cytosol. The second cytosolictransglutaminase, which has distinct kinetic andphysical properties from the first, does notcross-react and is not essential for formation ofthe keratinocyte cross-linked envelope in vitro.The anti-transglutaminase antibodies stain themore differentiated layers of epidermis in apattern similar to that given by anti-involucrinantiserum. These observations support thehypothesis that the transglutaminase so", "metadata": {}}
+{"_id": "44500794", "title": "", "text": "The effects of genetic and pharmacologicalblockade of the CB1 cannabinoid receptor onanxiety.The aim of this study was to compare theeffects of the genetic and pharmacologicaldisruption of CB1 cannabinoid receptors on theelevated plus-maze test of anxiety. In the firstexperiment, the behaviour of CB1-knockout miceand wild-type mice was compared. In the secondexperiment, the cannabinoid antagonistSR141716A (0, 1, and 3 mg/kg) wasadministered to both CB1-knockout and wildtype mice. Untreated CB1-knockout mice showeda reduced exploration of the open arms of theplus-maze apparatus, thus appearing moreanxious than the wild-type animals, however nochanges in locomotion were noticed. Thevehicle-injected CB1-knockout mice from thesecond experiment also showed increasedanxiety as compared with wild types.Surprisingly, the cannabinoid antagonistSR141716A reduced anxiety in both wild typeand CB1 knockout mice. Locomotor behaviour", "metadata": {}}
+{"_id": "44562058", "title": "", "text": "Immune activation and HIV persistence:implications for curative approaches to HIVinfection.Despite complete or near-completesuppression of human immunodeficiency virus(HIV) replication with combination antiretroviraltherapy, both HIV and chronicinflammation/immune dysfunction persistindefinitely. Untangling the association betweenthe virus and the host immune environmentduring therapy might lead to novel interventionsaimed at either curing the infection or preventingthe development of inflammation-associatedend-organ disease. Chronic inflammation andimmune dysfunction might lead to HIVpersistence by causing virus production,generating new target cells, enabling infecting ofactivated and resting target cells, altering themigration patterns of susceptible target cells,increasing the proliferation of infected cells, andpreventing normal HIV-specific clearancemechanisms from function. Chronic HIVproduction or replication might contribute to", "metadata": {}}
+{"_id": "44562221", "title": "", "text": "Tissue-specific alterations in the glucocorticoidsensitivity of immune cells following repeatedsocial defeat in miceEndogenous glucocorticoids(GC) play an important role in the termination ofthe inflammatory response following infectionand tissue injury. However, recent findingsindicate that stress can impair theanti-inflammatory capacities of these hormones.Lipopolysaccharide (LPS)-stimulated splenocytesof mice that were repeatedly subjected to socialdisruption (SDR) stress were less sensitive to theimmunosuppressive effects of corticosterone(CORT) as demonstrated by an increasedproduction of pro-inflammatory cytokines andenhanced cell survival. Myeloid cells expressingthe marker CD11b were shown to play a key rolein this process. Here we investigated the role ofthe bone marrow as a potential source of theGC-insensitive cells. The study revealed thatLPS-stimulated bone marrow cells, in theabsence of experimental stress, were virtuallyGC-resistant and retained high levels of cell", "metadata": {}}
+{"_id": "44562904", "title": "", "text": "Delays in the diagnosis of lungcancer.BACKGROUND Many patients with lungcancer report delays in diagnosing their disease.This may contribute to advanced stage atdiagnosis and poor long term survival. This studyexplores the delays experienced by patientsreferred to a regional cancer centre with lungcancer. METHODS A prospective cohort ofpatients referred with newly diagnosed lungcancer were surveyed over a 3 month period toassess delays in diagnosis. Patients were askedwhen they first experienced symptoms, saw theirdoctor, what tests were done, when they saw aspecialist and when they started treatment.Descriptive statistics were used to summarizethe different time intervals. RESULTS 56 of 73patients consented (RR 77%). However only 52patients (30M, 22F) were interviewed as 2 diedbefore being interviewed and two could not becontacted. The mean age was 68yrs. Stagedistribution was as follows (IB/IIA 10%, stageIIIA 20%, IIIB/IV 70%). Patients waited a", "metadata": {}}
+{"_id": "44572913", "title": "", "text": "Calcium and peak bone mass.On the basis ofprevious epidemiological, clinical andexperimental studies, it was demonstrated thatadequate calcium intake during growth mayinfluence peak bone mass/density, and may beinstrumental in preventing subsequentpostmenopausal and senile osteoporosis.Calcium intake during adolescence appears toaffect skeletal calcium retention directly, and acalcium intake of up to 1600 mg d-1 may berequired. Therefore, adolescent females at thetime of puberty probably represent the optimalpopulation for early prevention of osteoporosiswith calcium. Young individuals must be inpositive calcium balance to provide the calciumnecessary for skeletal modelling andconsolidation, but the degree of positive balancerequired to achieve peak bone mass and densityis unknown. To assess calcium requirements inyoung individuals, and also to evaluate thedeterminants of calcium metabolism during theperiod of acquisition of peak bone mass, 487", "metadata": {}}
+{"_id": "44586415", "title": "", "text": "Most clinical tests cannot accurately diagnoserotator cuff pathology: a systematicreview.QUESTION Do clinical tests accuratelydiagnose rotator cuff pathology? DESIGN Asystematic review of investigations into thediagnostic accuracy of clinical tests for rotatorcuff pathology. PARTICIPANTS People withshoulder pain who underwent clinical testing inorder to diagnose rotator cuff pathology.OUTCOME MEASURES The diagnostic accuracy ofclinical tests was determined using likelihoodratios. RESULTS Thirteen studies met theinclusion criteria. The 13 studies evaluated 14clinical tests in 89 separate evaluations ofdiagnostic accuracy. Only one evaluation,palpation for supraspinatus ruptures, resulted insignificant positive and negative likelihood ratios.Eight of the 89 evaluations resulted in eithersignificant positive or negative likelihood ratios.However, none of these eight positive ornegative likelihood ratios were found in otherstudies. Of the 89 evaluations of clinical tests 71", "metadata": {}}
+{"_id": "44614949", "title": "", "text": "Skeletal muscle interleukin\u00006 regulatesmetabolic factors in iWAT during HFD andexercise trainingOBJECTIVE To investigate therole of skeletal muscle (SkM) interleukin (IL)-6 inthe regulation of adipose tissue metabolism.METHODS Muscle-specific IL-6 knockout (IL-6MKO) and IL-6(loxP/loxP) (Floxed) mice weresubjected to standard rodent diet (Chow),high-fat diet (HFD), or HFD in combination withexercise training (HFD ExTr) for 16 weeks.RESULTS Total fat mass increased (P < 0.05) inboth genotypes with HFD. However, HFD IL-6MKO mice had lower (P < 0.05) inguinal adiposetissue (iWAT) mass than HFD Floxed mice.Accordingly, iWAT glucose transporter 4 (GLUT4)protein content, 5'AMP activated protein kinase(AMPK)(Thr172) phosphorylation, and fatty acidsynthase (FAS) mRNA content were lower (P <0.05) in IL-6 MKO than Floxed mice on Chow. Inaddition, iWAT AMPK(Thr172) andhormone-sensitive lipase (HSL)(Ser565)phosphorylation as well as perilipin protein", "metadata": {}}
+{"_id": "44624045", "title": "", "text": "Risk of hospitalization or death from ischemicheart disease among British vegetarians andnonvegetarians: results from the EPIC-Oxfordcohort study.BACKGROUND Few previousprospective studies have examined differences inincident ischemic heart disease (IHD) riskbetween vegetarians and nonvegetarians.OBJECTIVE The objective was to examine theassociation of a vegetarian diet with risk ofincident (nonfatal and fatal) IHD. DESIGN A totalof 44,561 men and women living in England andScotland who were enrolled in the EuropeanProspective Investigation into Cancer andNutrition (EPIC)-Oxford study, of whom 34%consumed a vegetarian diet at baseline, werepart of the analysis. Incident cases of IHD wereidentified through linkage with hospital recordsand death certificates. Serum lipids and bloodpressure measurements were available for 1519non cases, who were matched to IHD cases bysex and age. IHD risk by vegetarian status wasestimated by using multivariate Cox proportional", "metadata": {}}
+{"_id": "44629665", "title": "", "text": "The Supporting Independent Immunization andVaccine Advisory Committees (SIVAC) initiative:a country-driven, multi-partner program tosupport evidence-based decision making.Multiplehealth priorities, limited human resources andlogistical capacities, as well as expensivevaccines with limited funds available increase theneed for evidence-based decision making inimmunization programs. The aim of theSupporting Independent Immunization andVaccine Advisory Committees (SIVAC) Initiativeis to support countries in the establishment orstrengthening of National ImmunizationTechnical Advisory Groups (NITAGs) that providerecommendations on immunization policies andprograms (e.g., vaccination schedules,improvements of routine immunization coverage,new vaccine introduction, etc.). SIVAC, aprogram funded by the Bill & Melinda GatesFoundation, is based on a country-driven,step-by-step process that ensures its support istailored to country needs and emphasizes NITAG", "metadata": {}}
+{"_id": "44640124", "title": "", "text": "Redox-relevant aspects of the extracellularmatrix and its cellular contacts viaintegrins.SIGNIFICANCE The extracellular matrix(ECM) fulfills essential functions in multicellularorganisms. It provides the mechanical scaffoldand environmental cues to cells. Upon cellattachment, the ECM signals into the cells. Inthis process, reactive oxygen species (ROS) arephysiologically used as signalizing molecules.RECENT ADVANCES ECM attachment influencesthe ROS-production of cells. In turn, ROS affectthe production, assembly and turnover of theECM during wound healing and matrixremodeling. Pathological changes of ROS levelslead to excess ECM production and increasedtissue contraction in fibrotic disorders anddesmoplastic tumors. Integrins are cell adhesionmolecules which mediate cell adhesion and forcetransmission between cells and the ECM. Theyhave been identified as a target ofredox-regulation by ROS. Cysteine-basedredox-modifications, together with structural", "metadata": {}}
+{"_id": "44660616", "title": "", "text": "Prevalence of hypertension and pre-hypertensionamong adolescents.OBJECTIVE To determine theprevalence of hypertension and pre-hypertensionon the basis of the 2004 National High BloodPressure Education Program Working Groupguidelines in an adolescent school-screeningpopulation. STUDY DESIGN Cross-sectionalassessment of blood pressure (BP) in 6790adolescents (11-17 years) in Houston schoolswas conducted from 2003 to 2005. Initialmeasurements included height, weight, and 4oscillometric BP readings. Repeat measurementswere obtained on 2 subsequent occasions instudents with persistently elevated BP. Finalprevalence was adjusted for loss to follow-up andlogistic regression used to assess risk factors.RESULTS BP distribution at initial screen was81.1% normal, 9.5% pre-hypertension, and9.4% hypertension (8.4% Stage 1; 1% Stage 2).Prevalence after 3 screenings was 81.1%normal, 15.7% pre-hypertension, and 3.2%hypertension (2.6% Stage 1; 0.6% Stage 2).", "metadata": {}}
+{"_id": "44672703", "title": "", "text": "Increased short- and long-term risk ofinflammatory bowel disease after salmonella orcampylobacter gastroenteritis.BACKGROUND &AIMS Various commensal enteric and potentiallypathogenic bacteria may be involved in thepathogenesis of inflammatory bowel diseases(IBD). We compared the risk of IBD between acohort of patients with documented Salmonellaor Campylobacter gastroenteritis and an age-and gender-matched control group from thesame population in Denmark. METHODS Weidentified 13,324 patients withSalmonella/Campylobacter gastroenteritis fromlaboratory registries in North Jutland and Aarhuscounties, Denmark, from 1991 through 2003,and 26,648 unexposed controls from the samecounties. Of these, 176 exposed patients withIBD before the infection, their 352 unexposedcontrols, and 80 unexposed individuals with IBDbefore the Salmonella/Campylobacter infectionwere excluded. The final study cohort of 13,148exposed and 26,216 unexposed individuals were", "metadata": {}}
+{"_id": "44674301", "title": "", "text": "Establishment of a cell line (NPC/HK1) from adifferentiated squamous carcinoma of thenasopharynx.A long-term cell culture epithelioidcell line was established from a recurrentsquamous carcinoma of the nasopharynx of aChinese male 17 1/2 years after radiationtherapy. The cell line, designated NPC/HK1, hasbeen passed 72 times over a period 1 year. Thecells have been shown by light and electronmicroscopies to be of the squamous epithelialtype. When they were transplantedsubcutaneously into the back of athymic nudeBALB/c (nu/nu) mice, tumors developed at thesites of inoculation, which on histologicalexamination were shown to be well-differentiatedsquamous carcinomas, similar in morphology tothe recurrent human tumor from which theywere derived. Karyotypic analysis of cells fromthe cell line demonstrates an aneuploid humantype with a modal chromosome number of 74with both numerical and structural aberrations.Viral particles or Epstein-Barr viral nuclear", "metadata": {}}
+{"_id": "44693226", "title": "", "text": "Effect of lipid restriction on mitochondrial freeradical production and oxidative DNAdamage.Many studies have shown that caloricrestriction (40%) decreases mitochondrialreactive oxygen species (ROS) generation inrodents. Moreover, we have recently found that7 weeks of 40% protein restriction withoutstrong caloric restriction also decreases ROSproduction in rat liver. This is interesting since ithas been reported that protein restriction canalso extend longevity in rodents. In the presentstudy we have investigated the possible role ofdietary lipids in the effects of caloric restrictionon mitochondrial oxidative stress. Usingsemipurified diets, the ingestion of lipids in maleWistar rats was decreased by 40% belowcontrols, while the other dietary componentswere ingested at exactly the same level as inanimals fed ad libitum. After 7 weeks oftreatment the liver mitochondria oflipid-restricted animals showed significantincreases in oxygen consumption with complex", "metadata": {}}
+{"_id": "44724517", "title": "", "text": "Kruppel-like factor 2 is a transcriptional regulatorof chronic and acute inflammation.Althoughmyeloid cell activation is requisite for an optimalinnate immune response, this process must betightly controlled to prevent collateral host tissuedamage. Kruppel-like factor 2 (KLF2) is a potentregulator of myeloid cell proinflammatoryactivation. As an approximately 30% to 50%reduction in KLF2 levels has been observed inhuman subjects with acute or chronicinflammatory disorders, we studied the biologicalresponse to inflammation in KLF2(+/-) mice.Herein, we show that partial deficiency of KLF2modulates the in vivo response to acute (sepsis)and subacute (skin) inflammatory challenge.Mechanistically, we link the anti-inflammatoryeffects of KLF2 to the inhibition of NF-κBtranscriptional activity. Collectively, theobservations provide biologically relevantinsights into KLF2-mediated modulation of theseinflammatory processes that could potentially bemanipulated for therapeutic gain.", "metadata": {}}
+{"_id": "44737533", "title": "", "text": "Simian immunodeficiency viruses replicationdynamics in African non-human primate hosts:common patterns and species-specificdifferences.METHODS To define potentialcommon features of simian immunodeficiencyvirus (SIV) infections in different naturallyinfected host species, we compared thedynamics of viral replication in 31 African greenmonkeys (10 sabeus, 15 vervets and sevenCaribbean AGMs), 14 mandrills and three sootymangabeys (SMs) that were experimentallyinfected with their species-specific viruses.RESULTS After infection, these SIVs replicatedrapidly reaching viral loads (VLs) of 10(5)-10(9)copies/ml of plasma between days 9-14post-infection (p.i). Set point viremia wasestablished between days 42 and 60 p.i., withlevels of approximately 10(5)-10(6) copies/ml inSM and mandrills, and lower levels (10(3)-10(5)copies/ml) in AGMs. VL during the chronic phasedid not correlate with viral genome structure:SIVmnd-2 (a vpx-containing virus) and", "metadata": {}}
+{"_id": "44801733", "title": "", "text": "The role of the transcription factor KLF2 invascular development and disease.Thezinc-finger transcription factor KLF2 transducesthe physical forces exerted by blood flow intomolecular signals responsible for a wide range ofbiological responses. Following its initialrecognition as a flow-responsive endothelialtranscription factor, KLF2 is now known to beexpressed in a range of cell types and toparticipate in a number of processes duringdevelopment and disease such as endothelialhomeostasis, vasoregulation, vasculargrowth/remodeling, and inflammation. In thisreview, we summarize the current understandingabout KLF2 with a focus on its effects on vascularbiology.", "metadata": {}}
+{"_id": "44827480", "title": "", "text": "Implementation of contemporary oral antiplatelettreatment guidelines in patients with acutecoronary syndrome undergoing percutaneouscoronary intervention: a report from the GReekAntiPlatelet rEgistry (GRAPE).BACKGROUND Fewdata exist about the implementation ofcontemporary oral antiplatelet treatmentguidelines in patients with acute coronarysyndrome (ACS) undergoing percutaneouscoronary intervention (PCI). METHODS GReekAntiPlatelet rEgistry (GRAPE), initiated onJanuary 2012, is a prospective, observational,multicenter cohort study focusing oncontemporary use of P2Y12 inhibitors. In 1434patients we evaluated appropriateness of P2Y12selection initially and at discharge by applying aneligibility-assessing algorithm based on P2Y12inhibitors' contraindications/specific warningsand precautions. RESULTS Appropriate, lesspreferable and inappropriate P2Y12 inhibitorselections were made initially in 45.8%, 47.2%and 6.6% and at discharge in 64.1%, 29.2% and", "metadata": {}}
+{"_id": "44830890", "title": "", "text": "Comorbidity of depressive and anxiety disordersin chronic daily headache and itssubtypes.OBJECTIVE To investigate thefrequency of depressive and anxiety disorders inpatients with chronic daily headache.BACKGROUND There is a lack of data in theliterature on the extent of psychiatriccomorbidity in patients with different subtypes ofchronic daily headache. METHODS We recruitedconsecutive patients with chronic daily headacheseen in a headache clinic from November 1998 toDecember 1999. The subtypes of chronic dailyheadache were classified according to the criteriaproposed by Silberstein et al. A psychiatristevaluated the patients according to thestructured Mini-International NeuropsychiatricInterview to assess the comorbidity ofdepressive and anxiety disorders. RESULTS Twohundred sixty-one patients with chronic dailyheadache were recruited. The mean age was 46years, and 80% were women. Transformedmigraine was diagnosed in 152 patients (58%)", "metadata": {}}
+{"_id": "44935041", "title": "", "text": "The precursor form of IL-1alpha is an intracrineproinflammatory activator oftranscription.Although most cytokines arestudied for biological effects after engagement oftheir specific cell surface membrane receptors,increasing evidence suggests that some functionin the nucleus. In the present study, theprecursor form of IL-1alpha was overexpressedin various cells and assessed for activity in thepresence of saturating concentrations of IL-1receptor antagonist to prevent receptorsignaling. Initially diffusely present in thecytoplasm of resting cells, IL-1alpha translocatedto the to nucleus after activation by endotoxin, aToll-like receptor ligand. The IL-1alphaprecursor, but not the C-terminal mature form,activated the transcriptional machinery in theGAL4 system by 90-fold; a 50-fold increase wasobserved using only the IL-1alpha propiece,suggesting that transcriptional activation waslocalized to the N terminus where the nuclearlocalization sequence resides. Under conditions", "metadata": {}}
+{"_id": "44947611", "title": "", "text": "Three-dimensional structure of the AAH26994.1protein from Mus musculus, a putativeeukaryotic Urm1.We have used NMRspectroscopy to determine the solution structureof protein AAH26994.1 from Mus musculus andpropose that it represents the firstthree-dimensional structure of a ubiquitin-relatedmodifier 1 (Urm1) protein. Amino acid sequencecomparisons indicate that AAH26994.1 belongsto the Urm1 family of ubiquitin-like modifierproteins. The best characterized member of thisfamily has been shown to be involved in nutrientsensing, invasive growth, and budding in yeast.Proteins in this family have only a weaksequence similarity to ubiquitin, and thestructure of AAH26994.1 showed a much closerresemblance to MoaD subunits of molybdopterinsynthases (known structures are of threebacterial MoaD proteins with 14%-26% sequenceidentity to AAH26994.1). The structures ofAAH26994.1 and the MoaD proteins each containthe signature ubiquitin secondary structure fold,", "metadata": {}}
+{"_id": "45015767", "title": "", "text": "Concurrent endometrial carcinoma in womenwith a biopsy diagnosis of atypical endometrialhyperplasia: a Gynecologic Oncology Groupstudy.BACKGROUND Adenocarcinoma of theendometrium is the most common gynecologicmalignancy in the United States, accounting forapproximately 36,000 diagnoses of invasivecarcinoma annually. The most common histologictype, endometrioid adenocarcinoma (EC),accounts for 75-80% of patients. The objectiveof this work was to estimate the prevalence ofconcurrent carcinoma in women with a biopsydiagnosis of the precursor lesion, atypicalendometrial hyperplasia (AEH). METHODS Thisprospective cohort study included women whohad a community diagnosis of AEH. Diagnosticbiopsy specimens were reviewed independentlyby three gynecologic pathologists who usedInternational Society of GynecologicPathologists/World Health Organization criteria.Study participants underwent hysterectomywithin 12 weeks of entry onto protocol without", "metadata": {}}
+{"_id": "45027320", "title": "", "text": "The prevalence and clustering of four majorlifestyle risk factors in an English adultpopulation.BACKGROUND The aim of this studywas to examine the clustering of four majorlifestyle risk factors (smoking, heavy drinking,lack of fruit and vegetables consumption, andlack of physical activity), and to examine thevariation across different socio-demographicgroups in the English adult population. METHODSThe study population was derived from the 2003Health Survey for England (n=11,492).Clustering was examined by comparing theobserved and expected prevalence of thedifferent possible combinations. A multinomialmultilevel regression model was conducted toexamine the socio-demographic variation in theclustering of the four risk factors. RESULTS Thestudy found that, when using British healthrecommendations, a majority of the Englishpopulation have multiple lifestyle risk factors atthe same time. Clustering was found at bothends of the lifestyle spectrum and was more", "metadata": {}}
+{"_id": "45096063", "title": "", "text": "Cutting edge: interleukin 17 signals through aheteromeric receptor complex.IL-17 is aninflammatory cytokine produced primarily by aunique lineage of CD4 T cells that plays criticalroles in the pathogenesis of multipleautoimmune diseases. IL-17RA is a ubiquitouslyexpressed receptor that is essential for IL-17biologic activity. Despite widespread receptorexpression, the activity of IL-17 is mostclassically defined by its ability to induce theexpression of inflammatory cytokines,chemokines, and other mediators by stromalcells. The lack of IL-17 responsiveness in mousestromal cells genetically deficient in IL-17RA ispoorly complemented by human IL-17RA,suggesting the presence of an obligate ancillarycomponent whose activity is species specific.This component is IL-17RC, a distinct member ofthe IL-17R family. Thus, the biologic activity ofIL-17 is dependent on a complex composed ofIL-17RA and IL-17RC, suggesting a newparadigm for understanding the interactions", "metadata": {}}
+{"_id": "45143088", "title": "", "text": "Long non-coding RNAs with low expression levelsin cells are enriched in secreted exosomes.Longnon-coding RNAs (lncRNAs) are involved inregulating chromatin modifications, genetranscription, mRNA translation, and proteinfunction. We recently reported a high variation inthe basal expression levels of a panel of lncRNAsin HeLa and MCF-7 cells and their differentialresponse to DNA damage induction. Here, wehypothesized that lncRNA molecules withdifferent cellular expression may have adifferential abundance in secreted exosomes,and their exosome levels would reflect cellularresponse to DNA damage. MALAT1, HOTAIR,lincRNA-p21, GAS5, TUG1, CCND1-ncRNA inexosomes secreted from cultured cells werecharacterized. A different expression pattern oflncRNAs in exosomes was seen compared tocells. RNA molecules with relative low expressionlevels (lincRNA-p21, HOTAIR, ncRNA-CCND1)were highly enriched in exosomes. TUG1 andGAS5 levels were moderately elevated in", "metadata": {}}
+{"_id": "45153864", "title": "", "text": "Olanzapine depot exposure in male rats:Dose-dependent lipogenic effects withoutconcomitant weight gain.Treatment withsecond-generation antipsychotic agents such asolanzapine frequently results in metabolicadverse effects, e.g. hyperphagia, weight gainand dyslipidaemia in patients of both genders.The molecular mechanisms underlying metabolicadverse effects are still largely unknown, andstudies in rodents represent an importantapproach in their exploration. However, thevalidity of the rodent model is hampered by thefact that antipsychotics induce weight gain infemale, but not male, rats. When administeredorally, the short half-life of olanzapine in ratsprevents stable plasma concentrations of thedrug. We recently showed that a singleintramuscular injection of long-acting olanzapineformulation yields clinically relevant plasmaconcentrations accompanied by severaldysmetabolic features in the female rat. In thecurrent study, we show that depot injections of", "metadata": {}}
+{"_id": "45154987", "title": "", "text": "Glutamate mediates the function of melanocortinreceptor 4 on Sim1 neurons in body weightregulation.The melanocortin receptor 4 (MC4R) isa well-established mediator of body weighthomeostasis. However, the neurotransmitter(s)that mediate MC4R function remain largelyunknown; as a result, little is known about thesecond-order neurons of the MC4R neuralpathway. Single-minded 1 (Sim1)-expressingbrain regions, which include the paraventricularnucleus of hypothalamus (PVH), represent keybrain sites that mediate melanocortin action. Weconditionally restored MC4R expression in Sim1neurons in the background of Mc4r-null mice.The restoration dramatically reduced obesity inMc4r-null mice. The anti-obesity effect wascompletely reversed by selective disruption ofglutamate release from those same Sim1neurons. The reversal was caused by lowerenergy expenditure and hyperphagia.Corroboratively, selective disruption of glutamaterelease from adult PVH neurons led to rapid", "metadata": {}}
+{"_id": "45166582", "title": "", "text": "Intracellular sterol dynamics.We review thecellular mechanisms implicated in cholesteroltrafficking and distribution. Recent studies haveprovided new information about the distributionof sterols within cells, including analysis of itstransbilayer distribution. The cholesterolinteraction with other lipids and its engagementin various trafficking processes will determine itsproper level in a specific membrane; making thecholesterol distribution uneven among thevarious intracellular organelles. The cholesterolcontent is important since cholesterol plays anessential role in membranes by controlling theirphysicochemical properties as well as key cellularevents such as signal transduction and proteintrafficking. Cholesterol movement betweencellular organelles is highly dynamic, and can beachieved by vesicular and non-vesicularprocesses. Various studies have analyzed theproteins that play a significant role in theseprocesses, giving us new information about therelative importance of these two trafficking", "metadata": {}}
+{"_id": "45199834", "title": "", "text": "A plasma membrane component able to bind andalter virions of poliovirus type 1: studies oncell-free alteration using a simplifiedassay.Abstract Intact HeLa cells can bind virionsof poliovirus type 1 and can subsequentlyconvert them to altered particles by incubation at37°. Altered particles sediment more slowly thanvirions, have lost VP-4, and are disrupted bysodium dodecyl sulfate, but their RNA is intactand ribonuclease insensitive. Thesecharacteristics allow assay of altered particlesand of particles that have released their RNA,using nuclease digestion with or without sodiumdodecyl sulfate treatment. With this simple assayprocedure, quantitative parameters of bindingand alteration can be measured. Thebinding-altering activity can be localized inplasma membranes, and pure membranes canbe shown to carry out alteration. Themembrane-bound activity is abolished byproteases and by nonionic detergents. Onlyaltered particles are formed by membranes;", "metadata": {}}
+{"_id": "45200347", "title": "", "text": "Resequencing studies of nonmodel organismsusing closely related reference genomes: optimalexperimental designs and bioinformaticsapproaches for population genomics.Decreasingcosts of next-generation sequencing (NGS)experiments have made a wide range of genomicquestions open for study with nonmodelorganisms. However, experimental designs andanalysis of NGS data from less well-knownspecies are challenging because of the lack ofgenomic resources. In this work, we investigatethe performance of alternative experimentaldesigns and bioinformatics approaches inestimating variability and neutrality tests basedon the site-frequency-spectrum (SFS) fromindividual resequencing data. We pay particularattention to challenges faced in the study ofnonmodel organisms, in particular the absence ofa species-specific reference genome, althoughphylogenetically close genomes are assumed tobe available. We compare the performance ofthree alternative bioinformatics approaches –", "metadata": {}}
+{"_id": "45218443", "title": "", "text": "Thalassemia and malaria: new insights into anold problem.The hemoglobinopathies areprobably the world's most common geneticdiseases: The World Health Organization hasestimated that at least 5% of the population arecarriers for one or other of the most seriousforms, the alpha- and beta-thalassemias and thestructural variant hemoglobins S, C, and E, whichare found at polymorphic frequencies in manycountries. All these hemoglobinopathies arebelieved to provide protection against malaria,and it is thought that, in malarial regions of theworld, natural selection has been responsible forelevating and maintaining their genefrequencies, an idea first proposed 50 years agoby J.B.S. Haldane. Epidemiological studiesundertaken in the 1950s on hemoglobin S inAfrica provided support for the \"malariahypothesis,\" but until recently it has provedextremely difficult to verify it for thethalassemias. The application of molecularmethods has, however, provided new", "metadata": {}}
