spalde-v3-lexical
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Secreted frizzled-related protein 5 (Sfrp5) has been shown to function as an extracellular inhibitor of non-canonical Wnt signaling that is expressed at relatively high levels in white adipose tissue. The aim of this study was to investigate the role of Sfrp5 in the heart under ischemic stress. Sfrp5 KO and WT mice were subjected to ischemia/reperfusion (I/R). Although Sfrp5-KO mice exhibited no detectable phenotype when compared with WT control at baseline, they displayed larger infarct sizes, enhanced cardiac myocyte apoptosis, and diminished cardiac function following I/R. The ischemic lesions of Sfrp5-KO mice had greater infiltration of Wnt5a-positive macrophages and greater inflammatory cytokine and chemokine gene expression when compared with WT mice. In bone marrow-derived macrophages, Wnt5a promoted JNK activation and increased inflammatory gene expression, whereas treatment with Sfrp5 blocked these effects. These results indicate that Sfrp5 functions to antagonize inflammatory responses after I/R in the heart, possibly through a mechanism involving non-canonical Wnt5a/JNK signaling. | Secreted Frizzled-related Protein 5 Diminishes Cardiac Inflammation and Protects the Heart from Ischemia/Reperfusion Injury. |
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"28685": 0.5925496220588684, "28711": 1.1134753227233887, "28828": 1.004473328590393, "28868": 0.15023678541183472, "29053": 0.2026219218969345, "29129": 0.052318159490823746, "29215": 0.18329764902591705, "29401": 0.18816383183002472, "29458": 0.8247235417366028} | 22309946 | BACKGROUND Technological advancements in neuroimaging and the increased use of these diagnostic modalities are responsible for the discovery of incidentally identified anomalies within the CNS. In addition to the identification of unanticipated brain MRI abnormalities suggestive of demyelinating disease in patients undergoing neuroimaging for a medical reason other than evaluation for multiple sclerosis (MS), asymptomatic spinal cord lesions are periodically identified. OBJECTIVE To determine if asymptomatic spinal cord lesions are associated with clinical progression in subjects with radiologically isolated syndrome (RIS). METHODS A retrospective review of RIS cases at the University of California, San Francisco Multiple Sclerosis Center was performed. The presence of asymptomatic cervical spinal cord MRI lesions was analyzed as a potential predictor for clinical progression. RESULTS Twenty-five of 71 subjects with RIS possessed findings within the cervical spine that were highly suggestive of demyelinating disease. Of these subjects, 21 (84%) progressed clinically to clinically isolated syndrome (n = 19) or primary progressive multiple sclerosis (n = 2) over a median time of 1.6 years from the date of RIS identification (interquartile range 0.8-3.8). The sensitivity, specificity, and positive predictive value of an asymptomatic spinal cord lesion for subsequent development of either a first demyelinating attack or primary progressive MS were 87.5%, 91.5%, and 84%, respectively. The odds ratio of clinical progression was 75.3 (95% confidence interval 16.1-350.0, p < 0.0001). This association remained significant after adjusting for potential confounders. CONCLUSION These findings suggest that the presence of asymptomatic spinal cord lesions place subjects with RIS at substantial risk for clinical conversion to either an acute or progressive event, a risk that is independent of brain lesions on MRI. | Asymptomatic spinal cord lesions predict disease progression in radiologically isolated syndrome. |
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"26835": 0.16359257698059082, "26874": 0.10818854719400406, "27441": 1.1635169982910156, "27491": 0.4318077862262726, "27642": 0.35128939151763916, "27854": 0.01934296265244484, "27942": 1.178053855895996, "28835": 0.4356052577495575, "29206": 0.04953393340110779} | 22312627 | Previous results have demonstrated that the silencing of adjacent genes encoding NADPH-dependent furfural oxidoreductases (yqhD dkgA) is responsible for increased furfural tolerance in an E. coli strain EMFR9 [Miller et al., Appl Environ Microbiol 75:4315–4323, 2009]. This gene silencing is now reported to result from the spontaneous insertion of an IS10 into the coding region of yqhC, an upstream gene. YqhC shares homology with transcriptional regulators belonging to the AraC/XylS family and was shown to act as a positive regulator of the adjacent operon encoding YqhD and DkgA. Regulation was demonstrated by constructing a chromosomal deletion of yqhC, a firefly luciferase reporter plasmid for yqhC, and by a direct comparison of furfural resistance and NADPH-dependent furfural reductase activity. Closely related bacteria contain yqhC, yqhD, and dkgA orthologs in the same arrangement as in E. coli LY180. Orthologs of yqhC are also present in more distantly related Gram-negative bacteria. Disruption of yqhC offers a useful approach to increase furfural tolerance in bacteria. | YqhC regulates transcription of the adjacent Escherichia coli genes yqhD and dkgA that are involved in furfural tolerance |
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"25950": 0.3019835948944092, "26014": 0.03831886500120163, "26131": 0.255429208278656, "26243": 0.09228714555501938, "26244": 0.05970508232712746, "26402": 0.8682814836502075, "26520": 0.3262358605861664, "26601": 0.29981520771980286, "26773": 0.6102113127708435, "26874": 0.17020416259765625, "27144": 0.026976587250828743, "27295": 0.18004031479358673, "27598": 0.4974553883075714, "27642": 0.9425065517425537, "27854": 0.19541899859905243, "27998": 0.680370569229126, "28283": 0.8813109993934631, "28636": 0.09317722171545029, "28691": 0.25995752215385437, "28775": 0.7565253376960754, "29053": 0.0606246218085289, "29206": 1.1211429834365845, "29290": 0.24248650670051575, "29461": 0.2145126610994339} | 22317868 | Compartmentalization of signals generated by receptor tyrosine kinase (RTK) endocytosis has emerged as a major determinant of various cell functions. Here, using tumour-associated Met-activating mutations, we demonstrate a direct link between endocytosis and tumorigenicity. Met mutants exhibit increased endocytosis/recycling activity and decreased levels of degradation, leading to accumulation on endosomes, activation of the GTPase Rac1, loss of actin stress fibres and increased levels of cell migration. Blocking endocytosis inhibited mutants’ anchorage-independent growth, in vivo tumorigenesis and metastasis while maintaining their activation. One mutant resistant to inhibition by a Met-specific tyrosine kinase inhibitor was sensitive to endocytosis inhibition. Thus, oncogenicity of Met mutants results not only from activation but also from their altered endocytic trafficking, indicating that endosomal signalling may be a crucial mechanism regulating RTK-dependent tumorigenesis. | A direct role for Met endocytosis in tumorigenesis |
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0.00875066313892603, "23320": 0.0038986403960734606, "23683": 0.3177432417869568, "23805": 0.12728634476661682, "23969": 0.10555581003427505, "24137": 0.8091925978660583, "24226": 0.06795065850019455, "24562": 0.11430477350950241, "24798": 0.35128939151763916, "24920": 0.34922540187835693, "25344": 0.5370414853096008, "25711": 0.4574742913246155, "25750": 0.07884006202220917, "25866": 0.16276304423809052, "26014": 0.4831010699272156, "26287": 0.12038381397724152, "26378": 0.3464667797088623, "26497": 0.7737906575202942, "26651": 0.0770333781838417, "26745": 0.7163142561912537, "26855": 0.09584271162748337, "27010": 0.15777134895324707, "27360": 0.10291612148284912, "27756": 0.026976587250828743, "28322": 0.10379679501056671, "28767": 0.40285754203796387, "28797": 0.014542185701429844, "29171": 0.03360854089260101, "29180": 0.9005423784255981, "29212": 0.29328158497810364} | 22328290 | The subjective and behavioural responses of 20 healthy volunteers taking droperidol 5 mg as part of a cognitive challenge programme were catalogued. Some form of akathisia was universally experienced. Half of the subjects were dysphoric, but there appeared to be a number of different inputs to their dysphoria and a range of other effects were noted, including sedation, dissociative experiences, alterations in sensation and subtle changes in physiognomy. The duration of these effects varied from a few hours to over a week. In the acute phase, insight as to the origin of what was happening was mixed. The results have implications for the interpretation of cognitive challenge tests, the nature of akathisia, clinical therapeutics and drug development. © 1998 John Wiley & Sons, Ltd. | Immediate effects of droperidol |
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0.28082266449928284, "27754": 0.27712854743003845, "27759": 0.6006163358688354, "27921": 0.0029254043474793434, "28166": 0.08154398202896118, "28414": 0.08871890604496002, "28730": 0.09317722171545029, "28742": 0.736154317855835, "28775": 0.07884006202220917, "28863": 0.13925230503082275, "29090": 1.0094679594039917, "29165": 0.2576959431171417, "29477": 0.053244512528181076, "29566": 0.9037119746208191, "29596": 0.42990362644195557} | 22334300 | The toxic effects of Nerium oleander were evaluated in capuchin monkeys (Cebus apella) by examination of clinical signs, hematologic and serum chemical values, and gross and microscopic lesions. Dried and ground oleander leaves were given at intervals of 48 h in doses of 30, 7.5, and 3 mg/kg body weight. The cumulative lethal dose ranged from 30 to 60 mg/kg body weight in monkeys that were given doses of 30 and 7.5 mg/kg body weight. Monkeys that received doses of 3 mg/kg body weight (total cumulative dose: 60 mg/kg) survived. Clinical signs were vomiting, salivation, polyuria, bradycardia, vaginal hemorrhage, abortion, anorexia, constipation, loss of body weight, narcosis, restlessness, weakness, and shallow and rapid respirations. Changes in blood values were leukocytosis; neutrophilia; increased potassium, glutamic-oxalacetic transaminase, glutamic-pyruvic transaminase, blood urea nitrogen and α-globulins; reticulo-cytopenia; and decreased calcium, glucose, total serum protein, albumin, γ-globulin leve... | Toxicity of Nerium oleander in the monkey (Cebus apella). |
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"28290": 0.1229778528213501, "28327": 0.8004589080810547, "28370": 0.1693800985813141, "28518": 0.12814582884311676, "28685": 0.09050461649894714, "28828": 0.33675122261047363, "28829": 0.07341018319129944, "28842": 0.47584590315818787, "28873": 0.10818854719400406, "29197": 0.09495500475168228, "29333": 0.009718249551951885} | 22358449 | The promyelocytic leukaemia zinc finger (Plzf) protein (encoded by the gene Zfp145) belongs to the POZ/zinc-finger family of transcription factors. Here we generate Zfp145−/− mice and show that Plzf is essential for patterning of the limb and axial skeleton. Plzf inactivation results in patterning defects affecting all skeletal structures of the limb, including homeotic transformations of anterior skeletal elements into posterior structures. We demonstrate that Plzf acts as a growth-inhibitory and pro-apoptotic factor in the limb bud. The expression of members of the abdominal b (Abdb) Hox gene complex, as well as genes encoding bone morphogenetic proteins (Bmps), is altered in the developing limb of Zfp145−/− mice. Plzf regulates the expression of these genes in the absence of aberrant polarizing activity and independently of known patterning genes. Zfp145−/− mice also exhibit anterior-directed homeotic transformation throughout the axial skeleton with associated alterations in Hox gene expression. Plzf is therefore a mediator of anterior-to-posterior (AP) patterning in both the axial and appendicular skeleton and acts as a regulator of Hox gene expression. | Plzf regulates limb and axial skeletal patterning |
