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| 14550841 | Hematopoietic stem cells (HSCs) in adult marrow are believed to be derived from fetal liver precursors. To study cell kinetics involved in long-term hematopoiesis, we studied single-sorted candidate HSCs from fetal liver that were cultured in the presence of a mixture of stimulatory cytokines. After 8–10 d, the number of cells in primary cultures varied from 10,000 cells. Single cells in slow growing colonies were recloned upon reaching a 100–200 cell stage. Strikingly, the number of cells in subclones varied widely again. These results are indicative of asymmetric divisions in primitive hematopoietic cells in which proliferative potential and cell cycle properties are unevenly distributed among daughter cells. The continuous generation of functional heterogeneity among the clonal progeny of HSCs is in support of intrinsic control of stem cell fate and provides a model for the long-term maintenance of hematopoiesis in vitro and in vivo. | Asymmetric Cell Divisions Sustain Long-Term Hematopoiesis from Single-sorted Human Fetal Liver Cells |
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reprogramming of somatic cells to an induced pluripotent stem cell (iPSC) state, many mechanistic questions still remain. To gain insight into the earliest events in the reprogramming process, we systematically analyzed the transcriptional and epigenetic changes that occur during early factor induction after discrete numbers of divisions. We observed rapid, genome-wide changes in the euchromatic histone modification, H3K4me2, at more than a thousand loci including large subsets of pluripotency-related or developmentally regulated gene promoters and enhancers. In contrast, patterns of the repressive H3K27me3 modification remained largely unchanged except for focused depletion specifically at positions where H3K4 methylation is gained. These chromatin regulatory events precede transcriptional changes within the corresponding loci. Our data provide evidence for an early, organized, and population-wide epigenetic response to ectopic reprogramming factors that clarify the temporal order through which somatic identity is reset during reprogramming. | Reprogramming factor expression initiates widespread targeted chromatin remodeling. |
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relationship of migraine and stroke is complex. Stroke may be coincidental with migraine but migraine may confer an increased risk of stroke in women under 45 years of age and possibly in men who have migraine with aura. Stroke may mimic migraine but migraine syndromes may be symptomatic of underlying cerebrovascular disorders. True migraine-induced stroke is rare. The mechanisms of stroke induced during a migraine attack remain to be determined but probably involve an interaction between the dynamic shifts in cerebral blood flow and stroke risk factors. | Stroke and migraine--the spectrum of cause and effect. |
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0.029824240133166313, "29206": 0.29981520771980286, "29290": 0.5057345628738403, "29458": 0.1619328260421753, "29494": 0.5871354341506958} | 14581009 | The Polycomb Group (PcG) of chromatin modifiers regulates pluripotency and differentiation. Mammalian genomes encode multiple homologs of the Polycomb repressive complex 1 (PRC1) components, including five orthologs of the Drosophila Polycomb protein (Cbx2, Cbx4, Cbx6, Cbx7, and Cbx8). We have identified Cbx7 as the primary Polycomb ortholog of PRC1 complexes in embryonic stem cells (ESCs). The expression of Cbx7 is downregulated during ESC differentiation, preceding the upregulation of Cbx2, Cbx4, and Cbx8, which are directly repressed by Cbx7. Ectopic expression of Cbx7 inhibits differentiation and X chromosome inactivation and enhances ESC self-renewal. Conversely, Cbx7 knockdown induces differentiation and derepresses lineage-specific markers. In a functional screen, we identified the miR-125 and miR-181 families as regulators of Cbx7 that are induced during ESC differentiation. Ectopic expression of these miRNAs accelerates ESC differentiation via regulation of Cbx7. These observations establish a critical role for Cbx7 and its regulatory miRNAs in determining pluripotency. | MicroRNA Regulation of Cbx7 Mediates a Switch of Polycomb Orthologs during ESC Differentiation |
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14584755 | The renin-angiotensin-aldosterone system plays a major role in the pathophysiology of hypertension and closely related cardio- and cerebrovascular events. Although both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) are equally important in the treatment of hypertension, according to the results of recent years, there might be substantial differences in their cardiovascular protective effects, and these differences might be explained by our increasing knowledge of their non-overlapping mechanisms of action. The number of studies investigating how ACE inhibitors and ARB agents differ will certainly be increasing in the future. ACE inhibitors are the safe therapeutic opportunity for hypertensive patients at high risk, with a cardiological comorbidity. | Differences in the Clinical Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: A Critical Review of the Evidence |
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0.16524957120418549, "27343": 0.03266380727291107, "27462": 0.4425300657749176, "27633": 1.178053855895996, "27697": 0.2539152204990387, "27781": 0.46363574266433716, "27790": 0.4518963396549225, "27854": 0.8674615025520325, "28041": 0.3318578004837036, "28105": 0.10731173306703568, "28117": 0.12038381397724152, "28522": 0.8559102416038513, "28636": 0.8821197748184204, "28715": 0.2026219218969345, "28788": 0.7638313174247742, "28873": 1.1834511756896973, "29060": 0.04487626627087593, "29107": 0.08782484382390976, "29489": 0.669430673122406} | 14591894 | Cells such as fibroblasts and endothelial cells migrate through the coordinated responses of discrete integrin-containing focal adhesions and complexes. In contrast, little is known about the organization of integrins on the highly motile T lymphocyte. We have investigated the distribution, activity, and cytoskeletal linkage of the integrin lymphocyte function associated antigen-1 (LFA-1) on human T lymphocytes migrating on endothelial cells and on ligand intercellular adhesion molecule-1 (ICAM-1). The pattern of total LFA-1 varies from low expression in the lamellipodia to high expression in the uropod. However, high affinity, clustered LFA-1 is restricted to a mid-cell zone that remains stable over time and over a range of ICAM-1 densities. Talin is essential for the stability and formation of the LFA-1 zone. Disruption of the talin–integrin link leads to loss of zone integrity and a substantial decrease in speed of migration on ICAM-1. This adhesive structure, which differs from the previously described integrin-containing attachments displayed by many other cell types, we have termed the “focal zone. ” | A talin-dependent LFA-1 focal zone is formed by rapidly migrating T lymphocytes |
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"25456": 0.8691008687019348, "25604": 0.259204238653183, "25690": 0.1212492436170578, "25778": 0.23324857652187347, "25817": 0.10467668622732162, "25862": 1.0144377946853638, "26089": 0.08871890604496002, "26243": 0.036437395960092545, "26402": 0.3027053773403168, "26445": 0.14179791510105133, "26456": 1.0848461389541626, "26775": 0.025073638185858727, "27204": 0.0058422754518687725, "27321": 0.17431432008743286, "27484": 0.3070250153541565, "28093": 0.0354953333735466, "28436": 0.01934296265244484, "28774": 0.058784693479537964, "29212": 0.2501201331615448, "29299": 0.09495500475168228, "29398": 0.11604541540145874, "29441": 0.8829278349876404, "29477": 0.16442140936851501} | 14606752 | OBJECTIVE To evaluate the efficacy and relative adverse effects of tricyclic antidepressants in the treatment of migraine, tension-type, and mixed headaches. DESIGN Meta-analysis. DATA SOURCES Medline, Embase, the Cochrane Trials Registry, and PsycLIT. Studies reviewed Randomised trials of adults receiving tricyclics as only treatment for a minimum of four weeks. DATA EXTRACTION Frequency of headaches (number of headache attacks for migraine and number of days with headache for tension-type headaches), intensity of headache, and headache index. RESULTS 37 studies met the inclusion criteria. Tricyclics significantly reduced the number of days with tension-type headache and number of headache attacks from migraine than placebo (average standardised mean difference -1.29, 95% confidence interval -2.18 to -0.39 and -0.70, -0.93 to -0.48) but not compared with selective serotonin reuptake inhibitors (-0.80, -2.63 to 0.02 and -0.20, -0.60 to 0.19). The effect of tricyclics increased with longer duration of treatment (β=-0.11, 95% confidence interval -0.63 to -0.15; P<0.0005). Tricyclics were also more likely to reduce the intensity of headaches by at least 50% than either placebo (tension-type: relative risk 1.41, 95% confidence interval 1.02 to 1.89; migraine: 1.80, 1.24 to 2.62) or selective serotonin reuptake inhibitors (1.73, 1.34 to 2.22 and 1.72, 1.15 to 2.55). Tricyclics were more likely to cause adverse effects than placebo (1.53, 95% confidence interval 1.11 to 2.12) and selective serotonin reuptake inhibitors (2.22, 1.52 to 3.32), including dry mouth (P<0.0005 for both), drowsiness (P<0.0005 for both), and weight gain (P<0.001 for both), but did not increase dropout rates (placebo: 1.22, 0.83 to 1.80, selective serotonin reuptake inhibitors: 1.16, 0.81 to 2.97). CONCLUSIONS Tricyclic antidepressants are effective in preventing migraine and tension-type headaches and are more effective than selective serotonin reuptake inhibitors, although with greater adverse effects. The effectiveness of tricyclics seems to increase over time. | Tricyclic antidepressants and headaches: systematic review and meta-analysis |
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We are investigating functionality of a set of long noncoding antisense transcripts, collectively called COOLAIR, produced at Arabidopsis FLOWERING LOCUS C (FLC). COOLAIR initiates just downstream of the major sense transcript poly(A) site and terminates either early or extends into the FLC promoter region. We now show that splicing of COOLAIR is functionally important. This was revealed through analysis of a hypomorphic mutation in the core spliceosome component PRP8. The prp8 mutation perturbs a cotranscriptional feedback mechanism linking COOLAIR processing to FLC gene body histone demethylation and reduced FLC transcription. The importance of COOLAIR splicing in this repression mechanism was confirmed by disrupting COOLAIR production and mutating the COOLAIR proximal splice acceptor site. Our findings suggest that altered splicing of a long noncoding transcript can quantitatively modulate gene expression through cotranscriptional coupling mechanisms. | Functional Consequences of Splicing of the Antisense Transcript COOLAIR on FLC Transcription |
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0.26146242022514343, "27854": 0.19622190296649933, "27881": 0.9409833550453186, "28086": 0.06703783571720123, "28154": 0.0174254160374403, "28156": 0.66441810131073, "28286": 0.9958525896072388, "28311": 1.0382318496704102, "28403": 0.8796916007995605, "28674": 0.03360854089260101, "28788": 0.08244366943836212, "28873": 0.09938567131757736, "28896": 0.23710809648036957, "29170": 0.1685553640127182, "29191": 0.18004031479358673, "29288": 0.129004567861557, "29543": 0.17020416259765625, "29726": 0.21372433006763458} | 14615911 | We developed a novel mouse model of malignant pleural effusion (MPE) by injecting Lewis lung cancer (LLC) cells directly into the pleural space of syngeneic C57B/6 mice. The pleural effusions in this model share common cellular and biochemical features with human MPEs. Implantation and growth of pleural tumors triggers a host inflammatory response characterized by a mixed inflammatory cell influx into the pleural fluid. LLC cells exhibited high basal nuclear factor (NF)-κB activity in vitro and in vivo, which we used to drive expression of a NF-κB–dependent green fluorescent protein-firefly luciferase fusion reporter construct. NF-κB–dependent reporter expression allowed intravital tracing of pleural tumors. Inhibition of NF-κB in LLC cells did not affect cell viability in culture; however, injection of LLC cells expressing a dominant NF-κB inhibitor resulted in decreased tumor burden, decreased pleural effusion volume, and decreased pleural effusion TNF-α levels. These studies indicate that tumor NF-κB a... | Nuclear Factor-�B Affects Tumor Progression in a Mouse Model of Malignant Pleural Effusion |
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0.17759032547473907, "28756": 0.043007105588912964, "28775": 0.1808556467294693, "28847": 0.32270604372024536, "28965": 0.14518201351165771, "28987": 0.8764448165893555, "29090": 0.2018241584300995, "29107": 0.4228905141353607, "29160": 0.4318077862262726, "29212": 1.1300151348114014, "29347": 0.9783848524093628, "29461": 0.0354953333735466, "29610": 0.3346569836139679} | 14626540 | PURPOSE To estimate the maximum tolerated dose (MTD) of single-agent PF-04449913, and to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity in patients with advanced tumors. EXPERIMENTAL DESIGN A 3+3 design was used in this open-label, multicenter, phase I study and dose escalation/de-escalation applied until identification of the MTD. PF-04449913 was orally administered once daily in continuous 28-day treatment cycles. The starting dose was 80 mg. RESULTS A total of 23 patients were enrolled; 19 were evaluable for first-cycle dose-limiting toxicity (DLT). The first-cycle DLT rate at the 640 mg dose level was 33.3%, and the MTD was estimated to be 320 mg once daily. The recommended phase II dose was not determined. PF-04449913 was generally well tolerated at doses of 80 to 320 mg once daily. The most common treatment-related adverse events (AE) were grade 1-2 dysgeusia, fatigue, decreased appetite, nausea, dizziness, dehydration, and diarrhea. Treatment-related grade 3 AEs only occurred in patients receiving PF-04449913 640 mg once daily. No treatment-related grade 4-5 AEs were reported. Pharmacokinetic analysis indicated a generally dose-proportional kinetics with biphasic elimination, supporting once-daily dosing. PF-04449913 modulated hedgehog signaling at the dose levels tested, as demonstrated by >80% downregulation of GLI1 expression in the skin of treated patients. Eight patients (34.8%) achieved stable disease; none had complete or partial response. Three patients with disease progression at enrollment had prolonged disease stabilization (≥6 months). CONCLUSIONS The results obtained in this study support further evaluation of PF-04449913 in patients with advanced solid tumors. | A phase I study of PF-04449913, an oral hedgehog inhibitor, in patients with advanced solid tumors. |
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of these highly basic proteins when DNA replication slows down or stops. Although chromosomal histones are stable, excess (non-chromatin bound) histones are rapidly degraded in a Rad53 (radiation sensitive 53) kinase-dependent manner in Saccharomyces cerevisiae. Here we demonstrate that excess histones associate with Rad53 in vivo and seem to undergo modifications such as tyrosine phosphorylation and polyubiquitylation, before their proteolysis by the proteasome. We have identified the Tyr 99 residue of histone H3 as being critical for the efficient ubiquitylation and degradation of this histone. We have also identified the ubiquitin conjugating enzymes (E2) Ubc4 and Ubc5, as well as the ubiquitin ligase (E3) Tom1 (temperature dependent organization in mitotic nucleus 1), as enzymes involved in the ubiquitylation of excess histones. Regulated histone proteolysis has major implications for the maintenance of epigenetic marks on chromatin, genomic stability and the packaging of sperm DNA. | Histone levels are regulated by phosphorylation and ubiquitylation dependent proteolysis |
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0.1946154683828354, "26773": 0.2160874605178833, "26835": 0.7047978043556213, "26942": 0.8161250352859497, "27099": 0.7546905279159546, "27295": 0.20739519596099854, "27321": 0.24325250089168549, "27781": 0.2231435477733612, "27854": 0.176772341132164, "28156": 0.1889725625514984, "28227": 0.4431571960449219, "28696": 0.037378571927547455, "28788": 0.6833335757255554, "28873": 0.35813871026039124, "29170": 0.1808556467294693, "29290": 0.28597161173820496} | 14644164 | TLR sense microbial infections, and control activation of immune responses. Dendritic cells, macrophages, and B lymphocytes express TLR and the TLR-signaling adaptor protein MyD88. The impact of TLR-activated B cells on T cell-mediated inflammation is unknown. In this study, we have used mice carrying B cell-restricted deficiencies in MyD88 or in distinct TLR to examine the impact of TLR-activated B cells on a T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis (EAE). We demonstrate that TLR-signaling in B cells suppresses inflammatory T cell responses (both Th1 and Th17), and stimulates recovery from EAE. Only certain TLR are required on B cells for resolution of EAE, and these are dispensable for disease initiation, indicating that a category of TLR agonists preferentially triggers a suppressive function in B cells and thereby limits autoimmune disease. The TLR agonists controlling the regulatory function of B cells are provided by components of Mycobacterium tuberculosis present in the adjuvant. Thus, MyD88 signaling in B cells antagonizes MyD88 signaling in other cells, which drives differentiation of Th17 cells and is required for induction of EAE. Altogether, our data indicate that B cells link recognition of microbial products via TLR to suppression of a T cell-mediated autoimmune disease. | TLR-activated B cells suppress T cell-mediated autoimmunity. |
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"25884": 0.20501139760017395, "26402": 0.42353010177612305, "26591": 0.055094651877880096, "26604": 0.03831886500120163, "26773": 0.11081436276435852, "26886": 0.29619070887565613, "26892": 0.8625272512435913, "27144": 0.3850763738155365, "27152": 0.7370892763137817, "27159": 0.10555581003427505, "27226": 0.8933739066123962, "27354": 0.09584271162748337, "27781": 0.28450319170951843, "28389": 0.22157983481884003, "28475": 0.12642613053321838, "28732": 0.13243216276168823, "28774": 0.2696990668773651, "28788": 0.3554046154022217, "28805": 0.06246116757392883, "28873": 0.31845372915267944, "28896": 0.23633737862110138, "29290": 0.6265231370925903, "29461": 1.5297857522964478} | 14647747 | Strategies to prevent organ transplant rejection whilst minimizing long-term immunosuppression are currently under intense investigation with regulatory T cells (Tregs) nearing clinical application. The clinical trial, ThRIL, recently commenced at King's College London, proposes to use Treg cell therapy to induce tolerance in liver transplant recipients, the success of which has the potential to revolutionize the management of these patients and enable a future of drug-free transplants. This is the first report of the manufacture of clinical grade Tregs from prospective liver transplant recipients via a CliniMACS-based GMP isolation technique and expanded using anti-CD3/CD28 beads, IL-2 and rapamycin. We report the enrichment of a pure, stable population of Tregs (>95% CD4(+)CD25(+)FOXP3(+)), reaching adequate numbers for their clinical application. Our protocol proved successful in, influencing the expansion of superior functional Tregs, as compared to freshly isolated cells, whilst also preventing their conversion to Th17 cells under pro-inflammatory conditions. We conclude with the manufacture of the final Treg product in the clinical research facility (CRF), a prerequisite for the clinical application of these cells. The data presented in this manuscript together with the much-anticipated clinical results from ThRIL, will undoubtedly inform the improved management of the liver transplant recipient. | Successful expansion of functional and stable regulatory T cells for immunotherapy in liver transplantation |
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0.31132611632347107, "29206": 0.07884006202220917, "29339": 0.016465263441205025, "29458": 1.094698429107666, "29486": 0.13414156436920166} | 14652521 | The prediction of novel pre-microRNA (miRNA) from genomic sequence has received considerable attention recently. However, the majority of studies have focused on the human genome. Previous studies have demonstrated that sensitivity (correctly detecting true miRNA) is sustained when human-trained methods are applied to other species, however they have failed to report the dramatic drop in specificity (the ability to correctly reject non-miRNA sequences) in non-human genomes. Considering the ratio of true miRNA sequences to pseudo-miRNA sequences is on the order of 1:1000, such low specificity prevents the application of most existing tools to non-human genomes, as the number of false positives overwhelms the true predictions. We here introduce a framework (SMIRP) for creating species-specific miRNA prediction systems, leveraging sequence conservation and phylogenetic distance information. Substantial improvements in specificity and precision are obtained for four non-human test species when our framework is applied to three different prediction systems representing two types of classifiers (support vector machine and Random Forest), based on three different feature sets, with both human-specific and taxon-wide training data. The SMIRP framework is potentially applicable to all miRNA prediction systems and we expect substantial improvement in precision and specificity, while sustaining sensitivity, independent of the machine learning technique chosen. | A framework for improving microRNA prediction in non-human genomes |
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DCL patients have a poor cellular immune response leading to chronicity. It has been proposed that CD8 T lymphocytes (CD8) play a crucial role in infection clearance, although the role of CD8 cytotoxicity in disease control has not been elucidated. Lesions of DCL patients have been shown to harbor low numbers of CD8, as compared to patients with LCL, and leishmanicidal treatment restores CD8 numbers. The marked response of CD8 towards Leishmania parasites led us to analyze possible functional differences between CD8 from patients with LCL and DCL. We compared IFNγ production, antigen-specific proliferation, and cytotoxicity of CD8 purified from PBMC against autologous macrophages (MO) infected with Leishmania mexicana (MOi). Additionally, we analyzed tissue biopsies from both groups of patients for evidence of cytotoxicity associated with apoptotic cells in the lesions. We found that CD8 cell of DCL patients exhibited low cytotoxicity, low antigen-specific proliferation and low IFNγ production when stimulated with MOi, as compared to LCL patients. Additionally, DCL patients had significantly less TUNEL+ cells in their lesions. These characteristics are similar to cellular "exhaustion" described in chronic infections. We intended to restore the functional capacity of CD8 cells of DCL patients by preincubating them with TLR2 agonists: Lm lipophosphoglycan (LPG) or Pam3Cys. Cytotoxicity against MOi, antigen-specific proliferation and IFNγ production were restored with both stimuli, whereas PD-1 (a molecule associated with cellular exhaustion) expression, was reduced. Our work suggests that CD8 response is associated with control of Lm infection in LCL patients and that chronic infection in DCL patients leads to a state of CD8 functional exhaustion, which could facilitate disease spread. This is the first report that shows the presence of functionally exhausted CD8 T lymphocytes in DCL patients and, additionally, that pre-stimulation with TLR2 ligands can restore the effector mechanisms of CD8 T lymphocytes from DCL patients against Leishmania mexicana-infected macrophages. | CD8 Cells of Patients with Diffuse Cutaneous Leishmaniasis Display Functional Exhaustion: The Latter Is Reversed, In Vitro, by TLR2 Agonists |