+{"_id": "45244537", "title": "", "text": "Endocrine control of spermatogenesis: Role ofFSH and LH/ testosterone.Evaluation of testicularfunctions (production of sperm and androgens) isan important aspect of preclinical safetyassessment and testicular toxicity iscomparatively far more common than ovariantoxicity. This chapter focuses (1) on thehistological sequelae of disturbed reproductiveendocrinology in rat, dog and nonhumanprimates and (2) provides a review of ourcurrent understanding of the roles ofgonadotropins and androgens. The response ofthe rodent testis to endocrine disturbances isclearly different from that of dog and primateswith different germ cell types and spermatogenicstages being affected initially and also that theend-stage spermatogenic involution is morepronounced in dog and primates compared torodents. Luteinizing hormone (LH)/testosteroneand follicle-stimulating hormone (FSH) are thepivotal endocrine factors controlling testicularfunctions. The relative importance of either", "metadata": {}}
+{"_id": "45276789", "title": "", "text": "Extravasation injuries on regional neonatalunits.This survey of regional neonatal intensivecare units determined a prevalence of 38 per1000 neonates who sustained an extravasationinjury that caused skin necrosis. Most injuriesoccurred in infants of 26 weeks gestation or less,with parenteral nutrition infused throughintravenous cannulae. Common treatments wereexposing wounds to the air, infiltration withhyaluronidase and saline, and occlusivedressings.", "metadata": {}}
+{"_id": "45287266", "title": "", "text": "Nonstructural protein 3-4A: the Swiss army knifeof hepatitis C virus.Hepatitis C virus (HCV)nonstructural protein 3-4A (NS3-4A) is acomplex composed of NS3 and its cofactor NS4A.It harbours serine protease as well asNTPase/RNA helicase activities and is essentialfor viral polyprotein processing, RNA replicationand virion formation. Specific inhibitors of theNS3-4A protease significantly improve sustainedvirological response rates in patients with chronichepatitis C when combined with pegylatedinterferon-α and ribavirin. The NS3-4A proteasecan also target selected cellular proteins, therebyblocking innate immune pathways andmodulating growth factor signalling. Hence,NS3-4A is not only an essential component of theviral replication complex and prime target forantiviral intervention but also a key player in thepersistence and pathogenesis of HCV. Thisreview provides a concise update on thebiochemical and structural aspects of NS3-4A, itsrole in the pathogenesis of chronic hepatitis C", "metadata": {}}
+{"_id": "45336190", "title": "", "text": "Phase 2 safety trial targeting amyloid betaproduction with a gamma-secretase inhibitor inAlzheimer disease.OBJECTIVE To evaluate thesafety, tolerability, and amyloid beta (Abeta)response to the gamma-secretase inhibitorLY450139 in Alzheimer disease. DESIGNMulticenter, randomized, double-blind,dose-escalation, placebo-controlled trial.SETTING Community-based clinical researchcenters. Patients Fifty-one individuals with mildto moderate Alzheimer disease were randomizedto receive placebo (n=15) or LY450139 (100 mg[n=22] or 140 mg [n=14]), with 43 completingthe treatment phase. Intervention The LY450139groups received 60 mg/d for 2 weeks, then 100mg/d for 6 weeks, and then either 100 or 140mg/d for 6 additional weeks. MAIN OUTCOMEMEASURES Primary outcome measures wereadverse events, plasma and cerebrospinal fluidAbeta levels, vital signs, electrocardiographicdata, and laboratory safety test results.Secondary outcome measures included the", "metadata": {}}
+{"_id": "45341480", "title": "", "text": "Reduction in skin grafting after the introductionof hydrofiber dressings in partial thicknessburns: a comparison between a hydrofiber andsilver sulphadiazine.AIM/PURPOSE The aim ofthis study was to compare clinical outcome ofchildren with scald burns treated with ahydrofiber dressing (Aquacel(®), Convatec Inc.)with the former standard of care with silversulfadiazine (Flammazine(®); SolvayPharmaceuticals), considering surgicalintervention and length of stay (LOS). METHODSA retrospective study of all consecutive childrenfrom zero to four years with primary scald burnsup to 10% admitted to the Burn Centre of theMaasstad Hospital Rotterdam between January1987 and January 2010 were reviewed. For datacollection a prospective computerized databasewas used. For comparison the study period wasdivided into two periods representing the periodbefore and after the introduction of thehydrofiber dressing (HFD), respectively1987-1999 (period 1) and 1999-2010 (period 2).", "metadata": {}}
+{"_id": "45364685", "title": "", "text": "Induction of the heat-shock response by carbondioxide in Chironomus thummi.The effects of aset of stress treatments on gene expression ofChironomus thummi salivary gland cells havebeen analyzed. Among the treatments assayed,only during recovery from carbon dioxide havewe observed a response similar to thatpreviously described after heat-shock treatment:induction of the heat-shock puffs and synthesisof the heat-shock polypeptides. In theseconditions, puffing and transcription of telomericregions were observed, which led to theappearance of the temperature-inducibletelomeric Balbiani ring T-BR-III. Othertreatments failed to induce the heat-shockresponse, despite promoting real stressconditions to C. thummi larvae or salivary glandcells.", "metadata": {}}
+{"_id": "45401535", "title": "", "text": "Candida albicans-Staphylococcus aureuspolymicrobial peritonitis modulates host innateimmunity.Despite advances in medical devicefabrication and antimicrobial treatmenttherapies, fungal-bacterial polymicrobialperitonitis remains a serious complication forsurgery patients, those on peritoneal dialysis,and the critically ill. Using a murine model ofperitonitis, we have demonstrated thatmonomicrobial infection with Candida albicans orStaphylococcus aureus is nonlethal. However,coinfection with these same doses leads to a40% mortality rate and increased microbialburden in the spleen and kidney by day 1postinfection. Using a multiplex enzyme-linkedimmunosorbent assay, we have also identified aunique subset of innate proinflammatorycytokines (interleukin-6, granulocytecolony-stimulating factor, keratinocytechemoattractant, monocyte chemoattractantprotein-1, and macrophage inflammatoryprotein-1α) that are significantly increased", "metadata": {}}
+{"_id": "45408403", "title": "", "text": "Techniques and probes for the study of Xenopustropicalis development.The frog Xenopus laevishas provided significant insights intodevelopmental and cellular processes. However,X. laevis has an allotetraploid genome precludingits use in forward genetic analysis. Geneticanalysis may be applicable to Xenopus (Silurana)tropicalis, which has a diploid genome and ashorter generation time. Here, we show thatmany tools for the study of X. laevisdevelopment can be applied to X. tropicalis. Byusing the developmental staging system ofNieuwkoop and Faber, we find that X. tropicalisembryos develop at similar rates to X. laevis,although they tolerate a narrower range oftemperatures. We also show that many of theanalytical reagents available for X. laevis can beeffectively transferred to X. tropicalis. The X.laevis protocol for whole-mount in situhybridization to mRNA transcripts can besuccessfully applied to X. tropicalis withoutalteration. Additionally, X. laevis probes often", "metadata": {}}
+{"_id": "45414636", "title": "", "text": "Requirement of c-myb in T cell development andin mature T cell function.Previous reports havesuggested that the protooncogene c-mybparticipates in T cell development in the thymusand mature T cell proliferation. We havegenerated two T cell-specific c-myb knockoutmouse models, myb/LckCre and myb/CD4Cre.We have demonstrated that c-myb is requiredfor the development of thymocytes at the DN3stage, for survival and proliferation ofdouble-positive thymocytes, for differentiation ofsingle-positive CD4 and CD8 T cells, and for theproliferative responses of mature T cells. Inaddition, our data show that c-myb is directlyinvolved in the formation of double-positiveCD4+CD8+CD25+, CD4+CD25+, andCD8+CD25+ T cells, developmental processesthat may imply a role for c-myb in autoimmunedysfunction.", "metadata": {}}
+{"_id": "45447613", "title": "", "text": "Effect of losartan on ambulatory short-termblood pressure variability and cardiovascularremodeling in hypertensive patients onhemodialysis.OBJECTIVE Previous studies haveshown increases in ambulatory short-term bloodpressure (BP) variability to be related tocardiovascular disease. In this study, weexamined whether an angiotensin II type 1receptor blocker losartan would improveambulatory short-term BP variability inhypertensive patients on hemodialysis.METHODS Forty hypertensive patients onhemodialysis therapy were randomly assigned tothe losartan treatment group (n=20) or thecontrol treatment group (n=20). At baseline and6 and 12 months after the treatment, 24-hambulatory BP monitoring was performed.Echocardiography and measurements ofbrachial-ankle pulse wave velocity (baPWV) andbiochemical parameters were also performedbefore and after therapy. RESULTS After 6- and12-months of treatment, nighttime short-term", "metadata": {}}
+{"_id": "45449835", "title": "", "text": "Interleukin-17 mRNA expression in blood andCSF mononuclear cells is augmented in multiplesclerosis.Myelin-directed autoimmunity isconsidered to play a key role in the pathogenesisof multiple sclerosis (MS). Increased productionof both pro- and anti-inflammatory cytokines is acommon finding in MS. Interleukin-17 (IL-17) isa recently described cytokine produced inhumans almost exclusively by activated memoryT cells, which can induce the production ofproinflammatory cytokines and chemokines fromparenchymal cells and macrophages. In situhybridisation with synthetic oligonucleotideprobes was adopted to detect and enumerateIL-17 mRNA expressing mononuclear cells (MNC)in blood and cerebrospinal fluid (CSF) frompatients with MS and control individuals.Numbers of IL-17 mRNA expressing blood MNCwere higher in patients with MS and acuteaseptic meningoencephalitis (AM) compared tohealthy individuals. Higher numbers of IL-17mRNA expressing blood MNC were detected in", "metadata": {}}
+{"_id": "45457778", "title": "", "text": "A European perspective on population studies ofdementia.The change in the world's agedemographics and the predicted rise in theincidence of age-related diseases, includingdementia, is a source of major public healthconcern. Major research effort in both the UnitedStates and Europe has been targeted towardunderstanding the pathogenesis andepidemiology of dementia. This article presents ageneral overview of the history of dementiaresearch in Europe and how it compares withthat in the United States. The review highlightsthe common issues which both U.S. andEuropean researchers have identified andattempted to tackle. To maximize informationgained from studies across the world, betterharmonization of methodology is needed, asinformed from current research practice.", "metadata": {}}
+{"_id": "45461275", "title": "", "text": "The cost of providing comprehensive HIVtreatment in PEPFAR-supportedprograms.BACKGROUND PEPFAR, nationalgovernments, and other stakeholders areinvesting unprecedented resources to provideHIV treatment in developing countries. Thisstudy reports empirical data on costs and costtrends in a large sample of HIV treatment sites.DESIGN In 2006-2007, we conducted costanalyses at 43 PEPFAR-supported outpatientclinics providing free comprehensive HIVtreatment in Botswana, Ethiopia, Nigeria,Uganda, and Vietnam. METHODS We collecteddata on HIV treatment costs over consecutive6-month periods starting from scale-up ofdedicated HIV treatment services at each site.The study included all patients receiving HIVtreatment and care at study sites [62,512antiretroviral therapy (ART) and 44,394 pre-ARTpatients]. Outcomes were costs per patient andtotal program costs, subdivided by major costcategories. RESULTS Median annual economic", "metadata": {}}
+{"_id": "45487164", "title": "", "text": "A sperm cytoskeletal protein that signals oocytemeiotic maturation and ovulation.Caenorhabditiselegans oocytes, like those of most animals,arrest during meiotic prophase. Sperm promotethe resumption of meiosis (maturation) andcontraction of smooth muscle-like gonadalsheath cells, which are required for ovulation.We show that the major sperm cytoskeletalprotein (MSP) is a bipartite signal for oocytematuration and sheath contraction. MSP alsofunctions in sperm locomotion, playing a roleanalogous to actin. Thus, during evolution, MSPhas acquired extracellular signaling andintracellular cytoskeletal functions forreproduction. Proteins with MSP-like domains arefound in plants, fungi, and other animals,suggesting that related signaling functions mayexist in other phyla.", "metadata": {}}
+{"_id": "45548062", "title": "", "text": "Unmet need for mental health care among U.S.children: variation by ethnicity and insurancestatus.OBJECTIVE Policy discussions regardingthe mental health needs of children andadolescents emphasize a lack of use of mentalhealth services among youth, but few nationalestimates are available. The authors use threenational data sets and examine ethnic disparitiesin unmet need (defined as having a need formental health evaluation but not using anyservices in a 1-year period) to provide suchestimates. METHOD The authors conductedsecondary data analyses in three nationallyrepresentative household surveys fielded in1996-1998: the National Health InterviewSurvey, the National Survey of AmericanFamilies, and the Community Tracking Survey.They determined rates of mental health serviceuse by children and adolescents 3-17 years ofage and differences by ethnicity and insurancestatus. Among the children defined as in need ofmental health services, defined by an estimator", "metadata": {}}
+{"_id": "45581752", "title": "", "text": "Conditional economic incentives for reducing HIVrisk behaviors: integration of psychology andbehavioral economics.OBJECTIVE This articlereviews psychology and behavioral economicapproaches to HIV prevention, and examines theintegration and application of these approachesin conditional economic incentive (CEI) programsfor reducing HIV risk behavior. METHODS Wediscuss the history of HIV preventionapproaches, highlighting the important insightsand limitations of psychological theories. Weprovide an overview of the theoretical tenets ofbehavioral economics that are relevant to HIVprevention, and utilize CEIs as an illustrativeexample of how traditional psychological theoriesand behavioral economics can be combined intonew approaches for HIV prevention. RESULTSBehavioral economic interventions cancomplement psychological frameworks forreducing HIV risk by introducing uniquetheoretical understandings about the conditionsunder which risky decisions are amenable to", "metadata": {}}
+{"_id": "45638119", "title": "", "text": "ALDH1 is a marker of normal and malignanthuman mammary stem cells and a predictor ofpoor clinical outcome.Application of stem cellbiology to breast cancer research has beenlimited by the lack of simple methods foridentification and isolation of normal andmalignant stem cells. Utilizing in vitro and in vivoexperimental systems, we show that normal andcancer human mammary epithelial cells withincreased aldehyde dehydrogenase activity(ALDH) have stem/progenitor properties. Thesecells contain the subpopulation of normal breastepithelium with the broadest lineagedifferentiation potential and greatest growthcapacity in a xenotransplant model. In breastcarcinomas, high ALDH activity identifies thetumorigenic cell fraction, capable of self-renewaland of generating tumors that recapitulate theheterogeneity of the parental tumor. In a seriesof 577 breast carcinomas, expression of ALDH1detected by immunostaining correlated with poorprognosis. These findings offer an important new", "metadata": {}}
+{"_id": "45651303", "title": "", "text": "Interleukin-6 and interleukin-8 levels in serumand synovial fluid of patients withosteoarthritis.Concentrations of interleukin (IL)-6and IL-8 in serum and synovial fluid obtainedfrom patients with osteoarthritis (OA) of theknee were determined by thechemiluminescence-ELISA (CL-ELISA) method,the sensitivity of which is 100-1,000 timesgreater than that of the conventional ELISAmethod. The results were compared with thoseobtained from patients with rheumatoid arthritis(RA) and from healthy subjects. The mean IL-6and IL-8 levels in synovial fluid indicated higherconcentrations in RA than in OA. The IL-6 andIL-8 levels in serum were significantly higher inRA and OA relative to controls. Among OApatients in whom remarkable improvement wasnoted in hydrarthrosis, the synovial fluid IL-6and IL-8 levels at the initial examination wererelatively higher, and were markedly decreasedafter treatment with sodium hyaluronate (NaHA).Among those in whom no improvement was", "metadata": {}}
+{"_id": "45764440", "title": "", "text": "Inhibition of SRC expression and activity inhibitstumor progression and metastasis of humanpancreatic adenocarcinoma cells in an orthotopicnude mouse model.The nonreceptor proteintyrosine kinase Src is overexpressed in 70% ofpancreatic adenocarcinomas. Here, we describethe effect of molecular and pharmacologicaldown-regulation of Src on incidence, growth, andmetastasis of pancreatic tumor cells in anorthotopic model. Src expression in L3.6plhuman pancreatic tumor cells was reduced bystable expression of a plasmid encoding smallinterfering RNA (siRNA) to c-src. In stable siRNAclones, Src expression was reduced >80%, withno change in expression of the related kinasesc-Yes and c-Lyn, and proliferation rates weresimilar in all clones. Phosphorylation of Akt andp44/42 Erk mitogen-activated protein kinase andproduction of VEGF and IL-8 in culturesupernatants were also reduced (P < 0.005). Onorthotopic implantation of varying cell numbersinto nude mice, tumor incidence was unchanged;", "metadata": {}}
+{"_id": "45770026", "title": "", "text": "Eicosapentaenoic acid is converted via ω-3epoxygenation to the anti-inflammatorymetabolite12-hydroxy-17,18-epoxyeicosatetraenoicacid.Eicosapentaenoic acid (EPA) has beneficialeffects in many inflammatory disorders. In thisstudy, dietary EPA was converted to17,18-epoxyeicosatetraenoic acid (17,18-EpETE)by ω-3 epoxygenation in the mouse peritonealcavity. Mediator lipidomics revealed a series ofnovel oxygenated metabolites of 17,18-EpETE,and one of the major metabolites,12-hydroxy-17,18-epoxyeicosatetraenoic acid(12-OH-17,18-EpETE), displayed a potentanti-inflammatory action by limiting neutrophilinfiltration in murine zymosan-inducedperitonitis. 12-OH-17,18-EpETE inhibitedleukotriene B4-induced neutrophil chemotaxisand polarization in vitro in a low nanomolarrange (EC50 0.6 nM). The complete structures oftwo natural isomers were assigned as12S-OH-17R,18S-EpETE and", "metadata": {}}
+{"_id": "45820464", "title": "", "text": "Scrapie in mice. Agent-strain differences in thedistribution and intensity of grey mattervacuolation.Five strains of scrapie agent wereused as intracerebral inocula for 2 inbred mousestrains, C57BL and VM, and their F1 cross. Thedegree of vacuolation in specified regions of thebrain, and the relative distribution of thisdamage in 9 regions represented as a “lesionprofile”, was different for each agent. Any of the5 scrapie agents could be distinguished from theothers with a very high degree of reliability solelyon the basis of these histological parameters,using either strain of mouse. The lesion profilewas unaffected by the dose of the agent, usingdoses of ME7 agent ranging over 6 orders ofmagnitude in C57BL mice. The genotype ofmouse had a marked effect on the overall degreeof vacuolation and on the shape of the lesionprofile: these effects were more profound withsome agents than others. In certain areas of thebrain, depending upon the strain of agent used,the (C57BL × VM)F1 cross was found to have", "metadata": {}}
+{"_id": "45875990", "title": "", "text": "Cyclin A2 is an RNA binding protein that controlsMre11 mRNA translationCyclin A2 activates thecyclin-dependent kinases Cdk1 and Cdk2 and isexpressed at elevated levels from S phase untilearly mitosis. We found that mutant mice thatcannot elevate cyclin A2 are chromosomallyunstable and tumor-prone. Underlying thechromosomal instability is a failure toup-regulate the meiotic recombination 11(Mre11) nuclease in S phase, which leads toimpaired resolution of stalled replication forks,insufficient repair of double-stranded DNAbreaks, and improper segregation of sisterchromosomes. Unexpectedly, cyclin A2controlled Mre11 abundance through aC-terminal RNA binding domain that selectivelyand directly binds Mre11 transcripts to mediatepolysome loading and translation. These datareveal cyclin A2 as a mechanistically diverseregulator of DNA replication combiningmultifaceted kinase-dependent functions with akinase-independent, RNA binding–dependent", "metadata": {}}
+{"_id": "45908102", "title": "", "text": "Cluster sampling to assess immunizationcoverage: a review of experience with asimplified sampling method.The ExpandedProgram on Immunization (EPI) is using asimplified cluster sampling method, based on therandom selection of 210 children in 30 clusters of7 children each, to estimate immunizationcoverage levels. This article analyzes the resultsof this method in actual and computer simulatedsurveys. Results from 60 actual surveysconducted in 25 countries were available foranalysis, for a total of 446 sample estimations ofimmunization coverage. 83% of the sampleresults had 95% confidence limits within + or -10%, and none of the surveys had 95%confidence limits exceeding + or - 13%. Inaddition, 12 hypothetical population strata withimmunization coverage rates ranging from10%-99% were established for the purposes ofcomputer simulation, and 10 hypotheticalcommunities were established by allocating tothem various proportions of each of the strata.", "metadata": {}}
+{"_id": "45920278", "title": "", "text": "Gender differences in the utilization of healthcare services.BACKGROUND Studies have shownthat women use more health care services thanmen. We used important independent variables,such as patient sociodemographics and healthstatus, to investigate gender differences in theuse and costs of these services. METHODS Newadult patients (N = 509) were randomly assignedto primary care physicians at a universitymedical center. Their use of health care servicesand associated charges were monitored for 1year of care. Self-reported health status wasmeasured using the Medical Outcomes StudyShort Form-36 (SF-36). We controlled for healthstatus, sociodemographic information, andprimary care physician specialty in the statisticalanalyses. RESULTS Women had significantlylower self-reported health status and lower meaneducation and income than men. Women had asignificantly higher mean number of visits totheir primary care clinic and diagnostic servicesthan men. Mean charges for primary care,", "metadata": {}}
+{"_id": "46112052", "title": "", "text": "Recombinant human tumor necrosis factoradministered as a 24-hour intravenous infusion.A phase I and pharmacologic study.Recombinanthuman tumor necrosis factor (rH-TNF) is acytokine with direct antitumor properties. In aphase I trial we continuously infused rH-TNF for24 hours. We gave a total of 115 courses oftherapy to 50 patients. Doses ranged from 4.5 to645 micrograms of rH-TNF/m2. Systemictoxicity, including fever, chills, fatigue, andhypotension, increased with the dose of rH-TNFadministered. Doses greater than 454micrograms/m2 frequently caused severelethargy and fatigue, which precluded hospitaldischarge of the patient at the completion oftherapy. The dose-limiting toxicity washypotension, and five patients treated at the twohighest dose levels required dopaminetreatment. Other organ-specific toxicity wasmodest and spontaneously resolved after 48hours. The 24-hour infusions of rH-TNF wereassociated with significant decreases in serum", "metadata": {}}
+{"_id": "46127781", "title": "", "text": "Detection and comparison of epidermal growthfactor receptor mutations in cells and fluid ofmalignant pleural effusion in non-small cell lungcancer.Cells or cell-free fluid of malignant pleuraleffusion could be important clinical specimen forepidermal growth factor receptor (EGFR)mutation screening in advanced non-small celllung cancer (NSCLC) patients. However, theirusefulness in mutation detection has not beenwell compared. In this study we recruited 26East Asian NSCLC patients with malignant pleuraleffusion, determined the mutation status ofEGFR in both cells and matched cell-free fluidwith the use of sequencing and mutant-enrichedPCR. After comparing the mutation spectrums,we found both the cells and cell-free pleural fluidmay be feasible clinical specimen for EGFRmutation detection in unresectable NSCLC givensensitive genotyping assays employed. Directsequencing could miss a significant portion ofmutations in these heterogeneous specimens.More sensitive methods, such as", "metadata": {}}
+{"_id": "46135768", "title": "", "text": "Materials and Methods Figs. S1 to S15References Supporting OnlineMaterialsEndosomal Toll-like receptors (TLRs) 7and 9 recognize viral pathogens and inducesignals leading to the activation of nuclear factorκB (NF-κB)-dependent proinflammatorycytokines and interferon regulatory factor 7(IRF7)-dependent type I interferons (IFNs).Recognition of viral nucleic acids by TLR9requires its cleavage in the endolysosomalcompartment. Here, we show that TLR9 signalsleading to the activation of type I IFN, but notproinflammatory cytokine genes, require TLR9trafficking from endosomes to a specializedlysosome-related organelle. Furthermore, weidentify adapter protein-3 as the protein complexresponsible for the trafficking of TLR9 to thissubcellular compartment. Our results reveal anintracellular mechanism for bifurcation of TLR9signals by selective receptor trafficking withinthe endosomal system.", "metadata": {}}
+{"_id": "46153874", "title": "", "text": "Sedimentation velocity method in the analyticalultracentrifuge for the study of protein-proteininteractions.Sedimentation analysis in theanalytical ultracentrifuge can be employed todetect macromolecular interactions. Whenevertwo molecules interact the mass of the resultingcomplex is increased and this is reflected in thesedimentation behavior. In this chapter wediscuss how this phenomenon can be utilized todetermine quantitative parameters of aninteraction. An example, interaction ofsingle-stranded DNA binding protein with asubunit of DNA polymerase III holoenzyme isgiven together with a thorough treatment of therelating theory and a description of evaluationalgorithms.", "metadata": {}}
+{"_id": "46182525", "title": "", "text": "Structural trends in the aging femoral neck andproximal shaft: analysis of the Third NationalHealth and Nutrition Examination Surveydual-energy X-ray absorptiometry data.Hip scansof U.S. adults aged 20-99 years acquired in theThird National Health and Nutrition ExaminationSurvey (NHANES III) using dual-energy X-rayabsorptiometry (DXA) were analyzed with astructural analysis program. The programanalyzes narrow (3 mm wide) regions at specificlocations across the proximal femur to measurebone mineral density (BMD) as well ascross-sectional areas (CSAs), cross-sectionalmoments of inertia (CSMI), section moduli,subperiosteal widths, and estimated meancortical thickness. Measurements are reportedhere on a non-Hispanic white subgroup of 2,719men and 2,904 women for a cortical regionacross the proximal shaft 2 cm distal to thelesser trochanter and a mixed cortical/trabecularregion across the narrowest point of the femoralneck. Apparent age trends in BMD and section", "metadata": {}}
+{"_id": "46193388", "title": "", "text": "Turning blood into brain: cells bearing neuronalantigens generated in vivo from bonemarrow.Bone marrow stem cells give rise to avariety of hematopoietic lineages and repopulatethe blood throughout adult life. We show that, ina strain of mice incapable of developing cells ofthe myeloid and lymphoid lineages, transplantedadult bone marrow cells migrated into the brainand differentiated into cells that expressedneuron-specific antigens. These findings raisethe possibility that bone marrow-derived cellsmay provide an alternative source of neurons inpatients with neurodegenerative diseases orcentral nervous system injury.", "metadata": {}}
+{"_id": "46193478", "title": "", "text": "A negative staining method for high resolutionelectron microscopy of viruses.Abstract A simpletechnique has been developed for the study ofthe external form and structure of virus particles.High contrast with good preservation is obtainedby mixing virus preparations with 1%phosphotungstic acid adjusted to pH 7.5 andspraying directly onto electron microscopesupporting films made from evaporated carbon.The application of the technique to tobaccomosaic virus and turnip yellow mosaic virus isdescribed. Structural details suggested by X-raydiffraction methods have been resolved.", "metadata": {}}
+{"_id": "46202852", "title": "", "text": "Nef induces multiple genes involved incholesterol synthesis and uptake in humanimmunodeficiency virus type 1-infected Tcells.Several recent reports indicate thatcholesterol might play an important role inhuman immunodeficiency virus type 1 (HIV-1)replication. We investigated the effects of HIV-1infection on cholesterol biosynthesis and uptakeusing microarrays. HIV-1 increased geneexpression of cholesterol genes in bothtransformed T-cell lines and primary CD4(+) Tcells. Consistent with our microarray data,(14)C-labeled mevalonate and acetateincorporation was increased in HIV-1-infectedcells. Our data also demonstrate that changes incholesterol biosynthesis and uptake are onlyobserved in the presence of functional Nef,suggesting that increased cholesterol synthesismay contribute to Nef-mediated enhancement ofvirion infectivity and viral replication.", "metadata": {}}
+{"_id": "46248894", "title": "", "text": "Long noncoding RNA as modular scaffold ofhistone modification complexesLong intergenicnoncoding RNAs (lincRNAs) regulate chromatinstates and epigenetic inheritance. Here, we showthat the lincRNA HOTAIR serves as a scaffold forat least two distinct histone modificationcomplexes. A 5' domain of HOTAIR bindspolycomb repressive complex 2 (PRC2), whereasa 3' domain of HOTAIR binds theLSD1/CoREST/REST complex. The ability totether two distinct complexes enablesRNA-mediated assembly of PRC2 and LSD1 andcoordinates targeting of PRC2 and LSD1 tochromatin for coupled histone H3 lysine 27methylation and lysine 4 demethylation. Ourresults suggest that lincRNAs may serve asscaffolds by providing binding surfaces toassemble select histone modification enzymes,thereby specifying the pattern of histonemodifications on target genes.", "metadata": {}}
+{"_id": "46266579", "title": "", "text": "Therapeutic Clearance of Amyloid by Antibodiesto Serum Amyloid P Component.BACKGROUNDThe amyloid fibril deposits that cause systemicamyloidosis always contain the nonfibrillarnormal plasma protein, serum amyloid Pcomponent (SAP). The drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC) efficiently depletesSAP from the plasma but leaves some SAP inamyloid deposits that can be specifically targetedby therapeutic IgG anti-SAP antibodies. Inmurine amyloid A type amyloidosis, the bindingof these antibodies to the residual SAP inamyloid deposits activates complement andtriggers the rapid clearance of amyloid bymacrophage-derived multinucleated giant cells.METHODS We conducted an open-label,single-dose-escalation, phase 1 trial involving 15patients with systemic amyloidosis. After firstusing CPHPC to deplete circulating SAP, weinfused a fully humanized monoclonal IgG1anti-SAP antibody. Patients with clinical evidence", "metadata": {}}