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One class of small regulatory RNAs, termed the endogenous small interfering RNAs (endo siRNAs), is thought to negatively regulate cellular transcripts via an RNA interference (RNAi)-like mechanism termed endogenous RNAi (endo RNAi). A complex of proteins composed of ERI-1/3/5, RRF-3, and DICER (the ERI/DICER complex) mediates endo RNAi processes in Caenorhabditis elegans. We conducted a genetic screen to identify additional components of the endo RNAi machinery. Our screen recovered alleles of eri-9, which encodes a novel DICER-interacting protein, and a missense mutation within the helicase domain of DICER [DCR-1(G492R)]. ERI-9(-) and DCR-1(G492) animals exhibit defects in endo siRNA expression and a concomitant failure to regulate mRNAs that exhibit sequence homology to these endo siRNAs, indicating that ERI-9 and the DCR-1 helicase domain function in the C. elegans endo RNAi pathway. We define a subset of Eri mutant animals (including eri-1, rrf-3, eri-3, and dcr-1, but not eri-9 or ergo-1) that exhibit temperature-sensitive, sperm-specific sterility and defects in X chromosome segregation. Among these mutants we find multiple aberrations in sperm development beginning with cytokinesis and extending through terminal differentiation. These results identify novel components of the endo RNAi machinery, demonstrate differential requirements for the Eri factors in the sperm-producing germline, and begin to delineate the functional requirement for the ERI/DICER complex in sperm development. | Requirement for the ERI/DICER complex in endogenous RNA interference and sperm development in Caenorhabditis elegans. |
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0.15442965924739838, "25468": 0.3241194784641266, "25856": 1.3128622770309448, "25947": 0.09584271162748337, "25950": 0.04860413447022438, "26577": 0.04860413447022438, "26616": 0.23402166366577148, "26646": 0.0842406153678894, "26718": 0.36426326632499695, "26721": 0.07341018319129944, "26745": 0.17267228662967682, "26835": 0.26296505331993103, "27099": 0.10467668622732162, "27144": 0.5092619061470032, "27321": 0.4574742913246155, "27391": 0.0317181795835495, "27598": 0.2018241584300995, "27697": 0.10906458646059036, "27781": 0.8161250352859497, "27790": 0.14939609169960022, "28041": 0.15610189735889435, "28102": 0.5551415085792542, "28144": 0.040196798741817474, "28297": 0.48670899868011475, "28696": 0.026976587250828743, "28873": 0.5086748600006104, "29076": 0.9805850982666016, "29264": 0.015504186972975731, "29290": 0.23402166366577148, "29486": 0.688742995262146} | 22371455 | Although drugs are a common cause of acute immune-mediated thrombocytopenia in adults, the drug etiology is often initially unrecognized. Most cases of drug-induced thrombocytopenia (DITP) are caused by drug-dependent antibodies that are specific for the drug structure and bind tightly to platelets by their Fab regions but only in the presence of the drug. A comprehensive database of 1301 published reports describing 317 drugs, available at www.ouhsc.edu/platelets, provides information on the level of evidence for a causal relation to thrombocytopenia. Typically, DITP occurs 1 to 2 weeks after beginning a new drug or suddenly after a single dose when a drug has previously been taken intermittently. However, severe thrombocytopenia can occur immediately after the first administration of antithrombotic agents that block fibrinogen binding to platelet GP IIb-IIIa, such as abciximab, tirofiban, and eptifibatide. Recovery from DITP usually begins within 1 to 2 days of stopping the drug and is typically complete within a week. Drug-dependent antibodies can persist for many years; therefore, it is important that the drug etiology be confirmed and the drug be avoided thereafter. | Drug-induced thrombocytopenia: pathogenesis, evaluation, and management. |
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"25481": 0.30989447236061096, "25613": 0.23402166366577148, "25845": 0.07068414986133575, "25848": 0.030771657824516296, "26004": 0.10203468054533005, "26022": 0.1677299439907074, "26462": 0.18329764902591705, "26702": 0.21135559678077698, "26909": 0.10026945173740387, "26972": 0.2539152204990387, "27118": 0.25694093108177185, "27204": 0.678390383720398, "27574": 0.08064348995685577, "27749": 0.3005385100841522, "28032": 0.30558720231056213, "28093": 0.020300358533859253, "28139": 0.15526613593101501, "28348": 0.03266380727291107, "28667": 0.2800849378108978, "28935": 0.48670899868011475, "29174": 0.06795065850019455} | 22401061 | The marginal costs and benefits of converting malaria programmes from a control to an elimination goal are central to strategic decisions, but empirical evidence is scarce. We present a conceptual framework to assess the economics of elimination and analyse a central component of that framework-potential short-term to medium-term financial savings. After a review that showed a dearth of existing evidence, the net present value of elimination in five sites was calculated and compared with effective control. The probability that elimination would be cost-saving over 50 years ranged from 0% to 42%, with only one site achieving cost-savings in the base case. These findings show that financial savings should not be a primary rationale for elimination, but that elimination might still be a worthy investment if total benefits are sufficient to outweigh marginal costs. Robust research into these elimination benefits is urgently needed. | Costs and financial feasibility of malaria elimination |
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Multiple angiogenic polypeptides are known, and we have determined the expression of seven of these in primary human breast cancers; the relationship of expression to estrogen receptor and vascular density was also examined. Vascular endothelial growth factor (VEGF) and its four isoforms (121, 165, 189, and 206 amino acids), transforming growth factor (TGF)-beta1, pleiotrophin, acidic and basic fibroblast growth factor (FGF), placental growth factor, and thymidine phosphorylase (platelet-derived endothelial cell growth factor) were quantitated by RNase protection analysis. beta-FGF was also measured by ELISA. The estrogen receptor (ER), epidermal growth factor receptor, and vascular density were analyzed in 64 primary breast cancers. All tumors expressed at least six different vascular growth factors. VEGF was most abundant, and the transcript for the 121-amino acid form predominated. Other angiogenic factors expressed at high levels were thymidine phosphorylase and TGF-beta1. Expression of most of the angiogenic factors did not correlate with that of ER or vascular density. However, thymidine phosphorylase did, with a correlation coefficient of 0.3 (P = 0.03). There were significant associations of pleiotrophin with acidic FGF expression (P = 0.001) and TGF-beta with platelet-derived endothelial cell growth factor expression (P = 0.001). Thus, angiogenesis may involve a coordinate regulation of some vascular growth factors. High VEGF expression correlated with poor prognosis in univariate analysis (P = 0.03), as did ER and epidermal growth factor receptor expression. Basic FGF was also assessed by ELISA and was more highly expressed in tumors than normal breast tissues (median, 346 microg/ml cytosol; range, 54-1323 versus median, 149; range, 32-509; P = 0.01). Implications for therapy are that broad spectrum agents that block features common to these factors may be useful (e.g., antagonism of heparin-binding activity agents), because so many angiogenic factors are expressed. Inhibiting endothelial migration or agents directly toxic to endothelium would be of value in a combined approach to therapy. | Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenes |
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Kinetochore–spindle binding and chromosome segregation are mediated by the multi-copy KNL1Spc105, MIS12Mtw1 and NDC80Ndc80 complexes that form the so-called KMN network. KMN–spindle attachment is regulated by the Aurora BIpl1 and MPS1Mps1 kinases. It is unclear whether other mechanisms exist that support KMN activity during the cell cycle. Using budding yeast, we show that kinetochore protein Cnn1 localizes to the base of the Ndc80 complex and promotes a functionally competent configuration of the KMN network. Cnn1 regulates KMN activity in a spatiotemporal manner by inhibiting the interaction between its complexes. Cnn1 activity peaks in anaphase and is driven by the Cdc28, Mps1 and Ipl1 kinases. | Cnn1 inhibits the interactions between the KMN complexes of the yeast kinetochore |
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Recently, it has become evident that most adult tissue macrophages originate during embryonic development and not from circulating monocytes. Each tissue has its own composition of embryonically derived and adult-derived macrophages, but it is unclear whether macrophages of distinct origins are functionally interchangeable or have unique roles at steady state. This new understanding also prompts reconsideration of the function of circulating monocytes. Classical Ly6c(hi) monocytes patrol the extravascular space in resting organs, and Ly6c(lo) nonclassical monocytes patrol the vasculature. Inflammation triggers monocytes to differentiate into macrophages, but whether resident and newly recruited macrophages possess similar functions during inflammation is unclear. Here, we define the tools used for identifying the complex origin of tissue macrophages and discuss the relative contributions of tissue niche versus ontological origin to the regulation of macrophage functions during steady state and inflammation. | Origin and functions of tissue macrophages. |
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"25022": 0.37371641397476196, "25223": 0.03831886500120163, "25969": 0.0913962796330452, "26279": 0.19782574474811554, "26419": 1.216973900794983, "26492": 0.6931471824645996, "26728": 0.2719337046146393, "26745": 0.052318159490823746, "26835": 0.11168810725212097, "26957": 0.1751343309879303, "27144": 0.22001366317272186, "27242": 0.20421554148197174, "27770": 0.01934296265244484, "27794": 0.8161250352859497, "28093": 0.013579257763922215, "28389": 0.12470348179340363, "28648": 0.38041436672210693, "28696": 0.9776504039764404, "29125": 0.7845434546470642, "29251": 0.03266380727291107, "29288": 0.1011524572968483} | 22414304 | There is little information about treatment outcome in patients with smear-negative pulmonary tuberculosis (PTB) or extrapulmonary tuberculosis (EPTB) treated under routine programme conditions in subsaharan Africa. A prospective study was carried out to determine treatment outcome in an unselected cohort of TB patients admitted to Zomba General Hospital, Malawi. Eight hundred and twenty-seven adult TB patients (451 men and 376 women) were registered between 1 July and 31 December 1995. Standardized treatment outcomes of treatment completion, death, default, and transfer to another district were assessed in relation to type of TB, human immunodeficiency virus (HIV) serostatus, age and gender. Two hundred and fifty-four patients (31%) died by the end of treatment, half of the deaths occurring in the first month. Death rates were 19% among 386 patients with smear-positive PTB, 46% among 211 patients with smear-negative PTB, and 37% among 230 patients with EPTB; 77% of the patients were HIV seropositive. Among new patients, HIV-positive patients had higher death rates than HIV-negative patients (hazard ratio [HR] 2.5; 95% confidence interval [95% CI] 1.6-3.8). Smear-negative patients had the highest death rates (HR 3.9; 95% CI 2.7-5.5 compared to smear-positive patients), followed by EPTB patients (HR 2.6, 95% CI 1.8-3.7 compared to smear-positive patients). Death rates increased with age but were similar in men and women. Adult patients in Malawi with smear-negative PTB and EPTB have low treatment completion and high death rates, related to high levels of HIV infection. National TB control programmes in areas of high HIV prevalence should no longer ignore treatment outcomes in patients with smear-negative PTB or EPTB. | Treatment outcome of an unselected cohort of tuberculosis patients in relation to human immunodeficiency virus serostatus in Zomba Hospital, Malawi. |