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Here, we track the evolution of promoters and enhancers active in liver across 20 mammalian species from six diverse orders by profiling genomic enrichment of H3K27 acetylation and H3K4 trimethylation. We report that rapid evolution of enhancers is a universal feature of mammalian genomes. Most of the recently evolved enhancers arise from ancestral DNA exaptation, rather than lineage-specific expansions of repeat elements. In contrast, almost all liver promoters are partially or fully conserved across these species. Our data further reveal that recently evolved enhancers can be associated with genes under positive selection, demonstrating the power of this approach for annotating regulatory adaptations in genomic sequences. These results provide important insight into the functional genetics underpinning mammalian regulatory evolution. | Enhancer Evolution across 20 Mammalian Species |
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In this study, we performed (13)C metabolic flux analysis on a panel of isogenic cell lines containing heterozygous IDH1/2 mutations. We observed that under hypoxic conditions, IDH1-mutant cells exhibited increased oxidative tricarboxylic acid metabolism along with decreased reductive glutamine metabolism, but not IDH2-mutant cells. However, selective inhibition of mutant IDH1 enzyme function could not reverse the defect in reductive carboxylation activity. Furthermore, this metabolic reprogramming increased the sensitivity of IDH1-mutant cells to hypoxia or electron transport chain inhibition in vitro. Lastly, IDH1-mutant cells also grew poorly as subcutaneous xenografts within a hypoxic in vivo microenvironment. Together, our results suggest therapeutic opportunities to exploit the metabolic vulnerabilities specific to IDH1 mutation. | IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism. |
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"24759": 0.40741631388664246, "24848": 0.0038986403960734606, "24965": 0.08692999184131622, "25086": 0.16607704758644104, "25095": 0.09938567131757736, "25409": 0.8699195384979248, "25468": 0.29619070887565613, "25708": 1.2759300470352173, "25714": 0.15442965924739838, "25778": 0.5573811531066895, "26179": 0.11343330889940262, "26237": 1.175042748451233, "26268": 0.29255300760269165, "26520": 0.23479416966438293, "26563": 0.015504186972975731, "26721": 0.06337817758321762, "26739": 0.014542185701429844, "26745": 1.0271050930023193, "26785": 0.9052929878234863, "26872": 0.15777134895324707, "26886": 0.2409527748823166, "26901": 0.058784693479537964, "27144": 0.3662964701652527, "27711": 1.130645751953125, "27781": 0.25995752215385437, "27843": 1.1726272106170654, "27854": 0.030771657824516296, "27881": 0.2160874605178833, "27885": 0.49626702070236206, "28207": 0.20660123229026794, "28297": 0.11691460013389587, "28424": 0.574020504951477, "28667": 0.8957691192626953, "28691": 0.13157635927200317, "28711": 1.210009217262268, "28794": 0.05786345899105072, "28873": 1.105748176574707, "29107": 0.11517547070980072, "29166": 0.9980146884918213, "29251": 0.7881022095680237, "29264": 0.7067264318466187, "29299": 0.020300358533859253, "29392": 0.7951818704605103, "29458": 0.2659635543823242, "29610": 0.0606246218085289} | 14664424 | The aim of this study is to determine the prognostic value of tumor markers, as squamous cell carcinoma antigen (SCCAg) and cytokeratin-19 fragment (CYFRA 21.1) and interleukin 6 (IL-6), vascular endothelial growth factor (VEGF), soluble tumor necrosis factor receptor I (sTNF RI), and sTNF RII in patients with squamous cell carcinoma of the cervix. The subjects of analysis were 138 patients with stage I-IVA according to the International Federation of Gynecology and Obstetrics (FIGO) classification. The collected research material comes from one oncology center. During the 10 years of follow-up, 56 relapses and 53 deaths were observed, and recurrent disease in early stage was confirmed in 45 % of patients. The pretreatment serum levels of SCCAg and CYFRA 21.1, and cytokines IL-6, VEGF, sTNF RI, and sTNF RII were determined in all patients. The probability of disease-free survival (DFS) and overall survival (OS) was evaluated using the log-rank test and the Cox regression model. Based on the ROC curve analysis for patients with recurrence, the largest area under the curve was demonstrated for SCCAg and IL-6 and for patients who died, for SCCAg and VEGF. Cox analysis demonstrated that independent prognostic factor for DFS was only SCCAg and for OS cytokine IL-6 and SCCAg, but in patients with early stage the prognostic value for DFS was VEGF, whereas IL-6 and CYFRA 21.1 for OS. Serum level of VEGF, CYFRA 21.1 and IL-6 before treatment in patients with early stage cervical cancer appears to be an important prognostic factor. | The assessment of the prognostic value of tumor markers and cytokines as SCCAg, CYFRA 21.1, IL-6, VEGF and sTNF receptors in patients with squamous cell cervical cancer, particularly with early stage of the disease |
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0.6862877607345581, "28358": 0.33115679025650024, "28389": 0.4950772523880005, "28436": 0.0029254043474793434, "28474": 0.06886265426874161, "28522": 0.08871890604496002, "28591": 0.2026219218969345, "28739": 0.9857001900672913, "28788": 0.22937409579753876, "28873": 0.10993985831737518, "29107": 0.021256839856505394, "29295": 0.13243216276168823, "29299": 0.762009859085083, "29361": 0.04767346754670143, "29458": 0.823009729385376, "29490": 0.04953393340110779, "29610": 0.058784693479537964} | 14672919 | The aim of this study is to search the most powerful prognostic factor from routine blood test for esophageal squamous cell cancer (ESCC) patients. Multiple laboratory tests were evaluated including those reflecting red blood cell parameters (hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), and red blood cell distribution width (RDW)), platelet morphological parameters (mean platelet volume (MPV) and platelet count (PLT)), blood coagulation status (D-dimer), and tumor biomarker (CA19-9). Known inflammatory indices (NLR and PLR) were also calculated. A total of 468 patients who were diagnosed with ESCC between December 2005 and December 2008 were retrospectively analyzed in this study. By utilizing univariate and multivariate Cox proportional hazard analyses, we found that PLT and MPV were significantly associated with overall survival (OS) and disease-free survival (DFS) of ESCC patients, with optimal cutoff values of 212 and 10.6, respectively. Moreover, the combination of the preoperative PLT and MPV (COP-MPV) was calculated as follows: patients with both PLT (≥212 × 10(9) L(-1)) and MPV (≥10.6 fL) elevation were assigned a score of 2, and patients with one or neither were assigned a score of 1 and 0. The COP-MPV was an independent prognostic factor for OS (hazard ratio (HR) 0.378, 95 % confidence interval (CI) 0.241 to 0.593, P < 0.001, 0/2) and DFS (HR 0.341, 95 % CI 0.218 to 0.534, P < 0.001, 0/2) in multivariate analyses. In subgroup analyses for early (stages I and II) and locally (stage III) advanced stage patients, COP-MPV was found significantly associated with OS and DFS in each group (P = 0.025 and P = 0.018 for OS and P = 0.029 and P = 0.002 for DFS). In conclusion, we considered that COP-MPV is a promising predictor for postoperative survival in ESCC patients. | Combination of platelet count and mean platelet volume (COP-MPV) predicts postoperative prognosis in both resectable early and advanced stage esophageal squamous cell cancer patients |
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"28767": 1.5365312099456787, "29299": 0.06795065850019455, "29373": 0.23015019297599792, "29458": 0.045809537172317505, "29516": 0.1693800985813141} | 14682243 | BACKGROUND Results of the few cohort studies from countries with low incomes or middle incomes suggest a lower incidence of dementia than in high-income countries. We assessed incidence of dementia according to criteria from the 10/66 Dementia Research Group and Diagnostic and Statistical Manual of Mental Disorders (DSM) IV, the effect of dementia at baseline on mortality, and the independent effects of age, sex, socioeconomic position, and indicators of cognitive reserve. METHODS We did a population-based cohort study of all people aged 65 years and older living in urban sites in Cuba, the Dominican Republic, and Venezuela, and rural and urban sites in Peru, Mexico, and China, with ascertainment of incident 10/66 and DSM-IV dementia 3-5 years after cohort inception. We used questionnaires to obtain information about age in years, sex, educational level, literacy, occupational attainment, and number of household assets. We obtained information about mortality from all sites. For participants who had died, we interviewed a friend or relative to ascertain the likelihood that they had dementia before death. FINDINGS 12,887 participants were interviewed at baseline. 11,718 were free of dementia, of whom 8137 (69%) were reinterviewed, contributing 34,718 person-years of follow-up. Incidence for 10/66 dementia varied between 18·2 and 30·4 per 1000 person-years, and were 1·4-2·7 times higher than were those for DSM-IV dementia (9·9-15·7 per 1000 person-years). Mortality hazards were 1·56-5·69 times higher in individuals with dementia at baseline than in those who were dementia-free. Informant reports suggested a high incidence of dementia before death; overall incidence might be 4-19% higher if these data were included. 10/66 dementia incidence was independently associated with increased age (HR 1·67; 95% CI 1·56-1·79), female sex (0·72; 0·61-0·84), and low education (0·89; 0·81-0·97), but not with occupational attainment (1·04; 0·95-1·13). INTERPRETATION Our results provide supportive evidence for the cognitive reserve hypothesis, showing that in middle-income countries as in high-income countries, education, literacy, verbal fluency, and motor sequencing confer substantial protection against the onset of dementia. FUNDING Wellcome Trust Health Consequences of Population Change Programme, WHO, US Alzheimer's Association, FONACIT/ CDCH/ UCV. | Dementia incidence and mortality in middle-income countries, and associations with indicators of cognitive reserve: a 10/66 Dementia Research Group population-based cohort study |
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"27144": 0.10993985831737518, "27642": 0.66441810131073, "27781": 0.1510767638683319, "28848": 0.18816383183002472, "29109": 0.04394211992621422, "29111": 0.09672962874174118, "29536": 0.175953671336174} | 14692646 | Extracellular vesicles, including exosomes, are small membrane vesicles derived from multivesicular bodies or from the plasma membrane. Most, if not all, cell types release extracellular vesicles, which then enter the bodily fluids. These vesicles contain a subset of proteins, lipids and nucleic acids that are derived from the parent cell. It is thought that extracellular vesicles have important roles in intercellular communication, both locally and systemically, as they transfer their contents, including proteins, lipids and RNAs, between cells. Extracellular vesicles are involved in numerous physiological processes, and vesicles from both non-immune and immune cells have important roles in immune regulation. Moreover, extracellular vesicle-based therapeutics are being developed and clinically tested for the treatment of inflammatory diseases, autoimmune disorders and cancer. Given the tremendous therapeutic potential of extracellular vesicles, this Review focuses on their role in modulating immune responses, as well as their potential therapeutic applications. | Regulation of immune responses by extracellular vesicles |
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of risk of cancer after protracted low doses of ionising radiation and to strengthen the scientific basis of radiation protection standards for environmental, occupational, and medical diagnostic exposures. DESIGN Multinational retrospective cohort study of cancer mortality. SETTING Cohorts of workers in the nuclear industry in 15 countries. PARTICIPANTS 407 391 workers individually monitored for external radiation with a total follow-up of 5.2 million person years. MAIN OUTCOME MEASUREMENTS Estimates of excess relative risks per sievert (Sv) of radiation dose for mortality from cancers other than leukaemia and from leukaemia excluding chronic lymphocytic leukaemia, the main causes of death considered by radiation protection authorities. RESULTS The excess relative risk for cancers other than leukaemia was 0.97 per Sv, 95% confidence interval 0.14 to 1.97. Analyses of causes of death related or unrelated to smoking indicate that, although confounding by smoking may be present, it is unlikely to explain all of this increased risk. The excess relative risk for leukaemia excluding chronic lymphocytic leukaemia was 1.93 per Sv (< 0 to 8.47). On the basis of these estimates, 1-2% of deaths from cancer among workers in this cohort may be attributable to radiation. CONCLUSIONS These estimates, from the largest study of nuclear workers ever conducted, are higher than, but statistically compatible with, the risk estimates used for current radiation protection standards. The results suggest that there is a small excess risk of cancer, even at the low doses and dose rates typically received by nuclear workers in this study. | Risk of cancer after low doses of ionising radiation: retrospective cohort study in 15 countries. |
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0.5596157908439636, "27781": 0.13414156436920166, "27854": 0.6533012986183167, "27881": 0.8074519634246826, "27989": 0.9417452812194824, "28207": 0.10993985831737518, "28466": 0.15359249711036682, "28522": 0.2145126610994339, "28644": 0.04207121208310127, "28691": 1.387270450592041, "28873": 0.11081436276435852, "29480": 0.45623743534088135} | 14706752 | The multifunctional signaling protein p75 neurotrophin receptor (p75(NTR)) is a central regulator and major contributor to the highly invasive nature of malignant gliomas. Here, we show that neurotrophin-dependent regulated intramembrane proteolysis (RIP) of p75(NTR) is required for p75(NTR)-mediated glioma invasion, and identify a previously unnamed process for targeted glioma therapy. Expression of cleavage-resistant chimeras of p75(NTR) or treatment of animals bearing p75(NTR)-positive intracranial tumors with clinically applicable gamma-secretase inhibitors resulted in dramatically decreased glioma invasion and prolonged survival. Importantly, proteolytic processing of p75(NTR) was observed in p75(NTR)-positive patient tumor specimens and brain tumor initiating cells. This work highlights the importance of p75(NTR) as a therapeutic target, suggesting that gamma-secretase inhibitors may have direct clinical application for the treatment of malignant glioma. | Gamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated by the p75 Neurotrophin Receptor |
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"28793": 0.021256839856505394, "28828": 0.20421554148197174, "28879": 0.23247487843036652, "29048": 0.2983669638633728, "29090": 0.31132611632347107, "29122": 0.7482418417930603, "29125": 0.03831886500120163, "29288": 0.04113444685935974, "29454": 0.2837681770324707, "29525": 0.2145126610994339, "29536": 0.3485364317893982, "29566": 0.9394577741622925, "29607": 0.25845035910606384} | 14711483 | CONTEXT Vaso-occlusion is central to the painful crises and acute and chronic organ damage in sickle cell disease. Abnormal nitric oxide-dependent regulation of vascular tone, adhesion, platelet activation, and inflammation contributes to the pathophysiology of vaso-occlusion. Nitric oxide may have promise as a mechanism-of-disease-based therapy for treatment of vaso-occlusion. OBJECTIVE To explore the efficacy and safety of inhaled nitric oxide (INO) for treatment of vaso-occlusive crisis in pediatric patients. DESIGN Prospective, double-blind, placebo-controlled, randomized clinical trial with enrollment between September 1999 and October 2001. SETTING Urban, tertiary care children's hospital in the United States. PARTICIPANTS Twenty patients aged 10 to 21 years with sickle cell disease and severe acute vaso-occlusive crisis. INTERVENTION Patients were randomly assigned to receive INO (80 ppm with 21% final concentration of inspired oxygen; n = 10), or placebo (21% inspired oxygen; n = 10) for 4 hours. MAIN OUTCOME MEASURES Change in pain at 4 hours of inhalation compared with preinhalation pain, measured on a 10-cm visual analog scale (VAS); secondary outcome measures were pain over 6 hours, parenteral narcotic use over 24 hours, duration of hospitalization, blood pressure, oxygen saturation, and methemoglobin concentration. RESULTS Preinhalation VAS pain scores were similar in the INO and placebo groups (P =.80). The decrease in VAS pain scores at 4 hours was 2.0 cm in the INO group and 1.2 cm in the placebo group (P =.37). Repeated-measures analysis of variance for hourly pain scores showed a 1-cm/h greater reduction in the INO group than the placebo group (P =.02). Morphine use over 6 hours was significantly less in the INO group (mean cumulative use, 0.29 vs 0.44 mg/kg; P =.03) but was not different over 4 hours (0.26 vs 0.32 mg/kg; P =.21) or 24 hours (0.63 vs 0.91 mg/kg; P =.15). Duration of hospitalization was 78 and 100 hours in the INO and placebo groups, respectively (P =.19). No INO toxicity was observed. CONCLUSIONS Results of this exploratory study suggest that INO may be beneficial for acute vaso-occlusive crisis. These preliminary results warrant further investigation. | Preliminary assessment of inhaled nitric oxide for acute vaso-occlusive crisis in pediatric patients with sickle cell disease. |
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"27777": 0.0606246218085289, "28041": 0.22937409579753876, "28207": 0.33115679025650024, "28685": 0.06154331564903259, "28828": 0.562402069568634, "28829": 0.1229778528213501, "29206": 0.06703783571720123, "29248": 0.0019512200960889459, "29458": 0.08513788133859634} | 14717213 | Over the years, methods of cytogenetic analysis evolved and became part of routine laboratory testing, providing valuable diagnostic and prognostic information in hematologic disorders. Karyotypic aberrations contribute to the understanding of the molecular pathogenesis of disease and thereby to rational application of therapeutic modalities. Most of the progress in this field stems from the application of metaphase cytogenetics (MC), but recently, novel molecular technologies have been introduced that complement MC and overcome many of the limitations of traditional cytogenetics, including a need for cell culture. Whole genome scanning using comparative genomic hybridization and single nucleotide polymorphism arrays (CGH-A; SNP-A) can be used for analysis of somatic or clonal unbalanced chromosomal defects. In SNP-A, the combination of copy number detection and genotyping enables diagnosis of copy-neutral loss of heterozygosity, a lesion that cannot be detected using MC but may have important pathogenetic implications. Overall, whole genome scanning arrays, despite the drawback of an inability to detect balanced translocations, allow for discovery of chromosomal defects in a higher proportion of patients with hematologic malignancies. Newly detected chromosomal aberrations, including somatic uniparental disomy, may lead to more precise prognostic schemes in many diseases. | Corresponding author: |
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"26597": 0.15610189735889435, "26601": 0.02792670577764511, "26633": 0.19541899859905243, "26741": 0.9515975713729858, "26835": 0.03831886500120163, "28024": 1.0815403461456299, "28042": 0.1913948506116867, "28102": 0.9052929878234863, "28177": 0.4374985992908478, "28252": 0.11517547070980072, "28290": 0.014542185701429844, "29206": 0.2689530849456787, "29276": 0.06795065850019455, "29458": 0.2089812457561493, "29602": 0.6684301495552063} | 14717500 | Genome-wide association studies (GWAS) have now identified at least 2,000 common variants that appear associated with common diseases or related traits (http://www.genome.gov/gwastudies), hundreds of which have been convincingly replicated. It is generally thought that the associated markers reflect the effect of a nearby common (minor allele frequency >0.05) causal site, which is associated with the marker, leading to extensive resequencing efforts to find causal sites. We propose as an alternative explanation that variants much less common than the associated one may create "synthetic associations" by occurring, stochastically, more often in association with one of the alleles at the common site versus the other allele. Although synthetic associations are an obvious theoretical possibility, they have never been systematically explored as a possible explanation for GWAS findings. Here, we use simple computer simulations to show the conditions under which such synthetic associations will arise and how they may be recognized. We show that they are not only possible, but inevitable, and that under simple but reasonable genetic models, they are likely to account for or contribute to many of the recently identified signals reported in genome-wide association studies. We also illustrate the behavior of synthetic associations in real datasets by showing that rare causal mutations responsible for both hearing loss and sickle cell anemia create genome-wide significant synthetic associations, in the latter case extending over a 2.5-Mb interval encompassing scores of "blocks" of associated variants. In conclusion, uncommon or rare genetic variants can easily create synthetic associations that are credited to common variants, and this possibility requires careful consideration in the interpretation and follow up of GWAS signals. | Rare Variants Create Synthetic Genome-Wide Associations |
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0.33115679025650024, "23750": 0.05970508232712746, "24269": 0.3141832649707794, "24278": 0.03925827145576477, "24644": 0.27044451236724854, "24879": 0.0797421783208847, "24987": 0.18492233753204346, "25181": 0.3897167444229126, "25194": 0.48068851232528687, "25222": 0.22392450273036957, "25459": 0.6624060273170471, "25502": 0.15023678541183472, "25533": 0.24171993136405945, "25714": 0.22392450273036957, "25761": 0.3622259199619293, "26226": 0.31489628553390503, "26243": 0.06795065850019455, "26402": 0.25088030099868774, "26651": 0.08603433519601822, "26657": 0.21214580535888672, "26837": 0.14518201351165771, "26942": 0.6016870141029358, "27020": 0.5127768516540527, "27099": 0.4113073945045471, "27295": 0.22157983481884003, "27427": 0.1510767638683319, "27774": 0.2516399025917053, "27854": 0.3012613356113434, "28938": 0.3963087201118469, "29170": 0.18978065252304077, "29248": 0.3784096837043762} | 14719322 | Cytoplasmic Ca(2+) oscillations are a universal signaling mode that activates numerous cellular responses [1, 2]. Oscillations are considered the physiological mechanism of Ca(2+) signaling because they occur at low levels of stimulus intensity [3]. Ca(2+) oscillations are proposed to convey information in their amplitude and frequency, leading to activation of specific downstream targets [4-6]. Here, we report that the spatial Ca(2+) gradient within the oscillation is key. Ca(2+) oscillations in mast cells evoked over a range of agonist concentrations in the presence of external Ca(2+) were indistinguishable from those in the absence of Ca(2+) when plasmalemmal Ca(2+) extrusion was suppressed. Nevertheless, only oscillations with accompanying Ca(2+) entry through store-operated CRAC channels triggered gene expression. Increased cytoplasmic Ca(2+) buffering prevented oscillations but not gene activation. Local Ca(2+) influx and not global Ca(2+) oscillations therefore drives gene expression at physiological levels of stimulation. Rather than serving to maintain Ca(2+) oscillations by replenishing stores, we suggest that the role of oscillations might be to activate CRAC channels, thereby ensuring the generation of spatially restricted physiological Ca(2+) signals driving gene activation. Furthermore, we show that the spatial profile of a Ca(2+) oscillation provides a novel mechanism whereby a pleiotropic messenger specifically activates gene expression. | Decoding of Cytoplasmic Ca2+ Oscillations through the Spatial Signature Drives Gene Expression |