+{"_id": "46277811", "title": "", "text": "LPA Gene, Ethnicity, and CardiovascularEventsBackground: The relationship of LPA singlenucleotide polymorphisms (SNPs),apolipoprotein(a) isoforms, and lipoprotein(a)[Lp(a)] levels with major adverse cardiovascularevents (MACE) in different ethnic groups is notwell known. Methods: LPA SNPs,apolipoprotein(a) isoforms, Lp(a), and oxidizedphospholipids on apolipoprotein B-100(OxPL-apoB) levels were measured in 1792black, 1030 white, and 597 Hispanic subjectsenrolled in the Dallas Heart Study. Theirinterdependent relationships and prospectiveassociation with MACE after median 9.5-yearfollow-up were determined. Results: LPA SNPrs3798220 was most prevalent in Hispanics(42.38%), rs10455872 in whites (14.27%), andrs9457951 in blacks (32.92%). The correlation ofeach of these SNPs with the majorapolipoprotein(a) isoform size was highlyvariable and in different directions among ethnicgroups. In the entire cohort, Cox regression", "metadata": {}}
+{"_id": "46305977", "title": "", "text": "Protein kinase CK2 modulates developmentalfunctions of the abscisic acid responsive proteinRab17 from maize.The maize abscisic acidresponsive protein Rab17 is a highlyphosphorylated late embryogenesis abundantprotein involved in plant responses to stress. Inthis study, we provide evidence of theimportance of Rab17 phosphorylation by proteinkinase CK2 in growth-related processes understress conditions. We show the specificinteraction of Rab17 with the CK2 regulatorysubunits CK2 beta-1 and CK2 beta-3, and thatthese interactions do not depend on thephosphorylation state of Rab17. Live-cellfluorescence imaging of both CK2 and Rab17indicates that the intracellular dynamics ofRab17 are regulated by CK2 phosphorylation. Wefound both CK2 beta subunits and Rab17distributed over the cytoplasm and nucleus. Bycontrast, catalytic CK2 alpha subunits and aRab17 mutant protein (mRab17) that is not asubstrate for CK2 phosphorylation remain", "metadata": {}}
+{"_id": "46328296", "title": "", "text": "Reduced plasma concentrations of nitrogen oxidein individuals with essentialhypertension.Patients with essentialhypertension exhibit bluntedendothelium-dependent vasodilator responses,which may be largely attributable to reducedbioactivity of nitric oxide (NO). Therefore, wemeasured the end product of NO, nitrate plusnitrite (nitrogen oxide), and examined therelationship between the degree of hypertensionand plasma nitrate plus nitrite levels in patientswith essential hypertension. The combinedplasma concentration of nitrate plus nitrite, endproducts of NO metabolism, was reduced inindividuals with essential hypertension relative tothat in control subjects (15.7+/-1.1 versus22.8+/-1.4 mmol x L(-1), P<.001); individualswith borderline hypertension showed values thatwere intermediate between those of the othertwo groups (18.2+/-1.2 mmol x L(-1), P<.001).The plasma nitrogen oxide concentration showedsignificant inverse correlations with both systolic", "metadata": {}}
+{"_id": "46346525", "title": "", "text": "Isolation of superoxide dismutase mutants inEscherichia coli: is superoxide dismutasenecessary for aerobic life?Mu transposonscarrying the chloramphenicol resistance markerhave been inserted into the cloned Escherichiacoli genes sodA and sodB coding for manganesesuperoxide dismutase (MnSOD) and ironsuperoxide dismutase (FeSOD) respectively,creating mutations and gene fusions. Themutated sodA or sodB genes were introducedinto the bacterial chromosome by allelicexchange. The resulting mutants were shown tolack the corresponding SOD by activitymeasurements and immunoblot analysis.Aerobically, in rich medium, the absence ofFeSOD or MnSOD had no major effect on growthor sensitivity to the superoxide generator,paraquat. In minimal medium aerobic growthwas not affected, but the sensitivity to paraquatwas increased, especially in the sodA mutant. AsodA sodB double mutant completely devoid ofSOD was also obtained. It was able to grow", "metadata": {}}
+{"_id": "46353045", "title": "", "text": "Late presentation of HIV-infected individuals.Latepresentation remains a major concern despitethe dramatically improved prognosis realized byART. We define a first presentation for HIV careduring the course of HIV infection as 'late' if anAIDS-defining opportunistic disease is apparent,or if CD4+ T-cells are <200/microl. In theWestern world, approximately 10 and 30% ofHIV-infected individuals still present with CD4+T-cells <50 and <200/microl, respectively;estimates are substantially higher for developingcountries. Diagnosis and treatment ofopportunistic diseases and intense supportivein-hospital care take precedence over ART.Benefits of starting ART without delay, that is,when opportunistic diseases are still active,include faster resolution of opportunistic diseasesand a decreased risk of recurrence. Thedownside of starting ART without delay couldinclude toxicity, drug interactions and immunereconstitution inflammatory syndrome (IRIS).Among asymptomatic or oligosymptomatic", "metadata": {}}
+{"_id": "46355579", "title": "", "text": "Rapid clearance of human papillomavirus andimplications for clinical focus on persistentinfections.Health professionals and the publicneed to understand the natural history of humanpapillomavirus (HPV) infections of the cervix tobest use the information provided by newmolecular screening tests. We investigatedoutcomes of 800 carcinogenic HPV infectionsdetected in 599 women at enrollment into apopulation-based cohort (Guanacaste, CostaRica). For individual infections, we calculatedcumulative proportions of three outcomes (viralclearance, persistence without cervicalintraepithelial neoplasia grade 2 or worse[CIN2+], or persistence with new diagnosis ofCIN2+) at successive 6-month time points forthe first 30 months of follow-up. Cervicalspecimens were tested for carcinogenic HPVgenotypes using an L1 degenerate-primerpolymerase chain reaction method. Infectionstypically cleared rapidly, with 67% (95%confidence interval [CI] = 63% to 70%) clearing", "metadata": {}}
+{"_id": "46437558", "title": "", "text": "The role of alcohol in the Russian mortalitycrisis.AIMS Alcohol is believed to be an importantfactor behind the sharp rise in mortality duringthe period 1990-94 in Russia. However, the risein the standard alcohol consumption proxy doesnot seem to be sufficient to explain all theincrease in mortality. This study adopts a novelapproach to exploring the role of the alcoholfactor in the increased mortality by investigatingwhether the mismatch between trends inmortality and recorded alcohol consumption isdue to an underestimation of the consumptionincrease. DESIGN AND MEASUREMENTS First,the alcohol effect on the male accident rate wasestimated using data for the period 1959-89.Next, the estimated alcohol effect and theobserved accident mortality rate for the period1990-98 were used to backcast alcoholconsumption during that period. Thirdly, thebackcasted alcohol series was used to predicttrajectories in alcohol poisoning mortality, thehomicide rate and all-cause mortality during the", "metadata": {}}
+{"_id": "46451940", "title": "", "text": "The lateral hypothalamus: a primary sitemediating excitatory amino acid-elicitedeating.Lateral hypothalamic (LH) injections ofthe excitatory neurotransmitter glutamate, or itsexcitatory amino acid (EAA) agonists, kainic acid(KA),D,L-alpha-amino-3-hydroxy-5-methyl-isoxazolepropionic acid (AMPA), or N-methyl-D-asparticacid (NMDA), can rapidly elicit an intense feedingresponse in satiated rats. To determine whetherthe LH is the actual locus of this effect, wecompared these compounds' ability to stimulatefeeding when injected into the LH, versus wheninjected into sites bracketing this region. Foodintake in groups of adult male rats was measured1 h after injection of glutamate (30-900 nmol),KA (0.1-1.0 nmol), AMPA (0.33-3.3 nmol), NMDA(0.33-33.3 nmol) or vehicle, through chronicallyimplanted guide cannulas, into one of sevenbrain sites. These sites were: the LH, theanterior and posterior tips of the LH, thethalamus immediately dorsal to the LH, the", "metadata": {}}
+{"_id": "46478393", "title": "", "text": "A Gateway® compatible vector for gene silencingin bloodstream form Trypanosoma brucei.RNAinterference is the most rapid method forgeneration of conditional knockdown mutants inTrypanosoma brucei. The dual T7 promoter(pZJM) and the stem-loop vectors have beenwidely used to generate stable inducible RNAi celllines with the latter providing tighter regulatorycontrol. However, the steps for cloning stem-loopconstructs are cumbersome requiring eithermultiple cloning steps or multi-fragment ligationreactions. We report the development of a vector(pTrypRNAiGate) derived from pLEW100 thatutilizes the Gateway® recombination system tofacilitate easy production of hairpin RNAconstructs. This approach allows the finalstem-loop RNAi construct to be generated from asingle cloning step of the PCR-derived genefragment followed by an in vitro recombinationreaction. The new vector facilitateshigh-throughput applications for gene silencingand provides a tool for functional genomics in T.", "metadata": {}}
+{"_id": "46485368", "title": "", "text": "Prolonged effect of calcium supplementation onrisk of colorectal adenomas in a randomizedtrial.BACKGROUND Calcium supplementation hasbeen shown to decrease the risk of recurrence ofcolorectal adenomas in randomized trials.However, the duration of this protective effectafter cessation of active supplementation is notknown. METHODS In the Calcium PolypPrevention Study, 930 subjects with a previouscolorectal adenoma were randomly assignedfrom November 1988 through April 1992 toreceive placebo or 1200 mg of elemental calciumdaily for 4 years. The Calcium Follow-up Studywas an observational phase of the trial thattracked adenoma occurrence for an average of 7years after the end of randomized treatment andgathered information regarding the use ofmedications, vitamins, and supplements duringthat time. We obtained follow-up information for822 subjects, 597 of whom underwent at leastone colonoscopy after the end of study treatmentand are included in this analysis. Generalized", "metadata": {}}
+{"_id": "46517055", "title": "", "text": "Influence of DNA on the activities and inhibitionof neutrophil serine proteases in cystic fibrosissputum.Uncontrolled proteolysis by neutrophilserine proteases (NSPs) in lung secretions is ahallmark of cystic fibrosis (CF). We have shownthat the active neutrophil elastase, protease 3,and cathepsin G in CF sputum resist inhibition inpart by exogenous protease inhibitors. Thisresistance may be due to their binding toneutrophil extracellular traps (NETs) secreted bythe activated neutrophils in CF sputum and togenomic DNA released from senescent and deadneutrophils. Treating CF sputum with DNasedramatically increases its elastase activity, whichcan then be stoichiometrically inhibited byexogenous elastase inhibitors. However, DNasetreatment does not increase the activities ofprotease 3 and cathepsin G, indicating theirdifferent distribution and/or binding in CFsputum. Purified blood neutrophils secrete NETswhen stimulated by the opportunistic CF bacteriaPseudomonas aeruginosa and Staphylococcus", "metadata": {}}
+{"_id": "46565020", "title": "", "text": "Clinical effects of Abeta immunization (AN1792)in patients with AD in an interruptedtrial.BACKGROUND AN1792 (beta-amyloid[Abeta]1-42) immunization reduces Abetaplaque burden and preserves cognitive functionin APP transgenic mice. The authors report theresults of a phase IIa immunotherapy trial ofAN1792(QS-21) in patients with mild tomoderate Alzheimer disease (AD) that wasinterrupted because of meningoencephalitis in6% of immunized patients. METHODS Thisrandomized, multicenter, placebo-controlled,double-blind trial of IM AN1792 225 microg plusthe adjuvant QS-21 50 microg (300 patients)and saline (72 patients) included patients aged50 to 85 years with probable AD, Mini-MentalState Examination (MMSE) 15 to 26. Injectionswere planned for months 0, 1, 3, 6, 9, and 12.Safety and tolerability were evaluated, and pilotefficacy (AD Assessment Scale-CognitiveSubscale [ADAS-Cog], MRI, neuropsychologicaltest battery [NTB], CSF tau, and Abeta42) was", "metadata": {}}
+{"_id": "46565968", "title": "", "text": "Quantitative characterization of metastaticdisease in the spine. Part I. Semiautomatedsegmentation using atlas-based deformableregistration and the level setmethod.Quantitative assessment of metastaticdisease in bone is often consideredimmeasurable and, as such, patients withskeletal metastases are often excluded fromclinical trials. In order to effectively quantify theimpact of metastatic tumor involvement in thespine, accurate segmentation of the vertebra isrequired. Manual segmentation can be accuratebut involves extensive and time-consuming userinteraction. Potential solutions to automatingsegmentation of metastatically involvedvertebrae are demons deformable imageregistration and level set methods. The purposeof this study was to develop a semiautomatedmethod to accurately segment tumor-bearingvertebrae using the aforementioned techniques.By maintaining morphology of an atlas, thedemons-level set composite algorithm was able", "metadata": {}}
+{"_id": "46594244", "title": "", "text": "Activation of lysosomal function during dendriticcell maturation.In response to a variety ofstimuli, dendritic cells (DCs) transform fromimmature cells specialized for antigen captureinto mature cells specialized for T cellstimulation. During maturation, the DCs acquirean enhanced capacity to form and accumulatepeptide-MHC (major histocompatibility complex)class II complexes. Here we show that a keymechanism responsible for this alteration wasthe generalized activation of lysosomal function.In immature DCs, internalized antigens wereslowly degraded and inefficiently used forpeptide loading. Maturation induced activation ofthe vacuolar proton pump that enhancedlysosomal acidification and antigen proteolysis,facilitating efficient formation of peptide-MHCclass II complexes. Lysosomal function in DCsthus appears to be specialized for thedevelopmentally regulated processing ofinternalized antigens.", "metadata": {}}
+{"_id": "46602807", "title": "", "text": "Comparison of agar dilution, microdilution, anddisk elution methods for measuring the synergyof cefotaxime and its metabolite againstanaerobes.The activities of cefotaxime (CTX) anddesacetyl cefotaxime (des-CTX) were tested bothsingly and in combination against 173 anaerobicclinical isolates. The MIC of CTX for 50% of 60Bacteroides fragilis isolates was 22.4micrograms/ml in broth, compared with 47.4micrograms/ml in agar. This reduced efficacy inagar was seen with all species tested and is inapparent conflict with reported clinical efficacy ofthe drug. Synergy between CTX and des-CTXwas observed with 70 to 100% of the isolates,including 60% of all Bacteroides spp. tested. Thesusceptibility results in a synergy systemcorrelated well with those noted in a broth-diskelution method incorporating 32 micrograms ofCTX and 8 micrograms of des-CTX per ml. Thecorrelation was poorer when the broth-diskmethod contained 16 micrograms of CTX and 8micrograms of des-CTX per ml.", "metadata": {}}
+{"_id": "46617075", "title": "", "text": "Retinoblastoma regulatory pathway in lungcancer.Lung cancer is the leading cause ofcancer related deaths accounting for moredeaths than breast, colon and prostate cancerscombined. The Rb-p16 regulatory pathway playsan essential role in tumor suppression in the lungepithelium. This is evidenced by the nearlyuniversal alterations in Rb-p16 pathwaycomponents in lung cancer, and the increasedincidence of pulmonary carcinomas in personswith germline Rb mutations. Interestingly, p16loss and Rb mutations preferentially occur inphenotypically distinct lung cancer subtypes.Analysis of human tumors has identifiedprogressive preneoplastic lesions thataccumulate molecular alterations in an orderlysequence. Epigenetic p16 gene modificationsrepresent an early event in lung cancerprogression. This review summarizes the humanstudies that demonstrate a critical role for theRb-p16 tumor suppressor pathway in lungcarcinogenesis, and discusses how these findings", "metadata": {}}
+{"_id": "46695481", "title": "", "text": "Human papillomavirus and Papanicolaou tests toscreen for cervical cancer.BACKGROUNDScreening for cervical cancer based on testing forhuman papillomavirus (HPV) increases thesensitivity of detection of high-grade (grade 2 or3) cervical intraepithelial neoplasia, but whetherthis gain represents overdiagnosis or protectionagainst future high-grade cervical epithelialneoplasia or cervical cancer is unknown.METHODS In a population-based screeningprogram in Sweden, 12,527 women 32 to 38years of age were randomly assigned at a 1:1ratio to have an HPV test plus a Papanicolaou(Pap) test (intervention group) or a Pap testalone (control group). Women with a positiveHPV test and a normal Pap test result wereoffered a second HPV test at least 1 year later,and those who were found to be persistentlyinfected with the same high-risk type of HPVwere then offered colposcopy with cervicalbiopsy. A similar number of double-blinded Papsmears and colposcopies with biopsy were", "metadata": {}}
+{"_id": "46743299", "title": "", "text": "Chronic Exercise Increases Both Inducible andEndothelial Nitric Oxide Synthase GeneExpression in Endothelial Cells of RatAortaChronic exercise upregulates endothelialnitric oxide synthase (eNOS) gene expression.Whether the expression of inducible nitric oxidesynthase (iNOS) is affected by exercise isunknown. We therefore investigated the effectsof chronic exercise on iNOS and eNOS expressionin isolated rat aortic endothelial and smoothmuscle cells separately. Five-week-old maleWistar rats were randomly divided into controland exercise groups. After 10 weeks of runningtraining, animals were sacrificed under etheranesthesia. The standard curve quantitativecompetitive reverse transcriptase-polymerasechain reaction method was used to quantify NOSmRNA expression in isolated endothelial/smoothmuscle cells. To evaluate the functional role ofiNOS, we examined phenylephrine-inducedvascular responses with or without pretreatmentwith aminoguanidine. We found that (1)", "metadata": {}}
+{"_id": "46764350", "title": "", "text": "Frontal stroke syndromes.The frontal lobe is thelargest lobe of the brain, and it is thus commonlyinvolved in stroke. Moreover, almost one in fivestrokes is limited to the prerolandic areas. Thishigh frequency of anatomical involvement is insharp contrast with the apparent rarity of clinicalfrontal dysfunction in stroke. It is remarkablethat frontal behavioral syndromes have beenrather uncommonly reported in patients withstroke as compared to patients with otherdiseases, such as brain tumor. This fact isparadoxical, because an acute process (stroke) isexpected to yield more clinical dysfunction than amore chronic disease (tumor). A volume effectmay be the main factor leading to thisphenomenon. Another interesting aspect offrontal strokes is the contribution of so-called'silent' strokes, the recurrence of which maynevertheless lead to intellectual decline andcompromise recovery from another stroke withmore specific neurologic dysfunction. Thecontribution of stroke to understanding of frontal", "metadata": {}}
+{"_id": "46765242", "title": "", "text": "Interaction of cytosine arabinoside and lovastatinin human leukemia cells.Cytosine arabinoside(ara-C) is widely used for the treatment ofleukemias and displays significant toxicities.Lovastatin, an HMG-CoA reductase inhibitor, isextensively used to treat hypercholesterolemia.To determine whether lovastatin could augmentara-C's activity we have examined their effects inthe human erythroleukemia K562 cell line andthe ara-C resistant ARAC8D cell line. Asynergistic interaction between the two drugswas found. We have demonstrated that theinteraction does not occur at the level of RAS butmay involve lovastatin's effect of downregulatingMAPK activity and preventing ara-C-inducedMAPK activation. These studies represent thefirst description of a potentially beneficialinteraction between lovastatin and ara-C thatcould be applied to the treatment of humanleukemia.", "metadata": {}}
+{"_id": "46816158", "title": "", "text": "The crystal structure of TAL effector PthXo1bound to its DNA target.DNA recognition by TALeffectors is mediated by tandem repeats, each33 to 35 residues in length, that specifynucleotides via unique repeat-variable diresidues(RVDs). The crystal structure of PthXo1 bound toits DNA target was determined byhigh-throughput computational structureprediction and validated by heavy-atomderivatization. Each repeat forms a left-handed,two-helix bundle that presents anRVD-containing loop to the DNA. The repeatsself-associate to form a right-handed superhelixwrapped around the DNA major groove. The firstRVD residue forms a stabilizing contact with theprotein backbone, while the second makes abase-specific contact to the DNA sense strand.Two degenerate amino-terminal repeats alsointeract with the DNA. Containing several RVDsand noncanonical associations, the structureillustrates the basis of TAL effector-DNArecognition.", "metadata": {}}
+{"_id": "46837626", "title": "", "text": "Prediction of creatinine clearance from serumcreatinine.A formula has been developed topredict creatinine clearance (Ccr) from serumcreatinine (Scr) in adult males: (see article)(15%less in females). Derivation included therelationship found between age and 24-hourcreatinine excretion/kg in 249 patients aged18-92. Values for Ccr were predicted by thisformula and four other methods and the resultscompared with the means of two 24-hour Ccr'smeasured in 236 patients. The above formulagave a correlation coefficient between predictedand mean measured Ccr's of 0.83; on average,the difference predicted and mean measuredvalues was no greater than that between pairedclearances. Factors for age and body weightmust be included for reasonable prediction.", "metadata": {}}
+{"_id": "46926352", "title": "", "text": "Dendritic cells, T cells and lymphatics: dialoguesin migration and beyond.Immune cellscontinuously recirculate through lymph vesselsen route from peripheral tissues to the blood.Leuyte trafficking into and within lymph vesselsis mediated by an interply with lymphaticendothelial cells (LECs). However, lymphaticvessels are much more than mere conduits forfluid and immune cell transport. Dataaccumulating during past several years indicatethat LECs support T cell survival, inducetolerance to self-antigens, inhibit exaggerated Tcell proliferation during immune response andmaintain T cell memory. Reciprocally, leukocytesimpact LEC biology: lymphatic vesselpermeability depends on DCs while lymphocytesregulate LEC proliferation during inflammation.Altogether, these novel results provide importantinsights on intimate connections between LECsand leukocytes that contribute to theunderstanding of immune responses.", "metadata": {}}
+{"_id": "47018050", "title": "", "text": "CRISPR–Cas9 genome editing induces ap53-mediated DNA damage responseHere, wereport that genome editing by CRISPR–Cas9induces a p53-mediated DNA damage responseand cell cycle arrest in immortalized humanretinal pigment epithelial cells, leading to aselection against cells with a functional p53pathway. Inhibition of p53 prevents the damageresponse and increases the rate of homologousrecombination from a donor template. Theseresults suggest that p53 inhibition may improvethe efficiency of genome editing ofuntransformed cells and that p53 function shouldbe monitored when developing cell-basedtherapies utilizing CRISPR–Cas9.CRISPR–Cas9-induced DNA damage triggers p53to limit the efficiency of gene editing inimmortalized human retinal pigment epithelialcells.", "metadata": {}}
+{"_id": "47240151", "title": "", "text": "Comparative Structural Analysis of Lipid BindingSTART DomainsBACKGROUND Steroidogenicacute regulatory (StAR) protein related lipidtransfer (START) domains are small globularmodules that form a cavity where lipids and lipidhormones bind. These domains can transportligands to facilitate lipid exchange betweenbiological membranes, and they have beenpostulated to modulate the activity of otherdomains of the protein in response to ligandbinding. More than a dozen human genes encodeSTART domains, and several of them areimplicated in a disease. PRINCIPAL FINDINGSWe report crystal structures of the humanSTARD1, STARD5, STARD13 and STARD14 lipidtransfer domains. These represent four of the sixfunctional classes of START domains.SIGNIFICANCE Sequence alignments based onthese and previously reported crystal structuresdefine the structural determinants of humanSTART domains, both those related to structuralframework and those involved in ligand", "metadata": {}}
+{"_id": "49208216", "title": "", "text": "Staphylococcus aureus infectiondynamicsStaphylococcus aureus is a humancommensal that can also cause systemicinfections. This transition requires evasion of theimmune response and the ability to exploitdifferent niches within the host. However, thedisease mechanisms and the dominant immunemediators against infection are poorlyunderstood. Previously it has been shown thatthe infecting S. aureus population goes through apopulation bottleneck, from which very fewbacteria escape to establish the abscesses thatare characteristic of many infections. Here weexamine the host factors underlying thepopulation bottleneck and subsequent clonalexpansion in S. aureus infection models, toidentify underpinning principles of infection. Thebottleneck is a common feature between modelsand is independent of S. aureus strain.Interestingly, the high doses of S. aureusrequired for the widely used \"survival\" modelresults in a reduced population bottleneck,", "metadata": {}}
+{"_id": "49429882", "title": "", "text": "Strategies for optimizing maternal nutrition topromote infant developmentBACKGROUND Thegrowing appreciation of the multi-facetedimportance of optimal maternal nutrition to thehealth and development of the infant and youngchild is tempered by incompletely resolvedstrategies for combatting challenges. OBJECTIVETo review the importance of maternal nutritionand strategies being employed to optimizeoutcomes. METHODS Selected data from recentliterature with special focus on rationale for andcurrently published results of maternal nutritionsupplements, including lipid based nutritionsupplements. RESULTS 1) An impelling rationalefor improving the maternal and in uteroenvironment of low resource populations hasemerged to achieve improved fetal andpost-natal growth and development. 2) Basedpartly on population increases in adult heightover one-two generations, much can be achievedby reducing poverty. 3) Maternal, newborn andinfant characteristics associated with low", "metadata": {}}
+{"_id": "49432306", "title": "", "text": "Key questions about the checkpoint blockade-aremicroRNAs an answer?The introduction ofimmune-checkpoint blockade in the cancertherapy led to a paradigm change of themanagement of late stage cancers. There arealready multiple FDA approved checkpointinhibitors and many other agents are undergoingphase 2 and early phase 3 clinical trials. Thetherapeutic indication of immune checkpointinhibitors expanded in the last years, but stillremains unclear who can benefit. MicroRNAs aresmall RNAs with no coding potential. Bycomplementary pairing to the 3' untranslatedregion of messenger RNA, microRNAs exertposttranscriptional control of protein expression.A network of microRNAs directly and indirectlycontrols the expression of checkpoint receptorsand several microRNAs can target multiplecheckpoint molecules, mimicking the therapeuticeffect of a combined immune checkpointblockade. In this review, we will describe themicroRNAs that control the expression of", "metadata": {}}
+{"_id": "49556906", "title": "", "text": "Metformin reverses established lung fibrosis in ableomycin modelFibrosis is a pathological resultof a dysfunctional repair response to tissue injuryand occurs in a number of organs, including thelungs1. Cellular metabolism regulates tissuerepair and remodelling responses to injury2-4.AMPK is a critical sensor of cellular bioenergeticsand controls the switch from anabolic to catabolicmetabolism5. However, the role of AMPK infibrosis is not well understood. Here, wedemonstrate that in humans with idiopathicpulmonary fibrosis (IPF) and in an experimentalmouse model of lung fibrosis, AMPK activity islower in fibrotic regions associated withmetabolically active and apoptosis-resistantmyofibroblasts. Pharmacological activation ofAMPK in myofibroblasts from lungs of humanswith IPF display lower fibrotic activity, along withenhanced mitochondrial biogenesis andnormalization of sensitivity to apoptosis. In ableomycin model of lung fibrosis in mice,metformin therapeutically accelerates the", "metadata": {}}
+{"_id": "50670403", "title": "", "text": "Are expert athletes 'expert' in the cognitivelaboratory? A meta-analytic review of cognitionand sport expertiseSUMMARY Recent literaturehas demonstrated the usefulness of fitness andcomputer-based cognitive training as a means toenhance cognition and brain function. However,it is unclear whether the combination of fitnessand cognitive training that results from years ofextensive sport training also results in superiorperformance on tests of cognitive processes. Inthis study we examine, in a quantitativemeta-analysis (k ¼20), the relationship betweenexpertise in sports and laboratory-basedmeasures of cognition. We found that athletesperformed better on measures of processingspeed and a category of variedattentionalparadigms,andathletesfrominterceptivesporttypesandmalesshowedthelargesteffects.Based on our results, more research should bedone with higher-level cognitive tasks, such astasks of executive function and more varied", "metadata": {}}
+{"_id": "51386222", "title": "", "text": "Effects of Age, Sex, and Ethnicity on theAssociation Between Apolipoprotein E Genotypeand Alzheimer Disease: AMeta-analysisObjective. —To examine moreclosely the association between apolipoprotein E(APOE) genotype and Alzheimer disease (AD) byage and sex in populations of various ethnic andracial denominations. Data Sources. —Fortyresearch teams contributed dataonAPOEgenotype, sex, age at disease onset, andethnic background for 5930 patients who metcriteria for probable or definite AD and 8607controls without dementia who were recruitedfrom clinical, community, and brain banksources. Main Outcome Measures. —Odds ratios(ORs) and 95% confidence intervals (Cls) for AD,adjusted for age and study and stratified bymajor ethnic group (Caucasian, AfricanAmerican, Hispanic, and Japanese) and source,were computed forAPOEgenotypes\u00002/\u00002,\u00002/\u00003,\u00002/\u00004,\u00003/\u00004 and \u00004/\u00004relative to the \u00003/\u00003 group. The influence of", "metadata": {}}
+{"_id": "51706771", "title": "", "text": "Comparison of glioblastoma (GBM) molecularclassification methods.Glioblastoma (GBM) is themost aggressive and common form of braincancer in adults. GBM is characterized by poorsurvival and remarkably high tumorsheterogeneity (both intertumoral andintratumoral), and lack of effective therapies.Recent high-throughput data revealedheterogeneous genetic/genomic/epigeneticfeatures and led to multiple methods aiming toclassify tumors according to the key molecularevents that drive the most aggressive cellularcomponents so that targeted therapies can bedeveloped for individual subtypes. However,GBM molecular subtypes have not led toimprovement of patients outcomes. Targeted ortailored therapies for specific mutations orsubtypes largely failed due to the complexitiesarising from intratumoral molecularheterogeneity. Most tumors develop resistanceto treatment and soon recur. GBM stem cells(GSCs) have been identified. Recent single cell", "metadata": {}}