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"29234": 0.33675122261047363, "29299": 0.3956514894962311, "29336": 0.4318077862262726, "29423": 1.0742288827896118, "29514": 0.02887592278420925} | 22420524 | CONTEXT Gallstone disease is a leading cause of morbidity in western countries and carries a high economic burden. Statins decrease hepatic cholesterol biosynthesis and may therefore lower the risk of cholesterol gallstones by reducing the cholesterol concentration in the bile. Data on this association in humans are scarce. OBJECTIVE To study the association between the use of statins, fibrates, or other lipid-lowering agents and the risk of incident gallstone disease followed by cholecystectomy. DESIGN, SETTING, AND PARTICIPANTS Case-control analysis using the UK-based General Practice Research Database. Incident patients between 1994 and 2008 and 4 controls per each patient were identified and matched on age, sex, general practice, calendar time, and years of history in the database. The study population was 76% women and the mean (SD) age was 53.4 (15.0) years at the index date. Conditional logistic regression was used to estimate the odds ratio (OR) of developing gallstones followed by cholecystectomy in relation to exposure to lipid-lowering agents, stratified by exposure timing and duration. The ORs and 95% confidence intervals (CIs) were adjusted for smoking, body mass index, ischemic heart disease, stroke, and estrogen use. MAIN OUTCOME MEASURE The adjusted OR (AOR) for developing gallstone disease followed by cholecystectomy in relation to exposure to lipid-lowering agents. RESULTS A total of 27,035 patients with cholecystectomy and 106,531 matched controls were identified, including 2396 patients and 8868 controls who had statin use. Compared with nonuse, current statin use (last prescription recorded within 90 days before the first-time diagnosis of the disease) was 1.0% for patients and 0.8% for controls (AOR, 1.10; 95% CI, 0.95-1.27) for 1 to 4 prescriptions; 2.6% vs 2.4% (AOR, 0.85; 95% CI, 0.77-0.93) for 5 to 19 prescriptions, and 3.2% vs 3.7% (AOR, 0.64; 95% CI, 0.59-0.70) for 20 or more prescriptions. The AORs for current use of statins defined as 20 or more prescriptions were similar (around 0.6) across age, sex, and body mass index categories, and across the statin class. CONCLUSION Long-term use of statins was associated with a decreased risk of gallstones followed by cholecystectomy. | Statin use and risk of gallstone disease followed by cholecystectomy. |
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Key pluripotency specific factors maintain an undifferentiated ES cell phenotype while lineage specific factors work in opposition to promote cell specialization. In addition to these important transcriptional regulators, epigenetic modifiers play a defining role in regulating the balance between pluripotency and differentiation by promoting changes in chromatin structure. | Chromatin remodeling in embryonic stem cells: regulating the balance between pluripotency and differentiation. |
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Meetings are held as needed but at least twice a year. The scope includes vaccines and immunization and other relevant infectious disease issues. NAGI also makes recommendations on vaccine schedules and formulations. Agendas are set by DoH and the Chairman of NAGI. NAGI brings together experts from a range of different fields relevant to vaccines and vaccinations and has been an important resource for guiding the Expanded Program of Immunization (EPI) in South Africa. | The National Advisory Group on Immunization (NAGI) of the Republic of South Africa. |
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0.10818854719400406, "29427": 0.8649974465370178} | 22442133 | OBJECTIVE To determine whether dietary n-3 long chain polyunsaturated fatty acid (LCPUFA) supplementation of pregnant women with a fetus at high risk of allergic disease reduces immunoglobulin E associated eczema or food allergy at 1 year of age. DESIGN Follow-up of infants at high hereditary risk of allergic disease in the Docosahexaenoic Acid to Optimise Mother Infant Outcome (DOMInO) randomised controlled trial. SETTING Adelaide, South Australia. PARTICIPANTS 706 infants at high hereditary risk of developing allergic disease whose mothers were participating in the DOMInO trial. INTERVENTIONS The intervention group (n=368) was randomly allocated to receive fish oil capsules (providing 900 mg of n-3 LCPUFA daily) from 21 weeks' gestation until birth; the control group (n=338) received matched vegetable oil capsules without n-3 LCPUFA. MAIN OUTCOME MEASURE Immunoglobulin E associated allergic disease (eczema or food allergy with sensitisation) at 1 year of age. RESULTS No differences were seen in the overall percentage of infants with immunoglobulin E associated allergic disease between the n-3 LCPUFA and control groups (32/368 (9%) v 43/338 (13%); unadjusted relative risk 0.68, 95% confidence interval 0.43 to 1.05, P=0.08; adjusted relative risk 0.70, 0.45 to 1.09, P=0.12), although the percentage of infants diagnosed as having atopic eczema (that is, eczema with associated sensitisation) was lower in the n-3 LCPUFA group (26/368 (7%) v 39/338 (12%); unadjusted relative risk 0.61, 0.38 to 0.98, P=0.04; adjusted relative risk 0.64, 0.40 to 1.02, P=0.06). Fewer infants were sensitised to egg in the n-3 LCPUFA group (34/368 (9%) v 52/338 (15%); unadjusted relative risk 0.61, 0.40 to 0.91, P=0.02; adjusted relative risk 0.62, 0.41 to 0.93, P=0.02), but no difference between groups in immunoglobulin E associated food allergy was seen. CONCLUSION n-3 LCPUFA supplementation in pregnancy did not reduce the overall incidence of immunoglobulin E associated allergies in the first year of life, although atopic eczema and egg sensitisation were lower. Longer term follow-up is needed to determine if supplementation has an effect on respiratory allergic diseases and aeroallergen sensitisation in childhood. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry ACTRN12610000735055 (DOMInO trial: ACTRN12605000569606). | Effect of n-3 long chain polyunsaturated fatty acid supplementation in pregnancy on infants’ allergies in first year of life: randomised controlled trial |
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The input is the atomic coordinates of the protein structure in the Protein Data Bank format, and the specification of the starting and ending residues of one or more segments to be modeled, containing no more than 20 residues in total. The output is the coordinates of the non-hydrogen atoms in the modeled segments. A user provides the input to the server via a simple web interface, and receives the output by e-mail. The server relies on the loop modeling routine in MODELLER that predicts the loop conformations by satisfaction of spatial restraints, without relying on a database of known protein structures. For a rapid response, ModLoop runs on a cluster of Linux PC computers. AVAILABILITY The server is freely accessible to academic users at http://salilab.org/modloop | ModLoop: automated modeling of loops in protein structures. |
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0.05786345899105072, "23795": 0.13157635927200317, "24010": 0.8682814836502075, "24039": 0.24018502235412598, "24343": 0.04674193635582924, "24501": 0.6420594453811646, "24952": 0.18654440343379974, "25022": 0.5640701055526733, "25090": 0.8492490649223328, "25409": 0.7701805830001831, "25428": 0.3381449282169342, "25468": 0.04674193635582924, "25613": 0.1064341589808464, "25778": 0.3554046154022217, "25947": 0.12814582884311676, "26435": 0.14686977863311768, "26623": 0.004870930220931768, "26886": 0.5827828645706177, "27144": 0.45251765847206116, "27606": 0.9621002674102783, "27615": 0.06246116757392883, "27881": 0.0038986403960734606, "29213": 0.33115679025650024, "29277": 0.47402387857437134, "29353": 0.06520967930555344} | 22446093 | Informal carers in cancer and palliative care are known to have high needs and psychological morbidity, yet a literature review identified few targeted interventions. This systematic review of interventions for carers of patients using home cancer and palliative care services searched Medline, CancerLit, Psycinfo and Cinahl databases. The terms used were carer(s), caregiver(s), palliative and cancer. Papers that reported interventions for adults actively providing informal care for noninstitutionalized cancer and palliative care patients were reviewed. Twenty-two interventions were identified, comprising home nursing care (four), respite services (three), social networks and activity enhancement (two), problem solving and education (three) and group work (10). Of these, nine were delivered solely to carers (i.e., were targeted services). Only six of the carers' interventions had been evaluated, two of these had used a randomized control trial (RCT; grades IB), three employed a single group methodology (two prospective grades IIIC and one retrospective grade IIIC) and one was evaluated using facilitator feedback. There was a lack of outcome evaluation designs, small sample sizes and a reliance on intervention descriptions and formative evaluations. Methodological challenges may mean alternatives to 'pure' RCTs should be considered. The current evidence contributes more to understanding feasibility and acceptability than to effectiveness. Practitioners and evaluators must prioritize the further development of intervention studies. | What is the best way to help caregivers in cancer and palliative care? A systematic literature review of interventions and their effectiveness. |
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"27162": 0.23633737862110138, "27484": 0.3443928062915802, "27520": 0.20501139760017395, "27718": 0.3339579105377197, "27724": 0.562402069568634, "27756": 0.28597161173820496, "28207": 0.2622140049934387, "28297": 0.06795065850019455, "28466": 0.11256109178066254, "28586": 0.4318077862262726, "28616": 0.2160874605178833, "28767": 0.07250232994556427, "29076": 0.14433705806732178, "29162": 0.15943801403045654, "29251": 0.05970508232712746, "29464": 0.05694137513637543, "29486": 0.009718249551951885, "29516": 0.07612881064414978} | 22467585 | Background: The loss of a child during pregnancy causes significant psychological distress for many women and their partners, and may lead to long-lasting psychiatric disorders. Internet-based interventions using exposure techniques and cognitive restructuring have proved effective for posttraumatic stress disorder (PTSD) and prolonged grief. This study compared the effects of an Internet-based intervention for parents after prenatal loss with a waiting list condition (WLC). Methods: The Impact of Event Scale - Revised assessed symptoms of PTSD; the Inventory of Complicated Grief and the Brief Symptom Inventory assessed depression, anxiety, and general mental health. The 228 participants (92% female) were randomly allocated to a treatment group (TG; n = 115) or a WLC group (n = 113). The TG received a 5-week cognitive behavioral intervention including (1) self-confrontation, (2) cognitive restructuring, and (3) social sharing. Results: The TG showed significantly reduced symptoms of posttraumatic stress, prolonged grief, depression, and anxiety relative to the WLC control group. Intention-to-treat analysis revealed treatment effects of between d = 0.84 and d = 1.02 for posttraumatic stress and prolonged grief from pre- to posttreatment time points. Further significant improvement in all symptoms of PTSD and prolonged grief was found from the posttreatment evaluation to the 12-month follow-up. The attrition rate of 14% was relatively low. Conclusions: The Internet-based intervention proved to be a feasible and cost-effective treatment, reducing symptoms of posttraumatic stress, grief, depression, anxiety, and general mental health after pregnancy loss. Low-threshold e-health interventions should be further evaluated and implemented routinely to improve psychological support after pregnancy loss. | Brief Internet-Based Intervention Reduces Posttraumatic Stress and Prolonged Grief in Parents after the Loss of a Child during Pregnancy: A Randomized Controlled Trial |