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1.1592369079589844, "25517": 0.1693800985813141, "25775": 0.20818853378295898, "26147": 0.10026945173740387, "26163": 0.7482418417930603, "26237": 0.3262358605861664, "26287": 0.0058422754518687725, "26319": 0.02316705882549286, "26378": 0.25694093108177185, "26462": 0.5635144114494324, "26692": 0.15442965924739838, "26906": 0.2089812457561493, "27354": 0.12728634476661682, "27641": 1.0144377946853638, "27651": 0.09761575609445572, "27896": 0.1358480453491211, "28093": 0.0842406153678894, "28177": 0.004870930220931768, "28329": 0.07068414986133575, "28436": 0.12038381397724152, "28549": 1.0437490940093994, "29251": 0.0038986403960734606, "29401": 0.20818853378295898} | 14724693 | CONTEXT Chronic low back pain (LBP) with degenerative lumbar osteoarthritis (OA) is widespread in the adult population. Although glucosamine is increasingly used by patients with chronic LBP, little is known about its effect in this setting. OBJECTIVE To investigate the effect of glucosamine in patients with chronic LBP and degenerative lumbar OA. DESIGN, SETTING, AND PARTICIPANTS A double-blind, randomized, placebo-controlled trial conducted at Oslo University Hospital Outpatient Clinic, Oslo, Norway, with 250 patients older than 25 years of age with chronic LBP (>6 months) and degenerative lumbar OA. INTERVENTIONS Daily intake of 1500 mg of oral glucosamine (n = 125) or placebo (n = 125) for 6 months, with assessment of effect after the 6-month intervention period and at 1 year (6 months postintervention). MAIN OUTCOME MEASURES The primary outcome was pain-related disability measured with the Roland Morris Disability Questionnaire (RMDQ). Secondary outcomes were numerical scores from pain-rating scales of patients at rest and during activity, and the quality-of-life EuroQol-5 Dimensions (EQ-5D) instrument. Data collection occurred during the intervention period at baseline, 6 weeks, 3 and 6 months, and again 6 months following the intervention at 1 year. Group differences were analyzed using linear mixed models analysis. RESULTS At baseline, mean RMDQ scores were 9.2 (95% confidence interval [CI], 8.4-10.0) for glucosamine and 9.7 (95% CI, 8.9-10.5) for the placebo group (P = .37). At 6 months, the mean RMDQ score was the same for the glucosamine and placebo groups (5.0; 95% CI, 4.2-5.8). At 1 year, the mean RMDQ scores were 4.8 (95% CI, 3.9-5.6) for glucosamine and 5.5 (95% CI, 4.7-6.4) for the placebo group. No statistically significant difference in change between groups was found when assessed after the 6-month intervention period and at 1 year: RMDQ (P = .72), LBP at rest (P = .91), LBP during activity (P = .97), and quality-of-life EQ-5D (P = .20). Mild adverse events were reported in 40 patients in the glucosamine group and 46 in the placebo group (P = .48). CONCLUSIONS Among patients with chronic LBP and degenerative lumbar OA, 6-month treatment with oral glucosamine compared with placebo did not result in reduced pain-related disability after the 6-month intervention and after 1-year follow-up. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00404079. | Effect of glucosamine on pain-related disability in patients with chronic low back pain and degenerative lumbar osteoarthritis: a randomized controlled trial. |
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"27196": 0.7105726003646851, "27339": 0.35950297117233276, "27491": 0.7638313174247742, "27532": 0.16276304423809052, "27597": 0.06154331564903259, "28021": 0.11081436276435852, "28173": 0.6634125709533691, "28246": 0.08871890604496002, "28353": 1.4283655881881714, "28530": 0.1011524572968483, "28667": 0.6921701431274414, "28697": 0.04394211992621422, "28711": 0.22937409579753876, "28915": 1.0526502132415771, "29048": 0.1384023278951645, "29166": 0.09938567131757736, "29212": 0.306306391954422, "29264": 0.41195443272590637, "29278": 0.1808556467294693, "29458": 0.040196798741817474, "29477": 0.08961215615272522} | 14726759 | BACKGROUND AND PURPOSE There are only few small studies assessing potential risk factors, comorbidity, and prognostic factors in adult spontaneous cervicocerebral artery dissection (CAD). METHODS We conducted a retrospective, hospital-based analysis on the prognostic factors and association of CAD with vascular risk factors in 301 consecutive Finnish patients, 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 with visual aura (63% of all migraineurs), and smoking were more common in patients with CAD compared with the general Finnish population. At 3 months, 247 (83%) patients reached a favorable outcome. Occlusion of the dissected artery, internal carotid artery dissection (ICAD), and recent infection in infarction patients were associated with a poorer outcome. ICAD patients had less often brain infarction, but the strokes they had were more severe. Seven (2.3%) patients died during the follow-up (mean 4.0 years, 1186 patient years). Six (2%) patients had verified CAD recurrence. CONCLUSIONS This study provides evidence for the association of CAD with male sex, and possible association with smoking and migraine. Occlusion of the dissected artery, ICAD, and infection appear to be associated with poorer outcome. | Adult cervicocerebral artery dissection: a single-center study of 301 Finnish patients. |
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0.2719337046146393, "26835": 0.08871890604496002, "26871": 0.7239188551902771, "26874": 0.1212492436170578, "26886": 0.5773153901100159, "26994": 0.0019512200960889459, "27233": 0.24018502235412598, "27354": 0.34023189544677734, "27373": 0.3743882179260254, "27711": 0.06703783571720123, "27717": 0.7038320899009705, "27881": 0.0797421783208847, "28105": 1.130645751953125, "28177": 0.8442239761352539, "28207": 0.0354953333735466, "28286": 0.9470623731613159, "28290": 0.006812678650021553, "28311": 0.5517725944519043, "28436": 0.4425300657749176, "28736": 0.022212404757738113, "28873": 0.034552380442619324, "28911": 0.2231435477733612, "29107": 0.10993985831737518, "29537": 0.7500885725021362} | 14729253 | BACKGROUND Data on genetic susceptibility to sporadic gastric carcinoma have been published at a growing pace, but to date no comprehensive overview and quantitative summary has been available. METHODS We conducted a systematic review and meta-analysis of the evidence on the association between DNA variation and risk of developing stomach cancer. To assess result credibility, summary evidence was graded according to the Venice criteria and false positive report probability (FPRP) was calculated to further validate result noteworthiness. Meta-analysis was also conducted for subgroups, which were defined by ethnicity (Asian vs Caucasian), tumour histology (intestinal vs diffuse), tumour site (cardia vs non-cardia) and Helicobacter pylori infection status (positive vs negative). RESULTS Literature search identified 824 eligible studies comprising 2 530 706 subjects (cases: 261 386 (10.3%)) and investigating 2841 polymorphisms involving 952 distinct genes. Overall, we performed 456 primary and subgroup meta-analyses on 156 variants involving 101 genes. We identified 11 variants significantly associated with disease risk and assessed to have a high level of summary evidence: MUC1 rs2070803 at 1q22 (diffuse carcinoma subgroup), MTX1 rs2075570 at 1q22 (diffuse), PSCA rs2294008 at 8q24.2 (non-cardia), PRKAA1 rs13361707 5p13 (non-cardia), PLCE1 rs2274223 10q23 (cardia), TGFBR2 rs3087465 3p22 (Asian), PKLR rs3762272 1q22 (diffuse), PSCA rs2976392 (intestinal), GSTP1 rs1695 11q13 (Asian), CASP8 rs3834129 2q33 (mixed) and TNF rs1799724 6p21.3 (mixed), with the first nine variants characterised by a low FPRP. We also identified polymorphisms with lower quality significant associations (n=110). CONCLUSIONS We have identified several high-quality biomarkers of gastric cancer susceptibility. These data will form the backbone of an annually updated online resource that will be integral to the study of gastric carcinoma genetics and may inform future screening programmes. | Genetic variation and gastric cancer risk: a field synopsis and meta-analysis. |
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"26773": 0.4950772523880005, "26835": 0.034552380442619324, "27166": 1.2655161619186401, "27169": 1.1888195276260376, "27208": 0.07612881064414978, "27321": 0.4437839686870575, "27336": 0.011650617234408855, "27532": 0.43875885009765625, "27777": 0.0174254160374403, "27846": 0.013579257763922215, "28086": 0.9256220459938049, "28625": 0.861702561378479, "28696": 0.371698260307312, "28788": 0.3662964701652527, "29060": 0.14179791510105133} | 14753395 | Neural signalling within the central nervous system (CNS) requires a highly controlled microenvironment. Cells at three key interfaces form barriers between the blood and the CNS: the blood-brain barrier (BBB), blood-CSF barrier and the arachnoid barrier. The BBB at the level of brain microvessel endothelium is the major site of blood-CNS exchange. The structure and function of the BBB is summarised, the physical barrier formed by the endothelial tight junctions, and the transport barrier resulting from membrane transporters and vesicular mechanisms. The roles of associated cells are outlined, especially the endfeet of astrocytic glial cells, and pericytes and microglia. The embryonic development of the BBB, and changes in pathology are described. The BBB is subject to short and long-term regulation, which may be disturbed in pathology. Any programme for drug discovery or delivery, to target or avoid the CNS, needs to consider the special features of the BBB. | Structure and function of the blood–brain barrier |
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The detailed regulation of this process remains unclear. We report here that golli protein, an alternatively spliced product of the myelin basic protein gene, plays a critical role in regulating calcium influx in T cells. Golli-deficient T cells were hyperproliferative and showed enhanced calcium entry upon T cell receptor stimulation. We further found that golli regulates calcium influx in T cells through the inhibition of the store depletion-induced calcium influx. Mutation of the myristoylation site on golli disrupted its association with the plasma membrane and reversed its inhibitory action on Ca2+ influx, indicating that membrane association of golli was essential for its inhibitory action. These results indicate that golli functions in a unique way to regulate T cell activation through a mechanism involving the modulation of the calcium homeostasis. | Golli protein negatively regulates store depletion-induced calcium influx in T cells. |
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0.004870930220931768, "26402": 0.22704219818115234, "26775": 0.9100211262702942, "26982": 0.043007105588912964, "27086": 0.812664806842804, "27144": 0.4412745535373688, "27295": 0.6022219061851501, "27881": 0.27712854743003845, "28040": 0.06612417846918106, "28086": 0.20977331697940826, "28207": 0.1358480453491211, "28297": 0.5784112811088562, "28522": 0.02792670577764511, "28636": 0.3134697377681732, "28723": 0.13157635927200317, "28788": 0.06429435312747955, "29109": 0.2160874605178833, "29206": 0.8517522215843201, "29290": 0.3297532796859741, "29480": 0.09228714555501938, "29486": 0.1384023278951645} | 14768471 | Renal carcinomas have been shown to contain a population of cancer stem cells (CSCs) that present self-renewing capacity and support tumor growth and metastasis. CSCs were shown to secrete large amount of extracellular vesicles (EVs) that can transfer several molecules (proteins, lipids and nucleic acids) and induce epigenetic changes in target cells. Mesenchymal Stromal Cells (MSCs) are susceptible to tumor signalling and can be recruited to tumor regions. The precise role of MSCs in tumor development is still under debate since both pro- and anti-tumorigenic effects have been reported. In this study we analysed the participation of renal CSC-derived EVs in the interaction between tumor and MSCs. We found that CSC-derived EVs promoted persistent phenotypical changes in MSCs characterized by an increased expression of genes associated with cell migration (CXCR4, CXCR7), matrix remodeling (COL4A3), angiogenesis and tumor growth (IL-8, Osteopontin and Myeloperoxidase). EV-stimulated MSCs exhibited in vitro an enhancement of migration toward the tumor conditioned medium. Moreover, EV-stimulated MSCs enhanced migration of renal tumor cells and induced vessel-like formation. In vivo, EV-stimulated MSCs supported tumor development and vascularization, when co-injected with renal tumor cells. In conclusion, CSC-derived EVs induced phenotypical changes in MSCs that are associated with tumor growth. | Extracellular vesicles derived from renal cancer stem cells induce a pro-tumorigenic phenotype in mesenchymal stromal cells |
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0.9348671436309814, "29516": 0.11951763927936554} | 14782049 | The cognitive deficits observed in children with cyanotic congenital heart disease suggest involvement of the developing hippocampus. Chronic postnatal hypoxia present during infancy in these children may play a role in these impairments. To understand the biochemical mechanisms of hippocampal injury in chronic hypoxia, a neurochemical profile consisting of 15 metabolite concentrations and 2 metabolite ratios in the hippocampus was evaluated in a rat model of chronic postnatal hypoxia using in vivo 1H NMR spectroscopy at 9.4 T. Chronic hypoxia was induced by continuously exposing rats (n = 23) to 10% O2 from postnatal day (P) 3 to P28. Fifteen metabolites were quantified from a volume of 9-11 microl centered on the left hippocampus on P14, P21, and P28 and were compared with normoxic controls (n = 14). The developmental trajectory of neurochemicals in chronic hypoxia was similar to that seen in normoxia. However, chronic hypoxia had an effect on the concentrations of the following neurochemicals: aspartate, creatine, phosphocreatine, GABA, glutamate, glutamine, glutathione, myoinositol, N-acetylaspartate (NAA), phosphorylethanolamine, and phosphocreatine/creatine (PCr/Cr) and glutamate/glutamine (Glu/Gln) ratios (P < 0.001 each, except glutamate, P = 0.04). The increased PCr/Cr ratio is consistent with decreased brain energy consumption. Given the well-established link between excitatory neurotransmission and brain energy metabolism, we postulate that elevated glutamate, Glu/Gln ratio, and GABA indicate suppressed excitatory neurotransmission in an energy-limited environment. Decreased NAA and phosphorylethanolamine suggest reduced neuronal integrity and phospholipid metabolism. The altered hippocampal neurochemistry during its development may underlie some of the cognitive deficits present in human infants at risk of chronic hypoxia. | In vivo effect of chronic hypoxia on the neurochemical profile of the developing rat hippocampus. |
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The functional significance of this widespread noncoding transcription is mostly unknown. We show that Arabidopsis RNA polymerase IVb/Pol V, a multisubunit nuclear enzyme required for siRNA-mediated gene silencing of transposons and other repeats, transcribes intergenic and noncoding sequences, thereby facilitating heterochromatin formation and silencing of overlapping and adjacent genes. Pol IVb/Pol V transcription requires the chromatin-remodeling protein DRD1 but is independent of siRNA biogenesis. However, Pol IVb/Pol V transcription and siRNA production are both required to silence transposons, suggesting that Pol IVb/Pol V generates RNAs or chromatin structures that serve as scaffolds for siRNA-mediated heterochromatin-forming complexes. Pol IVb/Pol V function provides a solution to a paradox of epigenetic control: the need for transcription in order to transcriptionally silence the same region. | Noncoding Transcription by RNA Polymerase Pol IVb/Pol V Mediates Transcriptional Silencing of Overlapping and Adjacent Genes |
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"26226": 0.5712664127349854, "26282": 1.154322862625122, "26396": 0.11343330889940262, "26402": 0.176772341132164, "26419": 0.09406650811433792, "26591": 0.5816917419433594, "26721": 0.011650617234408855, "26780": 0.2247048318386078, "26835": 0.33953672647476196, "27226": 0.03925827145576477, "27833": 0.9515975713729858, "28156": 0.5640701055526733, "28268": 0.2983669638633728, "28517": 0.11778303235769272, "28691": 0.022212404757738113, "29090": 0.4412745535373688, "29166": 1.0312920808792114, "29167": 0.026025565341114998, "29193": 0.6950984001159668, "29295": 0.3191637098789215, "29358": 0.7047978043556213, "29458": 0.09317722171545029, "29494": 0.500420093536377} | 14803797 | Intestinal microbiota metabolism of choline and phosphatidylcholine produces trimethylamine (TMA), which is further metabolized to a proatherogenic species, trimethylamine-N-oxide (TMAO). We demonstrate here that metabolism by intestinal microbiota of dietary L-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosis in mice. Omnivorous human subjects produced more TMAO than did vegans or vegetarians following ingestion of L-carnitine through a microbiota-dependent mechanism. The presence of specific bacterial taxa in human feces was associated with both plasma TMAO concentration and dietary status. Plasma L-carnitine levels in subjects undergoing cardiac evaluation (n = 2,595) predicted increased risks for both prevalent cardiovascular disease (CVD) and incident major adverse cardiac events (myocardial infarction, stroke or death), but only among subjects with concurrently high TMAO levels. Chronic dietary L-carnitine supplementation in mice altered cecal microbial composition, markedly enhanced synthesis of TMA and TMAO, and increased atherosclerosis, but this did not occur if intestinal microbiota was concurrently suppressed. In mice with an intact intestinal microbiota, dietary supplementation with TMAO or either carnitine or choline reduced in vivo reverse cholesterol transport. Intestinal microbiota may thus contribute to the well-established link between high levels of red meat consumption and CVD risk. | Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis |
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"26402": 0.1946154683828354, "26591": 0.2026219218969345, "26886": 0.29036402702331543, "27058": 1.156782865524292, "27144": 0.1619328260421753, "27240": 0.2105647772550583, "27364": 0.9005423784255981, "27427": 0.6719275116920471, "27709": 0.9576126337051392, "27794": 0.8764448165893555, "28389": 1.4017986059188843, "28414": 1.1487655639648438, "29125": 0.9029204845428467, "29234": 0.31132611632347107, "29336": 0.1510767638683319, "29464": 0.6734226942062378, "29477": 0.0913962796330452} | 14806256 | CONTEXT Use of antiretroviral drugs, including protease inhibitors, for treatment of human immunodeficiency virus (HIV) infection has been anecdotally associated with hepatotoxicity, particularly in persons coinfected with hepatitis C or B virus. OBJECTIVES To ascertain if incidence of severe hepatotoxicity during antiretroviral therapy is similar for all antiretroviral drug combinations, and to define the role of chronic viral hepatitis in its development. DESIGN Prospective cohort study. SETTING University-based urban HIV clinic. PATIENTS A total of 298 patients who were prescribed new antiretroviral therapies between January 1996 and January 1998, 211 (71%) of whom received protease inhibitors as part of combination therapy (median follow-up, 182 days) and 87 (29%) of whom received dual nucleoside analog regimens (median follow-up, 167 days). Chronic hepatitis C and B virus infection was present in 154 (52%) and 8 (2.7%) patients, respectively. MAIN OUTCOME MEASURE Severe hepatotoxicity, defined as a grade 3 or 4 change in levels of serum alanine aminotransferase and aspartate aminotransferase, evaluated before and during therapy. RESULTS Severe hepatotoxicity was observed in 31 (10.4%) of 298 patients (95% confidence interval [CI], 7.2%-14.4%). Ritonavir use was associated with a higher incidence of toxicity (30%; 95% CI, 17.9% -44.6%). However, no significant difference was detected in hepatotoxicity incidence in other treatment groups, ie, nucleoside analogs (5.7%; 95% CI, 1.2%-12.9%), nelfinavir (5.9%; 95% CI, 1.2%-16.2%), saquinavir (5.9%; 95% CI, 0.15%-28.7%), and indinavir(6.8%; 95% CI, 3.0%-13.1 %). Although chronicviral hepatitis was associated with an increased risk of severe hepatotoxicity among patients prescribed nonritonavir regimens (relative risk, 3.7; 95% CI, 1.0-11.8), most patients with chronic hepatitis C or B virus infection (88%) did not experience significant toxic effects. Rate of severe toxicity with use of any protease inhibitor in patients with hepatitis C infection was 12.2% (13/107; 95% CI, 6.6%-19.9%). In multivariate logistic regression, only ritonavir (adjusted odds ratio [AOR], 8.6; 95% CI, 3.0-24.6) and a CD4 cell count increase of more than 0.05 x 10(9)/L (AOR, 3.6; 95% CI, 1.0-12.9) were associated with severe hepatotoxicity. No irreversible outcomes were seen in patients with severe hepatotoxicity. CONCLUSIONS Our data indicate that use of ritonavir may increase risk of severe hepatotoxicity. Although hepatotoxicity may be more common in persons with chronic viral hepatitis, these data do not support withholding protease inhibitor therapy from persons coinfected with hepatitis B or C virus. | Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. |
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"24271": 0.6892333030700684, "24278": 0.27342069149017334, "24873": 0.026976587250828743, "24921": 0.41389304399490356, "25226": 1.167778730392456, "25409": 0.15777134895324707, "25456": 1.2158164978027344, "25473": 0.07159364968538284, "25499": 0.6764062643051147, "25643": 0.05046287178993225, "25714": 0.5051454305648804, "26402": 0.9394577741622925, "26520": 0.03925827145576477, "26601": 0.06612417846918106, "26651": 0.11081436276435852, "26927": 0.14179791510105133, "26976": 0.014542185701429844, "27144": 0.24018502235412598, "27263": 0.13071982562541962, "27448": 0.3464667797088623, "27781": 0.037378571927547455, "27814": 0.0174254160374403, "27854": 0.14686977863311768, "28032": 0.9240728616714478, "28283": 0.6744182109832764, "28518": 0.004870930220931768, "28864": 0.28450319170951843, "29206": 0.7995813488960266, "29458": 0.66441810131073} | 14819804 | The novel phosphatidylinositol-3-kinase (PI3K) inhibitor PX-866 was tested against 13 experimental human tumor xenografts derived from cell lines of various tissue origins. Mutant PI3K (PIK3CA) and loss of PTEN activity were sufficient, but not necessary, as predictors of sensitivity to the antitumor activity of the PI3K inhibitor PX-866 in the presence of wild-type Ras, whereas mutant oncogenic Ras was a dominant determinant of resistance, even in tumors with coexisting mutations in PIK3CA. The level of activation of PI3K signaling measured by tumor phosphorylated Ser(473)-Akt was insufficient to predict in vivo antitumor response to PX-866. Reverse-phase protein array revealed that the Ras-dependent downstream targets c-Myc and cyclin B were elevated in cell lines resistant to PX-866 in vivo. Studies using an H-Ras construct to constitutively and preferentially activate the three best-defined downstream targets of Ras, i.e., Raf, RalGDS, and PI3K, showed that mutant Ras mediates resistance through its ability to use multiple pathways for tumorigenesis. The identification of Ras and downstream signaling pathways driving resistance to PI3K inhibition might serve as an important guide for patient selection as inhibitors enter clinical trials and for the development of rational combinations with other molecularly targeted agents. | Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance. |