+{"_id": "51728753", "title": "", "text": "Mesenchymal Stromal Cells: From Discovery toManufacturing and CommercializationOver thelast decades, mesenchymal stromal cells (MSC)have been the focus of intense research byacademia and industry due to their uniquefeatures. MSC can be easily isolated andexpanded through in vitro culture by taking fulladvantage of their self-renewing capacity. Inaddition, MSC exert immunomodulatory effectsand can be differentiated into various lineages,which makes them highly attractive for clinicalapplications in cell-based therapies. In thisreview, we attempt to provide a brief historicaloverview of MSC discovery, characterization, andthe first clinical studies conducted. The currentMSC manufacturing platforms are reviewed withspecial attention regarding the use of bioreactorsfor the production of GMP-compliant clinicallyrelevant cell numbers. The first commercialMSC-based products are also addressed, as wellas the remaining challenges to the widespreaduse of MSC-derived products.", "metadata": {}}
+{"_id": "51817902", "title": "", "text": "Delta–Notch—and then? Protein interactions andproposed modes of repression by Hes and HeybHLH factorsHes and Hey genes are themammalian counterparts of the Hairy andEnhancer-of-split type of genes in Drosophila andthey represent the primary targets of theDelta-Notch signaling pathway. Hairy-relatedfactors control multiple steps of embryonicdevelopment and misregulation is associatedwith various defects. Hes and Hey genes (alsocalled Hesr, Chf, Hrt, Herp or gridlock) encodetranscriptional regulators of the basichelix-loop-helix class that mainly act asrepressors. The molecular details of how Hes andHey proteins control transcription are still poorlyunderstood, however. Proposed modes of actioninclude direct binding to N- or E-box DNAsequences of target promoters as well as indirectbinding through other sequence-specifictranscription factors or sequestration oftranscriptional activators. Repression may relyon recruitment of corepressors and induction of", "metadata": {}}
+{"_id": "51865482", "title": "", "text": "The Long Noncoding RNA CAREL Controls CardiacRegeneration.BACKGROUND Adult mammalianheart loses regeneration ability followingischemic injury due to the loss of cardiomyocytemitosis. However, the molecular mechanismsunderlying the post-mitotic nature ofcardiomyocytes remain largely unknown.OBJECTIVES The purpose of this study was todefine the essential role of long noncodingribonucleic acids (lncRNAs) in heart regenerationduring postnatal and adult injury. METHODSMyh6-driving cardiomyocyte-specificlncRNA-CAREL transgenic mice andadenovirus-mediated in vivo silencing ofendogenous CAREL were used in this study. Theeffect of CAREL on cardiomyocyte replication andheart regeneration after apical resection ormyocardial infarction was assessed by detectingmitosis and cytokinesis. RESULTS An lncRNACAREL was found significantly up-regulated incardiomyocytes from neonatal mice (P7) inparallel with loss of regenerative capacity.", "metadata": {}}
+{"_id": "51952430", "title": "", "text": "BCAP links IL-1R to the PI3K–mTOR pathway andregulates pathogenic Th17 cell differentiationThetoll-like receptor (TLR) and interleukin (IL)-1family of receptors share several signalingcomponents, including the most upstreamadapter, MyD88. We previously reported thediscovery of B cell adapter for phosphoinositide3-kinase (BCAP) as a novel toll-IL-1 receptorhomology domain-containing adapter thatregulates inflammatory responses downstreamof TLR signaling. Here we find that BCAP plays acritical role downstream of both IL-1 and IL-18receptors to regulate T helper (Th) 17 and Th1cell differentiation, respectively. Absence of T cellintrinsic BCAP did not alter development ofnaturally arising Th1 and Th17 lineages but ledto defects in differentiation to pathogenic Th17lineage cells. Consequently, mice that lack BCAPin T cells had reduced susceptibility toexperimental autoimmune encephalomyelitis.More importantly, we found that BCAP is criticalfor IL-1R-induced phosphoinositide", "metadata": {}}
+{"_id": "51972698", "title": "", "text": "Adapting the WHO package of essentialnoncommunicable disease interventions,SamoaProblem Samoa has been struggling toaddress the burden of noncommunicablediseases at the health system, community andindividual levels. Approach The World HealthOrganization (WHO) package of essentialnoncommunicable disease interventions forprimary health care in low-resource settings wasadopted in seven villages throughout Samoa in2015. The National Steering Committee Membersdesigned and implemented a screening process,and local facilitators and health-care workerscollected health and lifestyle data. TheWHO/International Society of Hypertension riskassessment was used on villagers older than 40years to identify people at high risk ofnoncommunicable disease. Local setting Samoais a small island developing state with increasingmorbidity and mortality due to noncommunicablediseases. A national representative surveyindicated that 50.1% (595/1188) of the Samoan", "metadata": {}}
+{"_id": "52072815", "title": "", "text": "Alcohol use and burden for 195 countries andterritories, 1990–2016: a systematic analysis forthe Global Burden of Disease Study2016Summary Background Alcohol use is aleading risk factor for death and disability, but itsoverall association with health remains complexgiven the possible protective effects of moderatealcohol consumption on some conditions. Withour comprehensive approach to healthaccounting within the Global Burden of Diseases,Injuries, and Risk Factors Study 2016, wegenerated improved estimates of alcohol use andalcohol-attributable deaths anddisability-adjusted life-years (DALYs) for 195locations from 1990 to 2016, for both sexes andfor 5-year age groups between the ages of 15years and 95 years and older. Methods Using694 data sources of individual andpopulation-level alcohol consumption, along with592 prospective and retrospective studies on therisk of alcohol use, we produced estimates of theprevalence of current drinking, abstention, the", "metadata": {}}
+{"_id": "52095986", "title": "", "text": "The Dual Immunoregulatory function of Nlrp12 inT Cell-Mediated Immune Response: Lessonsfrom Experimental AutoimmuneEncephalomyelitisAlthough the etiology ofmultiple sclerosis (MS) remains enigmatic, therole of T cells is unquestionably central in thispathology. Immune cells respond to pathogensand danger signals via pattern-recognitionreceptors (PRR). Several reports implicateNlrp12, an intracellular PRR, in the developmentof a mouse MS-like disease, called ExperimentalAutoimmune Encephalomyelitis (EAE). In thisstudy, we used induced and spontaneous modelsof EAE, as well as in vitro T cell assays, to testthe hypothesis that Nlrp12 inhibits Th1 responseand prevents T-cell mediated autoimmunity. Wefound that Nlrp12 plays a protective role ininduced EAE by reducing IFNγ/IL-4 ratio inlymph nodes, whereas it potentiates thedevelopment of spontaneous EAE (spEAE) in 2D2T cell receptor (TCR) transgenic mice. Lookinginto the mechanism of Nlrp12 activity in T cell", "metadata": {}}
+{"_id": "52175065", "title": "", "text": "Acute and chronic exercise in patients with heartfailure with reduced ejection fraction: evidenceof structural and functional plasticity and intactangiogenic signalling in skeletal muscleKEYPOINTS The vascular endothelial growth factor(VEGF) responses to acute submaximal exerciseand training effects in patients with heart failurewith reduced ejection fraction (HFrEF) wereinvestigated. Six patients and six healthymatched controls performed knee-extensorexercise (KE) at 50% of maximum work ratebefore and after (only patients) KE training.Muscle biopsies were taken to assess skeletalmuscle structure and the angiogenic response.Before training, during this submaximal KEexercise, patients with HFrEF exhibited higher legvascular resistance and greater noradrenalinespillover. Skeletal muscle structure and VEGFresponse were generally not different betweengroups. Following training, resistance was nolonger elevated and noradrenaline spillover wascurtailed in the patients. Although, in the trained", "metadata": {}}
+{"_id": "52176296", "title": "", "text": "2017 revisions of McDonald criteria shorten thetime to diagnosis of multiple sclerosis in clinicallyisolated syndromesTo investigate the impact ofthe 2017 revisions of McDonald criteria on thediagnosis of multiple sclerosis (MS) in a cohort ofpatients with clinically isolated syndrome (CIS)and dissemination in space (DIS) ofdemyelinating lesions. We retrospectivelyanalyzed 137 patients with CIS + DIS from twoItalian MS centers. Application of the 2017revisions of McDonald criteria in our cohort led toa diagnosis of MS in 82.5% of the patients whocould have not been diagnosed with MSaccording to the previous criteria at the time ofthe first demyelinating event. After a follow-up of3.8 ± 2.9 years, 85.8% of these patientseventually satisfied also the previous (2010)criteria. Application of the 2017 revisions ofMcDonald criteria results in an earlier diagnosisof MS in a large percentage of CIS patientsdestined to convert to MS.", "metadata": {}}
+{"_id": "52180874", "title": "", "text": "Efficacy of PD-1 or PD-L1 inhibitors and PD-L1expression status in cancer:meta-analysisOBJECTIVE To evaluate the relativeefficacy of programmed cell death 1 (PD-1) orprogrammed cell death ligand 1 (PD-L1)inhibitors versus conventional drugs in patientswith cancer that were PD-L1 positive and PD-L1negative. DESIGN Meta-analysis of randomisedcontrolled trials. DATA SOURCES PubMed,Embase, Cochrane database, and conferenceabstracts presented at the American Society ofClinical Oncology and European Society ofMedical Oncology up to March 2018. REVIEWMETHODS Studies of PD-1 or PD-L1 inhibitors(avelumab, atezolizumab, durvalumab,nivolumab, and pembrolizumab) that hadavailable hazard ratios for death based on PD-L1positivity or negativity were included. Thethreshold for PD-L1 positivity or negativity wasthat PD-L1 stained cell accounted for 1% oftumour cells, or tumour and immune cells,assayed by immunohistochemistry staining", "metadata": {}}
+{"_id": "52188256", "title": "", "text": "Global cancer statistics 2018: GLOBOCANestimates of incidence and mortality worldwidefor 36 cancers in 185 countries.This articleprovides a status report on the global burden ofcancer worldwide using the GLOBOCAN 2018estimates of cancer incidence and mortalityproduced by the International Agency forResearch on Cancer, with a focus on geographicvariability across 20 world regions. There will bean estimated 18.1 million new cancer cases(17.0 million excluding nonmelanoma skincancer) and 9.6 million cancer deaths (9.5million excluding nonmelanoma skin cancer) in2018. In both sexes combined, lung cancer is themost commonly diagnosed cancer (11.6% of thetotal cases) and the leading cause of cancerdeath (18.4% of the total cancer deaths), closelyfollowed by female breast cancer (11.6%),prostate cancer (7.1%), and colorectal cancer(6.1%) for incidence and colorectal cancer(9.2%), stomach cancer (8.2%), and liver cancer(8.2%) for mortality. Lung cancer is the most", "metadata": {}}
+{"_id": "52805891", "title": "", "text": "Gut Microbiota Is a Key Modulator of InsulinResistance in TLR 2 Knockout MiceEnvironmentalfactors and host genetics interact to control thegut microbiota, which may have a role in thedevelopment of obesity and insulin resistance.TLR2-deficient mice, under germ-free conditions,are protected from diet-induced insulinresistance. It is possible that the presence of gutmicrobiota could reverse the phenotype of ananimal, inducing insulin resistance in an animalgenetically determined to have increased insulinsensitivity, such as the TLR2 KO mice. In thepresent study, we investigated the influence ofgut microbiota on metabolic parameters, glucosetolerance, insulin sensitivity, and signaling ofTLR2-deficient mice. We investigated the gutmicrobiota (by metagenomics), the metaboliccharacteristics, and insulin signaling in TLR2knockout (KO) mice in a non-germ free facility.Results showed that the loss of TLR2 inconventionalized mice results in a phenotypereminiscent of metabolic syndrome,", "metadata": {}}
+{"_id": "52824661", "title": "", "text": "TGF\u0000β\u0000mediated exosomal lnc\u0000MMP2\u00002regulates migration and invasion of lung cancercells to the vasculature by promoting MMP2expressionPrevious studies indicated thattransforming growth factor (TGF)-β-mediatedexosomal microRNAs (miRNAs) regulate themigration and invasion of lung cancer cells;however, whether and how TGF-β-mediatedexosomal long noncoding (lnc) RNAs regulatemigration and invasion of lung cancer cellsremains unclear. Here, coculture experimentsshowed that TGF-β pretreatment increased themigration and invasion potential of lung cancercells and TGF-β pretreated A549 cells increasesvascular permeability. Furthermore, we foundthat TGF-β-mediated exosomes, as carriers ofintercellular communication, regulated lungcancer invasion, and vascular permeability.Transcriptional analysis also revealed thatlnc-MMP2-2 was highly enriched inTGF-β-mediated exosomes and might function byincreasing the expression of matrix", "metadata": {}}
+{"_id": "52827184", "title": "", "text": "Surviving Sepsis Campaign: InternationalGuidelines for Management of Sepsis and SepticShock 2016Objective: To provide an update to“Surviving Sepsis Campaign Guidelines forManagement of Sepsis and Septic Shock: 2012. ”Design: A consensus committee of 55international experts representing 25international organizations was convened.Nominal groups were assembled at keyinternational meetings (for those committeemembers attending the conference). A formalconflict-of-interest (COI) policy was developed atthe onset of the process and enforcedthroughout. A stand-alone meeting was held forall panel members in December 2015.Teleconferences and electronic-based discussionamong subgroups and among the entirecommittee served as an integral part of thedevelopment. Methods: The panel consisted offive sections: hemodynamics, infection,adjunctive therapies, metabolic, and ventilation.Population, intervention, comparison, and", "metadata": {}}
+{"_id": "52850476", "title": "", "text": "Mitochondrial genome variation and the origin ofmodern humans.The analysis of mitochondrialDNA (mtDNA) has been a potent tool in ourunderstanding of human evolution, owing tocharacteristics such as high copy number,apparent lack of recombination, high substitutionrate and maternal mode of inheritance. However,almost all studies of human evolution based onmtDNA sequencing have been confined to thecontrol region, which constitutes less than 7% ofthe mitochondrial genome. These studies arecomplicated by the extreme variation insubstitution rate between sites, and theconsequence of parallel mutations causingdifficulties in the estimation of genetic distanceand making phylogenetic inferencesquestionable. Most comprehensive studies of thehuman mitochondrial molecule have been carriedout through restriction-fragment lengthpolymorphism analysis, providing data that are illsuited to estimations of mutation rate andtherefore the timing of evolutionary events.", "metadata": {}}
+{"_id": "52865789", "title": "", "text": "Deficiency of Interleukin-15 Confers Resistanceto Obesity by Diminishing Inflammation andEnhancing the Thermogenic Function of AdiposeTissuesOBJECTIVE IL-15 is an inflammatorycytokine secreted by many cell types. IL-15 isalso produced during physical exercise byskeletal muscle and has been reported to reduceweight gain in mice. Contrarily, our findings onIL-15 knockout (KO) mice indicate that IL-15promotes obesity. The aim of this study is toinvestigate the mechanisms underlying thepro-obesity role of IL-15 in adipose tissues.METHODS Control and IL-15 KO mice weremaintained on high fat diet (HFD) or normalcontrol diet. After 16 weeks, body weight,adipose tissue and skeletal mass, serum lipidlevels and gene/protein expression in theadipose tissues were evaluated. The effect ofIL-15 on thermogenesis and oxygenconsumption was also studied in primary culturesof adipocytes differentiated from mousepreadipocyte and human stem cells. RESULTS", "metadata": {}}
+{"_id": "52868579", "title": "", "text": "Chromatin signatures of pluripotent celllines.Epigenetic genome modifications arethought to be important for specifying thelineage and developmental stage of cells within amulticellular organism. Here, we show that theepigenetic profile of pluripotent embryonic stemcells (ES) is distinct from that of embryoniccarcinoma cells, haematopoietic stem cells (HSC)and their differentiated progeny. Silent,lineage-specific genes replicated earlier inpluripotent cells than in tissue-specific stem cellsor differentiated cells and had unexpectedly highlevels of acetylated H3K9 and methylated H3K4.Unusually, in ES cells these markers of openchromatin were also combined with H3K27trimethylation at some non-expressed genes.Thus, pluripotency of ES cells is characterized bya specific epigenetic profile wherelineage-specific genes may be accessible but, ifso, carry repressive H3K27 trimethylationmodifications. H3K27 methylation is functionallyimportant for preventing expression of these", "metadata": {}}
+{"_id": "52873726", "title": "", "text": "Regulation of Hippo pathway transcription factorTEAD by p38 MAPK-induced cytoplasmictranslocationThe Hippo pathway controls organsize and tissue homeostasis, with deregulationleading to cancer. The core Hippo components inmammals are composed of the upstreamserine/threonine kinases Mst1/2, MAPK4Ks andLats1/2. Inactivation of these upstream kinasesleads to dephosphorylation, stabilization, nucleartranslocation and thus activation of the majorfunctional transducers of the Hippo pathway, YAPand its paralogue TAZ. YAP/TAZ are transcriptionco-activators that regulate gene expressionprimarily through interaction with the TEAdomain DNA-binding family of transcriptionfactors (TEAD). The current paradigm forregulation of this pathway centres onphosphorylation-dependent nucleocytoplasmicshuttling of YAP/TAZ through a complex networkof upstream components. However, unlike othertranscription factors, such as SMAD, NF-κB,NFAT and STAT, the regulation of TEAD", "metadata": {}}
+{"_id": "52874170", "title": "", "text": "How do I perform a lumbar puncture and analyzethe results to diagnose bacterialmeningitis?CONTEXT Diagnostic lumbarpunctures (LPs), commonly used to rule outmeningitis, are associated with adverse events.OBJECTIVE To systematically review theevidence about diagnostic LP techniques thatmay decrease the risk of adverse events and theevidence about test accuracy of cerebrospinalfluid (CSF) analysis in adult patients withsuspected bacterial meningitis. DATA SOURCESWe searched the Cochrane Library, MEDLINE(using Ovid and PubMed) from 1966 to January2006 and EMBASE from 1980 to January 2006without language restrictions to identify relevantstudies and identified others from thebibliographies of retrieved articles. STUDYSELECTION We included randomized trials ofpatients aged 18 years or older undergoinginterventions to facilitate a successful diagnosticLP or to potentially reduce adverse events.Studies assessing the accuracy of biochemical", "metadata": {}}
+{"_id": "52887689", "title": "", "text": "Guidelines for the use and interpretation ofassays for monitoring autophagy.In 2008 wepublished the first set of guidelines forstandardizing research in autophagy. Since then,research on this topic has continued toaccelerate, and many new scientists haveentered the field. Our knowledge base andrelevant new technologies have also beenexpanding. Accordingly, it is important to updatethese guidelines for monitoring autophagy indifferent organisms. Various reviews havedescribed the range of assays that have beenused for this purpose. Nevertheless, therecontinues to be confusion regarding acceptablemethods to measure autophagy, especially inmulticellular eukaryotes. A key point that needsto be emphasized is that there is a differencebetween measurements that monitor thenumbers or volume of autophagic elements(e.g., autophagosomes or autolysosomes) at anystage of the autophagic process vs. those thatmeasure flux through the autophagy pathway", "metadata": {}}
+{"_id": "52893592", "title": "", "text": "Subversion of Systemic Glucose Metabolism as aMechanism to Support the Growth of LeukemiaCells.From an organismal perspective, cancer cellpopulations can be considered analogous toparasites that compete with the host foressential systemic resources such as glucose.Here, we employed leukemia models and humanleukemia samples to document a form ofadaptive homeostasis, where malignant cellsalter systemic physiology through impairment ofboth host insulin sensitivity and insulin secretionto provide tumors with increased glucose.Mechanistically, tumor cells induce high-levelproduction of IGFBP1 from adipose tissue tomediate insulin sensitivity. Further,leukemia-induced gut dysbiosis, serotonin loss,and incretin inactivation combine to suppressinsulin secretion. Importantly, attenuateddisease progression and prolonged survival areachieved through disruption of theleukemia-induced adaptive homeostasis. Ourstudies provide a paradigm for systemic", "metadata": {}}
+{"_id": "52925737", "title": "", "text": "Tumor-derived exosomes induce N2 polarizationof neutrophils to promote gastric cancer cellmigrationBACKGROUND Exosomes areextracellular vesicles that mediate cellularcommunication in health and diseases.Neutrophils could be polarized to a pro-tumorphenotype by tumor. The function oftumor-derived exosomes in neutrophil regulationremains unclear. METHODS We investigated theeffects of gastric cancer cell-derived exosomes(GC-Ex) on the pro-tumor activation ofneutrophils and elucidated the underlyingmechanisms. RESULTS GC-Ex prolongedneutrophil survival and induced expression ofinflammatory factors in neutrophils.GC-Ex-activated neutrophils, in turn, promotedgastric cancer cell migration. GC-Ex transportedhigh mobility group box-1 (HMGB1) thatactivated NF-κB pathway through interactionwith TLR4, resulting in an increased autophagicresponse in neutrophils. Blocking HMGB1/TLR4interaction, NF-κB pathway, and autophagy", "metadata": {}}
+{"_id": "52944377", "title": "", "text": "ROS-induced R loops trigger atranscription-coupled but BRCA1/2-independenthomologous recombination pathway throughCSBActively transcribed regions of the genomeare protected by transcription-coupled DNArepair mechanisms, includingtranscription-coupled homologous recombination(TC-HR). Here we used reactive oxygen species(ROS) to induce and characterize TC-HR at atranscribed locus in human cells. As canonicalHR, TC-HR requires RAD51. However, thelocalization of RAD51 to damage sites duringTC-HR does not require BRCA1 and BRCA2, butrelies on RAD52 and Cockayne Syndrome ProteinB (CSB). During TC-HR, RAD52 is recruited byCSB through an acidic domain. CSB in turn isrecruited by R loops, which are strongly inducedby ROS in transcribed regions. Notably, CSBdisplays a strong affinity for DNA:RNA hybrids invitro, suggesting that it is a sensor ofROS-induced R loops. Thus, TC-HR is triggeredby R loops, initiated by CSB, and carried out by", "metadata": {}}
+{"_id": "53033275", "title": "", "text": "Autophagy and its potent modulators fromphytochemicals in cancer treatmentAutophagy isa ubiquitous catabolic process by which damagedor harmful intracellular components are deliveredto the lysosomes for self-digestion and recycling.It is critical in cancer treatment.Therapy-induced autophagy predominantly actsas a pro-survival mechanism, but progressiveautophagy can lead to non-apoptotic cell death,also known as autophagic cell death. Plants orherbs contain various natural compounds thatare widely used in the treatment of many typesof malignancies. Emerging evidence indicatesthat phytochemicals targeting the autophagicpathway are promising agents for cancertreatment. However, these compounds playdifferent roles in autophagy. In this review, wediscussed the role of autophagy in cancerdevelopment and therapy, and focussed onelucidating the anti-cancer activities ofautophagic modulators, especiallyphytochemicals. Notably, we described a novel", "metadata": {}}
+{"_id": "53211308", "title": "", "text": "Exosomal miR-99a-5p is elevated in sera ofovarian cancer patients and promotes cancer cellinvasion by increasing fibronectin and vitronectinexpression in neighboring peritoneal mesothelialcellsBACKGROUND microRNAs (miRNAs) stablyexist in circulating blood and are encapsulated inextracellular vesicles such as exosomes. Theaims of this study were to identify whichexosomal miRNAs are highly produced fromepithelial ovarian cancer (EOC) cells, to analyzewhether serum miRNA can be used todiscriminate patients with EOC from healthyvolunteers, and to investigate the functional roleof exosomal miRNAs in ovarian cancerprogression. METHODS Exosomes were collectedfrom the culture media of serous ovarian cancercell lines, namely TYK-nu and HeyA8 cells. Anexosomal miRNA microarray revealed thatseveral miRNAs including miR-99a-5p werespecifically elevated in EOC-derived exosomes.Expression levels of serum miR-99a-5p in 62patients with EOC, 26 patients with benign", "metadata": {}}
+{"_id": "53302393", "title": "", "text": "The Pfam protein families database.Pfam is awidely used database of protein families,currently containing more than 13,000 manuallycurated protein families as of release 26.0. Pfamis available via servers in the UK(http://pfam.sanger.ac.uk/), the USA(http://pfam.janelia.org/) and Sweden(http://pfam.sbc.su.se/). Here, we report onchanges that have occurred since our 2010 NARpaper (release 24.0). Over the last 2 years, wehave generated 1840 new families and increasedcoverage of the UniProt Knowledgebase(UniProtKB) to nearly 80%. Notably, we havetaken the step of opening up the annotation ofour families to the Wikipedia community, bylinking Pfam families to relevant Wikipedia pagesand encouraging the Pfam and Wikipediacommunities to improve and expand thosepages. We continue to improve the Pfam websiteand add new visualizations, such as the'sunburst' representation of taxonomicdistribution of families. In this work we", "metadata": {}}
+{"_id": "53779698", "title": "", "text": "Exercise as a therapeutic approach to improveblood pressure in patients with peripheral arterialdisease: current literature and futuredirections.INTRODUCTION Patients withsymptomatic peripheral artery disease (PAD)exhibit reduced functional capacity and increasedmortality due to cardiovascular disease. Althoughexercise has been a cornerstone for clinicaltreatment to improve walking capacity inpatients with symptomatic PAD, its effects oncardiovascular parameters have been poorlyexplored. Areas covered: This review examinesthe role of exercise in improving blood pressurein patients with symptomatic PAD andsummarizes the current evidence on the acute(single bout of exercise) and chronic effects ofwalking and resistance exercise on bloodpressure and its determinants. Expertcommentary: In patients with symptomatic PAD,exercise promotes acute and chronic reductionsin blood pressure. These effects were observedparticularly after walking and resistance", "metadata": {}}
+{"_id": "54482327", "title": "", "text": "Morin Exhibits Anti-Inflammatory Effects onIL-1β-Stimulated Human OsteoarthritisChondrocytes by Activating the Nrf2 SignalingPathwayBackground/Aims: Osteoarthritis (OA) isa multifactorial disease that is associated withinflammation in joints. The purpose of thepresent study was to investigate theanti-inflammatory activity and mechanism ofmorin on human osteoarthritis chondrocytesstimulated by IL-1β. Methods: The levels of NOand PGE2 were measured by the Griess methodand ELISA. The levels of MMP1, MMP3, andMMP13 were also measured by ELISA. Results:The results revealed that IL-1β significantlyincreased the production of NO, PGE2, MMP1,MMP3, and MMP13. Additionally, the increaseswere significantly attenuated by treatment withmorin. Furthermore, IL-1β-induced NF-κBactivation was suppressed by morin. In addition,the expression of Nrf2 and HO-1 were increasedby morin and knockdown of Nrf2 could preventthe anti-inflammatory effects of morin.", "metadata": {}}
+{"_id": "54490092", "title": "", "text": "Impact of blood pressure variability oncardiovascular events in elderly patients withhypertension.Blood pressure variability is one ofthe characteristic features of hypertension in theelderly. However, its clinical significance remainsto be determined. We therefore examined theimpact of blood pressure variability on thedevelopment of cardiovascular events in elderlyhypertensive patients. A total of 106 consecutivehypertensive patients aged more than 60 yearsold (mean age, 73.9 +/- 8.1 years old; male,54%), all of whom underwent 24-h ambulatoryblood pressure monitoring, were followed up(median, 34 months; range, 3-60 months).During the follow-up period, 39 cardiovascularevents were observed, including 14 cases ofcerebral infarction and 7 cases of acutemyocardial infarction. The coefficient of variation(CV) of 24-h systolic blood pressure (SBP) valueswas used as an index of blood pressurevariability. The patients showed a mean CV valueof 10.6%, and were divided into two groups", "metadata": {}}
+{"_id": "54561384", "title": "", "text": "Reprogramming committed murine blood cells toinduced hematopoietic stem cells with definedfactors.Hematopoietic stem cells (HSCs) sustainblood formation throughout life and are thefunctional units of bone marrow transplantation.We show that transient expression of sixtranscription factors Run1t1, Hlf, Lmo2, Prdm5,Pbx1, and Zfp37 imparts multilineagetransplantation potential onto otherwisecommitted lymphoid and myeloid progenitorsand myeloid effector cells. Inclusion of Mycn andMeis1 and use of polycistronic viruses increasereprogramming efficacy. The reprogrammedcells, designated induced-HSCs (iHSCs), possessclonal multilineage differentiation potential,reconstitute stem/progenitor compartments, andare serially transplantable. Single-cell analysisrevealed that iHSCs derived under optimalconditions exhibit a gene expression profile thatis highly similar to endogenous HSCs. Thesefindings demonstrate that expression of a set ofdefined factors is sufficient to activate the gene", "metadata": {}}
+{"_id": "54561709", "title": "", "text": "Genetic variability in a frozen batch of MCF-7cells invisible in routine authentication affectingcell functionCommon recommendations for cellline authentication, annotation and qualitycontrol fall short addressing geneticheterogeneity. Within the Human ToxomeProject, we demonstrate that there can bemarked cellular and phenotypic heterogeneity ina single batch of the human breastadenocarcinoma cell line MCF-7 obtained directlyfrom a cell bank that are invisible with the usualcell authentication by short tandem repeat (STR)markers. STR profiling just fulfills the purpose ofauthentication testing, which is to detectsignificant cross-contamination and cell linemisidentification. Heterogeneity needs to beexamined using additional methods. Thisheterogeneity can have serious consequences forreproducibility of experiments as shown bymorphology, estrogenic growth dose-response,whole genome gene expression and untargetedmass-spectroscopy metabolomics for MCF-7", "metadata": {}}