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1.2726531028747559, "25708": 0.030771657824516296, "25714": 0.0029254043474793434, "26033": 0.09317722171545029, "26261": 1.0973093509674072, "26419": 0.037378571927547455, "26462": 0.007782140281051397, "26773": 0.4437839686870575, "27133": 1.1537069082260132, "27321": 0.01934296265244484, "27598": 0.8941729068756104, "27753": 0.01934296265244484, "27781": 0.1946154683828354, "27788": 0.6363908052444458, "27833": 0.6619023680686951, "28041": 0.36697331070899963, "28155": 0.11343330889940262, "28163": 0.1485546976327896, "28389": 0.5701626539230347, "28517": 0.1064341589808464, "28696": 1.0841858386993408, "28774": 0.11604541540145874, "28848": 0.791648268699646, "28873": 0.053244512528181076, "29129": 0.1873544454574585, "29278": 0.5495203733444214, "29290": 0.25239890813827515, "29490": 0.9798521995544434, "29513": 1.0881409645080566} | 22478394 | INTRODUCTION Triglyceride accumulation in the liver is an early feature in the development of nonalcoholic fatty liver disease (NAFLD) associated with human obesity, which is a multifactorial syndrome and whose underlying mechanisms are beginning to be understood. OBJECTIVES Liver peroxisome proliferator-activated receptor-γ (PPAR-γ) mRNA expression was measured as a signaling mechanism related to steatosis in obese patients with NAFLD. METHODS Liver PPAR-γ and sterol receptor element-binding protein 1c (SREBP-1c) mRNA (real-time RT-PCR), serum total adiponectin (RIA), and high molecular weight (HMW)-adiponectin (ELISA) levels, and insulin resistance (IR) evolution (homeostasis model assessment-IR) were determined in 22 obese NAFLD patients (16 with steatosis and six with steatohepatitis) who underwent subtotal gastrectomy with gastrojejunal anastomosis in Roux-en-Y and 16 nonobese subjects who underwent laparoscopic cholecystectomy (controls). RESULTS Liver PPAR-γ mRNA levels were 112 and 188% higher (P < 0.05) than control values in obese patients with steatosis and steatohepatitis, respectively, who also exhibited 70 and 62% increases in those of SREBP-1c, concomitantly with IR and lower levels of serum total adiponectin and HMW-adiponectin (P < 0.05). Liver PPAR-γ expression showed positive associations with SREBP-1c mRNA levels (r = 0.86; P < 0.0001), serum insulin levels (r = 0.39; P < 0.01), and homeostasis model assessment-IR (r = 0.60; P < 0.0001), and negative correlations with total adiponectin (r = -0.37; P < 0.01) and HMW-adiponectin (r = -0.51; P < 0.001) levels in serum. CONCLUSIONS PPAR-γ is up-regulated in the liver of obese patients with NAFLD, representing an additional reinforcing lipogenic mechanism to SREBP-1c induction in the development of hepatic steatosis. | Up-regulation of PPAR-gamma mRNA expression in the liver of obese patients: an additional reinforcing lipogenic mechanism to SREBP-1c induction. |
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precursors in otherwise normocellular bone marrow. In 40% of DBA patients, various physical anomalies are also present. Currently two genes are associated with the DBA phenotype--the ribosomal protein (RP) S19 mutated in 25% of DBA patients and RPS24 mutated in approximately 1.4% of DBA patients. Here we report the identification of a mutation in yet another ribosomal protein, RPS17. The mutation affects the translation initiation start codon, changing T to G (c.2T>G), thus eliminating the natural start of RPS17 protein biosynthesis. RNA analysis revealed that the mutated allele was expressed, and the next downstream start codon located at position +158 should give rise to a short peptide of only four amino acids (Met-Ser-Arg-Ile). The mutation arose de novo, since all healthy family members carry the wild-type alleles. The identification of a mutation in the third RP of the small ribosomal subunit in DBA patients further supports the theory that impaired translation may be the main cause of DBA pathogenesis. | Ribosomal protein S17 gene (RPS17) is mutated in Diamond-Blackfan anemia. |
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"24972": 0.3012613356113434, "25148": 0.8039615154266357, "25409": 1.0151457786560059, "25456": 0.10026945173740387, "25468": 0.13243216276168823, "25778": 0.3134697377681732, "25950": 0.7925328612327576, "26014": 0.8600510358810425, "26266": 0.2674594223499298, "26268": 0.6446255445480347, "26305": 0.3339579105377197, "26402": 0.25995752215385437, "26419": 0.029824240133166313, "26520": 0.9805850982666016, "26739": 0.4831010699272156, "27144": 1.0312920808792114, "27292": 0.04207121208310127, "27421": 0.03360854089260101, "27811": 0.5607312321662903, "27854": 0.2089812457561493, "27881": 0.35745587944984436, "28207": 0.13670019805431366, "28286": 1.2065086364746094, "28728": 0.036437395960092545, "28762": 0.02887592278420925, "28828": 0.15943801403045654, "28873": 0.00875066313892603, "28991": 1.0894558429718018, "29292": 0.03266380727291107} | 22482820 | Breast cancer (BC) is generally classified based on the receptors overexpressed on the cell nucleus, which include hormone receptors such as progesterone (PR) and estrogen (ER), and HER2. Triple-negative breast cancer (TNBC) is a type of cancer that lacks any of these three types of receptor proteins (ER/PR/HER2). Tumor cells exhibit drug resistant phenotypes that decrease the efficacy of chemotherapeutic treatments. Generally, drug resistance has a genetic basis that is caused by an abnormal gene expression, nevertheless, there are several types of drug resistance: efflux pumps reducing the cellular concentration of the drug, alterations in membrane lipids that reduce cellular uptake, increased or altered drug targets, metabolic alteration of the drug, inhibition of apoptosis, repair of the damaged DNA, and alteration of the cell cycle checkpoints. The use of "combination therapy" is recognized as an efficient solution to treat human diseases, in particular, breast cancer. In this review, we give examples of different nanocarriers used to co-deliver multiple therapeutics (chemotherapeutic agent and nucleic acid) to drug-resistant tumor cells, and lastly, we give our recommendations for the future directions for the co-delivery treatments. | An overview of the effective combination therapies for the treatment of breast cancer. |
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"28828": 0.3127557039260864, "28848": 1.0437490940093994, "28873": 0.05046287178993225, "28965": 0.018384648486971855, "29310": 0.674915611743927, "29398": 1.7579926252365112, "29486": 0.25694093108177185, "29490": 0.04860413447022438} | 22483580 | Bipolar disorder is a severe psychiatric disorder that is associated with persistent changes in the quality, duration and architecture of sleep. Currently there is no unifying hypothesis explaining the alterations in sleep observable in patients with bipolar disorder and management is often difficult though vital. Sleep is modified by various cytokines including IL-6. Elevated levels of IL-6 are associated with a poorer quality of sleep and changes in the architecture of sleep similar to those observed in bipolar disorder. Therapeutic administration of Interferon causes elevations of intrathecal IL-6 concentrations and appears to provoke a deteriorating quality of sleep. The blockade of IL-6 with tocilizumab in rheumatoid arthritis is associated with improvements in the quality of sleep. Bipolar disorder is associated with elevated levels of IL-6 and in particular elevated levels of mRNA coding for IL-6 in peripheral monocytes. We propose that the changes observed in the sleep of patients with bipolar disorder are related to the elevation of IL-6 and that this correlates with an elevated expression of mRNA coding for IL-6 expression in peripheral monocytes. | Disturbed sleep in bipolar disorder is related to an elevation of IL-6 in peripheral monocytes. |
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| 22488511 | To investigate the role of TGF-β and IL-6 in myofibroblasts (MFs) - lung cancer cell interactions, lung cancer cells (Lewis and CTM-167 cell lines) were stimulated by IL-6, MF-conditioned medium (MF-CM) or MFs, with or without TGF-β signaling inhibitor - SB431542 and/or JAK2/STAT3 inhibitor - JSI-124. MFs were stimulated by TGF-β, cancer cell-CM or cancer cells, with or without SB431542 and JSI-124. Cell proliferation, the levels of cytokines, expression of mRNA and protein were determined. Mice bearing xenograft tumors were intraperitoneally treated with SB431542 or JSI-124 and monitored for up to 45 days. In co-culture systems, MFs secreted high levels of IL-6, while cancer cells produced high levels of TGF-β. Recombinant IL-6 and MF-CM activated STAT3 and upregulated TGF-β in cancer cells. In contrast, cancer cell-CM or TGF-β stimulated MFs to produce IL-6. Blockade of JAK2/STAT3 and TGF-β signaling by specific inhibitors significantly inhibited cell proliferation in vitro and tumor growth in vivo of lung cancer cells. Our study demontrated that the TGF-β and IL-6/JAK2/STAT3 signaling pathways form a positive feedback signaling loop that mediated the interactions between MFs and lung cancer cells. Targeted inhibiton of this signaling loop could be a new approach for lung cancer prevention and therapy. | Targeted blockade of TGF-β and IL-6/JAK2/STAT3 pathways inhibits lung cancer growth promoted by bone marrow-derived myofibroblasts |
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The low success rate is believed to be associated with epigenetic errors, including abnormal DNA hypermethylation, but the mechanism of "reprogramming" is unclear. We have been able to develop a stable NT method in the mouse in which donor nuclei are directly injected into the oocyte using a piezo-actuated micromanipulator. Especially in the mouse, only a few laboratories can make clones from adult somatic cells, and cloned mice are never successfully produced from most mouse strains. However, this technique promises to be an important tool for future research in basic biology. For example, NT can be used to generate embryonic stem (NT-ES) cell lines from a patient's own somatic cells. We have shown that NT-ES cells are equivalent to ES cells derived from fertilized embryos and that they can be generated relatively easily from a variety of mouse genotypes and cell types of both sexes, even though it may be more difficult to generate clones directly. In general, NT-ES cell techniques are expected to be applied to regenerative medicine; however, this technique can also be applied to the preservation of genetic resources of mouse strain instead of embryos, oocytes and spermatozoa. This review describes how to improve cloning efficiency and NT-ES cell establishment and further applications. | Production of cloned mice and ES cells from adult somatic cells by nuclear transfer: how to improve cloning efficiency? |
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"27781": 0.015504186972975731, "27854": 0.12642613053321838, "28024": 0.32058215141296387, "28117": 0.16524957120418549, "28227": 0.07612881064414978, "28577": 0.1946154683828354, "28873": 0.176772341132164, "29105": 0.46363574266433716, "29125": 1.0087559223175049, "29290": 0.5871354341506958, "29443": 0.3883931338787079} | 22495397 | The Tat protein of human immunodeficiency virus type 1 (HIV-1) plays a key role as inducer of viral gene expression. We report that Tat function can be potently inhibited in human microglial cells by the recently described nuclear receptor cofactor chicken ovalbumin upstream promoter transcription factor-interacting protein 2 (CTIP2). Overexpression of CTIP2 leads to repression of HIV-1 replication, as a result of inhibition of Tat-mediated transactivation. In contrast, the related CTIP1 was unable to affect Tat function and viral replication. Using confocal microscopy to visualize Tat subcellular distribution in the presence of the CTIPs, we found that overexpression of CTIP2, and not of CTIP1, leads to disruption of Tat nuclear localization and recruitment of Tat within CTIP2-induced nuclear ball-like structures. In addition, our studies demonstrate that CTIP2 colocalizes and associates with the heterochromatin-associated protein HP1alpha. The CTIP2 protein harbors two Tat and HP1 interaction interfaces, the 145-434 and the 717-813 domains. CTIP2 and HP1alpha associate with Tat to form a three-protein complex in which the 145-434 CTIP2 domain interacts with the N-terminal region of Tat, while the 717-813 domain binds to HP1. The importance of this Tat binding interface and of Tat subnuclear relocation was confirmed by analysis of CTIP2 deletion mutants. Our findings suggest that inhibition of HIV-1 expression by CTIP2 correlates with recruitment of Tat within CTIP2-induced structures and relocalization within inactive regions of the chromatin via formation of the Tat-CTIP2-HP1alpha complex. These data highlight a new mechanism of Tat inactivation through subnuclear relocalization that may ultimately lead to inhibition of viral pathogenesis. | Recruitment of Tat to heterochromatin protein HP1 via interaction with CTIP2 inhibits human immunodeficiency virus type 1 replication in microglial cells. |