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| OBJECTIVES To examine trends in life expectancy at birth and age and cause specific patterns of mortality in the former German Democratic Republic (GDR) and Poland during political transition and throughout the 1990s in both parts of Germany and in Poland. METHODS Decomposition of life expectancy by age and cause of death. Changes in life expectancy during transition by cause of death were examined using data for 1988/89 and 1990/91 for the former GDR and Poland; examination of life expectancy changes after transition were based on 1992-97 data for Germany and 1991-96 data for Poland. RESULTS In both the former GDR and Poland male life expectancy at birth declined by almost one year during transition, mainly attributable to rising death rates from external causes and circulatory diseases. Female life expectancy in Poland deteriorated by 0.3 years, largely attributable to increasing circulatory mortality among the old, while in East German female rising death rates in children and young adults were nearly outbalanced by declining circulatory mortality among those over 70. Between 1991/92 and 1996/97, male life expectancy at birth increased by 2.4 years in the former GDR, 1.2 years in old Federal Republic, and 2.0 years in Poland (women: 2.3, 0.9, and 1.2 years). In East Germany and Poland, the overall improvement was largely attributable to falling mortality among men aged 40-64, while those over 65 contributed the largest proportion to life expectancy gains in women. The change in deaths among men aged 15-39 accounted for 0.4 of a year to life expectancy at birth in East Germany and Poland, attributable largely to greater decreases from external causes. Among those over 40, absolute contributions to changing life expectancy were greater in the former GDR than in the other two entities in both sexes, largely attributable to circulatory diseases. A persisting East-west life expectancy gap in Germany of 2.1 years in men in 1997 was largely attributable to external causes, diseases of the digestive system and circulatory diseases. Higher death rates from circulatory diseases among the elderly largely explain the female life expectancy gap of approximately one year. CONCLUSIONS This study provides further insights into the health effects of political transition. Post-transition improvements in life expectancy and mortality have been much steeper in East Germany compared with Poland. Changes in dietary pattern and, in Germany, medical care may have been important factors in shaping post-transition mortality trends. | Changing mortality patterns in East and West Germany and Poland. II: short-term trends during transition and in the 1990s. |
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"28228": 0.0019512200960889459, "28517": 0.0019512200960889459, "28687": 0.5410289764404297, "28711": 0.9739698171615601, "28835": 0.1064341589808464, "29273": 0.11343330889940262, "29290": 0.8715548515319824} | 14827874 | CONTEXT For the last 40 yr, the first line of treatment for anovulation in infertile women has been clomiphene citrate (CC). CC is a safe, effective oral agent but is known to have relatively common antiestrogenic endometrial and cervical mucous side effects that could prevent pregnancy in the face of successful ovulation. In addition, there is a significant risk of multiple pregnancy with CC, compared with natural cycles. Because of these problems, we proposed the concept of aromatase inhibition as a new method of ovulation induction that could avoid many of the adverse effects of CC. The objective of this review was to describe the different physiological mechanisms of action for CC and aromatase inhibitors (AIs) and compare studies of efficacy for both agents for ovulation induction. EVIDENCE ACQUISITION We conducted a systematic review of all the published studies, both controlled and noncontrolled, comparing CC and AI treatment, either alone or in combination with gonadotropins, for ovulation induction or augmentation, identified through the Entrez-PubMed search engine. EVIDENCE SYNTHESIS Because of the recent acceptance of the concept of using AIs for ovulation induction, few controlled studies were identified, and the rest of the studies were pilot or preliminary comparisons. Based on these studies, it appears that AIs are as effective as CC in inducing ovulation, are devoid of any antiestrogenic side effects, result in lower serum estrogen concentrations, and are associated with good pregnancy rates with a lower incidence of multiple pregnancy than CC. When combined with gonadotropins for assisted reproductive technologies, AIs reduce the dose of FSH required for optimal follicle recruitment and improve the response to FSH in poor responders. CONCLUSIONS Preliminary evidence suggests that AIs may replace CC in the future because of similar efficacy with a reduced side effect profile. Although worldwide experience with AIs for ovulation induction is increasing, at present, definitive studies in the form of randomized controlled trials comparing CC with AIs are lacking. | 0021-972X/06/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 91(3):760–771 Printed in U.S.A. Copyright © 2006 by The Endocrine Society doi: 10.1210/jc.2005-1923 REVIEW: Aromatase Inhibitors for Ovulation Induction |
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0.07793712615966797, "27144": 0.04207121208310127, "27204": 0.7737906575202942, "27208": 0.06337817758321762, "27480": 0.4855078160762787, "27491": 0.6543170213699341, "27815": 0.16607704758644104, "28179": 0.42735910415649414, "28285": 0.07341018319129944, "28297": 0.4487839937210083, "28350": 0.013579257763922215, "28467": 0.15693697333335876, "28790": 0.02412080205976963, "28915": 0.30558720231056213, "29166": 0.05046287178993225, "29242": 0.06612417846918106, "29251": 0.006812678650021553, "29361": 0.053244512528181076, "29391": 0.21214580535888672, "29454": 0.11778303235769272, "29486": 0.3339579105377197} | 14831629 | Patent ductus arteriosus (PDA) is a common diagnosis among extremely premature infants, especially in those with lung disease. Treatments are often used to close the PDA. Despite nearly three decades of research, the question of whether the benefits of treatments to prevent ductal patency or promote closure outweigh the risks of these treatments remains unanswered. The authors rarely use treatments designed to close the PDA. This article reviews three considerations in support of this restrained approach: rates of spontaneous closure of the ductus arteriosus; adverse effect of persistent ductal patency; and benefits and risks of treatments for closure. | Patent ductus arteriosus: lack of evidence for common treatments. |
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However, some biologics are accompanied with severe side effects, including tuberculosis and other types of infection. There is thus a critical need for nonsystemic and lesion-specific methods of delivering these therapeutic agents. We attempted to treat a mouse model of arthritis by using T cells that expressed a regulatory molecule and were specifically directed to the inflamed paw. To this end, we first identified the TCR alphabeta genes accumulating in the inflamed paw of mice with collagen-induced arthritis (CIA) by a combination of single-strand chain polymorphism analysis of TCR and single-cell sorting. We identified an expanded clone B47 which is autoreactive but is not specific to type II collagen. In vivo, TCR genes from B47-transduced T cells accumulated in the inflamed paw. Injection of cells cotransduced with the B47 and soluble TNFRIg genes resulted in a significant suppression of CIA. The suppression was correlated with the amount of TNFRIg transcripts in the hind paw, not with the serum concentrations of TNFRIg. Moreover, T cells cotransduced with the B47 and intracellular Foxp3 genes significantly suppressed CIA with reductions in TNF-alpha, IL-17A, and IL-1beta expression and bone destruction. T cells cotransduced with B47 and Foxp3 genes also suppressed the progression of established CIA. Therefore, immunosuppressive therapy with autoreactive TCR is a promising therapeutic strategy for arthritis whether the TCRs are used to deliver either soluble or intracellular suppressive molecules. | Gene therapy of arthritis with TCR isolated from the inflamed paw. |
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14835068 | Melatonin has been speculated to be mainly synthesized by mitochondria. This speculation is supported by the recent discovery that aralkylamine N-acetyltransferase/serotonin N-acetyltransferase (AANAT/SNAT) is localized in mitochondria of oocytes and the isolated mitochondria generate melatonin. We have also speculated that melatonin is a mitochondria-targeted antioxidant. It accumulates in mitochondria with high concentration against a concentration gradient. This is probably achieved by an active transportation via mitochondrial melatonin transporter(s). Melatonin protects mitochondria by scavenging reactive oxygen species (ROS), inhibiting the mitochondrial permeability transition pore (MPTP), and activating uncoupling proteins (UCPs). Thus, melatonin maintains the optimal mitochondrial membrane potential and preserves mitochondrial functions. In addition, mitochondrial biogenesis and dynamics is also regulated by melatonin. In most cases, melatonin reduces mitochondrial fission and elevates their fusion. Mitochondrial dynamics exhibit an oscillatory pattern which matches the melatonin circadian secretory rhythm in pinealeocytes and probably in other cells. Recently, melatonin has been found to promote mitophagy and improve homeostasis of mitochondria. | Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics |
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0.3269403576850891, "25775": 0.13243216276168823, "25860": 0.5381823778152466, "26094": 0.4286321699619293, "26290": 0.013579257763922215, "26319": 0.09317722171545029, "26378": 0.13670019805431366, "26452": 0.03360854089260101, "26453": 0.129004567861557, "26462": 0.14433705806732178, "26485": 0.5984715819358826, "26556": 0.1619328260421753, "26728": 0.05046287178993225, "26847": 0.06429435312747955, "26957": 0.011650617234408855, "27196": 0.06429435312747955, "27197": 0.9363996982574463, "27523": 0.7791815400123596, "27622": 0.27044451236724854, "27641": 0.9394577741622925, "27694": 0.03831886500120163, "27756": 0.12728634476661682, "28227": 0.11081436276435852, "28321": 0.2990913391113281, "28767": 0.1619328260421753, "29048": 0.25694093108177185, "29295": 0.05046287178993225, "29392": 0.0770333781838417, "29569": 0.14518201351165771, "29589": 0.029824240133166313} | 14843502 | BACKGROUND Self-reported health status in underserved population of prisoners has not been extensively explored. The purposes of this cross-sectional study were to assess self-reported health, quality of life, and access to health services in a sample of male prisoners of Italy. METHODS A total of 908 prisoners received a self-administered anonymous questionnaire pertaining on demographic and detention characteristics, self-reported health status and quality of life, access to health services, lifestyles, and participation to preventive, social, and rehabilitation programs. A total of 650 prisoners agreed to participate in the study and returned the questionnaire. RESULTS Respectively, 31.6% and 43.5% of prisoners reported a poor perceived health status and a poor quality of life, and 60% admitted that their health was worsened or greatly worsened during the prison stay. Older age, lower education, psychiatric disorders, self-reported health problems on prison entry, and suicide attempts within prison were significantly associated with a perceived worse health status. At the time of the questionnaire delivery, 30% of the prisoners self-reported a health problem present on prison entry and 82% present at the time of the survey. Most frequently reported health problems included dental health problems, arthritis or joint pain, eye problems, gastrointestinal diseases, emotional problems, and high blood pressure. On average, prisoners encountered general practitioners six times during the previous year, and the frequency of medical encounters was significantly associated with older age, sentenced prisoners, psychiatric disorders, and self-reported health problems on prison entry. CONCLUSIONS The findings suggest that prisoners have a perceived poor health status, specific care needs and health promotion programs are seldom offered. Programs for correction of risk behaviour and prevention of long-term effects of incarceration on prisoners' health are strongly needed. | Self-reported health status and access to health services in a sample of prisoners in Italy |
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In response to hypoxia, cells express a variety of genes, which allow adaptation to altered metabolic demands, decreased oxygen demands, and the removal of irreversibly damaged cells. Using polymerase chain reaction–based suppression subtractive hybridization to find genes that are differentially expressed in hypoxia, we identified the BH3-only Bcl-2 family protein Noxa. Noxa is a candidate molecule mediating p53-induced apoptosis. We show that Noxa promoter responds directly to hypoxia via hypoxia-inducible factor (HIF)-1α. Suppression of Noxa expression by antisense oligonucleotides rescued cells from hypoxia-induced cell death and decreased infarction volumes in an animal model of ischemia. Further, we show that reactive oxygen species and resultant cytochrome c release participate in Noxa-mediated hypoxic cell death. Altogether, our results show that Noxa is induced by HIF-1α and mediates hypoxic cell death. | BH3-only Protein Noxa Is a Mediator of Hypoxic Cell Death Induced by Hypoxia-inducible Factor 1α |
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defining antigen specificity in systemic lupus erythematosus (SLE) and related musculoskeletal disorders but the mechanisms responsible for their induction remain mysterious. That situation rapidly changed once neutrophil extracellular chromatin traps (NETs) were discovered and observed to play a conserved role in innate immune responses to a broad variety of microbial pathogens. At the center of an infectious process, neutrophils exert various antimicrobial defenses, including the release of nuclear chromatin into the extracellular space. The externalized NETs, a complex meshwork of nuclear chromatin and antimicrobial proteins, serve to immobilize and degrade microbial pathogens. Here, we critically evaluate the evidence supporting NETs versus apoptotic bodies as a source for nuclear antigens in autoimmunity. We also discuss the possibility that NET chromatin forms an essential component of immune deposits in the pathogenesis of glomerulonephritis in SLE and other autoimmune immune complex diseases. | Neutrophil extracellular chromatin traps connect innate immune response to autoimmunity |
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"25644": 0.1808556467294693, "25690": 0.20739519596099854, "25708": 0.04767346754670143, "25714": 0.23402166366577148, "25950": 1.001607894897461, "26001": 0.03266380727291107, "26288": 0.06154331564903259, "26305": 0.012615402229130268, "26402": 0.21530038118362427, "26512": 0.6634125709533691, "26520": 0.4462870955467224, "26534": 0.3777405619621277, "26741": 0.05046287178993225, "26773": 0.7220231294631958, "26775": 0.4734157919883728, "27099": 0.6471850275993347, "27144": 0.0019512200960889459, "27321": 0.7863243818283081, "27395": 0.2711893916130066, "27854": 0.05694137513637543, "28086": 0.06703783571720123, "28156": 0.33115679025650024, "28815": 1.0587663650512695, "28848": 0.010684899985790253, "29170": 0.29981520771980286, "29206": 0.05970508232712746} | 14863011 | Kit/SCF signaling and Mitf-dependent transcription are both essential for melanocyte development and pigmentation. To identify Mitf-dependent Kit transcriptional targets in primary melanocytes, microarray studies were undertaken. Among identified targets was BCL2, whose germline deletion produces melanocyte loss and which exhibited phenotypic synergy with Mitf in mice. BCL2's regulation by Mitf was verified in melanocytes and melanoma cells and by chromatin immunoprecipitation of the BCL2 promoter. Mitf also regulates BCL2 in osteoclasts, and both Mitf(mi/mi) and Bcl2(-/-) mice exhibit severe osteopetrosis. Disruption of Mitf in melanocytes or melanoma triggered profound apoptosis susceptible to rescue by BCL2 overexpression. Clinically, primary human melanoma expression microarrays revealed tight nearest neighbor linkage for MITF and BCL2. This linkage helps explain the vital roles of both Mitf and Bcl2 in the melanocyte lineage and the well-known treatment resistance of melanoma. | Bcl2 Regulation by the Melanocyte Master Regulator Mitf Modulates Lineage Survival and Melanoma Cell Viability |
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0.35745587944984436, "28031": 0.1485546976327896, "28297": 0.05970508232712746, "28309": 0.13925230503082275, "28479": 1.0655186176300049, "28488": 0.016465263441205025, "28696": 0.02316705882549286, "28848": 0.5979346632957458, "28964": 0.23556606471538544, "29206": 0.06612417846918106} | 14864285 | Longevity is regulated by the daf-2 gene network in Caenorhabditis elegans. Mutations in the daf-2 gene, which encodes a member of the insulin receptor family, confer the life extension (Age) phenotype and the constitutive dauer (a growth-arrested larval form specialized for dispersal) formation phenotype. The Age phenotype is mutually potentiated by two life extension mutations in the daf-2 gene and the clk-1 gene, a homologue of yeast CAT5/COQ7 known to regulate ubiquinone biosynthesis. In this study, we demonstrated that the daf-2 mutation also conferred an oxidative stress resistance (Oxr) phenotype, which was also enhanced by the clk-1 mutation. Similar to the Age phenotype, the Oxr phenotype was regulated by the genetic pathway of insulin-like signaling from daf-2 to the daf-16 gene, a homologue of the HNF-3/forkhead transcription factor. These findings led us to examine whether the insulin-like signaling pathway regulates the gene expression of antioxidant defense enzymes. We found that the mRNA level of the sod-3 gene, which encodes Mn-superoxide dismutase (SOD), was much higher in daf-2 mutants than in the wild type. Moreover, the increased sod-3 gene expression phenotype is regulated by the insulin-like signaling pathway. Although the clk-1 mutant itself did not display Oxr and the increased sod-3 expression phenotypes, the clk-1 mutation enhanced them in the daf-2 mutant, suggesting that clk-1 is involved in longevity in two ways: clk-1 composes the original clk-1 longevity program and the daf-2 longevity program. These observations suggest that the daf-2 gene network controls longevity by regulating the Mn-SOD-associated antioxidant defense system. This system appears to play a role in efficient life maintenance at the dauer stage. | YOKO HONDA AND SHUJI HONDA 1 |
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"24545": 0.15023678541183472, "24552": 0.9409833550453186, "25194": 0.1734936386346817, "25761": 0.013579257763922215, "26657": 0.14179791510105133, "26942": 0.1064341589808464, "27133": 1.160461664199829, "27321": 0.5370414853096008, "27427": 0.18492233753204346, "27753": 0.6704301834106445, "27833": 0.34023189544677734, "28024": 0.1930064558982849, "28031": 0.19381128251552582, "28147": 0.04487626627087593, "28156": 0.42735910415649414, "28166": 0.20818853378295898, "28517": 0.036437395960092545, "28799": 0.7845434546470642} | 14865329 | Brown fat is a specialized fat depot that can increase energy expenditure and produce heat. After the recent discovery of the presence of active brown fat in human adults and novel transcription factors controlling brown adipocyte differentiation, the field of the study of brown fat has gained great interest and is rapidly growing. Brown fat expansion and/or activation results in increased energy expenditure and a negative energy balance in mice and limits weight gain. Brown fat is also able to utilize blood glucose and lipid and results in improved glucose metabolism and blood lipid independent of weight loss. Prolonged cold exposure and beta adrenergic agonists can induce browning of white adipose tissue. The inducible brown adipocyte, beige adipocyte evolving by thermogenic activation of white adipose tissue have different origin and molecular signature from classical brown adipocytes but share the characteristics of high mitochondria content, UCP1 expression and thermogenic capacity when activated. Increasing browning may also be an efficient way to increase whole brown fat activity. Recent human studies have shown possibilities that findings in mice can be reproduced in human, making brown fat a good candidate organ to treat obesity and its related disorders. | Brown Fat and Browning for the Treatment of Obesity and Related Metabolic Disorders |
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0.32199856638908386, "29516": 1.4046790599822998} | 14874811 | Oxygen (O2) deprivation, or hypoxia, has profound effects on cell metabolism and growth. Cells can adapt to low O2 in part through activation of hypoxia-inducible factor (HIF). We report here that hypoxia inhibits mRNA translation by suppressing multiple key regulators, including eIF2alpha, eEF2, and the mammalian target of rapamycin (mTOR) effectors 4EBP1, p70S6K, and rpS6, independent of HIF. Hypoxia results in energy starvation and activation of the AMPK/TSC2/Rheb/mTOR pathway. Hypoxic AMP-activated protein kinase (AMPK) activation also leads to eEF2 inhibition. Moreover, hypoxic effects on cellular bioenergetics and mTOR inhibition increase over time. Mutation of the TSC2 tumor suppressor gene confers a growth advantage to cells by repressing hypoxic mTOR inhibition and hypoxia-induced G1 arrest. Together, eIF2alpha, eEF2, and mTOR inhibition represent important HIF-independent mechanisms of energy conservation that promote survival under low O2 conditions. | Hypoxia-induced energy stress regulates mRNA translation and cell growth. |
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0.9987343549728394, "27781": 0.8425432443618774, "27854": 0.15610189735889435, "28282": 0.33605360984802246, "28297": 0.9857001900672913, "28424": 0.13157635927200317, "28432": 0.40089741349220276, "28522": 1.0285027027130127, "28728": 0.14179791510105133, "28815": 0.21214580535888672, "28848": 0.18248429894447327, "28976": 0.15275461971759796, "29172": 0.03831886500120163, "29477": 0.029824240133166313, "29486": 0.3346569836139679} | 14893425 | The loss of a glutamic acid residue in the AAA-ATPase (ATPases associated with diverse cellular activities) torsinA is responsible for most cases of early onset autosomal dominant primary dystonia. In this study, we found that snapin, which binds SNAP-25 (synaptosome-associated protein of 25,000 Da) and enhances the association of the SNARE complex with synaptotagmin, is an interacting partner for both wild type and mutant torsinA. Snapin co-localized with endogenous torsinA on dense core granules in PC12 cells and was recruited to perinuclear inclusions containing mutant DeltaE-torsinA in neuroblastoma SH-SY5Y cells. In view of these observations, synaptic vesicle recycling was analyzed using the lipophilic dye FM1-43 and an antibody directed against an intravesicular epitope of synaptotagmin I. We found that overexpression of wild type torsinA negatively affects synaptic vesicle endocytosis. Conversely, overexpression of DeltaE-torsinA in neuroblastoma cells increases FM1-43 uptake. Knockdown of snapin and/or torsinA using small interfering RNAs had a similar inhibitory effect on the exo-endocytic process. In addition, down-regulation of torsinA causes the persistence of synaptotagmin I on the plasma membrane, which closely resembles the effect observed by the overexpression of the DeltaE-torsinA mutant. Altogether, these findings suggest that torsinA plays a role together with snapin in regulated exocytosis and that DeltaE-torsinA exerts its pathological effects through a loss of function mechanism. This may affect neuronal uptake of neurotransmitters, such as dopamine, playing a role in the development of dystonic movements. | The dystonia-associated protein torsinA modulates synaptic vesicle recycling. |