+{"_id": "54562433", "title": "", "text": "The Mammalian-Specific Protein Armcx1Regulates Mitochondrial Transport during AxonRegenerationMitochondrial transport is crucial forneuronal and axonal physiology. However,whether and how it impacts neuronal injuryresponses, such as neuronal survival and axonregeneration, remain largely unknown. In anestablished mouse model with robust axonregeneration, we show that Armcx1, amammalian-specific gene encoding amitochondria-localized protein, is upregulatedafter axotomy in this high regenerationcondition. Armcx1 overexpression enhancesmitochondrial transport in adult retinal ganglioncells (RGCs). Importantly, Armcx1 also promotesboth neuronal survival and axon regenerationafter injury, and these effects depend on itsmitochondrial localization. Furthermore, Armcx1knockdown undermines both neuronal survivaland axon regeneration in the high regenerativecapacity model, further supporting a key role ofArmcx1 in regulating neuronal injury responses", "metadata": {}}
+{"_id": "55040297", "title": "", "text": "A diversity of beta diversities: straightening up aconcept gone awry. Part 1. Defining betadiversity as a function of alpha and gammadiversityThe term beta diversity has been usedto refer to a wide variety of phenomena.Although all of these encompass some kind ofcompositional heterogeneity between places,many are not related to each other in anypredictable way. The present two-part reviewaims to put the different phenomena that havebeen called beta diversity into a commonconceptual framework, and to explain what eachof them measures. In this first part, the focus ison defining a beta component of diversity. Thisinvolves deciding what diversity is and how theobserved total or gamma diversity (g) ispartitioned into alpha (a) and beta (b)components. Several different definitions of‘‘beta diversity’’ that result from these decisionshave been used in the ecological literature. Truebeta diversity is obtained when the total effectivenumber of species in a dataset (true gamma", "metadata": {}}
+{"_id": "55128127", "title": "", "text": "A cross-cultural study of wine consumers withrespect to health benefits of wineThe objective ofthe present study was to examine consumerpreference and consumption behaviour withrespect to the health benefits of wine for twocontextually and culturally diverse consumergroups, namely Koreans and Australians.Participants were required to be wine consumersover the age of 18. Responses were collected bymeans of an online questionnaire. The resultsindicated that perceived health benefits of redwine were higher in the Australian sample thanthe Korean sample. Similarly, Australianconsumers had more health related wineknowledge than Korean consumers. Red winewas the preferred wine style for both Korean andAustralian consumers; however, the proportionof preference for red wine was significantlyhigher in the Korean sample. With respect to theexpenditure on wine products, AUD$11–$19 wasthe preferred price range for both groups. Theresults also indicated that health-oriented wine is", "metadata": {}}
+{"_id": "56391045", "title": "", "text": "DIASPORA BONDS: TAPPING THE DIASPORADURING DIFFICULT TIMESIndia and Israel haveraised over US$35 billion by tapping into thewealth of their diaspora communities. Thesediaspora bonds represent a stable and cheapsource of external finance, often when countrieslost access to international capital markets. Fordiaspora investors, these bonds offer theopportunity to help their country of origin whilealso providing an investment opportunity. Thepotential for diaspora bonds is significant formany countries with large diasporas abroad.However, diaspora bond issuance from countrieswith weak governance and high sovereign riskmay require support for institutional capacitybuilding and credit enhancement frommultilateral or bilateral agencies. Haiti, forinstance, could raise several hundred milliondollars by issuing diaspora bonds provided aguarantee structure is created to build trust inthe country's public institutions.", "metadata": {}}
+{"_id": "56486733", "title": "", "text": "Peroxisome Proliferator Activated Receptorgamma (PPARγ) Agonist RosiglitazoneAmeliorate Airway Inflammation by InhibitingToll-Like Receptor 2 (TLR2)/Nod-Like Receptorwith Pyrin Domain Containing 3 (NLRP3)Inflammatory Corpuscle Activation in AsthmaticMiceBACKGROUND The purpose of this study wasto explore the function and mechanism ofperoxisome proliferator activated receptoragonist (PPARγ) in the toll-like receptor 2(TLR2)/nod-like receptor with pyrin domaincontaining 3 (NLRP3) inflammatory corpusclepathway of asthmatic mice. MATERIAL ANDMETHODS Eighteen female mice (C57) wererandomly divided into 4 groups: the controlgroup, the asthma model group challenged byovalbumin (OVA), the rosiglitazone group, andthe PPARγ agonist rosiglitazone treatment group.The infiltration of peribronchial inflammatorycells as well as the proliferation and mucussecretion of bronchial epithelial goblet cells wereobserved by hematoxylin and eosin and periodic", "metadata": {}}
+{"_id": "56528795", "title": "", "text": "Omi/HtrA2 Participates in Age-RelatedAutophagic Deficiency in Rat LiverLiver is a vitalorgan with many important functions, and themaintenance of normal hepatic function isnecessary for health. As an essential mechanismfor maintaining cellular homeostasis, autophagyplays an important role in ensuring normal organfunction. Studies have indicated that thedegeneration of hepatic function is associatedwith autophagic deficiency in aging liver.However, the underlying mechanisms still remainunclear. The serine protease Omi/HtrA2 belongsto the HtrA family and promotes apoptosisthrough either the caspase-dependent orcaspase-independent pathway. Mice lackingOmi/HtrA2 exhibited progeria symptoms(premature aging), which were similar to thecharacteristics of autophagic insufficiency. In thisstudy, we demonstrated that both the proteinlevel of Omi/HtrA2 in liver and hepatic functionwere reduced as rats aged, and there was apositive correlation between them. Furthermore,", "metadata": {}}
+{"_id": "56893404", "title": "", "text": "Macrosomia and HyperinsulinaemicHypoglycaemia in Patients with HeterozygousMutations in the HNF4AGeneBackground  Macrosomia is associated withconsiderable neonatal and maternal morbidity.Factors that predict macrosomia are poorlyunderstood. The increased rate of macrosomia inthe offspring of pregnant women with diabetesand in congenital hyperinsulinaemia is mediatedby increased foetal insulin secretion. Weassessed the in utero and neonatal role of twokey regulators of pancreatic insulin secretion bystudying birthweight and the incidence ofneonatal hypoglycaemia in patients withheterozygous mutations in the maturity-onsetdiabetes of the young (MODY) genes HNF4A(encoding HNF-4α) and HNF1A/TCF1 (encodingHNF-1α), and the effect of pancreatic deletion ofHnf4a on foetal and neonatal insulin secretion inmice.", "metadata": {}}
+{"_id": "57121667", "title": "", "text": "ART adherence clubs: A long-term retentionstrategy for clinically stable patients receivingantiretroviral therapyThe ART-adherence clubmodel described here provides patient-friendlyaccess to antiretroviral therapy (ART) forclinically stable patients. It reduces the burdenthat stable patients place on healthcare facilities,increasing clinical human resources for newpatients, and those clinically unstable and at riskof failing treatment. In the model, 30 patientsare allocated to an ART club. The group meetseither at a facility or community venue for lessthan an hour every 2 months. Group meetingsare facilitated by a lay club facilitator whoprovides a quick clinical assessment, referralwhere necessary, and dispenses pre-packed ART.From January 2011 to December 2012, afteradoption for phased rollout by the Western CapeGovernment, more than 600 ART clubs wereestablished in Cape Town, providing ART care toover 16 000 patients. This extensive, rapidrollout demonstrates active buy-in from patients", "metadata": {}}
+{"_id": "57574395", "title": "", "text": "Exercise-linked FNDC5/irisin rescues synapticplasticity and memory defects in Alzheimer’smodelsDefective brain hormonal signaling hasbeen associated with Alzheimer's disease (AD), adisorder characterized by synapse and memoryfailure. Irisin is an exercise-induced myokinereleased on cleavage of the membrane-boundprecursor protein fibronectin type IIIdomain-containing protein 5 (FNDC5), alsoexpressed in the hippocampus. Here we showthat FNDC5/irisin levels are reduced in ADhippocampi and cerebrospinal fluid, and inexperimental AD models. Knockdown of brainFNDC5/irisin impairs long-term potentiation andnovel object recognition memory in mice.Conversely, boosting brain levels of FNDC5/irisinrescues synaptic plasticity and memory in ADmouse models. Peripheral overexpression ofFNDC5/irisin rescues memory impairment,whereas blockade of either peripheral or brainFNDC5/irisin attenuates the neuroprotectiveactions of physical exercise on synaptic plasticity", "metadata": {}}
+{"_id": "57762078", "title": "", "text": "Influence of antidepressant therapy on sick leavein primary care: ADAS, a comparativeobservational studyBackground Compared toother European countries, Sweden's yearly sickleave expenditures are moderate. Commonmental disorders (CMD) are important causes ofsick leave, affecting 10-15% of the adultpopulation. A Swedish register based studyindicates that antidepressant therapy for patientson long-term sick leave for CMD leads to longersick leave and higher frequency ofnon-time-limited sickness compensation ascompared to psychotherapy, work orientedrehabilitation, and other therapies. Aim To verifyif patients on antidepressant therapy and onlong-term sick leave for depression, anxiety andstress-related mental disorders have a longersick leave than patients treated with othertherapies. Method Prospective, observationalstudy at 28 primary health care centers in theRegion Västra Götaland, Sweden, including 192patients on sick leave for CMD. Outcome", "metadata": {}}
+{"_id": "57783564", "title": "", "text": "CDX2 inhibits the proliferation and tumorformation of colon cancer cells by suppressingWnt/β-catenin signaling via transactivation ofGSK-3β and Axin2 expressionCaudal-relatedhomeobox transcription factor 2 (CDX2), anintestine-specific nuclear transcription factor, hasbeen strongly implicated in the tumourigenesis ofvarious human cancers. However, the functionalrole of CDX2 in the development and progressionof colorectal cancer (CRC) is not well known. Inthis study, CDX2 knockdown in colon cancer cellspromoted cell proliferation in vitro, acceleratedtumor formation in vivo, and induced a cell cycletransition from G0/G1 to S phase, whereas CDX2overexpression inhibited cell proliferation.TOP/FOP-Flash reporter assay showed that CDX2knockdown or CDX2 overexpression significantlyincreased or decreased Wnt signaling activity.Western blot assay showed that downstreamtargets of Wnt signaling, including β-catenin,cyclin D1 and c-myc, were up-regulated ordown-regulated in CDX2-knockdown or", "metadata": {}}
+{"_id": "58006489", "title": "", "text": "Prostaglandin E2 mediates sensory nerveregulation of bone homeostasisWhether sensorynerve can sense bone density or metabolicactivity to control bone homeostasis is unknown.Here we found prostaglandin E2 (PGE2) secretedby osteoblastic cells activates PGE2 receptor 4(EP4) in sensory nerves to regulate boneformation by inhibiting sympathetic activitythrough the central nervous system. PGE2secreted by osteoblasts increases when bonedensity decreases as demonstrated inosteoporotic animal models. Ablation of sensorynerves erodes the skeletal integrity. Specifically,knockout of the EP4 gene in the sensory nervesor cyclooxygenase-2 (COX2) in the osteoblasticcells significantly reduces bone volume in adultmice. Sympathetic tone is increased in sensorydenervation models, and propranolol, aβ2-adrenergic antagonist, rescues bone loss.Furthermore, injection of SW033291, a smallmolecule to increase PGE2 level locally,significantly boostes bone formation, whereas", "metadata": {}}
+{"_id": "58050905", "title": "", "text": "The Bone and Joint Decade 2000-2010.TheWorld Health Organisation has declared theperiod 2000 to 2010 the Bone and Joint Decade.This is indeed timely and appropriate. Hundredsof millions of people in the world today are besetwith a host of disabilities caused by trauma,ageing and degeneration and other affections ofthe musculo-skeletal system. With the state ofart of orthopaedic surgery and rheumatology,sufferers of bone and joint disabilities havebenefited a great deal from advances inpharmacology, newer techniques of imaging,surgery and man-made materials to replacediseased or damaged bone and cartilage.However, man-made materials, being non-living,are subject to wear and tear and loosening in thehost bone. As we advance into the Bone andJoint Decade, further improvement in thetreatment of bone and joint diseases lies in morebasic cartilage and bone research. The HumanGenome Project has provided us with a betterunderstanding of disease genes and the", "metadata": {}}
+{"_id": "58564850", "title": "", "text": "Prevalence of late-life depression and gap inmental health service use across Europeanregions.Background We aimed to determine theprevalence and gap in use of mental healthservices for late-life depression in four Europeanregions (Western Europe, Scandinavia, SouthernEurope and Central and Eastern Europe) andexplore socio-demographic, social andhealth-related factors associated with it. MethodsWe conducted a cross-sectional study based ondata from the Survey on Health, Ageing andRetirement in Europe. Participants were apopulation-based sample of 28 796 persons(53% women, mean age 74 years old) residingin Europe. Mental health service use wasestimated using information about the diagnosisor treatment for depression. Results Theprevalence of late-life depression was 29% in thewhole sample and was highest in SouthernEurope (35%), followed by Central and EasternEurope (32%), Western Europe (26%) andlowest in Scandinavia (17%). Factors that had", "metadata": {}}
+{"_id": "59453688", "title": "", "text": "Impedance and Interface Properties ofAl/Methyl-Red/p-InP Solar CellAnAl/methyl-red/p-InP solar cell was fabricated viasolution-processing method and wascharacterized by using current-voltage (I-V) andcapacitance-voltage-frequency (C-V-f)measurements at room temperature. From darkI-V characteristics, the values of ideality factorand barrier height of the device were calculatedas 1.11 eV and 2.02, respectively. It has beenseen that the device exhibited a goodphotovoltaic behavior with a maximum opencircuit voltage of 0.38 V and short-circuit currentof 2.8 nA under only 200 lx light intensity. Thebarrier height and acceptor carrier concentrationvalues for the Al/methyl-red/p-InP devices wereextracted as 1.27 eV and from linear region of itscharacteristics, respectively. The differencebetween (I-V) and (C-V) for Al/methyl-red/p-InPdevice was attributed the different nature of theI-V and C-V measurements. Also, the energydistribution curves of the interface states and", "metadata": {}}
+{"_id": "60206680", "title": "", "text": "R: A Language for Data Analysis andGraphicsAbstract In this article we discuss ourexperience designing and implementing astatistical computing language. In developingthis new language, we sought to combine whatwe felt were useful features from two existingcomputer languages. We feel that the newlanguage provides advantages in the areas ofportability, computational efficiency, memorymanagement, and scoping.", "metadata": {}}
+{"_id": "60515890", "title": "", "text": "The Mouse Brain in Stereotaxic Coordinates\" TheMouse Brain in Stereotaxic Coordinates\" is themost widely used and cited atlas of the mousebrain in print. It provides researchers andstudents with both accurate stereotaxiccoordinates for laboratory use, and detaileddelineations and indexing of structures forreference. The accompanying DVD providesdrawings of brains structures that can be used astemplates for making figures for publication. The3rd edition is both a major revision and anexpansion of previous editions. Delineations andphotographs in the horizontal plane of sectionnow complement the coronal and sagittal series,and all the tissue sections are now shown in highresolution digital color photography. Thephotographs of the sections and the intermediatesections are also provided on the accompanyingDVD in high-resolution JP 2000 format. Thedelineations of structures have been revised, andnaming conventions made consistent withPaxinos and Watson's \"Rat Brain in Stereotaxic", "metadata": {}}
+{"_id": "61050894", "title": "", "text": "ggplot2: Elegant Graphics for DataAnalysisggplot2: Elegant Graphics for DataAnalysis is a new addition to the UseR! series bySpringer, probably the fastest expanding sourceof resources for computational statistics at thecurrent moment. The books in this series are alllinked with R, either presenting a new packagedeveloped by the own authors of the book ordescribing how to applying statistical techniqueswith the different packages available in R.ggplot2 is an implementation in R of TheGrammar of Graphics (Wilkinson 2005) asystematic approach to the specification ofstatistical graphics that was introduced in a bookpreviously reviewed in the Journal of StatisticalSoftware by Cox (2007). This implementationhas been developed by Hadley Wickham, who isalso the author of the book reviewed here.", "metadata": {}}
+{"_id": "63858430", "title": "", "text": "Multiple Imputation For Nonresponse InSurveysmultiple imputation for nonresponse insurveys is available in our book collection anonline access to it is set as public so you candownload it instantly. Our book servers hosts inmultiple locations, allowing you to get the mostless latency time to download any of our bookslike this one. Merely said, the multiple imputationfor nonresponse in surveys is universallycompatible with any devices to read.", "metadata": {}}
+{"_id": "67045088", "title": "", "text": "Inhibition of the dipeptidyl peptidase DPP4(CD26) reveals IL-33-dependenteosinophil-mediated control of tumorgrowthPost-translational modification ofchemokines mediated by the dipeptidyl peptidaseDPP4 (CD26) has been shown to negativelyregulate lymphocyte trafficking, and its inhibitionenhances T cell migration and tumor immunityby preserving functional chemokine CXCL10. Byextending those initial findings to pre-clinicalmodels of hepatocellular carcinoma and breastcancer, we discovered a distinct mechanism bywhich inhibition of DPP4 improves anti-tumorresponses. Administration of the DPP4 inhibitorsitagliptin resulted in higher concentrations ofthe chemokine CCL11 and increased migration ofeosinophils into solid tumors. Enhanced tumorcontrol was preserved in mice lackinglymphocytes and was ablated after depletion ofeosinophils or treatment with degranulationinhibitors. We further demonstrated thattumor-cell expression of the alarmin IL-33 was", "metadata": {}}
+{"_id": "67787658", "title": "", "text": "Cycling Quiescence in Temozolomide ResistantGlioblastoma Cells Is Partly Explained bymicroRNA-93 and -193-Mediated Decrease ofCyclin DGlioblastoma multiforme (GBM) is a fatalmalignancy of the central nervous system,commonly associated with chemoresistance. Thealkylating agent Temozolomide (TMZ) is thefront-line chemotherapeutic agent and hasundergone intense studies on resistance. Thesestudies reported on mismatch repair geneupregulation, ABC-targeted drug efflux, and cellcycle alterations. The mechanism by which TMZinduces cell cycle arrest has not beenwell-established. TMZ-resistant GBM cells havebeen linked to microRNA (miRNA) and exosomes.A cell cycle miRNA array identified distinctmiRNAs only in exosomes from TMZ-resistantGBM cell lines and primary spheres. Wenarrowed the miRs to miR-93 and -193 andshowed in computational analyses that theycould target Cyclin D1. Since Cyclin D1 is amajor regulator of cell cycle progression, we", "metadata": {}}
+{"_id": "68317730", "title": "", "text": "Longitudinal changes in maternal corin andmid-regional proatrial natriuretic peptide inwomen at risk of pre-eclampsiaObjectives Corin,an atrial natriuretic peptide-converting enzyme,has been found to promote trophoblast invasionand spiral artery remodeling. Reduced maternalplasma atrial natriuretic peptide (ANP) levels andelevated corin levels have been reported inpregnancies complicated by PE. The aim of thisstudy was to investigate longitudinal changes inmaternal plasma levels of corin and midregionalproatrial natriuretic peptide (MR-PANP) inpregnancies that develop preeclampsia (PE) andgestational hypertension (GH). Methods Nestedcase control study drawn from a largerprospective longitudinal study in singletonpregnancies identified by screening at 11 + 0 −13 + 6 weeks’ gestation as being at high risk forPE. Blood samples were taken every four weeksuntil delivery. Values were compared inpregnancies that developed preterm-PE(requiring delivery before 37 weeks), term-PE,", "metadata": {}}
+{"_id": "69045262", "title": "", "text": "Children's Exercise PhysiologyThe reorganizedand newly revised \"Children's ExercisePhysiology, Second Edition, \" presents the mostup-to-date research, methodology, andapproaches related to children's physiologicresponses to exercise. The book examines notonly the current major issues that separatechildren from adults, but also the underlyingmechanisms of these differences. Readers willlearn what makes children different from adultsphysiologically--such as size, biochemicaldifferences, neuromuscular differences, and lackof sexual and hormonal maturation--and thereasons for these differences. Those involvedwith young athletes, disease management, andhealth promotion will gain valuable insight intothe physiologic determinants of exerciseperformance. Children's exercise physiology is afast-moving field. In the eight years since thefirst edition of this book was published, muchnew information has surfaced. This streamlinednew edition contains 13 instead of 15 chapters,", "metadata": {}}
+{"_id": "70439309", "title": "", "text": "Cost-effectiveness in health and medicine1.Cost-Effectiveness Analysis as a Guide toResource Allocation in Health: Roles andLimitations 2. Theoretical Foundations ofCost-Effectiveness Analysis 3. Framing andDesigning the Cost-Effectiveness Analysis 4.Identifying and Valuing Outcomes 5. Assessingthe Effectiveness of Health Interventions 6.Estimating Costs in Cost-Effectiveness Analysis7. Time Preference 8. Reflecting Uncertainty inCost-Effectiveness Analysis 9. ReportingCost-Effectiveness Studies and Results AppendixA: Summary of Recommendations for theReference Case Appendix B: Cost-Effectivenessof Strategies to Prevent Neural Tube DefectsAppendix C: The Cost-Effectiveness of Dietaryand Pharmacologic Therapy for CholesterolReduction in Adults", "metadata": {}}
+{"_id": "70455704", "title": "", "text": "Weight gain during pregnancy: reexamining theguidelines.As women of childbearing age havebecome heavier, the trade-off between maternaland child health created by variation ingestational weight gain has become moredifficult to reconcile. Weight Gain DuringPregnancy responds to the need for areexamination of the 1990 Institute of Medicineguidelines for weight gain during pregnancy. Itbuilds on the conceptual framework thatunderscored the 1990 weight gain guidelines andaddresses the need to update them through acomprehensive review of the literature andindependent analyses of existing databases. Thebook explores relationships between weight gainduring pregnancy and a variety of factors (e.g.,the mother's weight and height beforepregnancy) and places this in the context of thehealth of the infant and the mother, presentingspecific, updated target ranges for weight gainduring pregnancy and guidelines for propermeasurement. New features of this book include", "metadata": {}}
+{"_id": "70516463", "title": "", "text": "To err is human. Building a safer healthsystemHuman beings, make errors HealthcareServices is a complex industry prone toaccidents. The IOM Report [1] points out thatsome systems are more prone to accidents thanothers. When a system fails there are oftenmultiple faults. In healthcare,human errors arethe greatest contributors to accidents,howeverwhen human error is to blame it often dependsupon failures within the system. These failuresexists in the system before the error occurs, thesame as with latent errors which are difficult toidentify since they may be hidden in computersor within the various managerial layers. Most ofthe errors can be prevented by designingsystems that make it hard for people to do thewrong thing and easy for people to do the rightthing. In healthcare, this means designingprocesses that are able to ensure that patientsare safe from accidental injury. As healthcareand the system that delivers it become morecomplex, the opportunities for errors abound.", "metadata": {}}
+{"_id": "70633421", "title": "", "text": "Excess risk of lymphomas, leukemia andmyeloma in patients with rheumatoidarthritisThe incidence of malignant neoplasmsamong 11 483 male and 34 618 femaleindividuals with rheumatoid arthritis was studiedusing two separate nationwide data registerscovering the whole Finnish population: the SocialInsurance Institution9s Population Data Register,which includes information on medication forcertain chronic diseases, and the Finnish CancerRegistry, with data on all cancer patientsdiagnosed in Finland. The follow-up comprised atotal of 213 911 person years. The totalincidence of all malignant neoplasms was higherin males and on the level expected in females.The expected number of cases of leukemia,lymphomas, Hodgkin9s disease and myeloma inboth sexes was 59·6 as compared with the 130cases observed. This difference is statisticallyhighly significant (p", "metadata": {}}
+{"_id": "70704988", "title": "", "text": "Advanced Human NutritionAdvanced HumanNutrition, Second Edition provides an in-depthoverview of the human body and details whynutrients are important from a biochemical,physiological, and molecular perspective. Figureshelp illustrate the content and bring the meaningto life to enhance the reader's understanding.Complex pathways, for example, are presentedin a student-friendly fashion, as are diagramsthat illustrate metabolism and the molecularfunctions of nutrients. Multiple elements withinthe text, such as \"Here's Where You Have Been\"and \"Here's Where You Are Going,\" help drivehome key points from the chapter and providereal-world examples to bring the content to life.Topics covered include: * cell aging, damage andrepair systems * human nutrition, digestion, andabsorption with relation to organs, exocrine andendocrine functions, histology, and absorptiveactivities * microflora and satiety/hungermechanisms * macronutrients during exerciseand the role of liquids and sports drinks *", "metadata": {}}
+{"_id": "70895396", "title": "", "text": "The Endothelium: Modulator of CardiovascularFunctionIntroduction. Methods To StudyEndothelium-Dependent Responses.Endothelium-Derived Relaxing Factor.Physiological Actions. Other Relaxing SubstancesReleased By the Endothelium. Production ofContracting Agents. Local Regulation ofEndothelium-Dependent Responses.Neurohumoral Regulation. Heterogeneity andChronic Modulation. Disease. TherapeuticImplications. References. Subject Index.", "metadata": {}}
+{"_id": "71341302", "title": "", "text": "Vegetarian vs. conventional diabetic diet – A1-year follow-upAbstract Objective Our previous6-month, randomized study demonstrated thebeneficial effect of a vegetarian (V) compared toa conventional diet (C) with similar caloricrestriction on cardiovascular risk factors forpatients with type 2 diabetes (T2D), namelyincreased insulin sensitivity, reduced bodyweight, reduced volume of visceral andsubcutaneous fat, decreased LDL-cholesterol andimproved oxidative stress markers and chosenadipokines. We conducted post-trial monitoringto determine whether the improved outcomespersisted 1 year after the end of the study.Methods 62 subjects with T2D who completedthe study were asked to come for a 1-yearfollow-up to measure weight, waistcircumference, HbA1c and blood lipids. Noattempts were made to maintain their previouslyassigned diets. Results 44 patients (71%)attended the post-trial monitoring. Hypoglycemicagents were increased by 14% in V and by 26%", "metadata": {}}
+{"_id": "71625969", "title": "", "text": "Alcohol, wine, and healthAbstract Background:For the past 20 years numerous epidemiologicalstudies have correlated the consumption ofalcohol and a variety of disease states: overallmortality, arteriosclerotic vascular diseases,hypertension, cancers, peptic ulcer, respiratoryinfections, gall stones, kidney stones,age-related macular degeneration, bone density,and cognitive function. Methods: A review ofthese articles reveals that each of these studieshas compared the outcome of individuals atvarious levels of alcohol consumption with that ofabstainers. Results: Each analysis has identifieda U-shaped or J-shaped curve of reduced relativerisk for a given disease state compared withabstainers. A clear definition of consumption inmoderation becomes evident: for men it shouldnot exceed 2 to 4 drinks per day, and for womenit should not exceed 1 to 2 drinks per day.Conclusions: Alcohol by itself has favorableeffects on the level of high-density lipoproteincholesterol, and inhibition of platelet", "metadata": {}}
+{"_id": "71628189", "title": "", "text": "Contraceptive practices of women requestingtermination of pregnancy : A study fromChinaAbstract In order to develop a program forprevention of unwanted pregnancies, weconducted a survey of contraceptive practicesand reasons for contraceptive failures of 1520women seeking abortion at eight large hospitalsin Zheng Zhou City, Henan Province, P.R. China,during the period from March 1996 to May 1996.The most frequent cause of the unplannedpregnancy was contraceptive failure (71.9%);61.7% (938) of these current pregnancies werepotentially predictable by virtue of nonuse ofcontraception (427) or by recognition ofcontraceptive failures (511). Among thecontraceptive failures, the proportion of condommishaps was the highest (29.7%), next was IUDfailures (23.5%), then rhythm miscalculation(15.9%). Most of abortion seekers (77.1%) usedsome contraceptive methods previously. But,only 19.7% of them used a contraceptivemethod at the first sexual intercourse. Among", "metadata": {}}
+{"_id": "72180760", "title": "", "text": "Oncologists' perceptions of the effects of cancerpatients' companions on physician-patientinteractionsTo determine physicians' perceptionsof the effects that the companions of cancerpatients have on physician-patientcommunication, semistructured interviews wereconducted with 12 oncologists (6 medical, 4surgical, and 2 radiation) from a total populationof 21 oncologists. The physicians estimated thatthreefourths of their patients broughtcompanions with them to consultations and saidthat these consultations were more complex forthe physician. The behaviors of the companionsvaried from domination to passive note taking,and the companions who were youngprofessional men or older women whoaccompanied their husbands were the mostassertive and asked the most questions. Allpossible coalitions were observed during medicalvisits. The physicians perceived that companionsand patients often had different agendas andnoted differences in the companions' behaviors", "metadata": {}}
+{"_id": "72372925", "title": "", "text": "Wolff's Headache and Other Head Pain.There hasnever been a book on headache that came closeto that of the late Harold Wolff. The secondedition was published 10 years ago; it was and isa masterpiece of writing, an exhaustive yetengrossing delineation of Wolff's long study andunderstanding of headache. The new edition,revised by Dalessio, serves to bring certainaspects of headache up to date, most of themhaving to do with drug therapy. The emphasis ontotal therapy rather than simply drug therapyhas been preserved, however. Dalessio hasaltered slightly the form of the book, althoughthe \"new chapters\" on cluster headache andtrigeminal neuralgia are merely transplants fromother sections of the original. Migraine, the mainpart of the book, has been reshaped, with someanecdotal portions removed, but little has beenadded. It is of interest that nothing in the sectionon observations of methysergide (UML-491 inWolff's", "metadata": {}}