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"25644": 0.6348392367362976, "25761": 0.20501139760017395, "25932": 0.07884006202220917, "26243": 0.0038986403960734606, "26402": 0.8022117614746094, "26468": 0.05046287178993225, "26520": 0.03360854089260101, "26524": 0.6096806526184082, "26534": 0.08064348995685577, "26721": 0.5893046259880066, "26773": 0.5290185213088989, "26775": 1.0066169500350952, "27099": 0.7144040465354919, "27295": 0.678390383720398, "27598": 0.07793712615966797, "27715": 0.1384023278951645, "28155": 0.7352184057235718, "28156": 0.1477125883102417, "28667": 0.5151132941246033, "28696": 1.0855059623718262, "29170": 0.32341301441192627, "29290": 0.24018502235412598} | 22500262 | During fasting, mammals maintain normal glucose homeostasis by stimulating hepatic gluconeogenesis. Elevations in circulating glucagon and epinephrine, two hormones that activate hepatic gluconeogenesis, trigger the cAMP-mediated phosphorylation of cAMP response element-binding protein (Creb) and dephosphorylation of the Creb-regulated transcription coactivator-2 (Crtc2)--two key transcriptional regulators of this process. Although the underlying mechanism is unclear, hepatic gluconeogenesis is also regulated by the circadian clock, which coordinates glucose metabolism with changes in the external environment. Circadian control of gene expression is achieved by two transcriptional activators, Clock and Bmal1, which stimulate cryptochrome (Cry1 and Cry2) and Period (Per1, Per2 and Per3) repressors that feed back on Clock-Bmal1 activity. Here we show that Creb activity during fasting is modulated by Cry1 and Cry2, which are rhythmically expressed in the liver. Cry1 expression was elevated during the night-day transition, when it reduced fasting gluconeogenic gene expression by blocking glucagon-mediated increases in intracellular cAMP concentrations and in the protein kinase A-mediated phosphorylation of Creb. In biochemical reconstitution studies, we found that Cry1 inhibited accumulation of cAMP in response to G protein-coupled receptor (GPCR) activation but not to forskolin, a direct activator of adenyl cyclase. Cry proteins seemed to modulate GPCR activity directly through interaction with G(s)α. As hepatic overexpression of Cry1 lowered blood glucose concentrations and improved insulin sensitivity in insulin-resistant db/db mice, our results suggest that compounds that enhance cryptochrome activity may provide therapeutic benefit to individuals with type 2 diabetes. | Cryptochrome Mediates Circadian Regulation of cAMP Signaling and Hepatic Gluconeogenesis |
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0.3601844012737274, "27339": 0.026976587250828743, "27833": 0.14939609169960022, "27854": 0.4462870955467224, "27894": 0.07793712615966797, "28093": 0.9732321500778198, "28290": 0.02792670577764511, "28436": 0.15023678541183472, "28873": 0.3560888469219208, "29278": 0.1221139207482338, "29308": 0.3443928062915802, "29610": 0.3297532796859741} | 22505190 | It remains controversial regarding the association between toll-like receptor 4 (TLR4) gene Asp299Gly (+896 A/G) polymorphism and myocardial infarction (MI) risk. Thus, a large-scale meta-analysis evaluating the potential association between this gene variant and MI risk is required. PubMed, Embase, Web of Science, CBMdisc, CNKI, and Google Scholar were searched until February 6, 2013. All the statistical tests were performed using Stata 11.0. Nine articles involving 10 studies were included in the final meta-analysis, covering a total of 8299 MI cases and 6849 controls. Overall, no significant association was found between the TLR4 gene Asp299Gly polymorphism and MI risk (G allele vs. A allele: OR=0.95, 95% CI=0.74-1.22, p=0.71; G/G vs. A/A: OR=1.03, 95% CI=0.54-1.98, p=0.93; G/G vs. A/G+A/A: OR=1.05, 95% CI=0.55-2.03, p=0.87; G/G+A/G vs. A/A: OR=0.92, 95% CI=0.75-1.13, p=0.42). In the subgroup analysis based on source of controls, there was also lack of evidence for significant association between the TLR4 gene Asp299Gly polymorphism and MI risk. In summary, the present meta-analysis indicated that the TLR4 gene Asp299Gly polymorphism was not associated with MI risk. | Toll-like receptor 4 gene Asp299Gly polymorphism in myocardial infarction: a meta-analysis of 15,148 subjects. |
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"24269": 0.1229778528213501, "24335": 0.7398891448974609, "24534": 0.8861536383628845, "24635": 0.011650617234408855, "24848": 0.08513788133859634, "25002": 0.06246116757392883, "25194": 0.05046287178993225, "25284": 0.9798521995544434, "25458": 0.2493593990802765, "25568": 0.42735910415649414, "25641": 0.04113444685935974, "25714": 0.9591107368469238, "26006": 0.6451379656791687, "26065": 0.09228714555501938, "26314": 0.8861536383628845, "26557": 0.757441520690918, "26692": 0.0354953333735466, "26785": 0.8625272512435913, "27321": 0.8600510358810425, "27528": 0.11430477350950241, "27641": 0.7491656541824341, "27651": 0.14686977863311768, "27781": 0.19622190296649933, "28281": 0.015504186972975731, "28286": 0.7809720039367676, "28691": 0.2231435477733612, "28696": 1.1555536985397339, "28788": 0.2493593990802765, "28828": 0.1602703034877777, "28873": 0.43623676896095276, "29166": 0.9944084882736206, "29490": 0.1384023278951645} | 22505710 | OBJECTIVE To examine by immunohistochemistry the relative distributions of 6 matrix metalloproteinases (MMPs 1, 2, 3, 8, 9, and 13) and the 2 proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha) in osteoarthritic (OA) cartilage compared with normal, age-matched articular cartilage. METHODS Articular cartilage samples were obtained from the tibial plateau of OA knees removed at arthroplasty and from normal, nonarthritic, knees obtained at autopsy. Specimens were promptly fixed in Carnoy's fixative, processed, embedded in paraffin, sectioned, and examined by immunohistochemistry for MMP and cytokine production. In addition, human articular chondrocytes (HAC) were treated in vitro with either IL-1beta, TNFalpha, or phorbol myristate acetate (PMA) to assess their potential to produce each of the MMPs, as determined by Western blotting and gelatin zymography. RESULTS Immunodetection of the collagenases (MMPs 1, 8, and 13) and stromelysin 1 (MMP-3) was demonstrated in a proportion of chondrocytes in the superficial zone of almost all of the OA specimens that had degenerative matrix changes. The gelatinases (MMPs 2 and 9) were also demonstrated by immunohistochemistry but were not so prominent. IL-1beta- and TNFalpha-positive chondrocytes were also observed in a proportion of cells in the superficial zones of OA specimens. Much less immunostaining for MMPs and cytokines was observed in the deep zone of all OA specimens, where the cartilage matrix and chondrocyte morphology appeared normal. In contrast, full-thickness normal cartilage specimens showed virtually no immunostaining for these MMPs or cytokines. Confirmation that chondrocytes can produce these 6 MMPs was obtained from HAC cultures treated with either IL-1beta, TNFalpha, or PMA; conditioned medium from activated HAC contained all the MMPs demonstrated by immunohistochemistry. Dual immunolocalization studies of OA cartilage specimens demonstrated the coexpression of IL-1 with MMP-8 by individual chondrocytes in situ. CONCLUSION These results indicate that the superficial zone of OA cartilage specimens, which is characterized by fibrillations, chondrocyte clusters, and degenerative matrix changes, contains a variable proportion of cells that immunostain for IL-1beta, TNFalpha, and 6 different MMPs. These observations support the concept that cytokine-MMP associations reflect a modified chondrocyte phenotype and an intrinsic process of cartilage degradation in OA. | Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: associations with degenerative changes. |
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However, a responsible WNT ligand has not been identified. To further clarify this question, we comparatively investigated 22 human breast cancer brain metastases as well as the highly invasive human breast cancer cell line MDA-MB-231 and the weakly motile MCF-7 as models for the basal-like and the luminal A subtype. WNT5A and B were found overexpressed in MDA-MB-231 cells as compared with MCF-7. This corresponded to reduction of MDA-MB-231 invasiveness by WNT inhibitors, whereas MCF-7 invasion was enhanced by recombinant WNT5B and abolished by WNT and Jun-N-terminal kinase antagonists. Expression and subcellular distribution of β-catenin remained uninfluenced. Consistently, β-catenin was not localized in the nuclei of brain metastases while there was strong nuclear c-Jun staining. Similar to MDA-MB-231, metastases showed expression of WNT5A/B and the alternative WNT receptors ROR1 and 2. These findings were validated using external gene expression datasets (Gene Expression Omnibus) of different breast cancer subtypes and brain metastases. Hierarchical cluster analysis yielded a close relation between basal-like cancers and brain metastases. Gene set enrichment analyses confirmed WNT pathway enrichment not only in basal-like primaries but also in cerebral metastases of all subtypes. In conclusion, WNT signaling seems highly relevant for basal-like and other subtypes of breast cancers metastasizing into the brain. β-catenin-independent WNT signaling, presumably via ROR1-2, plays a major role in this context. | β-catenin-independent WNT signaling in basal-like breast cancer and brain metastasis. |
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The aim of this study was to determine whether all-trans retinaldehyde (retinal), a vitamin A derivative, can inhibit inflammatory responses and joint destruction in DBA/1J mice with collagen-induced arthritis (CIA). The arthritis score and incidence of arthritis were lower in mice treated with retinal compared to those treated with cottonseed oil. Histopathologic evidence of joint damage was lower in mice treated with retinal, corresponding with a reduction in the infiltration of immune cells in mice treated with retinal type II collagen (CII)-stimulated spleen cells. In addition, the expression of proinflammatory cytokines, oxidative stress proteins, and osteoclast markers were significantly reduced in mice treated with retinal. In vitro, retinal induced increased Foxp3 expression and inhibited Th17 development. The proportion of Foxp3(+) Treg cells was increased in the spleens of mice treated with retinal, whereas the proportion of Th17 cells was reduced. In both mice and a human culture system, tartrate-resistant acid phosphatase (TRAP) positive mononuclear cells and multinucleated cells were significantly reduced after treatment with retinal. The expression of osteoclast differentiation markers was dramatically decreased upon addition of retinal. This is the first study to demonstrate the therapeutic effect of retinal on an autoimmune arthritis model in mice through reciprocal regulation of Th17 and regulatory T cells and protection of differentiation and activation of osteoclasts. Taken together, our findings indicate that retinal has profound immunoregulatory functions and potential value for the treatment of autoimmune inflammatory disorders. | Retinal attenuates inflammatory arthritis by reciprocal regulation of IL-17-producing T cells and Foxp3(+) regulatory T cells and the inhibition of osteoclastogenesis. |