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"28688": 1.0382318496704102, "28901": 0.10731173306703568, "28926": 0.055094651877880096, "29103": 0.4734157919883728, "29486": 0.4093637466430664} | 14893428 | This protocol describes a basic method for in vivo electroporation in the nervous system of embryonic mice. Delivery of electric pulses following microinjection of DNA into the brain ventricle or the spinal cord central canal enables efficient transfection of genes into the nervous system. Transfection is facilitated by forceps-type electrodes, which hold the uterus and/or the yolk sac containing the embryo. More than ten embryos in a single pregnant mouse can be operated on within 30 min. More than 90% of operated embryos survive and more than 90% of these survivors express the transfected genes appropriately. Gene expression in neurons persists for a long time, even at postnatal stages, after electroporation. Thus, this method could be used to analyze roles of genes not only in embryonic development but also in higher order function of the nervous system, such as learning. | In vivo electroporation in the embryonic mouse central nervous system |
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"26520": 0.1808556467294693, "26601": 0.08154398202896118, "26775": 0.8764448165893555, "26835": 0.4879087805747986, "27354": 0.015504186972975731, "27531": 0.04394211992621422, "27574": 0.045809537172317505, "27589": 0.052318159490823746, "27691": 0.3012613356113434, "28086": 0.3743882179260254, "28198": 0.025073638185858727, "28424": 0.3824150264263153, "28637": 0.00875066313892603, "28689": 0.10026945173740387, "29109": 0.7220231294631958, "29248": 0.13925230503082275, "29458": 0.03925827145576477} | 14915566 | Debate exists over how to incorporate information from multipartite sequence data in phylogenetic analyses. Strict combined-data approaches argue for concatenation of all partitions and estimation of one evolutionary history, maximizing the explanatory power of the data. Consensus/independence approaches endorse a two-step procedure where partitions are analyzed independently and then a consensus is determined from the multiple results. Mixtures across the model space of a strict combined-data approach and a priori independent parameters are popular methods to integrate these methods. We propose an alternative middle ground by constructing a Bayesian hierarchical phylogenetic model. Our hierarchical framework enables researchers to pool information across data partitions to improve estimate precision in individual partitions while permitting estimation and testing of tendencies in across-partition quantities. Such across-partition quantities include the distribution from which individual topologies relating the sequences within a partition are drawn. We propose standard hierarchical priors on continuous evolutionary parameters across partitions, while the structure on topologies varies depending on the research problem. We illustrate our model with three examples. We first explore the evolutionary history of the guinea pig (Cavia porcellus) using alignments of 13 mitochondrial genes. The hierarchical model returns substantially more precise continuous parameter estimates than an independent parameter approach without losing the salient features of the data. Second, we analyze the frequency of horizontal gene transfer using 50 prokaryotic genes. We assume an unknown species-level topology and allow individual gene topologies to differ from this with a small estimable probability. Simultaneously inferring the species and individual gene topologies returns a transfer frequency of 17%. We also examine HIV sequences longitudinally sampled from HIV+ patients. We ask whether posttreatment development of CCR5 coreceptor virus represents concerted evolution from middisease CXCR4 virus or reemergence of initial infecting CCR5 virus. The hierarchical model pools partitions from multiple unrelated patients by assuming that the topology for each patient is drawn from a multinomial distribution with unknown probabilities. Preliminary results suggest evolution and not reemergence. | Hierarchical phylogenetic models for analyzing multipartite sequence data. |
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"24396": 0.42544642090797424, "24558": 0.11691460013389587, "25100": 0.058784693479537964, "25531": 0.5427330136299133, "25802": 0.15359249711036682, "26285": 0.11951763927936554, "27354": 0.37102460861206055, "27425": 0.1685553640127182, "27467": 0.10906458646059036, "27530": 0.021256839856505394, "27642": 0.1718502640724182, "27645": 0.13670019805431366, "27854": 0.034552380442619324, "28079": 0.2954642176628113, "28332": 1.109619140625, "28424": 0.14349138736724854, "28648": 0.11168810725212097, "28893": 0.28597161173820496, "29297": 1.179255723953247} | 14920021 | Gold standard datasets on protein complexes are key to inferring and validating protein-protein interactions. Despite much progress in characterizing protein complexes in the yeast Saccharomyces cerevisiae, numerous researchers still use as reference the manually curated complexes catalogued by the Munich Information Center of Protein Sequences database. Although this catalogue has served the community extremely well, it no longer reflects the current state of knowledge. Here, we report two catalogues of yeast protein complexes as results of systematic curation efforts. The first one, denoted as CYC2008, is a comprehensive catalogue of 408 manually curated heteromeric protein complexes reliably backed by small-scale experiments reported in the current literature. This catalogue represents an up-to-date reference set for biologists interested in discovering protein interactions and protein complexes. The second catalogue, denoted as YHTP2008, comprises 400 high-throughput complexes annotated with current literature evidence. Among them, 262 correspond, at least partially, to CYC2008 complexes. Evidence for interacting subunits is collected for 68 complexes that have only partial or no overlap with CYC2008 complexes, whereas no literature evidence was found for 100 complexes. Some of these partially supported and as yet unsupported complexes may be interesting candidates for experimental follow up. Both catalogues are freely available at: http://wodaklab.org/cyc2008/. | Up-to-date catalogues of yeast protein complexes |
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(ESCs) in serum, to lineage-primed epiblast stem cells (EpiSCs). To investigate the role of DNA methylation (5mC) across distinct pluripotent states, we mapped genome-wide 5mC and 5-hydroxymethycytosine (5hmC) in multiple PSCs. Ground-state ESCs exhibit an altered distribution of 5mC and 5hmC at regulatory elements and dramatically lower absolute levels relative to ESCs in serum. By contrast, EpiSCs exhibit increased promoter 5mC coupled with reduced 5hmC, which contributes to their developmental restriction. Switch to 2i triggers rapid onset of both the ground-state gene expression program and global DNA demethylation. Mechanistically, repression of de novo methylases by PRDM14 drives DNA demethylation at slow kinetics, whereas TET1/TET2-mediated 5hmC conversion enhances both the rate and extent of hypomethylation. These processes thus act synergistically during transition to ground-state pluripotency to promote a robust hypomethylated state. | Synergistic Mechanisms of DNA Demethylation during Transition to Ground-State Pluripotency |
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Despite the high incidence of febrile seizures, their contribution to the development of epilepsy later in life has remained controversial. Combining a new rat model of complex febrile seizures and patch clamp techniques, we determined that hyperthermia-induced seizures in the immature rat cause a selective presynaptic increase in inhibitory synaptic transmission in the hippocampus that lasts into adulthood. The long-lasting nature of these potent alterations in synaptic communication after febrile seizures does not support the prevalent view of the 'benign' nature of early-life febrile convulsions. | Febrile seizures in the developing brain result in persistent modification of neuronal excitability in limbic circuits |
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"26862": 0.020300358533859253, "26874": 0.10026945173740387, "26944": 0.10203468054533005, "27195": 0.04860413447022438, "27480": 0.025073638185858727, "27674": 0.14179791510105133, "28290": 1.0492360591888428, "28685": 0.4770587682723999, "28828": 0.812664806842804, "28829": 0.7191727757453918, "28901": 0.8400169610977173, "28927": 0.37974658608436584, "28984": 0.8091925978660583, "29091": 0.010684899985790253, "29111": 0.4537591338157654, "29217": 0.02792670577764511, "29281": 0.1718502640724182} | 14926162 | The short stem and midrib (ssm) mutants of Arabidopsis thaliana show both semi-dwarf and wavy leaf phenotypes due to defects in the elongation of the stem internodes and leaves. Moreover, these abnormalities cannot be recovered by exogenous phytohormones. ssm was originally identified as a single recessive mutant of the ecotype Columbia (Col-0), but genetic crossing experiments have revealed that this mutant phenotype is restored by another gene that is functional in the ecotype Landsberg erecta (Ler) and not in Col-0. Map-based cloning of the gene that is defective in ssm mutants has uncovered a small deletion in the sixth intron of a gene encoding a syntaxin, VAM3/SYP22, which has been implicated in vesicle transport to the vacuole. This mutation appears to cause a peptide insertion in the deduced VAM3/SYP22 polypeptide sequence due to defective splicing of the shortened sixth intron. Significantly, when compared with the wild-type Ler genome, the wild-type Col-0 genome has a single base pair deletion causing a frameshift mutation in SYP23, a gene with the highest known homology to VAM3/SYP22. These findings suggest that VAM3/SYP22 and SYP23 have overlapping functions and that the vesicle transport mediated by these syntaxins is important for shoot morphogenesis. | Identification of an allele of VAM3/SYP22 that confers a semi-dwarf phenotype in Arabidopsis thaliana. |
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"27152": 0.5540198087692261, "27177": 1.4723286628723145, "27321": 0.5557019114494324, "27781": 0.3409265875816345, "27814": 0.022212404757738113, "28156": 0.5920094847679138, "28227": 0.6931471824645996, "28311": 0.7592713832855225, "28352": 1.1834511756896973, "28548": 0.21214580535888672, "28788": 0.6197150945663452, "28805": 0.20102575421333313, "28873": 0.5838727951049805, "28896": 0.49864232540130615, "29490": 0.39696553349494934, "29491": 0.9115922451019287} | 14934137 | CD8(+) T cells are required for protective immunity against intracellular pathogens such as Listeria monocytogenes. In this study, we used class Ia MHC-deficient mice, which have a severe reduction in circulating CD8(+) T cells, to determine the protective capacity of class Ib MHC-restricted T cells during L. monocytogenes infection. The K(b-/-)D(b-/-) mutation was backcrossed onto a C.B10 (BALB/c congenic at H-2 locus with C57BL/10) background, because BALB/c mice are more susceptible to Listeria infection than other commonly studied mouse strains such as C57BL/6. C.B10 K(b-/-)D(b-/-) mice immunized with a sublethal dose of L. monocytogenes were fully protected against a subsequent lethal infection. Adoptive transfer of Listeria-immune splenocyte subsets into naive K(b-/-)D(b-/-) mice indicated that CD8(+) T cells were the major component of this protective immune response. A CD8(+) T cell line isolated from the spleen of a Listeria-infected class Ia MHC-deficient mouse was shown to specifically recognize Listeria-infected cells in vitro, as determined by IFN-gamma secretion and cytotoxicity assays. Adoptive transfer of this T cell line alone resulted in significant protection against L. monocytogenes challenge. These results suggest that even a limited number of class Ib MHC-restricted T cells are sufficient to generate the rapid recall response required for protection against secondary infection with L. monocytogenes. | Class Ia MHC-deficient BALB/c mice generate CD8+ T cell-mediated protective immunity against Listeria monocytogenes infection. |
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Programmed death 1 (PD-1), a negative T cell regulator to maintain peripheral tolerance, induces negative signals to T cells during interaction with its ligands and is therefore a candidate gene in the development of SLE. In order to examine whether expression levels of PD-1 contribute to the pathogenesis of SLE, 30 patients with SLE and 30 controls were recruited and their PD-1 expression levels in peripheral blood mononuclear cells (PBMCs) were measured via flow cytometry and quantitative real-time-reverse transcription polymerase chain reaction (RT-PCR). Also, whether PD-1 expression levels are associated with the variant of the SNP rs36084323 and the SLE Disease Activity Index (SLEDAI) was studied in this work. The PD-1 expression levels of SLE patients were significantly increased compared with those of the healthy controls. The upregulated PD-1 expression levels in SLE patients were greatly associated with SLEDAI scores. No significant difference was found between PD-1 expression levels and SNP rs36084323. The results suggest that increased expression of PD-1 may correlate with the pathogenesis of SLE, upregulated PD-1 expression may be a biomarker for SLE diagnosis, and PD-1 inhibitor may be useful to SLE treatment. | Upregulated PD-1 Expression Is Associated with the Development of Systemic Lupus Erythematosus, but Not the PD-1.1 Allele of the PDCD1 Gene |
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Here we report on its extraglomerular localization, using a monospecific antibody which was obtained by affinity purification of IgG on nitrocellulose transfers of glomerular podocalyxin. By indirect immunofluorescence, podocalyxin was found in the blood vessels of several organs (lung, heart, kidney, small intestine, brain, pancreas, aorta, the periportal blood vessels in liver, and the central arteries of follicles of the spleen, but not in the endothelia that line the sinusoids of the latter organs). By immunoelectron microscopy--using immunogold conjugates in diffusion ("pre-embedding") and surface ("postembedding") procedures--podocalyxin was localized on the luminal membrane domain of endothelial cells, in a patchy distribution. The presence of podocalyxin was confirmed in SDS extracts of lung tissue by immunoblotting. We conclude that (a) podocalyxin is a widespread component of endothelial plasma membranes, (b) it is restricted to the luminal membrane domain, and (c) it is distributed unevenly on the endothelial cell surface. | Endothelial cell membranes contain podocalyxin--the major sialoprotein of visceral glomerular epithelial cells |
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0.5512100458145142, "29290": 0.3910386264324188} | 14972169 | Exposure during the organogenesis stage of the mouse embryo to the model teratogen, hydroxyurea (HU), induces curly tail and limb malformations. Oxidative stress contributes to the developmental toxicity of HU. Reactive oxygen species (ROS) interact with polyunsaturated bilipid membranes to form α,β-unsaturated reactive aldehydes; 4-hydroxy-2-nonenal (4-HNE), one of the most cytotoxic of these aldehydes, covalently adducts with proteins, lipids, and nucleic acids. The goal of the current study is to determine if HU exposure of CD1 mice on gestation day 9 generates region-specific 4-HNE-protein adducts in the embryo and to identify the proteins targeted. The formation of 4-HNE-protein adducts was elevated in the caudal region of control embryos; HU exposure further increased 4-HNE-protein adduct formation in this area. Interestingly, three of the 4-HNE-modified proteins, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), glutamate oxaloacetate transaminase 2, and aldolase 1, A isoform, are involved in energy metabolism. The formation of 4-HNE-GAPDH protein adducts reduced GAPDH enzymatic activity by 20% and attenuated lactate production by 40%. Furthermore, HU exposure induced the nuclear translocation of GAPDH in the caudal region of exposed embryos; this nuclear translocation may be associated with the reactivation of oxidized proteins involved in DNA repair, such as apurinic/apyrimidinic endonuclease-1, and the stimulation of E1A-associated P300 protein/creb-binding protein (p300/CBP) activity, initiating cell death in a p53-dependent pathway. We propose that GAPDH is a redox-sensitive target in the embryo and may play a role in a stress response during development. | Teratogen-Induced Oxidative Stress Targets Glyceraldehyde-3-Phosphate Dehydrogenase in the Organogenesis Stage Mouse Embryo |
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0.4286321699619293, "26206": 0.004870930220931768, "26226": 0.23402166366577148, "26525": 0.1221139207482338, "26846": 0.2501201331615448, "27065": 0.15943801403045654, "27144": 0.5651806592941284, "27788": 0.21530038118362427, "27881": 0.043007105588912964, "27963": 0.23402166366577148, "28093": 0.12986256182193756, "28155": 0.07884006202220917, "28207": 0.5450005531311035, "28297": 0.23864774405956268, "28353": 0.013579257763922215, "28667": 0.9987343549728394, "28879": 0.6451379656791687, "29251": 0.2763880789279938, "29264": 1.0312920808792114, "29278": 0.016465263441205025, "29361": 0.04674193635582924} | 14973286 | A small proportion of patients with deep vein thrombosis develop recurrent venous thromboembolic complications or bleeding during anticoagulant treatment. These complications may occur more frequently if these patients have concomitant cancer. This prospective follow-up study sought to determine whether in thrombosis patients those with cancer have a higher risk for recurrent venous thromboembolism or bleeding during anticoagulant treatment than those without cancer. Of the 842 included patients, 181 had known cancer at entry. The 12-month cumulative incidence of recurrent thromboembolism 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 a hazard ratio of 3.2 (95% CI, 1.9-5.4) The 12-month cumulative incidence of major bleeding was 12.4% (95% CI, 6.5%-18.2%) in patients with cancer and 4.9% (95% CI, 2.5%-7.4%) in patients without cancer, for a hazard ratio of 2.2 (95% CI, 1.2-4.1). Recurrence and bleeding were both related to cancer severity and occurred predominantly during the first month of anticoagulant therapy but could not be explained by sub- or overanticoagulation. Cancer patients with venous thrombosis are more likely to develop recurrent thromboembolic complications and major bleeding during anticoagulant treatment than those without malignancy. These risks correlate with the extent of cancer. Possibilities for improvement using the current paradigms of anticoagulation seem limited and new treatment strategies should be developed. | Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. |
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0.10731173306703568, "25837": 0.41195443272590637, "26163": 0.3353555500507355, "26237": 0.47584590315818787, "26319": 0.23864774405956268, "26633": 0.3601844012737274, "26657": 0.09672962874174118, "26743": 0.2983669638633728, "27203": 0.7047978043556213, "27354": 0.24859806895256042, "27487": 0.0009760859538801014, "27615": 0.021256839856505394, "28283": 0.5893046259880066, "28321": 0.09495500475168228, "28488": 0.007782140281051397, "28648": 0.20102575421333313, "28937": 0.1619328260421753, "29458": 0.13670019805431366} | 15040589 | BACKGROUND Multilevel models (MLM) offer complex survey data analysts a unique approach to understanding individual and contextual determinants of public health. However, little summarized guidance exists with regard to fitting MLM in complex survey data with design weights. Simulation work suggests that analysts should scale design weights using two methods and fit the MLM using unweighted and scaled-weighted data. This article examines the performance of scaled-weighted and unweighted analyses across a variety of MLM and software programs. METHODS Using data from the 2005-2006 National Survey of Children with Special Health Care Needs (NS-CSHCN: n = 40,723) that collected data from children clustered within states, I examine the performance of scaling methods across outcome type (categorical vs. continuous), model type (level-1, level-2, or combined), and software (Mplus, MLwiN, and GLLAMM). RESULTS Scaled weighted estimates and standard errors differed slightly from unweighted analyses, agreeing more with each other than with unweighted analyses. However, observed differences were minimal and did not lead to different inferential conclusions. Likewise, results demonstrated minimal differences across software programs, increasing confidence in results and inferential conclusions independent of software choice. CONCLUSION If including design weights in MLM, analysts should scale the weights and use software that properly includes the scaled weights in the estimation. | Fitting multilevel models in complex survey data with design weights: Recommendations |
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0.2696990668773651, "28756": 0.006812678650021553, "28767": 0.176772341132164, "28886": 0.011650617234408855, "29048": 0.8796916007995605, "29166": 0.11256109178066254, "29295": 0.0842406153678894, "29370": 0.06154331564903259} | 15041758 | OBJECTIVE To evaluate the effectiveness of integrated care for chronic physical diseases and depression in reducing disability and improving quality of life. DESIGN A randomised controlled trial of multi-condition collaborative care for depression and poorly controlled diabetes and/or risk factors for coronary heart disease compared with usual care among middle aged and elderly people SETTING Fourteen primary care clinics in Seattle, Washington. PARTICIPANTS Patients with diabetes or coronary heart disease, or both, and blood pressure above 140/90 mm Hg, low density lipoprotein concentration >3.37 mmol/L, or glycated haemoglobin 8.5% or higher, and PHQ-9 depression scores of ≥ 10. INTERVENTION A 12 month intervention to improve depression, glycaemic control, blood pressure, and lipid control by integrating a "treat to target" programme for diabetes and risk factors for coronary heart disease with collaborative care for depression. The intervention combined self management support, monitoring of disease control, and pharmacotherapy to control depression, hyperglycaemia, hypertension, and hyperlipidaemia. MAIN OUTCOME MEASURES Social role disability (Sheehan disability scale), global quality of life rating, and World Health Organization disability assessment schedule (WHODAS-2) scales to measure disabilities in activities of daily living (mobility, self care, household maintenance). RESULTS Of 214 patients enrolled (106 intervention and 108 usual care), disability and quality of life measures were obtained for 97 intervention patients at six months (92%) and 92 at 12 months (87%), and for 96 usual care patients at six months (89%) and 92 at 12 months (85%). Improvements from baseline on the Sheehan disability scale (-0.9, 95% confidence interval -1.5 to -0.2; P = 0.006) and global quality of life rating (0.7, 0.2 to 1.2; P = 0.005) were significantly greater at six and 12 months in patients in the intervention group. There was a trend toward greater improvement in disabilities in activities of daily living (-1.5, -3.3 to 0.4; P = 0.10). CONCLUSIONS Integrated care that covers chronic physical disease and comorbid depression can reduce social role disability and enhance global quality of life. Trial registration Clinical Trials NCT00468676. | Functional outcomes of multi-condition collaborative care and successful ageing: results of randomised trial |