+{"_id": "72580164", "title": "", "text": "Ansichten von Hausärzten zur Versorgung vonunheilbar kranken Patienten am Lebensende -Ergebnisse einer Befragung inNiedersachsenBackground: Family doctors playan important role in the health care for terminalill and patients. The current level of palliativecare in Germany is strongly criticised, however,empirical data is scare, particularly with respectto family doctors. Methods: Therefore, theattitudes of family doctors (sample: n= 257) infour representative regions in Lower Saxonywere studied by using semi-structured telephoneinterviews. This was part of a health systemresearchers’ expert report. Results: 71doctorscould be interviewed (28%). On the average,they cared for four palliative patients with cancerdiseases and eight palliative patients with otherdiseases than cancer at that time. Many of thedoctors were available for their patients aroundthe clock, particularly in the final phase. Themain area for improvement was considered to bethe psychosocial support – rather than pain", "metadata": {}}
+{"_id": "72933407", "title": "", "text": "Novel Risk Factors for Systemic Atherosclerosis:A Comparison of C-Reactive Protein, Fibrinogen,Homocysteine, Lipoprotein(a), and StandardCholesterol Screening as Predictors of PeripheralArterial DiseaseContextSeveral novel risk factorsfor atherosclerosis have recently been proposed,but few comparative data exist to guide clinicaluse of these emerging biomarkers. ObjectiveTocompare the predictive value of 11 lipid andnonlipid biomarkers as risk factors fordevelopment of symptomatic peripheral arterialdisease (PAD).Design, Setting, andParticipantsNested case-control study usingplasma samples collected at baseline from aprospective cohort of 14 916 initially healthy USmale physicians aged 40 to 84 years, of whom140 subsequently developed symptomatic PAD(cases); 140 age- and smoking status–matchedmen who remained free of vascular diseaseduring an average 9-year follow-up period wererandomly selected as controls. Main OutcomeMeasureIncident PAD, as determined by baseline", "metadata": {}}
+{"_id": "73136607", "title": "", "text": "Assessment of older people: Self-maintainingand instrumental activities of daily living.THE useof formal devices for assessing function isbecoming standard in agencies serving theelderly. In the Gerontological Society's recentcontract study on functional assessment (Howell,1968), a large assortment of rating scales,checklists, and other techniques in use in appliedsettings was easily assembled. The present stateof the trade seems to be one in which eachinvestigator or practitioner feels an innercompusion to make his own scale and to cry thatother existent scales cannot possibly fit his ownsetting. The authors join this company inpresenting two scales first standardized on theirown population (Lawton, 1969). They take somecomfort, however, in the fact that one scale, thePhysical Self-Maintenance Scale (PSMS), islargely a scale developed and used by otherinvestigators (Lowenthal, 1964), which wasadapted for use in our own institution. Thesecond of the scales, the Instrumental Activities", "metadata": {}}
+{"_id": "73323408", "title": "", "text": "Diabetes in pregnancy: management of diabetesand its complications from preconception to thepostnatal period (NG3)In February 2015 theNational Institute for Health and Care Excellence(NICE) published new guidance (NG3) on themanagement of diabetes in pregnancy. Careteams need to be aware of this guidance andimplement its recommendations. These includepreconception care with target HbA1c 48mmol/mol. Women at risk of gestational diabetesmellitus (GDM) should have a 75 g oral glucosetolerance test (OGTT). Diagnostic criteria forGDM have changed to fasting glucose of 5.6mmol/L or above or 2 hour glucose of 7.8mmol/L or above. Glycaemic targets in alldiabetic pregnancies have changed to fastingglucose below 5.3 mmol/L (4–5.2 mmol/L if oninsulin) and 1 hour postprandial glucose below7.8 mmol/L if these can be achieved safely.Continuous glucose monitoring and insulin pumptherapy should not be used routinely but can beused if glycaemic control is problematic. Capillary", "metadata": {}}
+{"_id": "73473433", "title": "", "text": "Mental health difficulties across childhood andmental health service use: findings from alongitudinal population-basedstudy.BACKGROUND Over the past 20 years theprevalence of child and adolescent mentaldisorders in high-income countries has notchanged despite increased investment in mentalhealth services. Insufficient contact with mentalhealth services may be a contributing factor;however, it is not known what proportion ofchildren have sufficient contact with healthprofessionals to allow delivery of treatmentmeeting minimal clinical practice guidelines, orhow long children experience symptoms prior toreceiving treatment. AimsTo investigate the levelof mental healthcare received by Australianchildren from age 4 years to 14 years. METHODTrajectories of mental health symptoms weremapped using the Strengths and DifficultiesQuestionnaire. Health professional attendancesand psychotropic medications dispensed wereidentified from linked national Medicare Benefits", "metadata": {}}
+{"_id": "74137632", "title": "", "text": "Rembrandt ScholzThis paper examines thepotential impact of changes in medical care onchanging population health in Lithuania, Hungaryand Romania, with west Germany included forcomparison. We used the concept of deaths fromcertain causes that should not occur in thepresence of timely and effective health care(amenable mortality) and calculated thecontribution of changes in mortality from theseconditions to changes in life expectancy betweenbirth and age 75 [e (0-75)] for the periods1980/81 to 1988 and 1992 to 1997. Temporarylife expectancy improved consistently in westGermany (men: 2.7 years, women: 1.6 years).In contrast, gains were relatively small in theother countries, except among Hungarianwomen, who gained 1.3 years. Romanian menlost 1.3 years. In the 1980s, falling infantmortality made a substantial contribution toimprovements in temporary life expectancy in allcountries, of about a quarter to half a year. Ofthis, more than half can be attributed to", "metadata": {}}
+{"_id": "74701974", "title": "", "text": "The Women's Interagency HIV StudyTheWomen's Interagency HIV Study comprises thelargest U.S. cohort to date of humanimmunodeficiency virus (HIV)-seropositivewomen (N = 2,058) with a comparison cohort ofseronegative women (N = 568). Themethodology, training, and quality assuranceactivities employed are described. The study pop", "metadata": {}}
+{"_id": "75636923", "title": "", "text": "Prevalence of the Metabolic Syndrome Among UsAdults: Findings From the Third National Healthand Nutrition Examination SurveyMetabolicsyndrome is diagnosed when three or more ofthe following criteria are met: abdominal obesity(waist circumference more than 102 cm in menand 88 cm in women); hypertriglyceridemia of150 mg/dl or above; a high-density lipoprotein(HDL) cholesterol level less than 40 mg/dl inmen or 50 mg/dl in women; blood pressure of130/85 mm Hg or higher; or fasting glucose of atleast 110 mg/dl. Individuals with metabolicsyndrome are likelier than others to developdiabetes and cardiovascular disease and haveincreased mortality from all causes (and fromcardiovascular disease in particular). Theinvestigators attempted to determine theprevalence of the syndrome in the United Statesby analyzing data on 8814 men and women 20years of age or older who took part in the ThirdNational Health and Nutrition ExaminationSurvey in the years 1988 to 1994. This is a", "metadata": {}}
+{"_id": "76415938", "title": "", "text": "Baseline cytology, human papillomavirus testing,and risk for cervical neoplasia: A 10-year cohortanalysisAs more is learned about thedevelopment of cervical cancer, the value ofannual Pap smear screening for all women isbeing questioned. This study was conducted toinvestigate whether women at higher risk for thedevelopment of cervical cancer could beidentified by testing for the presence of humanpapillomavirus (HPV) in the cervical smear.These women could be followed annually, andthe interval between screening Pap smears forwomen at lower risk could be increased. Studyparticipants were women enrolled in the KaiserPermanente healthcare plan in Portland, Oregon,who underwent annual Pap smear screeningbetween April 1989, and November 1990. Morethan 20,000 women (20,810 of 23,702) hadsatisfactory cervical smears with sufficientsamples for HPV testing, which was conductedusing a polymerase chain reaction-based methodwith MYO9/11 primers. Most women (83.6%)", "metadata": {}}
+{"_id": "76463821", "title": "", "text": "Preconception Care and the Risk of CongenitalAnomalies in the Offspring of Women WithDiabetes Mellitus: A Meta-AnalysisPreconceptioncare (PCC) and strict periconceptional glycemiccontrol are both used to minimize the risk ofcongenital birth defects in offspring of womenwith type 1 or type 2 diabetes mellitus (DM).These malformations are ascribed in largemeasure to poor periconceptional control. Thisstudy evaluated PCC by a meta-analysis ofpublished studies of PCC in women with DM,published from 1970 to 2000. Two reviewersindependently abstracted the data, and the rateand relative risk (RR) of major and minormalformations were pooled from eligible studiesusing a random effects model. Earlyfirst-trimester values of glycosylated hemoglobinwere recorded. Eight retrospective and eightprospective cohort studies were included; theywere carried out in Europe, the United Kingdom,the United States, and Israel. Most participantshad type 1 DM, but three studies included", "metadata": {}}
+{"_id": "76776022", "title": "", "text": "Behçet's disease associated with alymphoproliferative disorder, mixedcryoglobulinemia, and an immune complexmediated vasculitis.Abstract A woman, now 59has been followed for 13 years with severalmanifestations of Behcet's disease. These wereaphthous stomatitis, genital ulcers, uveitiscausing blindness, recurrent erythema nodosum,and synovitis. In 1970 a poorly differentiateddiffuse lymphocytic lymphoma appeared and wastreated with radiotherapy. In 1976 shedeveloped a mixed cryoglobulinemia and animmune complex mediated vasculitis manifestedby purpura and neuropathy which improved onprednisone and chlorambucil therapy. Thesubsequent course of her lymphoproliferativedisorder suggest that it was in fact benign.", "metadata": {}}
+{"_id": "77971703", "title": "", "text": "Older People at the End of Life: Delivery of Careand Needs for Improvement from the Perspectiveof Bereaved RelativesBACKGROUND Due todemographic changes with an increasing numberof older people with chronic illness andmultimorbidity palliative care for geriatricpatients has become increasingly important. Theaim of this study was to explore the perspectiveof bereaved relatives with regard to theirexperiences and expectations concerning thedelivery of care for older people in the last phaseof life. METHODS Qualitative interviews with 12relatives of deceased older patients (aged 60years or older). The interviews were recorded,transcribed, coded and analysed using theapproach of qualitative content analysisaccording to Mayring. RESULTS The bereavedrelatives perceived that the care for geriatricpatients in the last phase of life wasinappropriate in various respects. They criticisedovertreatment (e.g. skin cancer diagnostic) aswell as unmet needs (e.g. treatment of pain,", "metadata": {}}
+{"_id": "79231308", "title": "", "text": "Role of Computerized Physician Order EntrySystems in Facilitating Medication Errorsascompared with 103 (8.2 percent) in the controlgroup; the Kaplan-Meier estimates of thelikelihood of freedom from deep-vein thrombosisor pulmonary embolism at 90 days were 94.1percent (95 percent confidence interval, 92.5 to95.4 percent) and 90.6 percent (95 percentconfidence interval, 88.7 to 92.2 percent),respectively (P 0.001). The computer alertreduced the risk of deep-vein thrombosis orpulmonary embolism at 90 days by 41 percent(hazard ratio, 0.59; 95 percent confidenceinterval, 0.43 to 0.81; P 0.001). CONCLUSIONSThe institution of a computer-alert programincreased physicians’ use of prophylaxis andmarkedly reduced the rates of deep-veinthrombosis and pulmonary embolism amonghospitalized patients at risk. Editorial Comment:Most hospitals have adopted electronic systemsto alert physicians of drug interactions orpossible substitutions, as well as other measures", "metadata": {}}
+{"_id": "79336156", "title": "", "text": "Beta-band oscillations--signalling the statusquo?In this review, we consider the potentialfunctional role of beta-band oscillations, which atpresent is not yet well understood. We discussevidence from recent studies on top-downmechanisms involved in cognitive processing, onthe motor system and on the pathophysiology ofmovement disorders that suggest a unifyinghypothesis: beta-band activity seems related tothe maintenance of the current sensorimotor orcognitive state. We hypothesize that betaoscillations and/or coupling in the beta-band areexpressed more strongly if the maintenance ofthe status quo is intended or predicted, than if achange is expected. Moreover, we suggest thatpathological enhancement of beta-band activityis likely to result in an abnormal persistence ofthe status quo and a deterioration of flexiblebehavioural and cognitive control.", "metadata": {}}
+{"_id": "79696454", "title": "", "text": "Safety, pharmacokinetics and efficacy ofIMCgp100, a first-in-class soluble TCR-antiCD3bispecific t cell redirector with solid tumouractivity: Results from the FIH study inmelanoma.3016Background: T cell-basedbispecific agents have shown activity inhematologic cancers, but solid tumor efficacyremains elusive. IMCgp100 is a bispecific biologiccomprising an affinityenhanced TCR specific forgp100 and an anti-CD3 scFV. In vitro, IMCgp100binds gp100+ melanoma cells causingredirection of cytotoxicity and induction of potentimmune effects. Methods: The Phase I wasconducted in HLA-A2+ pts with advancedmelanoma, using a 3+3 design to define theMTD. Pts were treated with IMCgp100 (iv)weekly (QW, Arm 1) or daily (4QD3W, Arm 2) toevaluate safety, PK and efficacy. Therecommended phase 2 regimen (RP2D-QW) wasdefined. Results: In the Ph I dose escalation,31pts received doses from 5ng/kg to 900ng/kg. Inarm 1 dose-limiting toxicity of gr 3 or 4", "metadata": {}}
+{"_id": "80109277", "title": "", "text": "The Bitterest Pills: The Troubling Story ofAntipsychotic Drugs© Joanna Moncrieff 2013. Allrights reserved. A challenging reappraisal of thehistory of antipsychotics, revealing how theywere transformed from neurological poisons intomagical cures, their benefits exaggerated andtheir toxic effects minimized or ignored.", "metadata": {}}
+{"_id": "80522346", "title": "", "text": "Variables Affecting Kinetics of Minimal ResidualDisease Clearance in Children with LymphoblasticLeukaemia; Results of the United KingdomMedical Research Council (UK MRC) ProtocolsALL97, ALL97/99 and ALL2003.We studied theinfluence of patient, leukaemia and treatmentcharacteristics on the kinetics of MinimalResidual Disease (MRD) clearance in childrenwith lymphoblastic leukaemia treated using anintensive risk stratified approach. UK MRCprotocol ALL97 (1997–1999), and its amendedversion ALL 97/99 (1999–2002), compared theefficacy and toxicity of dexamethasone (DEX)with prednisolone (PRED), and 6-thioguanine(TG) with 6-Mercaptopurine (MP) in arandomised fashion. The trial produced a 5 yearevent-free survival (EFS) of 80%, with bettersystemic and Central Nervous System outcomesin DEX compared with PRED recipients but nodifference between TG and MP recipients.Several changes to the risk stratification andtreatment regimens during the period of the trial", "metadata": {}}
+{"_id": "81498132", "title": "", "text": "Chromosome numbers in certain Indian speciesofUtricularia L. (Lentibulariaceae)Chromosomenumbers from meiotic studies have beenreported for the following species ofUtricularia:U. aurea Lour. (n=21);U. baouleënsis A. Chev.(n=10);U. caerulea L. (n=20);U. inflexavar.stellaris (Linn.f.) P. Taylor (n=21);U.minutissima Vahl (n=8);U. scandens Benj. (n=6,7); andU. stricticaulis Stapf (n=7). There are twocyto-races inU. scandens.", "metadata": {}}
+{"_id": "82665667", "title": "", "text": "Detection of [Ca2+]I Changes In Sub-PlasmaMembrane Micro Domains in A Single Living CellBy an Optical Fiber-Based NanobiosensorAnoptical fiber-based nanobiosensor, for advanceddetection of [Ca 2+ ]i (i.e. intracellular Ca 2+concentration) changes in sub-plasmamembrane microdomains in a single livingsmooth muscle cell and a single livingcardiomyocyte, was successfully prepared bycoating silver and then immobilizing CalciumGreen-1 Dextran, a calcium ion sensitive dye, onthe distal end of the nanoprobe. The constructednanobiosensor was capable of detecting ultra-lowand local intracellular calcium ion concentrationwithin the nanomolar range, which is around thephysiological level of free cytosolic calcium ion ina single living cell. The response time was lessthan milliseconds enabling the detection oftransient elementary calcium ion signalingevents associated with calcium ionmicrodomains. The effects of stimulants such ashigh potassium buffer solution and", "metadata": {}}
+{"_id": "82971616", "title": "", "text": "Construction of plant bacterial artificialchromosome (BAC) libraries: an illustratedguide.J. Agric. Genomics, 5 ABSTRACT Bacterialartificial chromosome (BAC) libraries havebecome invaluable tools in plant geneticresearch. However, it is difficult for newpractitioners to create plant BAC libraries denovo because published protocols are notparticularly detailed, and plant cells possessfeatures that make isolation of clean, highmolecular weight DNA troublesome. In thisdocument we present an illustrated, step-by-stepprotocol for constructing plant BAC libraries. Thisprotocol is sufficiently detailed to be of use toboth new and experienced investigators. Wehope that by reducing the obstacles to BACcloning in plants, we will foster new andaccelerated progress in plant genomics.", "metadata": {}}
+{"_id": "83308790", "title": "", "text": "Activation by IKKα of a second, evolutionaryconserved, NF-κB signaling pathwayInmammals, the canonical nuclear factor κB(NF-κB) signaling pathway activated in responseto infections is based on degradation of IκBinhibitors. This pathway depends on the IκBkinase (IKK), which contains two catalyticsubunits, IKKα and IKKβ. IKKβ is essential forinducible IκB phosphorylation and degradation,whereas IKKα is not. Here we show that IKKα isrequired for B cell maturation, formation ofsecondary lymphoid organs, increasedexpression of certain NF-κB target genes, andprocessing of the NF-κB2 (p100) precursor. IKKαpreferentially phosphorylates NF-κB2, and thisactivity requires its phosphorylation by upstreamkinases, one of which may be NF-κB–inducingkinase (NIK). IKKα is therefore a pivotalcomponent of a second NF-κB activation pathwaybased on regulated NF-κB2 processing ratherthan IκB degradation.", "metadata": {}}
+{"_id": "83667891", "title": "", "text": "Identification and transmission of Piper yellowmottle virus and Cucumber mosaic virusinfecting black pepper (Piper nigrum) in SriLankaSri Lankan black pepper with symptoms ofyellow mottle disease contained a mixture ofviruses: Piper yellow mottle virus (PYMV)particles (30 × 130 nm), Cucumber mosaic virus(CMV, 30 nm diameter isometric particles), andunidentified, isometric virus-like particles (30 nmdiameter). An effective purification procedure isdescribed for PYMV. Immunosorbent andconventional electron microscopy successfullydetected badnavirus particles only when at leastpartially purified extracts were used. PYMV wasconfirmed as the cause of the disease, with theother two viruses apparently playing no part inproducing symptoms. PYMV was transmitted bygrafting, by the insect vectors citrus mealy bug(Planococcus citri) and black pepper lace bug(Diconocoris distanti), but not by mechanicalinoculation or through seeds. The CMV isolatewas transmitted to indicator plants by", "metadata": {}}
+{"_id": "83707680", "title": "", "text": "A forkhead-domain gene is mutated in a severespeech and language disorderIndividuals affectedwith developmental disorders of speech andlanguage have substantial difficulty acquiringexpressive and/or receptive language in theabsence of any profound sensory or neurologicalimpairment and despite adequate intelligenceand opportunity1. Although studies of twinsconsistently indicate that a significant geneticcomponent is involved1,2,3, most familiessegregating speech and language deficits showcomplex patterns of inheritance, and a gene thatpredisposes individuals to such disorders has notbeen identified. We have studied a uniquethree-generation pedigree, KE, in which a severespeech and language disorder is transmitted asan autosomal-dominant monogenic trait4. Ourprevious work mapped the locus responsible,SPCH1, to a 5.6-cM interval of region 7q31 onchromosome 7 (ref. 5). We also identified anunrelated individual, CS, in whom speech andlanguage impairment is associated with a", "metadata": {}}
+{"_id": "84085333", "title": "", "text": "The Growth and Sporulation of the Benign andMalignant Tertian Malarial Parasites in theCulture Tube and in the Human HostResearcheson the cultivation of the parasites of malaria inLiverpool were commenced some time ago at mysuggestion by Dr. Sinton, and then, with bettersuccess, by Drs. J. G. Thomson and McLellan,and by Dr. D. Thomson. We are greatly obligedto Sir Edwin Durning-Lawrence, Bart., for givingus the services of Dr. J. G. Thomson for thisimportant enquiry.— Ronald Ross, 21st May,1913.", "metadata": {}}
+{"_id": "84244109", "title": "", "text": "Innate immunity to a facultative intracellularbacterial pathogen.The murine response toListeria monocytogenes has long beenconsidered a paradigm of T-cell-mediatedimmunity. There is, however, substantialevidence that T-cell-deficient mice are capable ofsurviving a L. monocytogenes challenge.Recently, advances have been made in ourunderstanding of the cell biology andpathogenesis of infection.", "metadata": {}}
+{"_id": "84379954", "title": "", "text": "Diversity and Evenness: A Unifying Notation andIts ConsequencesThree commonly usedmeasures of diversity, Simpson's index,Shannon's entropy, and the total number ofspecies, are related to Renyi's definition of ageneralized entropy. A unified concept ofdiversity is presented, according to which thereis a continuum of possible diversity measures. Ina sense which becomes apparent, thesemeasures provide estimates of the effectivenumber of species present, and differ only intheir tendency to include or to ignore therelatively rarer species. The notion of thediversity of a community as opposed to that of asample is examined, and is related to theasymptotic form of the species—abundancecurve. A new and plausible definition of evennessis derived.", "metadata": {}}
+{"_id": "84580585", "title": "", "text": "Guide to yeast genetics and molecularbiologyThis volume and its companion, Volume350, are specifically designed to meet the needsof graduate students and postdoctoral studentsas well as researchers, by providing all theup-to-date methods necessary to study genes inyeast. Procedures are included that enablenewcomers to set up a yeast laboratory and tomaster basic manipulations. Relevantbackground and reference information given forprocedures can be used as a guide to developingprotocols in a number of disciplines. Specifictopics addressed in this book include cytology,biochemistry, cell fractionation, and cell biology.", "metadata": {}}
+{"_id": "84784389", "title": "", "text": "Cutadapt removes adapter sequences fromhigh-throughput sequencing readsWhen smallRNA is sequenced on current sequencingmachines, the resulting reads are usually longerthan the RNA and therefore contain parts of the3' adapter. That adapter must be found andremoved error-tolerantly from each read beforeread mapping. Previous solutions are either hardto use or do not offer required features, inparticular support for color space data. As aneasy to use alternative, we developed thecommand-line tool cutadapt, which supports454, Illumina and SOLiD (color space) data,offers two adapter trimming algorithms, and hasother useful features. Cutadapt, including itsMIT-licensed source code, is available fordownload at http://code.google.com/p/cutadapt/", "metadata": {}}
+{"_id": "84884645", "title": "", "text": "Reproductive physiology of marsupialsPreface 1.Historical introduction 2. Breeding biology ofmarsupials by family 3. Sexual differentiationand development 4. Male anatomy andspermatogenesis 5. The female urogenital tractand oogenesis 6. Ovarian function and control 7.Pregnancy and parturition 8. Lactation 9.Neuroendocrine control of seasonal breeding 10.Marsupials and the evolution of mammalianreproduction References Index.", "metadata": {}}
+{"_id": "85326624", "title": "", "text": "Stage-Specific and Differential NotchDependency at the αβ and γδ T LineageBifurcationSummary Signals transduced byNotch receptors are indispensable for T cellspecification and differentiation of αβ T lineagecells. However, the role of Notch signals duringαβ versus γδ T lineage decision remainscontroversial. Here, we addressed this questionby employing a clonal analysis of CD4 − CD8 −(DN) progenitor potential to position thedivergence of αβ and γδ T cell lineages to thelate DN2 to DN3 developmental stages.Accordingly, αβ and γδ precursor frequencieswithin these T cell progenitor subsets weredetermined, both in the presence and absence ofNotch signaling through Delta-like 1. Notchsignals were found to be critical for the DN toCD4 + CD8 + (DP) transition, irrespective of theidentity (pTαβ or γδ) of the inducing T cellreceptor complex, whereas γδ T cells developedfrom γδTCR-expressing T cell progenitors in theabsence of further Notch ligand interaction.", "metadata": {}}
+{"_id": "85394684", "title": "", "text": "Investigating the Intron Recognition Mechanismin EukaryotesRecent studies indicate that manyintrons, as well as the complex spliceosomalmechanism to remove them, were present earlyin eukaryotic evolution. This study examinesintron and exon characteristics from annotationsof whole genomes to investigate the intronrecognition mechanism. Exon definition uses theexon as the unit of recognition, placing lengthconstraints on the exon but not on the intron(allowing it a greater range of lengths). Incontrast, intron definition uses the intron itself asthe unit of recognition and thus removesconstraints on internal exon length forced by theuse of an exon definition mechanism. Thus,intron and exon lengths within a genome canreflect the constraints imposed by its splicing.This study shows that it is possible firstly torecover valid intron and exon information fromgenome annotation. We then compare internalintron and exon information from a range ofeukaryotic genomes and investigate possible", "metadata": {}}
+{"_id": "85665741", "title": "", "text": "BRAF mutation predicts for MEK-dependence innon-small cell lung cancer (NSCLC).5247Constitutive ERK signaling is common in humancancer and is often the result of activatingmutations of BRAF, RAS and upstream receptortyrosine kinases. Missense BRAF kinase domainmutations are frequently observed in melanoma,colon and thyroid cancers and less frequently inlung and other cancer types. The vast majority(>90%) involve a glutamic acid for valinesubstitution at codon 600 (V600E), which resultsin elevated BRAF kinase activity. BRAF kinasedomain mutations with intermediate andimpaired kinase activity have also beenidentified, most frequently in NSCLC. We havepreviously reported that tumors with V600EBRAF mutation are selectively sensitive to MEKinhibition. Using the potent and selective MEK1/2inhibitor PD0325901 (Pfizer), we examined apanel of NSCLC cell lines with mutant EGFR,KRAS, and/or low, intermediate and high-activityBRAF kinase domain mutations for MEK", "metadata": {}}
+{"_id": "85693958", "title": "", "text": "THE REGULATION OF NUMBERS OF TROPICALOCEANIC BIRDSSUMMARY    The ways in whichthe numbers of tropical sea-birds might belimited are considered; it is argued that food isthe only factor likely to be generally effective inlimiting numbers, but it seems improbable thatfood shortage could exert a density-dependentcontrol of the mortality of the birds outside thebreeding season. Wynne-Edwards' hypothesisthat colonies of sea-birds are able to keep theirown numbers below the level at which foodshortage would become acute, primarily byexerting control on the output of young, isrejected as unproven and improbable. It issuggested that colonies of tropical oceanic birdsdeplete the food in the waters round them, andthat as the populations increase competition forfood becomes more intense, and relatively feweradults succeed in raising chicks. This wouldprovide a density-dependent control of theoutput of young and could regulate the numbersof the birds. The peculiarities of long-lived", "metadata": {}}
+{"_id": "86129154", "title": "", "text": "Induced pluripotent stem cell lines derived fromhuman somatic cells.Somatic cell nucleartransfer allows trans-acting factors present in themammalian oocyte to reprogram somatic cellnuclei to an undifferentiated state. We show thatfour factors (OCT4, SOX2, NANOG, and LIN28)are sufficient to reprogram human somatic cellsto pluripotent stem cells that exhibit theessential characteristics of embryonic stem (ES)cells. These induced pluripotent human stemcells have normal karyotypes, expresstelomerase activity, express cell surface markersand genes that characterize human ES cells, andmaintain the developmental potential todifferentiate into advanced derivatives of allthree primary germ layers. Such inducedpluripotent human cell lines should be useful inthe production of new disease models and indrug development, as well as for applications intransplantation medicine, once technicallimitations (for example, mutation through viralintegration) are eliminated.", "metadata": {}}
+{"_id": "86160128", "title": "", "text": "Fenugreek (Trigonella foenum-graecum): AReview of Health Beneficial PhysiologicalEffectsAmong the spices that are esoteric foodadjuncts being used to enhance flavoring andcolor, fenugreek (Trigonella foenum-graecum)also modifies the texture of food. This seed spiceis also employed for medicinal purpose in manytraditional systems as antibacterial, gastricstimulant, against anorexia, antidiabetic agentand as a galactogogue. In recent decades,several health beneficial physiological attributesof fenugreek seeds have been seen in animalstudies as well as human trials. These includeantidiabetic effect, hypocholesterolemicinfluence, antioxidant potency, digestivestimulant action, and hepatoprotective effect.Among these beneficial physiological effects, theantidiabetic and hypocholesterolemic property offenugreek, both of which are mainly attributableto the intrinsic dietary fiber constituent, havepromising nutraceutical value. This articlepresents an overview of experimental evidence", "metadata": {}}
+{"_id": "86211914", "title": "", "text": "The Rat Brain in Stereotaxic CoordinatesThepreceding editions made \"The Rat Brain inStereotaxic Coordinates\" the second most citedbook in science. This Fifth Edition is the result ofyears of research providing the user with thedrawings of the completely new set of coronalsections, now from one rat, and with significantlyimproved resolution by adding a third additionalsection level as compared to earlier editions.Numerous new nuclei and structures also havebeen identified. The drawings are presented intwo color, providing a much better contrast foruse, and the accompanying CD-ROM contains allof the drawings from the atlas as well as thecorresponding color micrographs (which are notincluded in the book). Affordable,comprehensive, compact, and convenient, theFifth Edition continues the legacy of this majorneuroscience publication and is a guide to allstudents and scientists who study the rat brain.It contains 161 coronal diagrams based on asingle brain and includes a CD-ROM featuring all", "metadata": {}}