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"28873": 0.9348671436309814, "29109": 0.10555581003427505, "29206": 0.8013357520103455, "29264": 0.4512746334075928, "29295": 0.12986256182193756, "29300": 0.0606246218085289, "29458": 0.09761575609445572, "29477": 0.15693697333335876} | 22521091 | Hepatocellular carcinoma (HCC) is a fatal disease, primarily due to the limited effective therapies available for patients with advanced or recurrent stages of the disease. Therefore, in order to improve patient prognosis, it is important to identify an informative biomarker for HCC progression, as well as a molecular target for therapy. Neurotrophin receptor-interacting melanoma antigen-encoding protein (NRAGE), a member of the type II melanoma-associated antigen family, mediates apoptosis and cell death through interactions with a wide range of proteins, and is implicated as a tumor suppressor or oncoprotein depending on cell type. However, the role of NRAGE in HCC is currently unknown, therefore, the present study aimed to identify the underlying function of NRAGE in HCC tumorigenesis. Resected tumor and non-cancerous liver tissues from 151 patients with HCC, alongside HCC cell lines, were analyzed by polymerase chain reaction and immunohistochemical techniques to determine NRAGE expression levels, as well as the expression levels of potential genes encoding interacting proteins. It was demonstrated that the expression levels of NRAGE mRNA correlated significantly with those of apoptosis-antagonizing transcription factor (AATF), and were not affected by cirrhosis in non-cancerous liver tissues when compared to elevated levels in HCC tissues. The expression patterns of NRAGE protein and mRNA were consistent among 30 representative specimen pairs. Furthermore, increased NRAGE expression in patients with HCC correlated significantly with a shorter disease-specific survival time, and was identified as an independent prognostic factor via multivariate analysis (hazard ratio, 2.23; 95% confidence interval, 1.06-3.83; P=0.020). Therefore, the results of the present study indicated that increased NRAGE expression affects HCC progression via its interaction with AATF, and may represent a novel biomarker and molecular target for the treatment of HCC. | NRAGE promotes the malignant phenotype of hepatocellular carcinoma. |
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"25152": 1.2129170894622803, "25206": 0.03360854089260101, "25426": 0.034552380442619324, "25705": 0.27044451236724854, "25776": 0.1510767638683319, "26083": 0.1873544454574585, "26279": 0.371698260307312, "26305": 0.11691460013389587, "26356": 0.13414156436920166, "26520": 0.07341018319129944, "26601": 0.35813871026039124, "26610": 0.1229778528213501, "26874": 0.5635144114494324, "27170": 0.020300358533859253, "27226": 0.10906458646059036, "27642": 1.0101795196533203, "27697": 0.43875885009765625, "27790": 0.5500838756561279, "27989": 0.3526630103588104, "28024": 0.1889725625514984, "28086": 0.043007105588912964, "28591": 0.4574742913246155, "28667": 0.6128603219985962, "28820": 0.1873544454574585, "28847": 0.9363996982574463, "29206": 0.11256109178066254, "29258": 0.8941729068756104, "29602": 0.21765978634357452, "29611": 0.040196798741817474} | 22522432 | The stable contact of ISW2 with nucleosomal DNA approximately 20 bp from the dyad was shown by DNA footprinting and photoaffinity labeling using recombinant histone octamers to require the histone H4 N-terminal tail. Efficient ISW2 remodeling also required the H4 N-terminal tail, although the lack of the H4 tail can be mostly compensated for by increasing the incubation time or concentration of ISW2. Similarly, the length of extranucleosomal DNA affected the stable contact of ISW2 with this same internal nucleosomal site, with the optimal length being 70 to 85 bp. These data indicate the histone H4 tail, in concert with a favorable length of extranucleosomal DNA, recruits and properly orients ISW2 onto the nucleosome for efficient nucleosome remodeling. One consequence of this property of ISW2 is likely its previously observed nucleosome spacing activity. | Regulation of ISW2 by concerted action of histone H4 tail and extranucleosomal DNA. |
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"28788": 0.2918238639831543, "29166": 0.37035053968429565, "29200": 0.45623743534088135, "29206": 1.0894558429718018, "29278": 0.18004031479358673} | 22530842 | The experience accumulated in cardiac cell therapy suggests that regeneration of extensively necrotic myocardial areas is unlikely to be achieved by the sole paracrine effects of the grafted cells but rather requires the conversion of these cells into cardiomyocytes featuring the capacity to substitute for those which have been irreversibly lost. In this setting, the use of human pluripotent embryonic stem cells has a strong rationale. The experimental results obtained in animal models of myocardial infarction are encouraging. However, the switch to clinical applications still requires to address some critical issues, among which the optimization of the cardiac specification of the embryonic stem cells, the purification of the resulting progenitor cells so as to graft a purified population devoid from any contamination by residual pluripotent cells which carry the risk of tumorigenesis, and the control of the expected allogeneic rejection by clinically acceptable methods. If the solution to these problems is a prerequisite, the therapeutic success of this approach will also depend on the capacity to efficiently transfer the cells to the target tissue, to keep them alive once engrafted, and to allow them to spatially organize in such a way that they can contribute to the contractile function of the heart. | Embryonic Stem Cells for Severe Heart Failure: Why and How? |
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0.013579257763922215, "28370": 0.02792670577764511, "28436": 0.11865071207284927, "28687": 0.13071982562541962, "28711": 0.053244512528181076, "28762": 0.043007105588912964, "29242": 0.32270604372024536, "29290": 0.42096930742263794} | 22534357 | OBJECTIVE To compare pregnancy rates (PR) for letrozole and gonadotropins in individuals who failed to conceive with clomiphene citrate (CC). DESIGN Retrospective cohort study. SETTING University reproductive center. PATIENT(S) Individuals treated with letrozole or gonadotropins who failed to conceive with CC. INTERVENTION(S) Controlled ovarian hyperstimulation (COH), transvaginal ultrasound, ovulation induction, IUI. MAIN OUTCOME MEASURE(S) Pregnancy rates per cycle. RESULT(S) Among patients who failed to conceive with at least three cycles of CC, gonadotropins had a higher PR per cycle than letrozole. Among individuals who failed to conceive with less than three cycles of CC and whose medications were changed because of thin uterine lining or intolerable side effects, average PR per cycle for letrozole and gonadotropin treatments were equivalent. All patients conceived within three stimulation cycles with either gonadotropins or letrozole. CONCLUSION(S) In patients who failed to conceive with CC, gonadotropins have higher PR for ovulation induction than letrozole. However, PR were high enough with letrozole to justify its use in this population of patients. Letrozole and gonadotropins should not be used for more than three cycles without a conception. | A comparison of letrozole to gonadotropins for ovulation induction, in subjects who failed to conceive with clomiphene citrate. |
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"28767": 0.35334911942481995, "28828": 0.6664261221885681, "28829": 0.4974553883075714, "28927": 0.18573370575904846, "28935": 0.861702561378479, "29101": 0.16442140936851501, "29206": 1.3789432048797607, "29226": 0.1718502640724182, "29238": 0.0913962796330452} | 22543403 | The exploration of brain epigenomes, which consist of various types of DNA methylation and covalent histone modifications, is providing new and unprecedented insights into the mechanisms of neural development, neurological disease and aging. Traditionally, chromatin defects in the brain were considered static lesions of early development that occurred in the context of rare genetic syndromes, but it is now clear that mutations and maladaptations of the epigenetic machinery cover a much wider continuum that includes adult-onset neurodegenerative disease. Here, we describe how recent advances in neuroepigenetics have contributed to an improved mechanistic understanding of developmental and degenerative brain disorders, and we discuss how they could influence the development of future therapies for these conditions. | Epigenetic mechanisms in neurological disease |
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"27795": 0.2837681770324707, "27823": 0.010684899985790253, "28086": 0.1229778528213501, "28146": 0.043007105588912964, "28177": 0.08513788133859634, "28179": 0.7845434546470642, "28290": 0.1602703034877777, "28327": 1.0037577152252197, "28522": 0.9271688461303711, "28616": 0.35745587944984436, "28685": 0.3883931338787079, "28767": 0.22626367211341858, "28828": 0.7153595685958862, "28829": 0.18004031479358673, "28848": 0.5827828645706177, "28964": 0.2969166338443756, "29146": 0.6415454745292664, "29325": 0.029824240133166313, "29370": 0.38308101892471313, "29388": 0.304147332906723} | 22544171 | Hutchinson-Gilford progeria syndrome (HGPS) is a childhood premature aging disease caused by a spontaneous point mutation in lamin A (encoded by LMNA), one of the major architectural elements of the mammalian cell nucleus. The HGPS mutation activates an aberrant cryptic splice site in LMNA pre-mRNA, leading to synthesis of a truncated lamin A protein and concomitant reduction in wild-type lamin A. Fibroblasts from individuals with HGPS have severe morphological abnormalities in nuclear envelope structure. Here we show that the cellular disease phenotype is reversible in cells from individuals with HGPS. Introduction of wild-type lamin A protein does not rescue the cellular disease symptoms. The mutant LMNA mRNA and lamin A protein can be efficiently eliminated by correction of the aberrant splicing event using a modified oligonucleotide targeted to the activated cryptic splice site. Upon splicing correction, HGPS fibroblasts assume normal nuclear morphology, the aberrant nuclear distribution and cellular levels of lamina-associated proteins are rescued, defects in heterochromatin-specific histone modifications are corrected and proper expression of several misregulated genes is reestablished. Our results establish proof of principle for the correction of the premature aging phenotype in individuals with HGPS. | Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome |
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"28577": 0.14349138736724854, "28696": 1.2791962623596191, "29137": 0.34577593207359314, "29172": 0.06886265426874161, "29290": 0.3269403576850891} | 22545779 | Multiple hormones controlling energy homeostasis regulate the expression of neuropeptide Y (NPY) and agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus. Nevertheless, inactivation of the genes encoding NPY and/or AgRP has no impact on food intake in mice. Here we demonstrate that induced selective ablation of AgRP-expressing neurons in adult mice results in acute reduction of feeding, demonstrating direct evidence for a critical role of these neurons in the regulation of energy homeostasis. | Agouti-related peptide–expressing neurons are mandatory for feeding |
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22547508 | Acute paraquat poisoning is often fatal. Many studies have investigated successful treatment modalities, but no standard treatment yet exists. The purpose of this study was to determine the predictors of survival after acute paraquat poisoning in 602 patients. The paraquat exposure was assessed based on the amount of ingested paraquat and a semiquantitative measure of the urine level of paraquat. Initial clinical parameters including vital signs, hemoglobin, white-blood-cell count, pH, PaCO2, PaO2, blood urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, total bilirubin, amylase, and glucose were obtained at the time of arrival at the emergency room. Outcomes after acute paraquat poisoning were categorized as survivors and nonsurvivors. Multiple logistic regression analysis was applied to assess the predictors of survival after acute paraquat poisoning. Some patients (55.5%) survived after oral ingestion of paraquat, whereas all those exposed to paraquat percutaneous or inhalational route survived. The amount of paraquat (24.5% concentrate of 1,1'-dimethyl-4,4'-bipyridium dichloride) ingested was 45.6 +/- 74.1 mL (mean +/- SD). In addition to degree of paraquat exposure, survival after acute paraquat poisoning was associated with age, respiratory rate, pH, PaCO2, hemoglobin, white-blood-cell count, blood urea nitrogen, amylase, and the number of failed organs in multiple logistic regression analysis. In conclusion, young age, percutaneous or inhalational route, exposure to less paraquat, and lesser degrees of leukocytosis, acidosis, and renal, hepatic, and pancreatic failures on admission are good prognostic factors of survival after acute paraquat poisoning. | Predictors of survival after acute paraquat poisoning. |