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"29110": 0.0354953333735466, "29234": 0.44753631949424744, "29514": 0.08244366943836212} | 15048300 | BACKGROUND Data on absolute risks of outcomes and patterns of drug use in cost-effectiveness analyses are often based on randomised clinical trials (RCTs). The objective of this study was to evaluate the external validity of published cost-effectiveness studies by comparing the data used in these studies (typically based on RCTs) to observational data from actual clinical practice. Selective Cox-2 inhibitors (coxibs) were used as an example. METHODS AND FINDINGS The UK General Practice Research Database (GPRD) was used to estimate the exposure characteristics and individual probabilities of upper gastrointestinal (GI) events during current exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) or coxibs. A basic cost-effectiveness model was developed evaluating two alternative strategies: prescription of a conventional NSAID or coxib. Outcomes included upper GI events as recorded in GPRD and hospitalisation for upper GI events recorded in the national registry of hospitalisations (Hospital Episode Statistics) linked to GPRD. Prescription costs were based on the prescribed number of tables as recorded in GPRD and the 2006 cost data from the British National Formulary. The study population included over 1 million patients prescribed conventional NSAIDs or coxibs. Only a minority of patients used the drugs long-term and daily (34.5% of conventional NSAIDs and 44.2% of coxibs), whereas coxib RCTs required daily use for at least 6-9 months. The mean cost of preventing one upper GI event as recorded in GPRD was US$104k (ranging from US$64k with long-term daily use to US$182k with intermittent use) and US$298k for hospitalizations. The mean costs (for GPRD events) over calendar time were US$58k during 1990-1993 and US$174k during 2002-2005. Using RCT data rather than GPRD data for event probabilities, the mean cost was US$16k with the VIGOR RCT and US$20k with the CLASS RCT. CONCLUSIONS The published cost-effectiveness analyses of coxibs lacked external validity, did not represent patients in actual clinical practice, and should not have been used to inform prescribing policies. External validity should be an explicit requirement for cost-effectiveness analyses. | A Comparison of Cost Effectiveness Using Data from Randomized Trials or Actual Clinical Practice: Selective Cox-2 Inhibitors as an Example |
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"28873": 0.21293537318706512, "29290": 0.2749055027961731, "29489": 0.0038986403960734606, "29720": 0.05139094591140747} | 15058155 | EBI2, aka GPR183, is a G-couple receptor originally identified in 1993 as one of main genes induced in Burkitt's lymphoma cell line BL41 by Epstein-Barr virus (EBV) infection. After it was reported in 2009 that the receptor played a key role in regulating B cell migration and responses, we initiated an effort in looking for its endogenous ligand. In 2011 we and another group reported the identification of 7α, 25-dihydroxyxcholesterol (7α, 25-OHC), an oxysterol, as the likely physiological ligand of EBI2. A few subsequently published studies further elucidated how 7α, 25-OHC bound to EBI2, and how a gradient of 7α, 25-OHC could be generated 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-OHC as a G protein-coupled receptor ligand revealed a previously unknown signaling system of oxysterols, a class of molecules which exert profound biological functions. Dysregulation of the synthesis or functions of these molecules is believed to contribute to inflammation and autoimmune diseases, cardiovascular diseases, neurodegenerative diseases, cancer as well as metabolic diseases such as diabetes, obesity, and dyslipidemia. Therefore EBI2 may represent a promising target for therapeutic interventions for human diseases. | 7α, 25-dihydroxycholesterol-mediated activation of EBI2 in immune regulation and diseases |
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Thus, numerous mechanisms exist to complete genome duplication in the absence of a pristine DNA template, but identification of the enzymes involved remains incomplete. Here, we establish that Primase-Polymerase (PrimPol; CCDC111), an archaeal-eukaryotic primase (AEP) in eukaryotic cells, is involved in chromosomal DNA replication. PrimPol is required for replication fork progression on ultraviolet (UV) light-damaged DNA templates, possibly mediated by its ability to catalyze translesion synthesis (TLS) of these lesions. This PrimPol UV lesion bypass pathway is not epistatic with the Pol η-dependent pathway and, as a consequence, protects xeroderma pigmentosum variant (XP-V) patient cells from UV-induced cytotoxicity. In addition, we establish that PrimPol is also required for efficient replication fork progression during an unperturbed S phase. These and other findings indicate that PrimPol is an important player in replication fork progression in eukaryotic cells. | PrimPol Bypasses UV Photoproducts during Eukaryotic Chromosomal DNA Replication |
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"24294": 0.15023678541183472, "24335": 1.1659544706344604, "24582": 0.00875066313892603, "24759": 0.43053874373435974, "24940": 0.45623743534088135, "24960": 0.8100618124008179, "25128": 0.2954642176628113, "25206": 0.10026945173740387, "25409": 0.7510106563568115, "25456": 0.29619070887565613, "25468": 0.4450363218784332, "25714": 0.839173436164856, "26402": 0.846739649772644, "26632": 0.5232481360435486, "26745": 0.5925496220588684, "26778": 0.38041436672210693, "26986": 0.083342544734478, "27144": 0.151916041970253, "27295": 0.08603433519601822, "27512": 1.1406835317611694, "27781": 0.14095009863376617, "27881": 0.05417001247406006, "27929": 0.05786345899105072, "28207": 0.2652147710323334, "28788": 0.4556184411048889, "28873": 0.6369074583053589, "29480": 0.034552380442619324, "29490": 0.18004031479358673, "29610": 0.3134697377681732} | 15081770 | We previously reported a strong IL4I1 gene expression in primary mediastinal B-cell lymphoma (PMBL) and recently identified the protein as a secreted L-phenylalanine oxidase, physiologically expressed by myeloid cells, which inhibits T-cell proliferation in vitro. Here, we analyzed the pattern of IL4I1 protein expression in 315 human lymphoid and non-lymphoid malignancies. Besides PMBL, IL4I1 expression in tumors was very frequent. IL4I1 was detected in tumor-associated macrophages from most of the tumors and in neoplastic cells from follicular lymphoma, classic and nodular lymphocyte predominant Hodgkin lymphomas and small lymphocytic lymphoma, three of which are germinal center derived. IL4I1-positive tumor cells were also detected in rare cases of solid cancers, mainly mesothelioma. The enzymatic activity paralleled protein expression, suggesting that IL4I1 is functional in vivo. Depending on the tumor type, IL4I1 may impact on different infiltrating lymphocyte populations with consequences on tumor evolution. In the particular case of follicular lymphoma cells, which are susceptible to antitumor cytotoxic T cells killing but depend on interactions with local T helper cells for survival, a high level of IL4I1 expression seems associated with the absence of bone marrow involvement and a better outcome. These findings plead for an evaluation of IL4I1 as a prognosis factor. | The novel immunosuppressive enzyme IL4I1 is expressed by neoplastic cells of several B-cell lymphomas and by tumor-associated macrophages |
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0.11604541540145874, "27144": 0.436867892742157, "27263": 0.08782484382390976, "27292": 0.5865923762321472, "27354": 0.3325583338737488, "27854": 0.1064341589808464, "27881": 0.05417001247406006, "28032": 0.9650808572769165, "28093": 1.0312920808792114, "28283": 0.678390383720398, "28327": 0.9739698171615601, "28848": 0.7647408246994019, "28873": 0.08782484382390976, "28987": 0.8534175157546997, "29458": 0.5723689198493958} | 15113221 | Pathway-specific therapy is the future of cancer management. The oncogenic phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in solid tumors; however, currently, no reliable test for PI3K pathway activation exists for human tumors. Taking advantage of the observation that loss of PTEN, the negative regulator of PI3K, results in robust activation of this pathway, we developed and validated a microarray gene expression signature for immunohistochemistry (IHC)-detectable PTEN loss in breast cancer (BC). The most significant signature gene was PTEN itself, indicating that PTEN mRNA levels are the primary determinant of PTEN protein levels in BC. Some PTEN IHC-positive BCs exhibited the signature of PTEN loss, which was associated to moderately reduced PTEN mRNA levels cooperating with specific types of PIK3CA mutations and/or amplification of HER2. This demonstrates that the signature is more sensitive than PTEN IHC for identifying tumors with pathway activation. In independent data sets of breast, prostate, and bladder carcinoma, prediction of pathway activity by the signature correlated significantly to poor patient outcome. Stathmin, encoded by the signature gene STMN1, was an accurate IHC marker of the signature and had prognostic significance in BC. Stathmin was also pathway-pharmacodynamic in vitro and in vivo. Thus, the signature or its components such as stathmin may be clinically useful tests for stratification of patients for anti-PI3K pathway therapy and monitoring therapeutic efficacy. This study indicates that aberrant PI3K pathway signaling is strongly associated with metastasis and poor survival across carcinoma types, highlighting the enormous potential impact on patient survival that pathway inhibition could achieve. | Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. |
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Trypanosoma brucei causes human African trypanosomiasis and regularly switches its major surface antigen, VSG, in the bloodstream of its mammalian host to evade the host immune response. VSGs are expressed exclusively from subtelomeric loci, and we have previously shown that telomere proteins TbTIF2 and TbRAP1 play important roles in VSG switching and VSG silencing regulation, respectively. We now discover that the telomere duplex DNA-binding factor, TbTRF, also plays a critical role in VSG switching regulation, as a transient depletion of TbTRF leads to significantly more VSG switching events. We solved the NMR structure of the DNA-binding Myb domain of TbTRF, which folds into a canonical helix-loop-helix structure that is conserved to the Myb domains of mammalian TRF proteins. The TbTRF Myb domain tolerates well the bulky J base in T. brucei telomere DNA, and the DNA-binding affinity of TbTRF is not affected by the presence of J both in vitro and in vivo. In addition, we find that point mutations in TbTRF Myb that significantly reduced its in vivo telomere DNA-binding affinity also led to significantly increased VSG switching frequencies, indicating that the telomere DNA-binding activity is critical for TbTRF's role in VSG switching regulation. | Suppression of subtelomeric VSG switching by Trypanosoma brucei TRF requires its TTAGGG repeat-binding activity |
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disease with high mortality rate and limited treatment options. Immunotherapy based on tumor-targeting cytotoxic T cell responses represents a promising strategy. To assist in its development, we examined the possibility and efficacy of using CD4+ cytotoxic T cells. The regulatory mechanisms controlling CD4+ T cell-mediated cytotoxicity were also investigated. We found that naturally occurring granzyme B and perforin-expressing CD4+ cytotoxic T cells can be recovered from metastatic melanoma patients at significantly elevated frequencies compared to those from healthy controls. These CD4+ cytotoxic T cells were also capable of killing autologous tumor cells harvested from metastatic melanoma, independent of CD8+ T cells or any other cell types. However, several restricting factors were observed. First, the cytolytic activity by CD4+ T cells required high MHC class II expression on melanoma cells, which was not satisfied in a subset of melanomas. Second, the granzyme B and perforin release by activated CD4+ cytotoxic T cells was reduced after coculturing with autologous melanoma cells, characterized by low LAMP-1 expression and low granzyme B and perforin secretion in the supernatant. This suggested that inhibitory mechanisms were present to suppress CD4+ cytotoxic T cells. Indeed, blockade of PD-1 and CTLA-4 had increased the cytolytic activity of CD4+ T cells but was only effective in MHC class II high but not MHC class II low melanomas. Together, our study showed that CD4+ T cell-mediated cytotoxicity could eliminate primary melanoma cells but the efficacy depended on MHC class II expression. | CD4+ T cell-mediated cytotoxicity eliminates primary tumor cells in metastatic melanoma through high MHC class II expression and can be enhanced by inhibitory receptor blockade |
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"26099": 0.4734157919883728, "26236": 0.4450363218784332, "26237": 0.2689530849456787, "26305": 0.17840765416622162, "26616": 0.25088030099868774, "26770": 0.009718249551951885, "26835": 0.66441810131073, "26957": 0.14349138736724854, "27258": 0.9333322048187256, "28170": 0.10906458646059036, "28321": 0.48430517315864563, "28359": 0.09050461649894714, "28389": 1.5423963069915771, "28498": 0.27712854743003845, "28937": 1.1882244348526, "29458": 0.5186077356338501} | 15129362 | Hepatitis C virus (HCV) is a leading cause of liver cancer and cirrhosis, and Egypt has possibly the highest HCV prevalence worldwide. In this article we use a newly developed Bayesian inference framework to estimate the transmission dynamics of HCV in Egypt from sampled viral gene sequences, and to predict the public health impact of the virus. Our results indicate that the effective number of HCV infections in Egypt underwent rapid exponential growth between 1930 and 1955. The timing and speed of this spread provides quantitative genetic evidence that the Egyptian HCV epidemic was initiated and propagated by extensive antischistosomiasis injection campaigns. Although our results show that HCV transmission has since decreased, we conclude that HCV is likely to remain prevalent in Egypt for several decades. Our combined population genetic and epidemiological analysis provides detailed estimates of historical changes in Egyptian HCV prevalence. Because our results are consistent with a demographic scenario specified a priori, they also provide an objective test of inference methods based on the coalescent process. | The epidemiology and iatrogenic transmission of hepatitis C virus in Egypt: a Bayesian coalescent approach. |
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highlights methods for using geospatial analysis to assess, enhance, and improve recruitment efforts to ensure representativeness in study populations. We apply these methods to the Measurement to Understand Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) study, a longitudinal population health study focused on the city of Kannapolis and Cabarrus County, NC. Although efforts have been made to recruit a participant registry that is representative of the 18 ZIP code catchment region inclusive of Cabarrus County and Kannapolis, bias in such recruitment is inevitable. Participants in the MURDOCK study are geospatially referenced at entry, providing information that can be used to monitor and guide recruitment efforts. MURDOCK participant population representativeness was assessed using chi-squared tests to compare the MURDOCK population with 2010 Census data, relative to both the entire 18 ZIP code catchment area and for individual Census tracts. A logistic regression model was fit to characterize Census tracts with low recruitment, defined by fewer than 56 participants from that tract. The distance to the site at which participants enrolled was calculated, and median distance to enrollment site was used in the logistic regression. Tracts with low recruitment rates contained higher minority and younger populations, suggesting specific strategies for improving recruitment in these areas. Areal units farther away from enrollment sites were also not well-sampled, despite being in the specified study area, indicating that distance traveled to enrollment may be a barrier. These results have implications for targeting recruitment efforts and representative samples more generally, including in other population-based studies. | Improving population representation through geographic health information systems: mapping the MURDOCK study. |
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0.5232481360435486, "26944": 0.13157635927200317, "26994": 0.04207121208310127, "27080": 0.02316705882549286, "27423": 0.11865071207284927, "27642": 0.3656192123889923, "27963": 0.0354953333735466, "28093": 0.41195443272590637, "28329": 0.04767346754670143, "28873": 0.23710809648036957, "28911": 0.3012613356113434, "28937": 0.2637155055999756, "29458": 0.5267143249511719} | 15153602 | The direct detection of haplotypes from short-read DNA sequencing data requires changes to existing small-variant detection methods. Here, we develop a Bayesian statistical framework which is capable of modeling multiallelic loci in sets of individuals with non-uniform copy number. We then describe our implementation of this framework in a haplotype-based variant detector, FreeBayes. | Haplotype-based variant detection from short-read sequencing |
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0.22782009840011597, "25206": 0.1685553640127182, "25353": 0.015504186972975731, "25469": 0.08603433519601822, "25510": 0.8057082891464233, "25524": 0.45994341373443604, "25856": 0.9658246636390686, "25947": 0.0752234235405922, "26226": 1.25777268409729, "26270": 0.09850110858678818, "26305": 0.43623676896095276, "26521": 0.07341018319129944, "26601": 0.04113444685935974, "26741": 0.35128939151763916, "26745": 0.12986256182193756, "26976": 0.03266380727291107, "27197": 0.9591107368469238, "27480": 0.21135559678077698, "27814": 0.12728634476661682, "27833": 0.5833279490470886, "28024": 0.9363996982574463, "28093": 0.29473719000816345, "28154": 0.8298473954200745, "28177": 0.306306391954422, "28290": 0.2501201331615448, "28353": 0.4673144817352295, "28436": 0.10203468054533005, "28794": 0.0038986403960734606, "29101": 0.34922540187835693, "29206": 0.0752234235405922, "29458": 0.9386941194534302} | 15155862 | Cardiovascular disease (CVD) is the leading cause of death worldwide. Recent genome-wide association (GWA) studies have pinpointed many loci associated with CVD risk factors in adults. It is unclear, however, if these loci predict trait levels at all ages, if they are associated with how a trait develops over time, or if they could be used to screen individuals who are pre-symptomatic to provide the opportunity for preventive measures before disease onset. We completed a genome-wide association study on participants in the longitudinal Bogalusa Heart Study (BHS) and have characterized the association between genetic factors and the development of CVD risk factors from childhood to adulthood. We report 7 genome-wide significant associations involving CVD risk factors, two of which have been previously reported. Top regions were tested for replication in the Young Finns Study (YF) and two associations strongly replicated: rs247616 in CETP with HDL levels (combined P = 9.7 x 10(-24)), and rs445925 at APOE with LDL levels (combined P = 8.7 x 10(-19)). We show that SNPs previously identified in adult cross-sectional studies tend to show age-independent effects in the BHS with effect sizes consistent with previous reports. Previously identified variants were associated with adult trait levels above and beyond those seen in childhood; however, variants with time-dependent effects were also promising predictors. This is the first GWA study to evaluate the role of common genetic variants in the development of CVD risk factors in children as they advance through adulthood and highlights the utility of using longitudinal studies to identify genetic predictors of adult traits in children. | Longitudinal Genome-Wide Association of Cardiovascular Disease Risk Factors in the Bogalusa Heart Study |
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0.4132472574710846, "29458": 0.1332872211933136, "29477": 0.0354953333735466} | 15176526 | Epidermal homeostasis depends on a balance between stem cell renewal and differentiation and is regulated by extrinsic signals from the extracellular matrix (ECM). A powerful approach to analysing the pathways involved is to engineer single-cell microenvironments in which individual variables are precisely and quantitatively controlled. Here, we employ micropatterned surfaces to identify the signalling pathways by which restricted ECM contact triggers human epidermal stem cells to initiate terminal differentiation. On small (20 μm diameter) circular islands, keratinocytes remained rounded, and differentiated at higher frequency than cells that could spread on large (50 μm diameter) islands. Differentiation did not depend on ECM composition or density. Rather, the actin cytoskeleton mediated shape-induced differentiation by regulating serum response factor (SRF) transcriptional activity. Knockdown of SRF or its co-factor MAL inhibited differentiation, whereas overexpression of MAL stimulated SRF activity and involucrin expression. SRF target genes FOS and JUNB were also required for differentiation: c-Fos mediated serum responsiveness, whereas JunB was regulated by actin and MAL. Our findings demonstrate how biophysical cues are transduced into transcriptional responses that determine epidermal cell fate. | Actin and serum response factor transduce physical cues from the microenvironment to regulate epidermal stem cell fate decisions |
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reproducibility of QT dispersion from abnormal electrocardiograms in patients with previous myocardial infarction, and compared a user-interactive with an automatic measurement system. Standard 12-lead electrocardiograms, recorded at 25 mm.s-1, were randomly chosen from 70 patients following myocardial infarction. These were scanned into a personal computer, and specially designed software skeletonized and joined each image. The images were then available for user-interactive (mouse and computer screen), or automatic measurements using a specially designed algorithm. For all methods reproducibility of the RR interval was excellent (mean absolute errors 3-4 ms, relative errors 0.3-0.5%). Reproducibility of the mean QT interval was good; intrasubject error was 6 ms (relative error 1.4%), interobserver error was 7 ms (1.8%), and observers' vs automatic measurement errors were 10 and 11 ms (2.5, 2.8%). However QTc dispersion measurements had large errors for all methods; intrasubject error was 12 ms (17.3%), interobserver error was 15 ms (22.1%), and observers' vs automatic measurement were errors 30 and 28 ms (35.4, 31.9%). QT dispersion measurements rely on the most difficult to measure QT intervals, resulting in a problem of reproducibility. Any automatic system must not only recognize common T wave morphologies, but also these more difficult T waves, if it is to be useful for measuring QT dispersion. The poor reproducibility of QT dispersion limits its role as a useful clinical tool, particularly as a predictor of events. | Reproducibility and automatic measurement of QT dispersion. |