+{"_id": "86217760", "title": "", "text": "The Self-Incompatibility Genes of Brassica:Expression and Use in Genetic Ablation of FloralTissuesINTRODUCTION . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394POLLINATION AND POLLEN TUBE GROWTH . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . 395 Interaction s between the M ale Gameto phyte and Pistil . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . 395 SelfIncom patibili tySystems: Gameto phytic and S poro phyti cDetermin ation of Pollen Phenoty pe . . . . . . . . .. . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . 397 DEVELOPMENTALS TUDIES OF REPRODUCTIVE STRUCTURES . . . .. . . . .. . . ... . . . . 398 Tissues of the Pistil withSpecial Reference to Pollination Functions 398The Male Gametophyte . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . 399 MOLECULARANALYSIS OF SELF-INCOMPATIBILITY . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . 40 1 The S-M", "metadata": {}}
+{"_id": "86231298", "title": "", "text": "The Ulp1 SUMO isopeptidase distinct domainsrequired for viability, nuclear envelopelocalization, and substrate specificityProteinmodification by the ubiquitin-like SUMO proteincontributes to many cellular regulatorymechanisms. In Saccharomyces cerevisiae, bothsumoylating and desumoylating activities areessential for viability. Of its two knowndesumoylating enzymes, Ubl-specific protease(Ulp)1 and Ulp2/Smt4, Ulp1 is specificallyrequired for cell cycle progression. A\u0000200-residue segment, the Ulp domain (UD), isconserved among Ulps and includes a corecysteine protease domain that is even morewidespread. Here we demonstrate that the Ulp1UD by itself can support wild-type growth ratesand in vitro can cleave SUMO from substrates.However, in cells expressing only the UD of Ulp1,many SUMO conjugates accumulate to highlevels, indicating that the nonessential Ulp1NH2-terminal domain is important for activityagainst a substantial fraction of sumoylated", "metadata": {}}
+{"_id": "86326468", "title": "", "text": "Gastropathies in the LundehundThe mucinprofiles of the gastric mucosa in Lundehundssuffering from intestinal lymphangiectasia wereexamined and compared to the mucin profiles incontrol dogs from other breeds. A previous studyperformed on this material had shown that allexamined Lundehunds had gastritis and about30% had gastric carcinoma. Neutral and acidmucins were identified using the periodicacid-Schiff (PAS) and Alcian blue (pH 2.5)periodic acid-Schiff (AB-PAS) methods. The acidmucins were divided into sialomucins andsulfomucins based on their reaction withhigh-iron diamine Alcian blue, pH 2.5 (HID-AB).In Lundehunds with chronic atrophic gastritis inthe fundic and body regions the surface andfoveolar epithelium showed a predominantlynormal mucin profile although some Lundehundshad a reduced mucin content. The mucous neckcells extended from below the gastric foveolaetowards the muscularis mucosae. Morphometricexamination showed that the abnormal presence", "metadata": {}}
+{"_id": "86602746", "title": "", "text": "MicroRNAs: small RNAs with a big role in generegulationKey PointsMicroRNAs (miRNAs) are afamily of \u000021–25-nucleotide small RNAs thatnegatively regulate gene expression at thepost-transcriptional level. The founding membersof the miRNA family, lin-4 and let-7, wereidentified through genetic screens for defects inthe temporal regulation of Caenorhabditiselegans larval development. Owing togenome-wide cloning efforts, hundreds ofmiRNAs have now been identified in almost allmetazoans, including flies, plants and mammals.MiRNAs exhibit temporally and spatiallyregulated expression patterns during diversedevelopmental and physiological processes. Mostof the miRNAs that have been characterized sofar seem to regulate aspects of development,including larval developmental transitions andneuronal development in C. elegans, growthcontrol and apoptosis in Drosophilamelanogaster, haematopoietic differentiation inmammals, and leaf development, flower", "metadata": {}}
+{"_id": "86694016", "title": "", "text": "Molecular mechanisms of invadopodiumformation: the role of the N-WASP–Arp2/3complex pathway and cofilinInvadopodia areactin-rich membrane protrusions with a matrixdegradation activity formed by invasive cancercells. We have studied the molecularmechanisms of invadopodium formation inmetastatic carcinoma cells. Epidermal growthfactor (EGF) receptor kinase inhibitors blockedinvadopodium formation in the presence ofserum, and EGF stimulation of serum-starvedcells induced invadopodium formation. RNAinterference and dominant-negative mutantexpression analyses revealed that neural WASP(N-WASP), Arp2/3 complex, and their upstreamregulators, Nck1, Cdc42, and WIP, are necessaryfor invadopodium formation. Time-lapse analysisrevealed that invadopodia are formed de novo atthe cell periphery and their lifetime varies fromminutes to several hours. Invadopodia with shortlifetimes are motile, whereas long-livedinvadopodia tend to be stationary. Interestingly,", "metadata": {}}
+{"_id": "86704258", "title": "", "text": "Genome downsizing in polyploid plantsAll elsebeing equal, polyploids are expected to havelarger C-values (amount of DNA in theunreplicated gametic nucleus) than their diploidprogenitors, increasing in direct proportion withploidy. This expectation is observed in somepolyploid series, especially those newly formed,but there are examples suggesting that C-valuesin particular polyploids are less than expected.The availability of the Angiosperm DNA C-valuesdatabase (http://www.rbgkew.org.uk/cvavhomepage.html) hasallowed this question to be addressed across abroad range of angiosperms and has revealedstriking results deviating from expectation: (i)mean 1C DNA amount did not increase in directproportion with ploidy, and (ii) mean DNAamount per basic genome (calculated by dividingthe 2C value by ploidy) tended to decrease withincreasing ploidy. These results suggest that lossof DNA following polyploid formation, or genomedownsizing, may be a widespread phenomenon", "metadata": {}}
+{"_id": "87337034", "title": "", "text": "Construction of an antisense CYP86MF geneplasmid vector and production of a male-sterileChinese cabbage transformant by thepollen-tube methodSummaryA plant expressionvector pBIA9-AMF containing an antisensefragment of the CYP86MF gene and thetapetum-specific A9 promoter was constructed.Plasmid vectors were introduced by floral-dippingand pollen-tube transformation methods toChinese cabbage pak-choi (Brassica campestrisssp. chinensis (L.) Makino var. communis Tsen etLee, syn. B. rapa ssp. chinensis (L.) Makino var.communis Tsen et Lee) and flowering Chinesecabbage (B. campestris ssp. chinensis (L.)Makino var. parachinensis (Bailey) Tsen et Lee).Results showed that KanR seedlings could beobtained by the pollen-tube method throughgermination tests of T1 progeny seeds, but notby the floral-dipping method. One of the twoKanR seedlings proved that the antisensefragment of the CYP86MF gene was integratedinto the Chinese cabbage genome by PCR", "metadata": {}}
+{"_id": "87430549", "title": "", "text": "Stem Cells,Cancer and Cancer Stem CellsStemcells are defined as cells able to both extensivelyself-renew and differentiate into progenitors.Research data show that more resistant stemcells than common cancer cells exist in cancerpatients. To identify unrecognized differencesbetween cancer stem cells and cancer cells mightbe able to develope effectiveclassification,diagnose and treat ment for cancer.", "metadata": {}}
+{"_id": "87610599", "title": "", "text": "Characterization and culture of human embryonicstem cellsObjective To explore the in vitromaintenance and characterization of humanembryonic stem cells(hESCs).Methods hESCswere cultured on feeder layer with ES culturemedium,which consists of 20% Knockout SerumReplacement,Knockout DMEM and 10 ng/mLbFGF.Undifferentiated status of hESCs wasidentified by cell morphology,and theexpressions of cell surface markerSSEA-1,SSEA-3 and TRA-1-60.G bandingtechnique was employed for cell karyotypeanalysis. Pluropotency of cells were analyzed viain vitro embyoid body(EB) formation and in vivoterotoma formation. Results Most of cells showedundifferentiated properties in cell morphologyand normal karyotype throughout extendedculture periods. They maintained undifferentiatedstatus with positive immunoreactivity toSSEA-3,SSEA-4 and TRA-1-60.in vitro EBformation and in vivo teratoma formationdemonstrated the pluripotency of human ES", "metadata": {}}
+{"_id": "87986426", "title": "", "text": "Detection of Sugarcane bacilliform virus isolateand its influence on yield and quality of cane inYunnanSugarcane bacilliform virus(SCBV) wasdetected by PCR from sugarcane showingchlorosis and mottle symptom fromKaiyuan,Yunnan Province. Part sequence ofreplicase gene of the isolate SCBV-Kaiyuan wasdetermined. Sequence analysis indicated that the589 bp of SCBV-Kaiyuan shared identities of73.2%-74.0% and 83.1%-84.1% at nucleotideand amino acid levels with SCBV-Australiarespectively,66.7%-68.4% and 65.6%-67.7%with SCBV-Morocco. The quality and yield of thesugarcane infected with SCBV-Kaiyuan was alsoinvestigated. The juice extraction,sucrosecontent,gravity purity and average stalk weightwere decreased 1.55%,1.24%,2.22% and 0.26kg in plants infected with SCBV-Kaiyuan,butreducing sugar was increased by 0.21% ininfected plants.", "metadata": {}}
+{"_id": "90064424", "title": "", "text": "Mitotic chromosomes fold bycondensin-dependent helical winding ofchromatin loop arraysDuring mitosis,chromosomes fold into compacted rod shapedstructures. We combined imaging and Hi-C ofsynchronous DT40 cell cultures with polymersimulations to determine how interphasechromosomes are converted into compressedarrays of loops characteristic of mitoticchromosomes. We found that the interphaseorganization is disassembled within minutes ofprophase entry and by late prophasechromosomes are already folded as arrays ofconsecutive loops. During prometaphase, thisarray reorganizes to form a helical arrangementof nested loops. Polymer simulations reveal thatHi-C data are inconsistent with solenoidal coilingof the entire chromatid, but instead suggest acentrally located helically twisted axis from whichconsecutive loops emanate as in a spiralstaircase. Chromosomes subsequently shortenthrough progressive helical winding, with the", "metadata": {}}
+{"_id": "90756514", "title": "", "text": "REVIEW ON CLINICALLY DEVELOPINGANTIBIOTICSThe world is running out ofantibiotics. Between 1940 and 1962, more than20 new classes of antibiotics were marketed.Since then, only two new classes of antibioticswere marketed. Now, not enough analogues arereaching the market to stem the tide of antibioticresistance, particularly among gram-negativebacteria which indicates the need of novelantibiotics for their effective action. This reviewdescribes those antibiotics in late-stage clinicaldevelopment. Most of them belong to existingantibiotic classes and a few with a narrowspectrum of activity are novel compoundsdirected against novel targets. The reasons forsome of the past failures to find new moleculesand a path forward to help attract investments tofund the discovery of new antibiotics aredescribed.", "metadata": {}}
+{"_id": "94109411", "title": "", "text": "Improved Au/Zn/Au ohmic contacts for p-typeInPIn this work, an innovated Si3N4 as anout-diffusion barrier layer to Au/Zn/Au contactsystem for p-type InP has been proposed. Beforethe contacts were annealed, Si3N4 layer wasdeposited on the Au(200Å)/Zn(700Å)/Au(200Å),then the Si3N4 was removed by HF and a 2000Alayer of pure gold was deposited to facilitate wirebonding. The specific contact resistance droppedto a minimum value of 6×10-7 Ω • cm2 (for anacceptor concentration of about 3×1018 cm-3)and the contact became perfectly Ohmic.Besides, Si3N4 layer is an excellent passivationlayer and antireflection coating inInP/InGaAs/InP (p-i-n) photodiodes.", "metadata": {}}
+{"_id": "94365950", "title": "", "text": "The reclamation of brine generated fromdesalination process by bipolar membraneelectrodialysisAbstract Some techno-economicalanalyses and environmental impact evaluationhave proved that bipolar membraneelectrodialysis (BMED) is feasible for thereclamation of industrial saline water. However,to date, the technology cannot be put intopractice due to some unsolvedapplication-oriented problems, such as therequirements of BMED for feed solution, theavailability of the produced acid and base,relatively high salt concentration of the effluent,and relatively low desalinating efficiency andcapacity. In this work, a novel hybrid process,which coupled conventional electrodialysisinstalled with monovalent selectivecation-exchange membranes with BMED runningin a constant-voltage mode, was designed toreclaim brine generated from surface waterdesalination by the ion-exchange process.Subsequently, the response surface methodology", "metadata": {}}
+{"_id": "95102458", "title": "", "text": "Process analysis and economic evaluation forPoly(3-hydroxybutyrate) production byfermentationAbstract Several processes for theproduction and recovery ofpoly(3-hydroxybutyrate) (PHB) by Alcaligeneseutrophus, Alcaligenes latus, Methylobacteriumorganophilum, and recombinant Escherichia coliwere designed based on the previously reporteddata and analyzed by computer-aided bioprocessdesign. PHB productivity, content, and yieldsignificantly affected the final price of PHB. Forthe annual production of 2,850 tonnes of purifiedPHB, the process employing A. eutrophus withthe recovery method of surfactant-hypochloritedigestion resulted in lowest price of PHB, $5.58/kg. As the production scale increased toone million tonnes per year, the price of PHBdropped to $ 4.75/kg. The cost of carbonsubstrate significantly affected the overalleconomics in large production scale. Therefore,the production cost can be considerably loweredwhen agricultural wastes, such as whey and", "metadata": {}}
+{"_id": "95764370", "title": "", "text": "Modification in the chemical bath depositionapparatus, growth and characterization of CdSsemiconducting thin films for photovoltaicapplicationsAbstract In this paper, growth andcharacterization of CdS thin films by ChemicalBath Deposition (CBD) technique using thereaction between CdCl 2 , (NH 2 ) 2 CS and NH 3in an aqueous solution has been reported. Theparameters actively involved in the process ofdeposition have been identified. A commonlyavailable CBD system has been sucessfullymodified to obtain the precious control over thepH of the solution at 90°C during the depositionand studies have been made to understand thefundamental parameters like concentrations ofthe solution, pH and temperature of the solutioninvolved in the chemical bath deposition of CdS.It is confirmed that the pH of the solution plays avital role in the quality of the CBD–CdS films.Structural, optical and electrical properties havebeen analysed for the as-deposited and annealedfilms. XRD studies on the CBD–CdS films reveal", "metadata": {}}
+{"_id": "96222213", "title": "", "text": "Combined sampler robot and high-performanceliquid chromatography: a fully automated systemfor biological small-angle X-ray scatteringexperiments at the Synchrotron SOLEIL SWINGbeamlineSmall-angle X-ray scattering formacromolecules in solution is now widely used instructural biology to complement high-resolutionstructure determination obtained by X-raycrystallography or NMR. In the context ofthird-generation synchrotron sources, thisincreasing interest leads to developments insample environments and automation. Thepresence of an online purification system isjustified by the need for sample monodispersity.A combined system including an auto-samplerrobot and online high-performance liquidchromatography (HPLC) has been developed andoptimized at the SWING beamline of SynchrotronSOLEIL (Gif-sur-Yvette, France). In the samplechanger mode, a few microlitres of sample canbe injected between two air bubbles andcirculated at a controlled speed of typically 40 µl", "metadata": {}}
+{"_id": "97566194", "title": "", "text": "Feasibility assessment of desalination applicationin Australian traditional agricultureAbstractWithin some data limitations, the paper providesa first assessment of areas in Australia withpotential for implementing desalinationtechnologies to supply agricultural water. At thenational scale, these areas were identified basedon a set of selected criteria: distance from landcurrently used for irrigated agriculture andfeedlots; distance from town sites; exclusion ofareas of environmental protection; exclusion ofareas with surface elevation greater than 600 mAHD; and exclusion of regions with limitedgroundwater resources. Industries involved inthe production of high-value crops are mostlikely to benefit from desalinated water as theyuse more-efficient irrigation practices and havethe highest gross value of irrigated agriculturalproduction. Groundwater was identified as themost likely feedwater source for cost-effectivedesalination, which is also the case worldwide.Brine disposal is a major factor in overall cost", "metadata": {}}
+{"_id": "99829811", "title": "", "text": "Development of a specific monoclonal antibodyassay and a rapid testing strip for the detectionof apramycin residues in foodsamplesABSTRACTA specific monoclonalantibody (MAb) against apramycin (AP) wasproduced and used to develop an indirectcompetitive enzyme-linked immunosorbentassay (idcELISA) and a rapid testing strip for thedetection of AP residues in foods. MAb exhibitednegligible cross-reactivity with otheraminoglycosides. Under optimized conditions in0.01 M PBS, the half maximum inhibitoryconcentration (IC50) of MAb was 0.41 ng/ml witha limit of detection (LOD) of 0.15 ng/ml. TheELISA results were obtained within 90 min. Themean recoveries from all the spiked foodsamples were within the range of79.02–105.49%, with coefficients of variation inthe range of 2.21–11.4%. The strip test resultsobtained within 5 min had visual LODs in therange 2.5–5 µg/kg (ng/ml) for all food samplestested. Therefore, the developed strip test", "metadata": {}}
+{"_id": "104143831", "title": "", "text": "Utilization of Desalination Brine for SodiumHydroxide Production: Technologies, EngineeringPrinciples, Recovery Limits, and FutureDirectionsAs global desalination capacitycontinues its rapid growth, the impetus forreducing the adverse environmental impacts ofbrine discharge grows concurrently. Althoughmodern brine outfall designs have significantlylimited such impacts, they are costly. Recoveringvaluable components and chemical derivativesfrom brine has potential to resolve bothenvironmental and economic concerns. In thisarticle, methods for producing sodium hydroxide(“caustic”) from seawater reverse osmosis(SWRO) brine for internal reuse, which typicallyinvolve brine purification, brine concentration,and sodium chloride electrolysis, are reviewed.Because process energy consumption drivesprocess cost and caustic purity determinesproduct usability in drinking water systems,reviewed technologies are benchmarked againstthermodynamic minimum energy consumption", "metadata": {}}
+{"_id": "108886332", "title": "", "text": "Training toddlers seated on mobile robots todrive indoors amidst obstaclesThe goal of thisresearch is to train children seated on mobilerobots to purposefully and safely drive indoors.Our previous studies show that in about sixweeks of training, infants can learn to drivedirectly to a goal using conventional joysticks.However, they are unable to acquire theadvanced skill to avoid obstacles while driving.This limits mobility impaired children fromexploring their home environment safely, whichin turn impacts their cognitive and socialdevelopments in the important early years. Inthis paper, we describe results where toddlersare trained to drive a robot within an obstaclecourse. Using algorithms based on artificialpotential fields to avoid obstacles, we createforce field on the joystick that trains them tonavigate while avoiding obstacles. In this‘assist-as-needed’ approach, if the child steersthe mobile robot outside a force tunnel centeredaround the desired direction, the driver", "metadata": {}}
+{"_id": "109795294", "title": "", "text": "Coming soon to a Wal-Mart near youAccording tothe Web site of the Association for AutomaticIdentification and Data Capture Technologies[http://www.aimglobal.org/technologies/rfid],\"radio frequency identification (RFID) technologyis an automatic way to collect product, place,and time or transaction data quickly and easilywithout human intervention or error. \" With theability to track everything from crates ofdisposable razors to individual peanut-butter jarson the store shelves, RFID technology offers thepotential of \"real-time supply chain visibility. \"Promoters of RFID technology feel [C. Humer,2003] that \"RF tags are to this decade what theInternet was to the 1990's-a promise of radicalchange in the way business is done. \" However,before the full potential of RFID technology canbe realized, several hurdles need to beovercome: reliability, cost, lack of standards, andsecurity. As these hurdles gradually diminish,Wal-Mart publicly embraces the technology.", "metadata": {}}
+{"_id": "109946221", "title": "", "text": "Innovative beneficial reuse of reverse osmosisconcentrate using bipolar membraneelectrodialysis and electrochlorinationprocessesReverse osmosis (RO) is a widely usedand rapidly growing desalination technology. Amajor disadvantage of this process is that theconcentrate from the RO process, which could beas much as 25% of the feed stream, representsa polluting stream. This waste stream could posea significant challenge to the implementation ofthis process, particularly for inland communitieswhich do not have the option of ocean disposal.An excellent environmentally benign approach todisposal could be beneficial reuse of the wastestream. This study presents two innovativebeneficial reuse strategies for RO concentrateproduced by an integrated membrane system(IMS) from a wastewater reclamation facility.The technologies evaluated in this study includedbipolar membrane electrodialysis (BMED) forconversion of RO concentrate into mixed acidand mixed base streams, and electrochlorination", "metadata": {}}
+{"_id": "116075383", "title": "", "text": "Amplification of siRNA in Caenorhabditis elegansgenerates a transgenerational sequence-targetedhistone H3 lysine 9 methylationfootprintExogenous double-stranded RNA(dsRNA) has been shown to exerthomology-dependent effects at the level of bothtarget mRNA stability and chromatin structure.Using C. elegans undergoing RNAi as an animalmodel, we have investigated the generality,scope and longevity of dsRNA-targetedchromatin effects and their dependence oncomponents of the RNAi machinery. Usinghigh-resolution genome-wide chromatinprofiling, we found that a diverse set of genescan be induced to acquire locus-specificenrichment of histone H3 lysine 9 trimethylation(H3K9me3), with modification footprintsextending several kilobases from the site ofdsRNA homology and with locus specificitysufficient to distinguish the targeted locus fromthe other 20,000 genes in the C. elegansgenome. Genetic analysis of the response", "metadata": {}}
+{"_id": "116556376", "title": "", "text": "Physicians' initial management of acute low backpain versus evidence-based guidelines. Influenceof sciatica.BACKGROUND Little information isavailable on physician characteristics and patientpresentations that may influence compliancewith evidence-based guidelines for acute lowback pain. OBJECTIVE To assess whetherphysicians' management decisions are consistentwith the Agency for Health Research Quality'sguideline and whether responses varied with thepresentation of sciatica or by physiciancharacteristics. DESIGN Cross-sectional studyusing a mailed survey. PARTICIPANTSParticipants were randomly selected frominternal medicine, family practice, generalpractice, emergency medicine, and occupationalmedicine specialties. MEASUREMENTS Aquestionnaire asked for recommendations for 2case scenarios, representing patients withoutand with sciatica, respectively. RESULTS Sevenhundred and twenty surveys were completed(response rate=25%). In cases 1 (without", "metadata": {}}
+{"_id": "117907685", "title": "", "text": "Appropriate Critical Values When Testing for aSingle Multivariate Outlier by Using theMahalanobis DistanceThe Mahalanobis distance isa well-known criterion which may be used fordetecting outliers in multivariate data. However,there are some discrepancies about which criticalvalues are suitable for this purpose. Following acomparison with Wilks's method, this papershows that the previously recommended{p(n-1)/(n-p)}F p,n−p are unsuitable, andp(n-1) 2 F p,n−p−1 /n(n−p−1+pF p,n−p−1 )are the correct critical values when searching fora single outlier The importance of which criticalvalues should be used is illustrated whensearching for a single outlier in a clinicallaboratory data set containing 10 patients andfive variables. The jackknifed Mahalanobisdistance is also discussed and the relevantcritical values are given. Finally, upper boundsfor the usual Mahalanobis distance and thejackknifed version are discussed.", "metadata": {}}
+{"_id": "118215171", "title": "", "text": "How to calculate sample size in animalstudiesResearcher must calculate the samplesize before starting of any animal study. Itshould be adequate enough to detect a smallsignificant difference between the groups. Smallsample size is not only responsible for theinsignificant result but also for the less power ofthe study. Calculation of sample size involvescomplex statistics but it can be simplified to helpthe researchers who are not from statisticalbackground.", "metadata": {}}
+{"_id": "120385993", "title": "", "text": "On the Theory and Computation of EvolutionaryDistancesThis paper gives a formal definition ofthe biological concept of evolutionary distanceand an algorithm to compute it. For any set S offinite sequences of varying lengths this distanceis a real-valued function on $S \\times S$, and itis shown to be a metric under conditions whichare wide enough to include the biologicalapplication. The algorithm, introduced here,lends itself to computer programming andprovides a method to compute evolutionarydistance which is shorter than the other methodscurrently in use.", "metadata": {}}
+{"_id": "121001457", "title": "", "text": "Over 30% efficient InGaP/GaAs tandem solarcellsA two-terminal monolithic InGaP/GaAstandem solar cell with a new efficiency record of30.28% is realized with a practical large area of4 cm2 under one-sun air-mass 1.5 globalillumination. We report improvements of thetandem cell performance by introducing adouble-hetero (hereafter DH) structure InGaPtunnel junction, in which the InGaP layers aresurrounded by high band gap AlInP barriers. TheDH structure by AlInP barriers increase the peakcurrent of InGaP tunnel junction. The AlInPbarrier directly below the InGaP top cell, whichtakes the part of a back surface field (hereafterBSF) layer, is found to be considerably effectivein reflecting minority carriers in the top cell. TheAlInP BSF layer does not only form a highpotential barrier but also prevents the diffusionof zinc from a high doped tunnel junction towardthe top cell during epitaxial growth. Furthermore,an InGaP tunnel junction reduces the absorptionloss, which exists in a GaAs tunnel junction, and", "metadata": {}}
+{"_id": "121581019", "title": "", "text": "Electrical, optical, and structural properties ofindium-tin-oxide thin films for organiclight-emitting devicesHigh-qualityindium–tin–oxide (ITO) thin films (200–850 nm)have been grown by pulsed laser deposition(PLD) on glass substrates without apostdeposition annealing treatment. Thestructural, electrical, and optical properties ofthese films have been investigated as a functionof target composition, substrate depositiontemperature, background gas pressure, and filmthickness. Films were deposited from varioustarget compositions ranging from 0 to 15 wt %of SnO2 content. The optimum targetcomposition for high conductivity was 5 wt %SnO2+95 wt % In2O3. Films were deposited atsubstrate temperatures ranging from roomtemperature to 300 °C in O2 partial pressuresranging from 1 to 100 mTorr. Films weredeposited using a KrF excimer laser (248 nm, 30ns full width at half maximum) at a fluence of 2J/cm2. For a 150-nm-thick ITO film grown at", "metadata": {}}
+{"_id": "126549848", "title": "", "text": "Disaster Management and Community Planning,and Public Participation: How to AchieveSustainable Hazard MitigationThe paper offersfirst a brief historical overview of disastermanagement planning. Second, it reviewsAustralian and American research findings andshow that they urge the field of disastermanagement to shift its focus from response andrecovery to sustainable hazard mitigation. It isargued that in order for this shift to occur, it isnecessary to integrate disaster management andcommunity planning. Current practice seldomreflects such a synthesis, and this is one of thereasons why hazard awareness is absent fromlocal decision-making processes. Third, it isasserted that if mitigative strategies are to besuccessfully implemented, then the disastermanagement process must incorporate publicparticipation at the local decision-making level.The paper concludes with a case study ofCalifornia's Portola Valley, which demonstratesthat when public participation is integrated into", "metadata": {}}
+{"_id": "129199129", "title": "", "text": "A second generation of homogenized Canadianmonthly surface air temperature for climatetrend analysis[1] This study presents a secondgeneration of homogenized monthly meansurface air temperature data set for Canadianclimate trend analysis. Monthly means of dailymaximum and of daily minimum temperatureswere examined at 338 Canadian locations. Datafrom co-located observing sites were sometimescombined to create longer time series for use intrend analysis. Time series of observations werethen adjusted to account for nation-wide changein observing time in July 1961, affecting dailyminimum temperatures recorded at 120 synopticstations; these were adjusted using hourlytemperatures at the same sites. Next,homogeneity testing was performed to detectand adjust for other discontinuities. Twotechniques were used to detect non-climaticshifts in de-seasonalized monthly meantemperatures: a multiple linear regression basedtest and a penalized maximal t test. These", "metadata": {}}
+{"_id": "140098548", "title": "", "text": "Prevention ofradiographic-contrast-agent-induced reductionsin renal function by acetylcysteine.BACKGROUNDRadiographic contrast agents can cause areduction in renal function that may be due toreactive oxygen species. Whether the reductioncan be prevented by the administration ofantioxidants is unknown. METHODS Weprospectively studied 83 patients with chronicrenal insufficiency (mean [+/-SD] serumcreatinine concentration, 2.4+/-1.3 mg perdeciliter [216+/-116 micromol per liter]) whowere undergoing computed tomography with anonionic, low-osmolality contrast agent. Patientswere randomly assigned either to receive theantioxidant acetylcysteine (600 mg orally twicedaily) and 0.45 percent saline intravenously,before and after administration of the contrastagent, or to receive placebo and saline. RESULTSTen of the 83 patients (12 percent) had anincrease of at least 0.5 mg per deciliter (44micromol per liter) in the serum creatinine", "metadata": {}}