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"25608": 0.05139094591140747, "25644": 0.175953671336174, "25927": 0.04487626627087593, "26279": 0.10379679501056671, "26288": 1.0437490940093994, "26402": 0.05139094591140747, "26451": 0.17922431230545044, "26497": 0.7239188551902771, "26773": 0.5528968572616577, "26838": 0.7818660736083984, "27287": 0.9394577741622925, "27532": 0.014542185701429844, "28086": 0.1332872211933136, "28156": 0.1913948506116867, "28228": 0.06429435312747955, "28741": 1.022197961807251, "28767": 0.21765978634357452, "28873": 0.040196798741817474, "28896": 0.01934296265244484, "28931": 0.319873183965683, "28938": 0.24859806895256042, "29090": 0.48068851232528687, "29206": 0.21293537318706512, "29222": 0.06246116757392883, "29441": 0.13499516248703003, "29592": 0.848413348197937} | 22549449 | Adult neurogenesis has been shown to be regulated by a multitude of extracellular cues, including hormones, growth factors, and neurotransmitters. The cholinergic system of the basal forebrain is one of the key transmitter systems for learning and memory. Because adult neurogenesis has been implicated in cognitive performance, the present work aims at defining the role of cholinergic input for adult neurogenesis by using an immunotoxic lesion approach. The immunotoxin 192IgG-saporin was infused into the lateral ventricle of adult rats to selectively lesion cholinergic neurons of the cholinergic basal forebrain (CBF), which project to the two main regions of adult neurogenesis: the dentate gyrus and the olfactory bulb. Five weeks after lesioning, neurogenesis, defined by the number of cells colocalized for bromodeoxyuridine (BrdU) and the neuronal nuclei marker NeuN, declined significantly in the granule cell layers of the dentate gyrus and olfactory bulb. Furthermore, immunotoxic lesions to the CBF led to increased numbers of apoptotic cells specifically in the subgranular zone, the progenitor region of the dentate gyrus, and within the periglomerular layer of the olfactory bulb. We propose that the cholinergic system plays a survival-promoting role for neuronal progenitors and immature neurons within regions of adult neurogenesis, similar to effects observed previously during brain development. As a working hypothesis, neuronal loss within the CBF system leads not only to cognitive deficits but may also alter on a cellular level the functionality of the dentate gyrus, which in turn may aggravate cognitive deficits. | Decreased neurogenesis after cholinergic forebrain lesion in the adult rat. |
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"23130": 0.151916041970253, "23683": 0.23402166366577148, "23900": 0.0058422754518687725, "23924": 0.08513788133859634, "24073": 0.966567873954773, "24128": 0.20977331697940826, "24757": 0.27342069149017334, "24844": 0.5838727951049805, "25003": 1.0907690525054932, "25262": 0.27044451236724854, "25644": 0.0770333781838417, "25774": 0.13071982562541962, "25870": 0.4425300657749176, "25969": 0.05417001247406006, "26305": 0.7153595685958862, "26534": 0.06520967930555344, "26773": 0.8143964409828186, "27484": 0.9240728616714478, "28436": 0.27044451236724854, "28466": 0.06429435312747955, "28767": 0.2763880789279938, "28828": 0.1332872211933136, "28892": 0.06703783571720123, "29172": 0.03266380727291107, "29206": 1.4669378995895386, "29458": 0.10906458646059036} | 22551259 | Epigenetic mechanisms regulate gene expression, influencing protein levels and ultimately shaping phenotypes during life. However, both stochastic epigenetic variations and environmental reprogramming of the epigenome might influence neurodevelopment and ageing, and this may contribute to the origins of mental ill-health. Studying the role of epigenetic mechanisms is challenging, as genotype-, tissue- and cell type-dependent epigenetic changes have to be taken into account, while the nature of mental disorders also poses significant challenges for linking them with biological profiles. In this chapter, we summarise the current evidence suggesting the role of DNA methylation as a key epigenetic mechanism in major depressive disorder. | DNA Methylation in Major Depressive Disorder. |
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Here, we investigate the composition and structural organization of three different purified Tat complexes from Escherichia coli, Salmonella typhimurium and Agrobacterium tumefaciens. First, we demonstrate the functional activity of these Tat systems in vivo, since expression of the tatABC operons from S.typhimurium or A.tumefaciens in an E.coli tat null mutant strain resulted in efficient Tat-dependent export of an E.coli cofactor-containing substrate, TMAO reductase. The three isolated, affinity-tagged Tat complexes comprised TatA, TatB and TatC in each case, demonstrating a strong interaction between these three subunits. Single-particle electron microscopy studies of all three complexes revealed approximately oval-shaped, asymmetric particles with maximal dimensions up to 13 nm. A common feature is a number of stain-excluding densities surrounding more or less central pools of stain, suggesting protein-lined pores or cavities. The characteristics of size variation among the particles suggest a modular form of assembly and/or the recruitment of varying numbers of TatBC/TatA units. Despite low levels of sequence homology, the combined data indicate structural and functional conservation in the Tat systems of these three bacterial species. | Consensus structural features of purified bacterial TatABC complexes. |
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0.07068414986133575, "28896": 0.02412080205976963, "29217": 0.14686977863311768} | 22613657 | Allogeneic haematopoietic stem cell transplantation is used to treat a variety of disorders, but its efficacy is limited by the occurrence of graft-versus-host disease (GVHD). The past decade has brought impressive advances in our understanding of the role of stimulatory and suppressive elements of the adaptive and innate immune systems from both the donor and the host in GVHD pathogenesis. New insights from basic immunology, preclinical models and clinical studies have led to novel approaches for prevention and treatment. This Review highlights the recent advances in understanding the pathophysiology of GVHD and its treatment, with a focus on manipulations of the immune system that are amenable to clinical application. | Advances in graft-versus-host disease biology and therapy |
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Idiopathic pulmonary fibrosis (IPF) is a devastating disease. Antiinflammatory therapies, including corticosteroids, are of no benefit. The role of monocytes and macrophages is therefore controversial. OBJECTIVES To define the role of monocytes and macrophages during lung fibrogenesis and resolution, and explore the phenotype of the cells involved. METHODS We used multiple in vivo depletional strategies, backed up by adoptive transfer techniques. Further studies were performed on samples from patients with IPF. MEASUREMENTS AND MAIN RESULTS Depletion of lung macrophages during fibrogenesis reduced pulmonary fibrosis as measured by lung collagen (P = 0.0079); fibrosis score (P = 0.0051); and quantitative polymerase chain reaction for surrogate markers of fibrosis Col1 (P = 0.0083) and a-smooth muscle actin (P = 0.0349). There was an associated reduction in markers of the profibrotic alternative macrophage activation phenotype, Ym1 (P = 0.0179), and Arginase 1. The alternative macrophage marker CD163 was expressed on lung macrophages from patients with IPF. Depletion of Ly6Chi circulating monocytes reduced pulmonary fibrosis (P = 0.0052) and the number of Ym1- positive alternatively activated lung macrophages (P = 0.0310). Their adoptive transfer during fibrogenesis exacerbated fibrosis (P = 0.0304); however, adoptively transferred CD45.1 Ly6Chi cells were not found in the lungs of recipient CD45.2 mice. CONCLUSIONS We demonstrate the importance of circulating monocytes and lung macrophages during pulmonary fibrosis, and emphasize the importance of the alternatively activated macrophage phenotype. We show that Ly6Chi monocytes facilitate the progression of pulmonary fibrosis, but are not obviously engrafted into lungs thereafter. Finally, we provide empirical data to suggest that macrophages may have a resolution-promoting role during the reversible phase of bleomycin-induced pulmonary fibrosis. | Ly6Chi monocytes direct alternatively activated profibrotic macrophage regulation of lung fibrosis. |
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0.2976420819759369, "28774": 0.1619328260421753, "28848": 0.6022219061851501, "29300": 0.1873544454574585} | 22623275 | Members of the conserved family of eukaryotic RNA-dependent RNA polymerases (Rdrs) synthesize double-stranded RNA (dsRNA) intermediates in diverse pathways of small RNA (sRNA) biogenesis and RNA-mediated silencing. Rdr-dependent pathways of sRNA production are poorly characterized relative to Rdr-independent pathways, and the Rdr enzymes themselves are poorly characterized relative to their viral RNA-dependent RNA polymerase counterparts. We previously described a physical and functional coupling of the Tetrahymena thermophila Rdr, Rdr1, and a Dicer enzyme, Dcr2, in the production of approximately 24-nucleotide (nt) sRNA in vitro. Here we characterize the endogenous complexes that harbor Rdr1, termed RDRCs. Distinct RDRCs assemble to contain Rdr1 and subsets of the total of four tightly Rdr1-associated proteins. Of particular interest are two RDRC subunits, Rdn1 and Rdn2, which possess noncanonical ribonucleotidyl transferase motifs. We show that the two Rdn proteins are uridine-specific polymerases of separate RDRCs. Two additional RDRC subunits, Rdf1 and Rdf2, are present only in RDRCs containing Rdn1. Rdr1 catalytic activity is retained in RDRCs purified from cell extracts lacking any of the nonessential RDRC subunits (Rdn2, Rdf1, Rdf2) or if the RDRC harbors a catalytically inactive Rdn. However, specific disruption of each RDRC imposes distinct loss-of-function consequences at the cellular level and has a differential impact on the accumulation of specific 23-24-nt sRNA sequences in vivo. The biochemical and biological phenotypes of RDRC subunit disruption reveal a previously unanticipated complexity of Rdr-dependent sRNA biogenesis in vivo. | A single RNA-dependent RNA polymerase assembles with mutually exclusive nucleotidyl transferase subunits to direct different pathways of small RNA biogenesis. |
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"26591": 0.14264501631259918, "26702": 0.9673105478286743, "26835": 0.9650808572769165, "27572": 0.15275461971759796, "27781": 0.29981520771980286, "27854": 0.04767346754670143, "28286": 0.7144040465354919, "28548": 0.0038986403960734606, "28896": 0.034552380442619324, "29390": 0.2026219218969345, "29458": 0.23247487843036652} | 22632303 | Type VI protein secretion system (T6SS) is important for bacterial competition through contact-dependent killing of competitors. T6SS delivers effectors to neighboring cells and corresponding antagonistic proteins confer immunity against effectors that are delivered by sister cells. Although T6SS has been found in more than 100 gram-negative bacteria including many important human pathogens, few T6SS-dependent effector and immunity proteins have been experimentally determined. Here we report a high-throughput approach using transposon mutagenesis and deep sequencing (Tn-seq) to identify T6SS immunity proteins in Vibrio cholerae. Saturating transposon mutagenesis was performed in wild type and a T6SS null mutant. Genes encoding immunity proteins were predicted to be essential in the wild type but dispensable in the T6SS mutant. By comparing the relative abundance of each transposon mutant in the mutant library using deep sequencing, we identified three immunity proteins that render protection against killing by T6SS predatory cells. We also identified their three cognate T6SS-secreted effectors and show these are important for not only antibacterial and antieukaryotic activities but also assembly of T6SS apparatus. The lipase and muramidase T6SS effectors identified in this study underscore the diversity of T6SS-secreted substrates and the distinctly different mechanisms that target these for secretion by the dynamic T6SS organelle. | Identification of T6SS-dependent effector and immunity proteins by Tn-seq in Vibrio cholerae. |