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"25409": 0.6107416749000549, "25456": 1.020087480545044, "25468": 0.2576959431171417, "25714": 0.06520967930555344, "25950": 1.2094266414642334, "26014": 0.7163142561912537, "26394": 0.030771657824516296, "26402": 1.1450434923171997, "26709": 0.7426811456680298, "26773": 0.25088030099868774, "26901": 0.07431721687316895, "27144": 0.5301685929298401, "27292": 0.6487176418304443, "27321": 0.5174443125724792, "27354": 0.0842406153678894, "27854": 0.10379679501056671, "27915": 0.4574742913246155, "28522": 1.1530905961990356, "28625": 0.7500885725021362, "28835": 0.02316705882549286, "28848": 0.11168810725212097, "29021": 0.19541899859905243, "29206": 0.960606575012207, "29226": 0.02316705882549286, "29290": 0.37707099318504333, "29480": 0.5871354341506958, "29536": 0.4794800877571106} | 15215393 | Glioblastoma multiforme (GBM) is a particularly aggressive brain tumor and remains a clinically devastating disease. Despite innovative therapies for the treatment of GBM, there has been no significant increase in patient survival over the past decade. Enzymes that control epigenetic alterations are of considerable interest as targets for cancer therapy because of their critical roles in cellular processes that lead to oncogenesis. Several inhibitors of histone deacetylases (HDACs) have been developed and tested in GBM with moderate success. We found that treatment of GBM cells with HDAC inhibitors caused the accumulation of histone methylation, a modification removed by the lysine specific demethylase 1 (LSD1). This led us to examine the effects of simultaneously inhibiting HDACs and LSD1 as a potential combination therapy. We evaluated induction of apoptosis in GBM cell lines after combined inhibition of LSD1 and HDACs. LSD1 was inhibited by targeted short hairpin RNA or pharmacological means and inhibition of HDACs was achieved by treatment with either vorinostat or PCI-24781. Caspase-dependent apoptosis was significantly increased (>2-fold) in LSD1-knockdown GBM cells treated with HDAC inhibitors. Moreover, pharmacologically inhibiting LSD1 with the monoamine oxidase inhibitor tranylcypromine, in combination with HDAC inhibitors, led to synergistic apoptotic cell death in GBM cells; this did not occur in normal human astrocytes. Taken together, these results indicate that LSD1 and HDACs cooperate to regulate key pathways of cell death in GBM cell lines but not in normal counterparts, and they validate the combined use of LSD1 and HDAC inhibitors as a therapeutic approach for GBM. | Inhibition of LSD1 sensitizes glioblastoma cells to histone deacetylase inhibitors. |
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0.0029254043474793434, "27806": 1.072893738746643, "28283": 0.48430517315864563, "28297": 0.27044451236724854, "28556": 0.05694137513637543, "28863": 0.25088030099868774, "28896": 0.06977381557226181, "28935": 0.07341018319129944, "28961": 0.53589928150177, "29035": 1.0907690525054932, "29090": 0.06246116757392883, "29174": 0.15359249711036682, "29361": 0.1930064558982849, "29486": 0.14264501631259918, "29514": 0.966567873954773} | 15237660 | BACKGROUND Long-lasting insecticide treated nets (LLINs) and indoor residual house spraying (IRS) are the main interventions for the control of malaria vectors in Zanzibar. The aim of the present study was to assess the susceptibility status of malaria vectors against the insecticides used for LLINs and IRS and to determine the durability and efficacy of LLINs on the island. METHODS Mosquitoes were sampled from Pemba and Unguja islands in 2010-2011 for use in WHO susceptibility tests. One hundred and fifty LLINs were collected from households on Unguja, their physical state was recorded and then tested for efficacy as well as total insecticide content. RESULTS Species identification revealed that over 90% of the Anopheles gambiae complex was An. arabiensis with a small number of An. gambiae s.s. and An. merus being present. Susceptibility tests showed that An. arabiensis on Pemba was resistant to the pyrethroids used for LLINs and IRS. Mosquitoes from Unguja Island, however, were fully susceptible to all pyrethroids tested. A physical examination of 150 LLINs showed that two thirds were damaged after only three years in use. All used nets had a significantly lower (p < 0.001) mean permethrin concentration of 791.6 mg/m2 compared with 944.2 mg/m2 for new ones. Their efficacy decreased significantly against both susceptible An. gambiae s.s. colony mosquitoes and wild-type mosquitoes from Pemba after just six washes (p < 0.001). CONCLUSION The sustainability of the gains achieved in malaria control in Zanzibar is seriously threatened by the resistance of malaria vectors to pyrethroids and the short-lived efficacy of LLINs. This study has revealed that even in relatively well-resourced and logistically manageable places like Zanzibar, malaria elimination is going to be difficult to achieve with the current control measures. | Challenges for malaria elimination in Zanzibar: pyrethroid resistance in malaria vectors and poor performance of long-lasting insecticide nets |
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"29170": 0.22001366317272186, "29290": 0.8559102416038513, "29304": 0.3170322775840759} | 15248287 | Neutrophil apoptosis is a highly regulated process essential for inflammation resolution, the molecular mechanisms of which are only partially elucidated. In this study, we describe a survival pathway controlled by proliferating cell nuclear antigen (PCNA), a nuclear factor involved in DNA replication and repairing of proliferating cells. We show that mature neutrophils, despite their inability to proliferate, express high levels of PCNA exclusively in their cytosol and constitutively associated with procaspases, presumably to prevent their activation. Notably, cytosolic PCNA abundance decreased during apoptosis, and increased during in vitro and in vivo exposure to the survival factor granulocyte colony-stimulating factor (G-CSF). Peptides derived from the cyclin-dependent kinase inhibitor p21, which compete with procaspases to bind PCNA, triggered neutrophil apoptosis thus demonstrating that specific modification of PCNA protein interactions affects neutrophil survival. Furthermore, PCNA overexpression rendered neutrophil-differentiated PLB985 myeloid cells significantly more resistant to TNF-related apoptosis-inducing ligand- or gliotoxin-induced apoptosis. Conversely, a decrease in PCNA expression after PCNA small interfering RNA transfection sensitized these cells to apoptosis. Finally, a mutation in the PCNA interdomain-connecting loop, the binding site for many partners, significantly decreased the PCNA-mediated antiapoptotic effect. These results identify PCNA as a regulator of neutrophil lifespan, thereby highlighting a novel target to potentially modulate pathological inflammation. | Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival |
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"27642": 0.5092619061470032, "27691": 0.6461620330810547, "27800": 0.021256839856505394, "27815": 0.15860503911972046, "28024": 0.013579257763922215, "28041": 0.010684899985790253, "28062": 0.1011524572968483, "28086": 0.26820653676986694, "28314": 1.0506030321121216, "28436": 0.3910386264324188, "28498": 0.1221139207482338, "28848": 0.0354953333735466, "29458": 0.021256839856505394} | 15274349 | Almost immediately after a human being is born, so too is a new microbial ecosystem, one that resides in that person's gastrointestinal tract. Although it is a universal and integral part of human biology, the temporal progression of this process, the sources of the microbes that make up the ecosystem, how and why it varies from one infant to another, and how the composition of this ecosystem influences human physiology, development, and disease are still poorly understood. As a step toward systematically investigating these questions, we designed a microarray to detect and quantitate the small subunit ribosomal RNA (SSU rRNA) gene sequences of most currently recognized species and taxonomic groups of bacteria. We used this microarray, along with sequencing of cloned libraries of PCR-amplified SSU rDNA, to profile the microbial communities in an average of 26 stool samples each from 14 healthy, full-term human infants, including a pair of dizygotic twins, beginning with the first stool after birth and continuing at defined intervals throughout the first year of life. To investigate possible origins of the infant microbiota, we also profiled vaginal and milk samples from most of the mothers, and stool samples from all of the mothers, most of the fathers, and two siblings. The composition and temporal patterns of the microbial communities varied widely from baby to baby. Despite considerable temporal variation, the distinct features of each baby's microbial community were recognizable for intervals of weeks to months. The strikingly parallel temporal patterns of the twins suggested that incidental environmental exposures play a major role in determining the distinctive characteristics of the microbial community in each baby. By the end of the first year of life, the idiosyncratic microbial ecosystems in each baby, although still distinct, had converged toward a profile characteristic of the adult gastrointestinal tract. | Development of the Human Infant Intestinal Microbiota |
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0.6793810129165649, "26534": 0.025073638185858727, "26591": 0.41647201776504517, "26773": 0.16359257698059082, "26781": 0.09938567131757736, "26835": 0.18816383183002472, "26874": 0.5990082025527954, "27118": 0.4818955361843109, "27177": 0.03266380727291107, "27226": 0.1477125883102417, "27233": 1.6649022102355957, "27295": 0.09938567131757736, "27441": 1.1198691129684448, "27631": 0.0842406153678894, "27642": 0.29328158497810364, "27697": 0.255429208278656, "27777": 0.029824240133166313, "27790": 0.5723689198493958, "27891": 1.1524739265441895, "28177": 0.33325836062431335, "28667": 0.8264343738555908, "28715": 0.08244366943836212, "28835": 0.31845372915267944, "28935": 1.256105661392212, "29610": 0.23864774405956268} | 15282056 | Phosphoenolpyruvate (PEP) is an important precursor for anaerobic production of succinate and malate. Although inactivating PEP/carbohydrate phosphotransferase systems (PTS) could increase PEP supply, the resulting strain had a low glucose utilization rate. In order to improve anaerobic glucose utilization rate for efficient production of succinate and malate, combinatorial modulation of galactose permease (galP) and glucokinase (glk) gene expression was carried out in chromosome of an Escherichia coli strain with inactivated PTS. Libraries of artificial regulatory parts, including promoter and messenger RNA stabilizing region (mRS), were firstly constructed in front of β-galactosidase gene (lacZ) in E. coli chromosome through λ-Red recombination. Most regulatory parts selected from mRS library had constitutive strengths under different cultivation conditions. A convenient one-step recombination method was then used to modulate galP and glk gene expression with different regulatory parts. Glucose utilization rates of strains modulated with either galP or glk all increased, and the rates had a positive relation with expression strength of both genes. Combinatorial modulation had a synergistic effect on glucose utilization rate. The highest rate (1.64 g/L h) was tenfold higher than PTS− strain and 39% higher than the wild-type E. coli. These modulated strains could be used for efficient anaerobic production of succinate and malate. | Combinatorial modulation of galP and glk gene expression for improved alternative glucose utilization |
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0.12642613053321838, "27354": 0.037378571927547455, "27360": 0.6118015646934509, "27400": 0.06703783571720123, "28433": 0.12986256182193756, "28637": 0.12384103983640671, "28739": 0.083342544734478, "28922": 0.3519764244556427, "29458": 0.083342544734478, "29521": 0.24401791393756866} | 15286783 | Expression quantitative trait loci (eQTL) mapping aims to determine genomic regions that regulate gene transcription. Expression QTL is used to study the regulatory structure of normal tissues and to search for genetic factors in complex diseases such as cancer, diabetes, and cystic fibrosis. A modern eQTL dataset contains millions of SNPs and thousands of transcripts measured for hundreds of samples. This makes the analysis computationally complex as it involves independent testing for association for every transcript-SNP pair. The heavy computational burden makes eQTL analysis less popular, often forces analysts to restrict their attention to just a subset of transcripts and SNPs. As larger genotype and gene expression datasets become available, the demand for fast tools for eQTL analysis increases. We present a new method for fast eQTL analysis via linear models, called Matrix eQTL. Matrix eQTL can model and test for association using both linear regression and ANOVA models. The models can include covariates to account for such factors as population structure, gender, and clinical variables. It also supports testing of heteroscedastic models and models with correlated errors. In our experiment on large datasets Matrix eQTL was thousands of times faster than the existing popular software for QTL/eQTL analysis. Matrix eQTL is implemented as both Matlab and R packages and thus can easily be run on Windows, Mac OS, and Linux systems. The software is freely available at the following address: http://www.bios.unc.edu/research/genomic_software/Matrix_eQTL | Matrix eQTL: Ultra fast eQTL analysis via large matrix operations |
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"23653": 0.0354953333735466, "24024": 0.4574742913246155, "24104": 0.011650617234408855, "24163": 0.37102460861206055, "24309": 0.5010119676589966, "24345": 0.1485546976327896, "24862": 0.3127557039260864, "24879": 0.37640097737312317, "25117": 0.04487626627087593, "25281": 0.25694093108177185, "25524": 0.2969166338443756, "25531": 0.2637155055999756, "25580": 0.1734936386346817, "25672": 0.058784693479537964, "25743": 0.2026219218969345, "26106": 0.056018441915512085, "26282": 0.5773153901100159, "26296": 0.7408206462860107, "26489": 0.1685553640127182, "26573": 0.06886265426874161, "26591": 0.2026219218969345, "26601": 0.13499516248703003, "26651": 0.010684899985790253, "26691": 0.23247487843036652, "26718": 0.2018241584300995, "26835": 0.48670899868011475, "26872": 0.7482418417930603, "26924": 0.9178520441055298, "26927": 0.05139094591140747, "27441": 0.22937409579753876, "27631": 1.229617714881897, "27642": 0.151916041970253, "27668": 0.021256839856505394, "27699": 0.11256109178066254, "27755": 0.3134697377681732, "27790": 0.03925827145576477, "28024": 0.0029254043474793434, "28031": 0.24401791393756866, "28424": 1.190008521080017, "28667": 0.25694093108177185, "28911": 0.8583967685699463, "29060": 0.5438674688339233, "29076": 0.20580662786960602, "29350": 0.08692999184131622, "29408": 0.16524957120418549, "29587": 0.21372433006763458} | 15305881 | Deinococcus spp. are renowned for their amazing ability to recover rapidly from severe genomic fragmentation as a result of exposure to extreme levels of ionizing radiation or desiccation. Despite having been originally characterized over 50 years ago, the mechanism underlying this remarkable repair process is still poorly understood. Here, we report the 2.8 A structure of DdrB, a single-stranded DNA (ssDNA) binding protein unique to Deinococcus spp. that is crucial for recovery following DNA damage. DdrB forms a pentameric ring capable of binding single-stranded but not double-stranded DNA. Unexpectedly, the crystal structure reveals that DdrB comprises a novel fold that is structurally and topologically distinct from all other single-stranded binding (SSB) proteins characterized to date. The need for a unique ssDNA binding function in response to severe damage, suggests a distinct role for DdrB which may encompass not only standard SSB protein function in protection of ssDNA, but also more specialized roles in protein recruitment or DNA architecture maintenance. Possible mechanisms of DdrB action in damage recovery are discussed. | The structure of DdrB from Deinococcus: a new fold for single-stranded DNA binding proteins |
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0.8600510358810425, "27216": 0.4891071021556854, "27781": 0.0354953333735466, "28296": 0.8450632095336914, "28297": 0.03831886500120163, "28389": 0.15943801403045654, "28498": 0.045809537172317505, "28756": 0.09672962874174118, "28848": 0.04207121208310127, "28873": 0.1718502640724182, "29125": 0.9650808572769165, "29386": 0.18978065252304077, "29490": 0.29400965571403503, "29537": 0.5685047507286072} | 15319019 | Background The catalytically active 66-kDa subunit of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) consists of DNA polymerase, connection, and ribonuclease H (RNase H) domains. Almost all known RT inhibitor resistance mutations identified to date map to the polymerase domain of the enzyme. However, the connection and RNase H domains are not routinely analysed in clinical samples and none of the genotyping assays available for patient management sequence the entire RT coding region. The British Columbia Centre for Excellence in HIV/AIDS (the Centre) genotypes clinical isolates up to codon 400 in RT, and our retrospective statistical analyses of the Centre’s database have identified an N348I mutation in the RT connection domain in treatment-experienced individuals. The objective of this multidisciplinary study was to establish the in vivo relevance of this mutation and its role in drug resistance. Methods and Findings The prevalence of N348I in clinical isolates, the time taken for it to emerge under selective drug pressure, and its association with changes in viral load, specific drug treatment, and known drug resistance mutations was analysed from genotypes, viral loads, and treatment histories from the Centre’s database. N348I increased in prevalence from below 1% in 368 treatmentnao ¨ve individuals to 12.1% in 1,009 treatment-experienced patients (p ¼ 7.7 3 10 � 12 ). N348I appeared early in therapy and was highly associated with thymidine analogue mutations (TAMs) M41L and T215Y/F (p , 0.001), the lamivudine resistance mutations M184V/I (p , 0.001), and non-nucleoside RTI (NNRTI) resistance mutations K103N and Y181C/I (p , 0.001). The association with TAMs and NNRTI resistance mutations was consistent with the selection of N348I in patients treated with regimens that included both zidovudine and nevirapine (odds ratio 2.62, 95% confidence interval 1.43–4.81). The appearance of N348I was associated with a significant increase in viral load (p , 0.001), which was as large as the viral load increases observed for any of the TAMs. However, this analysis did not account for the simultaneous selection of other RT or protease inhibitor resistance mutations on viral load. To delineate the role of this mutation in RT inhibitor resistance, N348I was introduced into HIV-1 molecular clones containing different genetic backbones. N348I decreased zidovudine susceptibility 2- to 4-fold in the context of wildtype HIV-1 or when combined with TAMs. N348I also decreased susceptibility to nevirapine (7.4fold) and efavirenz (2.5-fold) and significantly potentiated resistance to these drugs when combined with K103N. Biochemical analyses of recombinant RT containing N348I provide supporting evidence for the role of this mutation in zidovudine and NNRTI resistance and give some insight into the molecular mechanism of resistance. Conclusions | N348I in the Connection Domain of HIV-1 Reverse Transcriptase Confers Zidovudine and Nevirapine Resistance |
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Malignant rhabdoid tumors (MRTs) are lethal pediatric cancers characterized by a deficiency in the SWI/SNF subunit SMARCB1. Here, we employ an integrated molecular profiling and chemical biology approach to demonstrate that the receptor tyrosine kinases (RTKs) PDGFRα and FGFR1 are coactivated in MRT cells and that dual blockade of these receptors has synergistic efficacy. Inhibitor combinations targeting both receptors and the dual inhibitor ponatinib suppress the AKT and ERK1/2 pathways leading to apoptosis. MRT cells that have acquired resistance to the PDGFRα inhibitor pazopanib are susceptible to FGFR inhibitors. We show that PDGFRα levels are regulated by SMARCB1 expression, and assessment of clinical specimens documents the expression of both PDGFRα and FGFR1 in rhabdoid tumor patients. Our findings support a therapeutic approach in cancers with SWI/SNF deficiencies by exploiting RTK coactivation dependencies. | Dual Targeting of PDGFRα and FGFR1 Displays Synergistic Efficacy in Malignant Rhabdoid Tumors |
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To overcome this problem, we developed a method that uses probabilistic data analysis to combine single-molecule measurements with X-ray crystallography data. The method determines not only the most likely position of a fluorescent dye molecule attached to the domain but also the complete three-dimensional probability distribution depicting the experimental uncertainty. With this approach, single-pair fluorescence resonance energy transfer measurements can now be used as a quantitative tool for investigating the position and dynamics of flexible domains within macromolecular complexes. We applied this method to find the position of the 5′ end of the nascent RNA exiting transcription elongation complexes of yeast (Saccharomyces cerevisiae) RNA polymerase II and studied the influence of transcription factor IIB on the position of the RNA. | A nano-positioning system for macromolecular structural analysis |
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0.15777134895324707, "26308": 0.4158279001712799, "26402": 0.12642613053321838, "26520": 0.2711893916130066, "26632": 1.310231328010559, "26745": 0.5838727951049805, "26786": 0.20977331697940826, "27144": 0.2990913391113281, "27321": 0.16442140936851501, "27673": 0.38174858689308167, "27711": 0.9123768210411072, "27781": 0.10555581003427505, "27881": 0.1384023278951645, "28086": 0.05417001247406006, "28194": 0.052318159490823746, "28207": 0.020300358533859253, "28344": 0.9147270321846008, "28353": 1.167778730392456, "28522": 0.9455460906028748, "28636": 0.46363574266433716, "28788": 0.2539152204990387, "28873": 0.4794800877571106, "29290": 0.5151132941246033, "29458": 0.14433705806732178, "29484": 0.2034190446138382} | 15335331 | BACKGROUND Both tumor-associated macrophages (TAMs) and the epithelial to mesenchymal transition (EMT) of cancer cells play key roles in promoting tumor progression. However, whether TAMs could induce EMT in the progression of oral squamous cell carcinoma (OSCC) remains undefined. RESULTS Here we detected the expression of macrophages markers CD68 and CD163, epithelial marker E-cadherin and mesenchymal marker vimentin in 127 OSCC patients by using semi-quantitative immunohistochemistry. CD68 and CD163 expression was not confined to the infiltrating TAMs, but also detected in cancer cells. The high number of CD68-positive macrophages was correlated with poor overall survival. Meanwhile, the expression of CD163 both in macrophages and in cancer cells was associated with poor overall survival and had a significant prognostic impact in OSCC. Importantly, the expression of CD163 in cancer cells had a significant relationship with E-cadherin and vimentin. Furthermore, the incubation of TAMs conditioned medium resulted in a fibroblast-like appearance of cancer cells (HN4, HN6 and SCC9) together with the decreased/increased expression of E-cadherin/ vimentin, which were correlated with the enhanced ability of migration and invasion. CONCLUSIONS Our results indicate that TAMs could promote the EMT of cancer cells, thereby leading to the progression of oral cancer. | Tumor-associated macrophages correlate with the clinicopathological features and poor outcomes via inducing epithelial to mesenchymal transition in oral squamous cell carcinoma |