+{"_id": "140907540", "title": "", "text": "Sample size calculation in epidemiologicalstudiesSummary Sample-size determination isoften an important step in planning anepidemiological study. There are severalapproaches to determining sample size. Itdepends on the type of the study. Descriptive,observational and randomized controlled studieshave different formulas to calculate sample size.In this article, we discuss the formulas that canhelp to estimate sample size in anepidemiological trial. We present a few examplesfrom clinical practice, which may contribute tothe understanding of this problem. Keywords:sample size determination Determining anappropriate sample size for a clinical trial is anessential step in the statistical design of thepro-ject. An adequate sample size helps ensurethat the stu-dy will yield reliable information,regardless of whether the ultimate data suggesta clinically important difference between thetreatments being studied, or the study isin-tended to measure the accuracy of a", "metadata": {}}
+{"_id": "142559798", "title": "", "text": "Tammarniit (Mistakes): Inuit Relocation in theEastern Arctic, 1939-63Preface Introduction 1.Are Inuit Indians?: Relief, Jurisdiction, andGovernment Responsibility 2. Social Welfare andSocial Crisis in the Eastern Arctic 3. Planning forRelocation in the Eastern Arctic 4. Recolonizingthe Arctic Islands: The 1953 Relocations toResolute Bay and Craig Harbour 5. The EnnadaiLake Relocations, 1950-60 6. The Garry LakeFamine 7. The Whale Cove Relocation 8.Relocation and Responsibility, 1955-63 NotesBibliography Index", "metadata": {}}
+{"_id": "142562844", "title": "", "text": "Levels of selection in evolutionEver since thegroundbreaking work of George Williams, W. D.Hamilton, and Richard Dawkins, evolutionarybiologists have recognized that natural selectiongenerally does not operate for the good of thegroup, but rather for the good of lower-levelunits such as the individual, the cell, even thegene. One of the fundamental problems ofbiology is: what keeps competition betweenthese various levels of natural selection fromdestroying the common interests to be gainedfrom cooperation? In this volume twelveprominent scientists explore this question,presenting a comprehensive survey of thecurrent theoretical and empirical research inevolutionary biology. Recent studies show that atmany levels of biological organization,mechanisms have evolved to prevent potentialconflict in natural selection. Editor LaurentKeller's aim in this book is to bring togetherleading researchers from all biological disciplinesto outline these potential conflicts and discuss", "metadata": {}}
+{"_id": "143381103", "title": "", "text": "A psychometric evaluation of the BeckDepression Inventory–II.This article providespsychometric information on the second editionof the Beck Depression Inventory (BDI-II; A. T.Beck, R. A. Steer, & G. K. Brown, 1996), withrespect to internal consistency, factorial validity,and gender differences. Both measuresdemonstrated high internal reliability in the fullstudent sample. Significant differences betweenthe mean BDI and BDI-II scores necessitated thedevelopment of new cutoffs for analogueresearch on the BDI-II. Results from exploratoryand confirmatory factor analyses indicated that a2-factor solution optimally summarized the datafor both versions of the inventory and accountedfor a cumulative 41% and 46% of the commonvariance in BDI and BDI-II responses,respectively. These factor solutions were reliablycross-validated, although the importance of eachfactor varied by gender. The authors concludethat the BDI-II is a stronger instrument than theBDI in terms of its factor structure.", "metadata": {}}
+{"_id": "143796742", "title": "", "text": "Why people feel crowded: An examination ofobjective and subjective crowdingPrior studieshave found only a modest relationship betweenobjective and subjective crowding, defying logicand commonsensical notions of why people feelcrowded. Using data from a representativesample of Bangkok, Thailand, where the level ofhousehold crowding is four times that in westernsocieties, we explore several possibilities of whythis is the case. Examining seven differentindicators of objective crowding, our analysessuggest that the modest relationship is not anartifact of measurement. Contrary to theassumption of prior investigations, the findingsindicate that the objective-subjective crowdingrelationship is nonlinear and that there is aceiling effect muting the impact of increasedobjective crowding. The analyses further suggestthat the strength of the relationship is mitigatedsomewhat, with part of the feeling of beingcrowded accounted for by householdcircumstances, such as the degree of control an", "metadata": {}}
+{"_id": "143868995", "title": "", "text": "Self-Report and Tests of Memory AgingMemorycomplaints have not correlated well with tests ofmemory. However, given self-report questions,which tap processes of everyday remembering.sixty volunteers aged 21-84 years adequatelyrated their memory competence. Categorizedinto four memory processes, self-report and sixtests of verbal, faces, story and nonverbalauditory, visual, and tactual memory ,werecanonically correlated (r = 0.67) and both sets ofmeasures declined with age in parallel. Thc oldwere more accurate than the young in theirratings but by no means on all tests andexpectation to perform poorly seemed to haveinfluenced some performances.", "metadata": {}}
+{"_id": "144555102", "title": "", "text": "Code of the Street: Decency, Violence, and theMoral Life of the Inner CityInner-city blackAmerica is often defined by random, senselessstreet violence. In fact, although violence is asalient feature, its use is far from random; it isregulated through an informal but well-knowncode of the street. How you dress, how you talk,whether you make eye-contact, yourunderstanding of the pecking order - such crucialdetails can have life-or-death consequences andyoung people are particularly at risk. In thisanatomy of the inner-city psyche, the authorshows how the code is a response to the lack ofwell-paid jobs; to the stigma of race; to rampantdrug use; to alienation and to lack of hope. Thepolice exercise no control, and the individual'ssafety and sense of worth are defined by howmuch respect he can command in public; thisdeference is based physical and psycholgicalcontrol and on an implied threat of violence. Themost powerful force counteracting the code isthe strong, loving decent family. Unfortunately,", "metadata": {}}
+{"_id": "144801076", "title": "", "text": "A generic measure of relationshipsatisfaction.The variety of interpersonalrelationships in contemporary societynecessitates the development of brief, reliablemeasures of satisfaction that are applicable tomany types of close relationships. This articledescribes the development of such a measure. InStudy I, the 7-item Relationship AssessmentScale (RAS) was administered to 125 subjectswho reported themselves to be \"in love. \"Analyses revealed a unifactorial scale structure,substantial factor loadings, and moderateintercorrelations among the items. The scalecorrelated significantly with measures of love,sexual attitudes, self-disclosure, commitment,and investment in a relationship. In Study II, thescale was administered to 57 couples in ongoingrelationships. Analyses supported a single factor,alpha reliability of .86, and correlations withrelevant relationship measures. The scalecorrelated .80 with a longer criterion measure,the Dyadic Adjustment Scale (Spanier, 1976),", "metadata": {}}
+{"_id": "145335387", "title": "", "text": "ECONOMIC RESTRUCTURING ANDSUBURBANIZATION IN CHINAAs in othercountries, suburbanization in China occurredafter the cities had experienced a period ofsustained industrial and population growth. Thisstudy examines suburbanization in Beijing,Shanghai, Shenyang, and Dalian. As a result ofeconomic restructuring, the urban coreregistered net population loss from 1982 to 1990because of decentralization while the innersuburbs gained population. Among the forcesdriving suburbanization were marketization ofurban land, the shift of industrial land to tertiaryuse, transportation improvement, the availabilityof foreign and domestic capital, housingrehabilitation in the city, and new housingconstruction in the suburbs. There were certainsimilarities but major differences betweenAmerican and Chinese suburbanization. Unlikethe current metropolitan landscape in the UnitedStates where suburban growth has given rise toa polycentric spatial structure, suburbanization in", "metadata": {}}
+{"_id": "145383432", "title": "", "text": "The Assumption of Caregiving: GrandmothersRaising the Children of the Crack CocaineEpidemic:In this article, selected findings arepresented from a study of the experiences of 71African American women who have become thesole caregivers for at least one grandchild orgreat-grandchild as a result of the involvementof the parent in use of crack cocaine. Despite theunique circumstances of each situation, threepatterns of the assumption of caregivingemerged from analysis of the intensiveinterviews and participant observation: suddenassumption, negotiated assumption, andinevitable assumption of the permanentcaregiver role. Each pattern is described alongsix dimensions: forewarning, initiation, thetrigger event, the caregiver's goal, her assumedtrajectory of the caregiving period, and herperceived influence on her own destiny. Theseaccounts provide important information for thosewho work with women, children, and families, aswell as unique insight into the consequences of", "metadata": {}}
+{"_id": "145416918", "title": "", "text": "The effect of information related to fat contentand taste on consumer responses to areduced-fat frankfurter and a reduced-fatchocolate barThe effects of product informationon responses to frankfurter sausages andchocolate bars were studied by comparingsensory and hedonic ratings in two conditions:blind tasting and tasting with informationpresent. Furthermore, the effect of informationalone was investigated by having the subjectsrate the expected sensory and hedonicintensities of the products on the basis ofpackages with different claims. Three groups ofsubjects were tested by giving them differentinformation: The basic group (no added claims, n= 31), the reduced-fat group (products claimedto have reduced-fat, n=29) and the flavorfulgroup (products claimed to have fullmeat/chocolate flavor, n = 31). Productinformation increased the rated pleasantness ofthe frankfurter in all three information groupscompared to the blind ratings. The information", "metadata": {}}
+{"_id": "145716849", "title": "", "text": "Transnationalism and identityTransnationalismand identity are concepts that inherently call forjuxtaposition. This is so because many peoples'transnational networks of exchange andparticipation are grounded upon some perceptionof common identity; conversely, the identities ofnumerous individuals and groups of people arenegotiated within social worlds that span morethan one place. In this introductory article, thetransnational perspective on migration studies isfirst discussed, followed by some critiques andoutstanding questions. The final sectionsummarises points raised by the contributingauthors of the main articles in this themed issueof JEMS, especially with regard to various waystransnational settings and dynamics affect theconstruction, negotiation and reproduction ofidentities.", "metadata": {}}
+{"_id": "146653163", "title": "", "text": "Social Isolation and Social Support: An AppliedPerspectiveConsiderable empirical evidencesubstantiates the importance of social networksand support to health and well-being among theelderly. But considerably more research isnecessary before successful interventions can bemore generally implemented to positively alteran elder's network. In this article, the authorsdiscuss social supportand isolationfrom anappliedperspective. They have combinedpresentations originally made at a NationalInstitute on Aging-sponsored symposium onapplied gerontology held in August 1992. Theymake some general observations concerning thefield of applied social relations in later life,describe the mental health aspects of theserelations, list some fundamental principles andexisting technology for this field, describe theuse of a brief screening instrument for socialisolation developed by one of the authors(Lubben), and explore varying domains ofknowledge concerning elder soical relations.", "metadata": {}}
+{"_id": "147107523", "title": "", "text": "Wine and health: faraway concepts?Purpose –The purpose of this paper is to exploreconsumers’ perceptions and beliefs in the healthbenefits of wine and the relationship with wineconsumption patterns.Design/methodology/approach – In storeface-to-face survey results from 402 wineconsumers were elaborated with two-step clusteranalysis. ANOVA confirmed differences amonggroups. Groups were profiled by a χ2 significanceanalysis when adequate. A multivariate binarylogistic regression estimated wine consumptioninfluence on healthiness perceptions. Findings –Consumers converge into four groups: twohealth-oriented – optimistic and medical; twonon-health-oriented – unintentional drinker andunconvinced. Groups are not significantlydifferentiated in socio-economic terms. Wineconsumption behaviour influences healthorientation, specifically for monthly and winedrinkers, vs weekly and other alcohol drinkers.Health-oriented consumers favourably welcome", "metadata": {}}
+{"_id": "153755807", "title": "", "text": "The Changing Problem of OvercrowdedHousingAbstract Overcrowding has increased inthe U.S. after decades of decline—dramaticallyso in some locales and for some ethnic groups.The nature of the problem and its very definitionfor policy purposes are also changing. Weexamine the special characteristics of theovercrowded, where they are located, why theincidence of crowding has resurged, and why it isconfined to specific locales. Ethnicity, age,immigration, and poverty play important roles,but housing market conditions appear much lessimportant. We also show that the planningstandard used to judge overcrowding is a relativeone that has varied over time, and that the socialnorms vary among ethnic groups. The issue ofovercrowding may exemplify the currentperplexities about imposing uniform standards inan evolving multiethnic society. Worst-casehousing needs would be better targeted in highlyimpacted locales by allowing more “placediversity” in the setting of standards.", "metadata": {}}
+{"_id": "154050141", "title": "", "text": "Best response dynamics and socially stablestrategiesAbstract An evolutionarily stablestrategy (Maynard Smith and Price, Nature(London) 246 (1973), 15–18) is a strategy whichis robust against a tiny invasion of mutants. Bestresponse dynamics is a dynamic process in whichthe frequency of a strategy increases only if it isa best response to the present strategydistribution. Gilboa and Matsui ( Econometrica 59(1991), 859–867) proposed a stability conceptdirectly derived from this dynamic process.Modifying the above two stability concepts, thispaper shows the equivalence between the staticconcept and the dynamic one. Their set-valuedversions always exist. Examples are given to seetheir usefulness in analyzing forward inductionand preplay communication.", "metadata": {}}
+{"_id": "154243324", "title": "", "text": "From youth to adult homelessnessGovernmentshave shown an interest in early interventionstrategies to reduce youth homelessness, butcritics say that early intervention programs lackclear outcomes. This paper investigates whathappens when early intervention programs arenot in place and young people progress to adulthomelessness. The paper assesses the 'socialadaptation' hypothesis that the longer youngpeople are homeless the more they adapt tohomelessness as a way of life. The paper usesinformation on 1,677 individuals who firstbecame homeless when they were 18 oryounger. Three-quarters of the sample hadprogressed to adult homelessness (defined as 25or older) and one-quarter were now young adultsaged 19 to 24. The findings confirm that thelonger people are homeless, the more difficult itbecomes to get out of homelessness. However,the social adaptation account overstates theextent to which people accept homelessness as a'way of life'. People can return to conventional", "metadata": {}}
+{"_id": "154549459", "title": "", "text": "Urban spatial development in the land policyreform era: evidence from BeijingThis paperexamines the characteristics of urban spatialdevelopment in Beijing and identifies the extentto which these characteristics can be attributedto the emerging land market in Beijing as well asthe impact of land policy reform. Based on theobservations of land use rights granted from1993 to the first half of 2000 in the built-up areaof Beijing, empirical analyses illustrate that bothland prices and land development densitydecrease with distance to the city core. It furtherprovides evidence that the slope of the land rentcurve also depends on land use types. This leadsto the conclusion that the land market influencesland development decisions and urban form.Finally, it shows that the slope of the land rentcurve and the elasticity of land-capitalsubstitution change over time. The formerdeclines, as expected. This is because Beijing'smassive investments in transport have reducedtransport costs, which in turn has shifted the", "metadata": {}}
+{"_id": "154763124", "title": "", "text": "The Mismatch Argument: The Construction of aHousing Orthodoxy in AustraliaAustralia'shousing policy discourse contains manyorthodoxies. While orthodoxies are never totallyaccepted within a discourse, they are thedominant notions within them and as such carrysignificant symbolic authority. One orthodoxythat has particular authority in Australia is thenotion that there is a 'mismatch' in the housingsystem between the available stock and the sizeof households to the extent that there issignificant underutilisation and underoccupancyof housing. The mismatch argument's power asorthodoxy is such that the idea is assumed inmuch housing policy discussion. Criticism of themismatch orthodoxy can take many approaches,such as empirical, conceptual and discursive. Thediscursive critique focuses not on the empiricalrelationship between households and dwellings,but on the statements about that relationship.The resulting analysis shows how the mismatchorthodoxy arose in Australia and its effects on", "metadata": {}}
+{"_id": "154796494", "title": "", "text": "Citizen Participation and Citizen Evaluation inDisaster RecoveryIn April 1997, Grand Forks,North Dakota, and East Grand Forks, Minnesota,experienced a disastrous flood. Both cities havebeen textbook examples of success according tothe Federal Emergency Management Agency.They have an updated infrastructure, paid forlargely by the federal government. Theirdowntowns are on the road to recovery with newconstruction and businesses. The paths of thetwo cities have diverged in the social and politicalaftermath of the flood. East Grand Forks,following consultant suggestions, institutedextensive citizen participation initiatives. EastGrand Forks has experienced political stabilityand citizen satisfaction. Grand Forks reliedprimarily on bureaucratic guidance to react tothe disaster. Grand Forks has experiencedchanges in government structure, turnover ofelected and appointed officials, and much lesspositive citizen evaluation. This study examinesthe effect of perceptions of citizen participation", "metadata": {}}
+{"_id": "155200372", "title": "", "text": "Population growth, urban sprawl and landscapeintegrity of Beijing CityThe detailed landscapepattern of the urban area within the 6th ringroad in Beijing City was identified using airborneremote sensing data acquired between 1997 and2002. The landscape indices at landscape levelwere computed using Fragstats 3.3, and changesin land use/cover types in Beijing from 1997 to2002 were examined. The results show thaturban built area (UBA) and farmland changedgreatly within the 6th ring road, and thatfarmland had been replaced by UBA. The numberof patches increased by 106.6%, mean patcharea decreased by 51.6%, the splitting indexincreased by 94.3%, and the landscape diversityindex increased by 17.8%. The landscapepattern had become more fragmented anddiversified in these 5 years. The main drivingforces for landscape change were the increasingdemand for land for construction due to thegrowing population, unreasonable urban growth,and improvements in housing standards. The", "metadata": {}}
+{"_id": "167469018", "title": "", "text": "Drink Choice: Factors Influencing the Intentionto Drink WineThis paper explores the reasonswhy consumers choose wine over other alcoholicbeverages, with a focus upon the beliefs held byconsumers towards the behaviour of winedrinking. The research findings show thatattitudes are somewhat more predictive of theintention to drink wine than perceived socialpressure. Nevertheless, both attitudinal andnormative elements are required to adequatelyexplain wine consumption. Despite the fact thatthe issue of health figured prominently amongstthe salient beliefs identified in the qualitativephase of the research, the subsequentquantitative research found that drinking winebecause of its purported health benefits was nota significant attitudinal or behavioural factor.Drinking wine because it provides ‘a variety oftastes and flavours’ and because it ‘goes wellwith food’ was found to be significantly moreimportant. The results suggest that efforts toactively promote awareness of the health", "metadata": {}}
+{"_id": "167944455", "title": "", "text": "Application of growth technologies in enhancingfood security and sustainabilityAnabolic steroidshave been widely used in the beef cattle industryfor over 50 years as safe and effectivegrowth-promoting agents, and today, more than90% of all feedlot cattle in the US receive sometype of steroidal implant during their lifetime(NAHMS, USDA 2000). A list of approval ofgrowth promotants by the FDA is shown in Table1. Generally, implants have been shown toincrease growth rate 8 to 28%, improve feedefficiency 5 to 20%, and enhance lean tissuemass of the carcass 3 to 10% (Duckett andOwens, 1997). This improvement in productionefficiency has multiple benefits: 1) it clearly anddramatically reduces production costs byreducing the amount of feed required per unit ofgain (Avery and Avery, 2007); 2) it reduces theamount of land necessary to produce equivalentamounts of food for consumers; 3) it limits theproduction of greenhouse gases by reducing thenumber of animals required to produce", "metadata": {}}
+{"_id": "168265642", "title": "", "text": "Metabolic modifiers as performance-enhancingtechnologies for livestock productionWith thecurrent and predicted increase in worldpopulation, growing global demand andconsumption of food will result in increasingcompetition for land, water, and energy. In turn,this will severely affect our ability to producefood as will the urgent requirement to reduce theimpact of food systems on the environment(Godfray et al., 2010). Globalization has boostedtrade in livestock inputs and products andresulted in industry growth, and concurrentlylivestock production has undergone a complexprocess of technical and geographical change(Gerber et al., 2007). This has resulted in achallenge to livestock producers; growingdemand for their produce with a dwindling supplyof resources, with the only solution being asignificant increase in efficiency. Also, asincomes increase in the burgeoning economies,so does the demand for high-quality animalproteins such as meat, milk, and eggs; thus the", "metadata": {}}
+{"_id": "195317463", "title": "", "text": "Assessment of hemodynamic efficacy and safetyof 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaClfluid replacement in patients with severe sepsis:The CRYSTMAS studyInadequate initialtreatment and delayed hemodynamicstabilization (HDS) may be associated withincreased risk of death in severe sepsis patients.In order to compare the hemodynamic efficacyand safety of 6% HES 130/0.4 and NaCl 0.9%for HDS in patients with severe sepsis, wedesigned a prospective, multicenter,active-controlled, double-blind, randomizedstudy in intensive care units. 174 out of 196patients reached HDS (88 and 86 patients forHES and NaCl, respectively). Significantly lessHES was used to reach HDS vs. NaCl (1,379±886 ml in the HES group and 1,709 ±1,164 mlin the NaCl group (mean difference = -331±1,033, 95% CI -640 to -21, P = 0.0185). Time toreach HDS was 11.8 10.1 hours vs. 14.3 ±11.1hours for HES and NaCl, respectively. Totalquantity of study drug infused over four", "metadata": {}}
+{"_id": "195680777", "title": "", "text": "Comparisons between differentpolychemotherapy regimens for early breastcancer: meta-analyses of long-term outcomeamong 100,000 women in 123 randomisedtrials.BACKGROUND Moderate differences inefficacy between adjuvant chemotherapyregimens for breast cancer are plausible, andcould affect treatment choices. We sought anysuch differences. METHODS We undertookindividual-patient-data meta-analyses of therandomised trials comparing: anytaxane-plus-anthracycline-based regimen versusthe same, or more, non-taxane chemotherapy(n=44,000); one anthracycline-based regimenversus another (n=7000) or versuscyclophosphamide, methotrexate, andfluorouracil (CMF; n=18,000); andpolychemotherapy versus no chemotherapy(n=32,000). The scheduled dosages of thesethree drugs and of the anthracyclinesdoxorubicin (A) and epirubicin (E) were used todefine standard CMF, standard 4AC, and CAF and", "metadata": {}}
+{"_id": "195683603", "title": "", "text": "Invariant NKT cells modulate the suppressiveactivity of IL-10-secreting neutrophilsdifferentiated with serum amyloid A.Neutrophilsare the main effector cells during inflammation,but they can also control excessive inflammatoryresponses by secreting anti-inflammatorycytokines. However, the mechanisms thatmodulate their plasticity remain unclear. We nowshow that systemic serum amyloid A 1 (SAA-1)controls the plasticity of neutrophildifferentiation. SAA-1 not only inducedanti-inflammatory interleukin 10(IL-10)-secreting neutrophils but also promotedthe interaction of invariant natural killer T cells(iNKT cells) with those neutrophils, a processthat limited their suppressive activity bydiminishing the production of IL-10 andenhancing the production of IL-12. BecauseSAA-1-producing melanomas promoteddifferentiation of IL-10-secreting neutrophils,harnessing iNKT cells could be usefultherapeutically by decreasing the frequency of", "metadata": {}}
+{"_id": "195689316", "title": "", "text": "Body-mass index and cause-specific mortality in900 000 adults: collaborative analyses of 57prospective studies.BACKGROUND The mainassociations of body-mass index (BMI) withoverall and cause-specific mortality can best beassessed by long-term prospective follow-up oflarge numbers of people. The ProspectiveStudies Collaboration aimed to investigate theseassociations by sharing data from many studies.METHODS Collaborative analyses wereundertaken of baseline BMI versus mortality in57 prospective studies with 894 576 participants,mostly in western Europe and North America(61% [n=541 452] male, mean recruitment age46 [SD 11] years, median recruitment year 1979[IQR 1975-85], mean BMI 25 [SD 4] kg/m(2)).The analyses were adjusted for age, sex,smoking status, and study. To limit reversecausality, the first 5 years of follow-up wereexcluded, leaving 66 552 deaths of known causeduring a mean of 8 (SD 6) further years offollow-up (mean age at death 67 [SD 10] years):", "metadata": {}}
+{"_id": "195689757", "title": "", "text": "Targeting metabolic remodeling in glioblastomamultiforme.A key aberrant biological differencebetween tumor cells and normal differentiatedcells is altered metabolism, whereby cancer cellsacquire a number of stable genetic andepigenetic alterations to retain proliferation,survive under unfavorable microenvironmentsand invade into surrounding tissues. A classicbiochemical adaptation is the metabolic shift toaerobic glycolysis rather than mitochondrialoxidative phosphorylation, regardless of oxygenavailability, a phenomenon termed the \"WarburgEffect\". Aerobic glycolysis, characterized by highglucose uptake, low oxygen consumption andelevated production of lactate, is associated witha survival advantage as well as the generation ofsubstrates such as fatty acids, amino acids andnucleotides necessary in rapidly proliferatingcells. This review discusses the role of keymetabolic enzymes and their association withaerobic glycolysis in Glioblastoma Multiforme(GBM), an aggressive, highly glycolytic and", "metadata": {}}
+{"_id": "196664003", "title": "", "text": "Signaling architectures that transmitunidirectional information despite retroactivityAsignaling pathway transmits information from anupstream system to downstream systems,ideally in a unidirectional fashion. A key obstacleto unidirectional transmission is retroactivity, theadditional reaction flux that affects a systemonce its species interact with those ofdownstream systems. This raises thefundamental question of whether signalingpathways have developed specializedarchitectures that overcome retroactivity andtransmit unidirectional signals. Here, we proposea general procedure based on mathematicalanalysis that provides an answer to thisquestion. Using this procedure, we analyze theability of a variety of signaling architectures totransmit one-way (from upstream todownstream) signals, as key biologicalparameters are tuned. We find that single stagephosphorylation and phosphotransfer systemsthat transmit signals from a kinase show a", "metadata": {}}
+{"_id": "198133135", "title": "", "text": "Association between pre-diabetes, type 2diabetes and trabecular bone score: The VietnamOsteoporosis Study.AIMS Trabecular bone score(TBS) is a surrogate indicator of bonemicroarchitecture. The presenent study sought toexamine the association between type 2 diabetes(T2D) and trabecular bone score (TBS) in adultVietnamese men and women. METHODS Thestudy was part of the Vietnam OsteoporosisStudy, in which 2702 women and 1398 menaged ≥30 yrs were recruited from the generalcommunity in Ho Chi Minh City. HbA1c levelswere measured by the ADAMS™ A1c HA-8160(Arkray, Kyoto, Japan), and classified into 3groups: normal if HbA1c <5.7%; pre-diabetes(5.7 to 6.4%); and diabetes (>6.4%). TBS wasevaluated by iNsight Software, version 2.1(Medimaps, Merignac, France) on lumbar spineBMD scan (Hologic Horizon). Differences in TBSbetween diabetic status were analyzed by themultivariable regression model with adjustmentfor age and body mass index. RESULTS The", "metadata": {}}
+{"_id": "198309074", "title": "", "text": "Adhesion molecules and chemokines: relation toanthropometric, body composition, biochemicaland dietary variablesIntroduction: Among theinflammatory mediators involved in thepathogenesis of obesity, the cell adhesionmolecules Pselectin, E-selectin, VCAM-1, ICAM-1and the chemokine MCP-1 stand out. They play acrucial role in adherence of cells to endothelialsurfaces, in the integrity of the vascular wall andcan be modulated by body composition anddietary pattern. Objectives: To describe anddiscuss the relation of these cell adhesionmolecules and chemokines to anthropometric,body composition, dietary and biochemicalmarkers. Methods: Papers were located usingscientific databases by topic searches with norestriction on year of publication. Results: Allmolecules were associated positively withanthropometric markers, but controversialresults were found for ICAM-1 and VCAM-1. Notonly obesity, but visceral fat is more stronglycorrelated with E-selectin and MCP-1 levels.", "metadata": {}}