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"27133": 1.0492360591888428, "27292": 0.6950984001159668, "27295": 0.05046287178993225, "27321": 0.018384648486971855, "27343": 0.10467668622732162, "27454": 0.06977381557226181, "27777": 0.2637155055999756, "27854": 0.04674193635582924, "28086": 0.40611594915390015, "28517": 0.06520967930555344, "28667": 0.46670228242874146, "28691": 0.03831886500120163, "28723": 0.007782140281051397, "28788": 0.14518201351165771, "29003": 0.13157635927200317, "29175": 0.1011524572968483, "29290": 0.09850110858678818} | 15337254 | Significant efforts have been directed to understanding the factors that influence the lineage commitment of stem cells. This paper demonstrates that cell shape, independent of soluble factors, has a strong influence on the differentiation of human mesenchymal stem cells (MSCs) from bone marrow. When exposed to competing soluble differentiation signals, cells cultured in rectangles with increasing aspect ratio and in shapes with pentagonal symmetry but with different subcellular curvature-and with each occupying the same area-display different adipogenesis and osteogenesis profiles. The results reveal that geometric features that increase actomyosin contractility promote osteogenesis and are consistent with in vivo characteristics of the microenvironment of the differentiated cells. Cytoskeletal-disrupting pharmacological agents modulate shape-based trends in lineage commitment verifying the critical role of focal adhesion and myosin-generated contractility during differentiation. Microarray analysis and pathway inhibition studies suggest that contractile cells promote osteogenesis by enhancing c-Jun N-terminal kinase (JNK) and extracellular related kinase (ERK1/2) activation in conjunction with elevated wingless-type (Wnt) signaling. Taken together, this work points to the role that geometric shape cues can play in orchestrating the mechanochemical signals and paracrine/autocrine factors that can direct MSCs to appropriate fates. | Geometric cues for directing the differentiation of mesenchymal stem cells. |
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"28767": 0.932563841342926, "28828": 0.6181373596191406, "28873": 0.02412080205976963, "28964": 1.0540125370025635, "29060": 0.04953393340110779, "29090": 0.6149744987487793, "29170": 0.04394211992621422, "29171": 0.03266380727291107, "29222": 0.2026219218969345, "29477": 0.05786345899105072, "29494": 0.53589928150177, "29720": 1.0008903741836548} | 15347087 | The amyloid cascade hypothesis posits that deposition of the amyloid β (Aβ) peptide in the brain is a key event in the initiation of Alzheimer's disease (AD). Nonetheless, it now seems increasingly unlikely that amyloid toxicity is the cause of sporadic AD, which leads to cognitive decline. Here, using accelerated-senescence nontransgenic OXYS rats, we confirmed that aggregation of Aβ is a later event in AD-like pathology. We showed that an age-dependent increase in the levels of Aβ₁₋₄₂ and extracellular Aβ deposits in the brain of OXYS rats occur later than do synaptic losses, neuronal cell death, mitochondrial structural abnormalities, and hyperphosphorylation of the tau protein. We identified the variants of the genes that are strongly associated with the risk of either late-onset or early-onset AD, including App, Apoe4, Bace1, Psen1, Psen2, and Picalm. We found that in OXYS rats nonsynonymous SNPs were located only in the genes Casp3 and Sorl1. Thus, we present proof that OXYS rats may be a model of sporadic AD. It is possible that multiple age-associated pathological processes may precede the toxic amyloid accumulation, which in turn triggers the final stage of the sporadic form of AD and becomes a hallmark event of the disease. | Amyloid accumulation is a late event in sporadic Alzheimer's disease-like pathology in nontransgenic rats |
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0.026025565341114998, "25416": 0.3883931338787079, "25510": 1.292155385017395, "25643": 1.0848461389541626, "25775": 0.05417001247406006, "25814": 0.35745587944984436, "26163": 0.02887592278420925, "26226": 0.0038986403960734606, "26236": 0.0058422754518687725, "26266": 0.7537717819213867, "26268": 0.6941232681274414, "26521": 0.6291293501853943, "26739": 0.7086513638496399, "26886": 0.2652147710323334, "26910": 0.10467668622732162, "27811": 0.151916041970253, "27833": 1.458796739578247, "27841": 0.08154398202896118, "28093": 0.43244171142578125, "28155": 0.04394211992621422, "28616": 0.39367714524269104, "28847": 0.15693697333335876, "28879": 0.08244366943836212, "29458": 0.0019512200960889459, "29536": 0.09050461649894714} | 15360986 | We compared low-density lipoprotein cholesterol (LDL) values obtained by the Friedewald formula--i.e., total cholesterol minus high-density lipoprotein (HDL) cholesterol minus very-low-density lipoprotein (VLDL) cholesterol (estimated as triglyceride divided by 5)--with those obtained by lipoprotein fractionation, using 4736 specimens. When triglycerides were less than 2.0 g/L, greater than 90% of estimated LDL cholesterol values were acceptable, within +/- 10% of measured values. At triglyceride concentrations of 2.0-4.0 g/L and 4.0-6.0 g/L, only 72% and 39%, respectively, of the estimates were acceptable. LDL values derived from an alternative formula, estimating VLDL as triglycerides divided by 6, were even less accurate. Nevertheless, the use of estimated LDL for risk classification based on the National Cholesterol Education Program Adult Treatment Panel cutpoints of 1.30 and 1.60 g/L was considered acceptable. At triglyceride concentrations less than or equal to 5.0 g/L, 88% of classifications based on estimated LDL (using triglycerides divided by 5) were concordant with those by measured LDL. Eleven percent of classifications were shifted across one cutpoint, evenly distributed between high and low. Fewer than 1% of classifications, all with Type III hyperlipoproteinemia, were misclassified two cutpoints high. Refinements in the estimation model did not substantially improve LDL estimation or concordance of risk classification. | Estimating low-density lipoprotein cholesterol by the Friedewald equation is adequate for classifying patients on the basis of nationally recommended cutpoints. |
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0.17840765416622162, "28333": 0.15610189735889435, "28466": 0.688742995262146, "28553": 0.8997484445571899, "28685": 0.11343330889940262, "28691": 0.19541899859905243, "28828": 0.43623676896095276, "28829": 0.22937409579753876, "29107": 0.18167030811309814, "29125": 0.2822965085506439, "29206": 0.11604541540145874, "29535": 0.11778303235769272, "29589": 0.10291612148284912} | 15365719 | The motor protein Kif3a and primary cilia regulate important developmental processes, but their roles in skeletogenesis remain ill-defined. Here we created mice deficient in Kif3a in cartilage and focused on the cranial base and synchondroses. Kif3a deficiency caused cranial base growth retardation and dysmorphogenesis, which were evident in neonatal animals by anatomical and micro-computed tomography (microCT) inspection. Kif3a deficiency also changed synchondrosis growth plate organization and function, and the severity of these changes increased over time. By postnatal day (P)7, mutant growth plates lacked typical zones of chondrocyte proliferation and hypertrophy, and were instead composed of chondrocytes with an unusual phenotype characterized by strong collagen II (Col2a1) gene expression but barely detectable expression of Indian hedgehog (Ihh), collagen X (Col10a1), Vegf (Vegfa), MMP-13 (Mmp13) and osterix (Sp7). Concurrently, unexpected developmental events occurred in perichondrial tissues, including excessive intramembranous ossification all along the perichondrial border and the formation of ectopic cartilage masses. Looking for possible culprits for these latter processes, we analyzed hedgehog signalling topography and intensity by monitoring the expression of the hedgehog effectors Patched 1 and Gli1, and of the hedgehog-binding cell-surface component syndecan 3. Compared with controls, hedgehog signaling was quite feeble within mutant growth plates as early as P0, but was actually higher and was widespread all along mutant perichondrial tissues. Lastly, we studied postnatal mice deficient in Ihh in cartilage; their cranial base defects only minimally resembled those in Kif3a-deficient mice. In summary, Kif3a and primary cilia make unique contributions to cranial base development and synchondrosis growth plate function. Their deficiency causes abnormal topography of hedgehog signaling, growth plate dysfunction, and un-physiologic responses and processes in perichondrial tissues, including ectopic cartilage formation and excessive intramembranous ossification. | Conditional Kif3a ablation causes abnormal hedgehog signaling topography, growth plate dysfunction, and excessive bone and cartilage formation during mouse skeletogenesis. |
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"25117": 0.28082266449928284, "25175": 0.2969166338443756, "25383": 0.956112265586853, "25456": 0.35403475165367126, "25502": 0.6624060273170471, "25714": 0.9037119746208191, "25971": 0.3134697377681732, "26029": 0.7898768186569214, "26180": 1.6364145278930664, "26261": 0.05139094591140747, "26402": 0.8877626657485962, "26651": 0.11778303235769272, "26721": 0.6022219061851501, "26785": 0.6907027959823608, "26821": 1.1708117723464966, "27144": 0.678390383720398, "27321": 0.25845035910606384, "27698": 0.0029254043474793434, "27781": 0.03925827145576477, "27854": 0.05694137513637543, "28032": 0.757441520690918, "28156": 0.3464667797088623, "28286": 1.0285027027130127, "28352": 1.1935672760009766, "28674": 0.9944084882736206, "28732": 0.045809537172317505, "29090": 0.3423145115375519, "29166": 0.7969439625740051, "29167": 0.176772341132164, "29290": 0.04487626627087593, "29490": 0.16690383851528168, "29543": 0.2247048318386078} | 15381976 | Asthma is one of the most common inflammatory diseases characterized by airway hyperresponsiveness, inflammation, and remodeling. Morin, an active ingredient obtained from Moraceae plants, has been demonstrated to have promising anti-inflammatory activities in a range of disorders. However, its impacts on pulmonary diseases, particularly on asthma, have not been clarified. This study was designed to investigate whether morin alleviates airway inflammation in chronic asthma with an emphasis on oxidative stress modulation. In vivo, ovalbumin- (OVA-) sensitized mice were administered with morin or dexamethasone before challenge. Bronchoalveolar lavage fluid (BALF) and lung tissues were obtained to perform cell counts, histological analysis, and enzyme-linked immunosorbent assay. In vitro, human bronchial epithelial cells (BECs) were challenged by tumor necrosis factor alpha (TNF-α). The supernatant was collected for the detection of the proinflammatory proteins, and the cells were collected for reactive oxygen species (ROS)/mitogen-activated protein kinase (MAPK) evaluations. Severe inflammatory responses and remodeling were observed in the airways of the OVA-sensitized mice. Treatment with morin dramatically attenuated the extensive trafficking of inflammatory cells into the BALF and inhibited their infiltration around the respiratory tracts and vessels. Morin administration also significantly suppressed goblet cell hyperplasia and collagen deposition/fibrosis and dose-dependently inhibited the OVA-induced increases in IgE, TNF-α, interleukin- (IL-) 4, IL-13, matrix metalloproteinase-9, and malondialdehyde. In human BECs challenged by TNF-α, the levels of proteins such as eotaxin-1, monocyte chemoattractant protein-1, IL-8 and intercellular adhesion molecule-1, were consistently significantly decreased by morin. Western blotting and the 2',7'-dichlorofluorescein assay revealed that the increases in intracellular ROS and MAPK phosphorylation were abolished by morin, implying that ROS/MAPK signaling contributes to the relief of airway inflammation. Our findings indicate for the first time that morin alleviates airway inflammation in chronic asthma, which probably occurs via the oxidative stress-responsive MAPK pathway, highlighting a novel profile of morin as a potent agent for asthma management. | Morin Attenuates Ovalbumin-Induced Airway Inflammation by Modulating Oxidative Stress-Responsive MAPK Signaling. |
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"28829": 0.6813592314720154, "28873": 1.4918501377105713, "28927": 0.38174858689308167, "29170": 0.06429435312747955, "29206": 0.08692999184131622, "29513": 0.009718249551951885, "29610": 0.5936289429664612} | 15405204 | The expression of self-antigen in the thymus is believed to be responsible for the deletion of autoreactive T lymphocytes, a critical process in the maintenance of unresponsiveness to self. The Autoimmune regulator (Aire) gene, which is defective in the disorder autoimmune polyglandular syndrome type 1, has been shown to promote the thymic expression of self-antigens. A clear link, however, between specific thymic self-antigens and a single autoimmune phenotype in this model has been lacking. We show that autoimmune eye disease in aire-deficient mice develops as a result of loss of thymic expression of a single eye antigen, interphotoreceptor retinoid-binding protein (IRBP). In addition, lack of IRBP expression solely in the thymus, even in the presence of aire expression, is sufficient to trigger spontaneous eye-specific autoimmunity. These results suggest that failure of thymic expression of selective single self-antigens can be sufficient to cause organ-specific autoimmune disease, even in otherwise self-tolerant individuals. | Spontaneous autoimmunity prevented by thymic expression of a single self-antigen |
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0.25694093108177185, "26835": 0.5398913025856018, "26874": 0.09761575609445572, "27152": 0.06520967930555344, "27521": 0.07250232994556427, "27631": 0.306306391954422, "27633": 0.11951763927936554, "27642": 0.3409265875816345, "27777": 0.08513788133859634, "28024": 0.5092619061470032, "28101": 0.22079704701900482, "28102": 0.19220098853111267, "28173": 0.030771657824516296, "28411": 0.08692999184131622, "28691": 0.2184450328350067, "28873": 0.32199856638908386, "29060": 0.36358460783958435, "29111": 0.6714286804199219, "29215": 1.3001704216003418, "29295": 0.02412080205976963, "29720": 0.48430517315864563} | 15414628 | Legionella pneumophila, the causative agent of Legionnaires' pneumonia, resides in a distinct vacuole structure called Legionella-containing vacuole (LCV). The LCV resists fusion with the lysosome and permits efficient bacterial replication in host macrophages, which requires a Dot/Icm type IVB secretion system. Dot/Icm-translocated effector SdhA is critical for L. pneumophila intracellular growth and functions to prevent host cell death. Here, we show that the absence of SdhA resulted in elevated caspase-1 activation and IL-1β secretion as well as macrophage pyroptosis during Legionella infection. These inflammasome activation phenotypes were independent of the established flagellin-NAIP5-NLRC4 axis, but relied on the DNA-sensing AIM2 inflammasome. We further demonstrate that Legionella DNA was released into macrophage cytosol, and this effect was significantly exaggerated by the absence of SdhA. SdhA bears a functional Golgi-targeting GRIP domain that is required for preventing AIM2 inflammasome activation. Ectopically expressed SdhA formed a unique ring-shape membrane structure, further indicating a role in membrane trafficking and maintaining LCV membrane integrity. Our data together suggest a possible link, mediated by the function of SdhA, between LCV trafficking/maturation and suppression of host innate immune detection. | Preventing bacterial DNA release and absent in melanoma 2 inflammasome activation by a Legionella effector functioning in membrane trafficking. |
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Two N-terminal caspase activation and recruitment domains (CARDs) transmit the signal, and the regulatory domain prevents signaling in the absence of viral RNA. 5'-triphosphate and double-stranded RNA (dsRNA) are two molecular patterns that enable RIG-I to discriminate pathogenic from self-RNA. However, the function of the DExH box helicase domain that is also required for activity is less clear. Using single-molecule protein-induced fluorescence enhancement, we discovered a robust adenosine 5'-triphosphate-powered dsRNA translocation activity of RIG-I. The CARDs dramatically suppress translocation in the absence of 5'-triphosphate, and the activation by 5'-triphosphate triggers RIG-I to translocate preferentially on dsRNA in cis. This functional integration of two RNA molecular patterns may provide a means to specifically sense and counteract replicating viruses. | Cytosolic viral sensor RIG-I is a 5'-triphosphate-dependent translocase on double-stranded RNA. |
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Interleukin-10 (IL-10) suppresses the maturation and cytokine production of dendritic cells (DCs), key regulators of adaptive immunity, and prevents the activation and polarization of naïve T cells towards protective gamma interferon-producing effectors. We hypothesized that human cytomegalovirus (HCMV) utilizes its viral IL-10 homolog (cmvIL-10) to attenuate DC functionality, thereby subverting the efficient induction of antiviral immune responses. RNA and protein analyses demonstrated that the cmvIL-10 gene was expressed with late gene kinetics. Treatment of immature DCs (iDCs) with supernatant from HCMV-infected cultures inhibited both the lipopolysaccharide-induced DC maturation and proinflammatory cytokine production. These inhibitory effects were specifically mediated through the IL-10 receptor and were not observed when DCs were treated with supernatant of cells infected with a cmvIL-10-knockout mutant. Incubation of iDCs with recombinant cmvIL-10 recapitulated the inhibition of maturation. Furthermore, cmvIL-10 had pronounced long-term effects on those DCs that could overcome this inhibition of maturation. It enhanced the migration of mature DCs (mDCs) towards the lymph node homing chemokine but greatly reduced their cytokine production. The inability of mDCs to secrete IL-12 was maintained, even when they were restimulated by the activated T-cell signal CD40 ligand in the absence of cmvIL-10. Importantly, cmvIL-10 potentiates these anti-inflammatory effects, at least partially, by inducing endogenous cellular IL-10 expression in DCs. Collectively, we show that cmvIL-10 causes long-term functional alterations at all stages of DC activation. | Human Cytomegalovirus-Encoded Interleukin-10 Homolog Inhibits Maturation of Dendritic Cells and Alters Their Functionality |
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"26757": 1.1337933540344238, "27002": 0.00875066313892603, "27142": 0.14179791510105133, "27169": 0.0174254160374403, "27790": 0.022212404757738113, "27854": 0.3656192123889923, "28173": 0.7827593088150024, "28251": 1.2781087160110474, "28436": 0.11778303235769272, "28507": 0.23787821829319, "28808": 1.2047537565231323, "29060": 0.16110190749168396, "29333": 0.016465263441205025, "29458": 0.00875066313892603, "29594": 0.8796916007995605} | 15426878 | A model for the unidirectional movement of dynein is presented based on structural observations and biochemical experimental results available. In this model, the binding affinity of dynein for microtubule is independent of its nucleotide state and the change between strong and weak microtubule-binding is determined naturally by the variation of relative orientation between the stalk and microtubule as the stalk rotates following nucleotide-state transition. Thus the enigmatic communication from the ATP binding site in the globular domain to the far MT-binding site in the tip of the stalk, which is prerequisite in conventional models, is not required. Using the present model, the previous experimental results such as the effect of ATP and ADP bindings on dissociation of dynein from microtubule, the processive movement of single-headed axonemal dyneins at saturating ATP concentration, the load dependence of step size for the processive movement of two-headed cytoplasmic dyneins and the dependence of stall force on ATP concentration can be well explained. | Model for unidirectional movement of axonemal and cytoplasmic dynein molecules |
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0.7473171949386597, "27854": 0.03266380727291107, "28156": 0.33605360984802246, "28788": 0.025073638185858727, "28873": 0.35745587944984436, "28896": 1.1230508089065552, "29491": 0.6275664567947388, "29720": 0.2852376699447632} | 15435343 | The inflammasome is a proteolysis complex that generates the active forms of the proinflammatory cytokines interleukin (IL)-1β and IL-18. Inflammasome activation is mediated by NLR proteins that respond to microbial and nonmicrobial stimuli. Among NLRs, NLRP3 senses the widest array of stimuli and enhances adaptive immunity. However, its role in antitumor immunity is unknown. Therefore, we evaluated the function of the NLRP3 inflammasome in the immune response using dendritic cell vaccination against the poorly immunogenic melanoma cell line B16-F10. Vaccination of Nlrp3(-/-) mice led to a relative 4-fold improvement in survival relative to control animals. Immunity depended on CD8(+) T cells and exhibited immune specificity and memory. Increased vaccine efficacy in Nlrp3(-/-) hosts did not reflect differences in dendritic cells but rather differences in myeloid-derived suppressor cells (MDSC). Although Nlrp3 was expressed in MDSCs, the absence of Nlrp3 did not alter either their functional capacity to inhibit T cells or their presence in peripheral lymphoid tissues. Instead, the absence of Nlrp3 caused a 5-fold reduction in the number of tumor-associated MDSCs found in host mice. Adoptive transfer experiments also showed that Nlrp3(-/-) MDSCs were less efficient in reaching the tumor site. Depleting MDSCs with an anti-Gr-1 antibody increased the survival of tumor-bearing wild-type mice but not Nlrp3(-/-) mice. We concluded that Nlrp3 was critical for accumulation of MDSCs in tumors and for inhibition of antitumor T-cell immunity after dendritic cell vaccination. Our findings establish an unexpected role for Nlrp3 in impeding antitumor immune responses, suggesting novel approaches to improve the response to antitumor vaccines by limiting Nlrp3 signaling. | The inflammasome component NLRP3 impairs antitumor vaccine by enhancing the accumulation of tumor-associated myeloid-derived suppressor cells. |
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"27781": 0.9944084882736206, "27881": 0.04394211992621422, "28466": 0.7473171949386597, "28788": 0.8957691192626953, "28873": 1.059443712234497, "29090": 0.34508460760116577, "29268": 0.05417001247406006, "29592": 0.9348671436309814} | 15462523 | Natural killer (NK) cells are potent cytotoxic effector cells for cancer therapy and potentially for severe viral infections. However, there are technical challenges to obtain sufficient numbers of functionally active NK cells from a patient's blood since they represent only 10% of the lymphocytes and are often dysfunctional. The alternative is to obtain cells from a healthy donor, which requires depletion of the allogeneic T cells to prevent graft-versus-host reactions. Cytotoxic cell lines have been established from patients with clonal NK-cell lymphoma. Those cells can be expanded in culture in the presence of IL-2. Except for the NK-92 cell line, though, none of the other six known NK cell lines has consistently and reproducibly shown high antitumor cytotoxicity. Only NK-92 cells can easily be genetically manipulated to recognize specific tumor antigens or to augment monoclonal antibody activity through antibody-dependent cellular cytotoxicity. NK-92 is also the only cell line product that has been infused into patients with advanced cancer with clinical benefit and minimal side effects. | Natural Killer Cells for Immunotherapy – Advantages of the NK-92 Cell Line over Blood NK Cells |
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