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IL-2 U and 26 x 10(6) LAK cells) and i.m. administration of IFN and TF; 71 patients also received a 3-day cycle of monthly IL-2 inhalations with a mean of 998 daily U. MRCC cases not treated by immunotherapy (n = 89) represent our historical controls. Adverse clinical side effects related to treatment were negligible. CR (n = 11) and PR (n = 13) were noticed in 24/122 patients. Of 24 responding patients, 17 resumed progression, whereas 7 remain in remission 11-69 months later. The overall median survival of treated patients (28 months) was 3.5-fold higher than the median survival of historical controls (7.5 months), and a Kaplan-Meier curve showed 25% survival 11 years after the beginning of immunotherapy. Apparently, the addition of IL-2 by inhalation improved survival. The present immunotherapy protocol appears to be efficacious, safe, devoid of adverse side effects, far less costly than others and able to offer a good quality of life to MRCC patients; if confirmed in a multicenter trial, it could set the basis for developing low-dose immunomodulatory treatments. | Immunotherapy of metastatic kidney cancer. |
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0.02887592278420925, "26651": 0.37974658608436584, "26773": 0.42353010177612305, "26835": 0.846739649772644, "27166": 1.475906491279602, "27321": 0.47463157773017883, "27781": 0.43623676896095276, "28309": 0.2026219218969345, "28696": 0.2674594223499298, "28788": 0.5324648022651672, "28873": 0.6823468804359436, "28896": 0.43875885009765625, "29215": 0.07250232994556427, "29313": 0.05970508232712746, "29610": 0.12384103983640671} | 22647695 | Autoreactive T cell responses have a crucial role in central nervous system (CNS) diseases such as multiple sclerosis. Recent data indicate that CNS autoimmunity can be mediated by two distinct lineages of CD4+ T cells that are defined by the production of either interferon-γ or interleukin-17. The activity of these CD4+ T cell subsets within the CNS influences the pathology and clinical course of disease. New animal models show that myelin-specific CD8+ T cells can also mediate CNS autoimmunity. This Review focuses on recent progress in delineating the pathogenic mechanisms, regulation and interplay between these different T cell subsets in CNS autoimmunity. | Autoimmune T cell responses in the central nervous system |
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0.29328158497810364} | 22674621 | Farnesoid X receptor (FXR), a bile-acid-activated member of the nuclear receptor superfamily, is essential in regulating bile-acid, cholesterol, and triglyceride homeostasis. Disruption of the FXR gene in mice results in a proatherosclerotic lipid profile with increased serum cholesterols and triglycerides. However, the role of FXR in foam-cell formation and atherosclerosis development remains unclear. The current study showed that the peritoneal macrophages isolated from FXR-null mice took up less oxidized LDL-cholesterol (oxLDL-C), which was accompanied by a marked reduction in CD36 expression in these cells. This result appears to be FXR-independent, as FXR was not detected in the peritoneal macrophages. To assess to what extent FXR modulates atherosclerosis development, FXR/ApoE double-null mice were generated. Female mice were used for atherosclerosis analysis. Compared to ApoE-null mice, the FXR/ApoE double-null mice were found to have less atherosclerotic lesion area in the aorta, despite a further increase in the serum cholesterols and triglycerides. Our results indicate that disruption of the FXR gene could attenuate atherosclerosis development, most likely resulting from reduced oxLDL-C uptake by macrophages. Our study cautions the use of serum lipid levels as a surrogate marker to determine the efficiency of FXR modulators in treating hyperlipidemia. | Effects of FXR in foam-cell formation and atherosclerosis development. |
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Zebrin II (ZII; antigen:aldolase C) and P-path (PP; antigen:90-acetyl glycolipids). We compared the normal staining pattern using these markers and an antibody to calbindin with that found in the reeler mutants (rl/rl), in which most Purkinje cell migration is halted beneath the cerebellar white matter. The results revealed that Purkinje cells in reeler mutants, despite their ectopic location in large subcortical masses, show a clear tendency to distribute into alternating zones that either stain for Zebrin II or for P-path, with variable transition zones of mixed labeling. However, the estimated number of zones was fewer than in the normal adult cortex: roughly 7–9 zones are revealed per side in the mutant compared with 14 major divisions in wild type mice. These results raise the possibility that neurons destined to express these markers are segregated during their migration and that the final phase of migration into the cortex might involve further splitting or interdigitation between cell sets expressing the two antigens. | Purkinje cell compartments in the reeler mutant mouse as revealed by Zebrin II and 90-acetylated glycolipid antigen expression |
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0.08871890604496002, "27159": 0.1873544454574585, "27166": 0.056018441915512085, "27384": 0.02792670577764511, "27431": 0.20102575421333313, "27532": 0.6202403903007507, "27881": 0.2763880789279938, "27891": 0.7239188551902771, "27975": 0.2247048318386078, "28397": 0.4914994537830353, "28574": 0.09761575609445572} | 22688699 | OBJECT Awake craniotomy was performed as the standard surgical approach to supratentorial intraaxial tumors, regardless of the involvement of eloquent cortex, in a prospective trial of 200 patients surgically treated by the same surgeon at a single institution. METHODS Patient presentations, comorbid conditions, tumor locations, and the histological characteristics of lesions were recorded. Brain mapping was possible in 195 (97.5%) of 200 patients. The total number of patients sustaining complications was 33 for an overall complication rate of 16.5%. There were two deaths in this series, for a mortality rate of 1%. New postoperative neurological deficits were seen in 13% of the patients, but these were permanent in only 4.5% of them. Complication rates were higher in patients who had gliomas or preoperative neurological deficits and in those who had undergone prior radiation therapy or surgery. No patient who entered the operating room neurologically intact sustained a permanent neurological deficit postoperatively. Of the most recent 50 patients treated, three (6%) required a stay in the intensive care unit, and the median total hospital stay was 1 day. CONCLUSIONS Use of awake craniotomy can result in a considerable reduction in resource utilization without compromising patient care by minimizing intensive care time and total hospital stay. Awake craniotomy is a practical and effective standard surgical approach to supratentorial tumors with a low complication rate, and provides an excellent alternative to craniotomy performed with the patient in the state of general anesthesia because it allows the opportunity for brain mapping and avoids general anesthesia. | Awake craniotomy with brain mapping as the routine surgical approach to treating patients with supratentorial intraaxial tumors: a prospective trial of 200 cases. |
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Here, we have uncovered a role for reactive oxygen species (ROS) as sensors of microbe size. By sensing the differential localization of ROS generated in response to microbes of different size, neutrophils tuned their interleukin (IL)-1β expression via the selective oxidation of NF-κB, in order to implement distinct inflammatory programs. Small microbes triggered ROS intracellularly, suppressing IL-1β expression to limit neutrophil recruitment as each phagocyte eliminated numerous pathogens. In contrast, large microbes triggered ROS extracellularly, amplifying IL-1β expression to recruit numerous neutrophils forming cooperative clusters. Defects in ROS-mediated microbe size sensing resulted in large neutrophil infiltrates and clusters in response to small microbes that contribute to inflammatory disease. These findings highlight the impact of ROS localization on signal transduction. | Reactive Oxygen Species Localization Programs Inflammation to Clear Microbes of Different Size |
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"28389": 0.1384023278951645, "28619": 0.02792670577764511, "28741": 0.4228905141353607, "28775": 0.777387797832489, "28788": 0.10993985831737518, "28828": 0.01934296265244484, "28835": 0.1619328260421753, "28873": 0.23787821829319, "29090": 0.11951763927936554, "29180": 0.151916041970253, "29206": 0.02316705882549286, "29290": 0.2659635543823242, "29726": 0.2918238639831543} | 22703082 | Infection with Helicobacter pylori (H. pylori) is a risk factor for the development of gastric cancer. Here we show that infection of gastric epithelial cells with 'cag' pathogenicity island (cagPAI)-positive H. pylori induced aberrant expression of activation-induced cytidine deaminase (AID), a member of the cytidine-deaminase family that acts as a DNA- and RNA-editing enzyme, via the IκB kinase–dependent nuclear factor-κB activation pathway. H. pylori–mediated upregulation of AID resulted in the accumulation of nucleotide alterations in the TP53 tumor suppressor gene in gastric cells in vitro. Our findings provide evidence that aberrant AID expression caused by H. pylori infection might be a mechanism of mutation accumulation in the gastric mucosa during H. pylori–associated gastric carcinogenesis. | Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium |
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"25775": 0.2493593990802765, "25969": 0.26446542143821716, "26013": 0.304147332906723, "26305": 0.07431721687316895, "26728": 0.15610189735889435, "26835": 0.6317287683486938, "26989": 0.176772341132164, "27152": 0.0317181795835495, "27754": 0.5973974466323853, "27781": 0.7086513638496399, "28024": 0.9425065517425537, "28227": 0.16524957120418549, "28466": 0.6492279767990112, "28684": 1.3372600078582764, "28873": 0.2696990668773651, "28896": 0.23402166366577148, "29125": 1.0901126861572266, "29477": 0.7791815400123596} | 22705234 | The African green monkey (AGM) is one of many African species endemically infected with simian immunodeficiency virus (SIV). Like the other natural hosts, AGMs do not succumb to AIDS and understanding the basis for this resistance to disease progression would be of enormous theoretical and practical importance. Early efforts by our group that concentrated on identifying immune mechanisms presumed to keep the virus under control failed to find any obvious candidates. The presumption of virus control was invalidated by the finding that SIVagm replicates in AGMs with the same vigor as HIV-1 does in humans. Focus therefore shifted to identifying possible immunopathologic features present in disease susceptible hosts but absent in the AGM natural host. The apparent immunologic tolerance of AGMs to the SIVagm core protein led to the development of a hypothesis implicating anti-Gag antibodies in the formation of immune complexes, virus trapping in the lymph nodes and immune dysfunction. The idea proved difficult to test in vivo and present work focuses on the possibility that Gag tolerance at the T-cell level plays an important role in preventing the catastrophic demise of the immune system characteristic of immunodeficiency virus infection of the heterologous primate host. | The role of the immune response during SIVagm infection of the African green monkey natural host. |
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0.9621002674102783, "28093": 0.24171993136405945, "28314": 0.9194108247756958, "28648": 0.46853771805763245, "28886": 0.037378571927547455, "28992": 0.176772341132164} | 22707413 | This article describes the development and validation of the S-LANSS score, a self-report version of the Leeds Assessment of Neuropathic Symptoms and Signs pain scale. The S-LANSS aims to identify pain of predominantly neuropathic origin, as distinct from nociceptive pain, without the need for clinical examination. Two hundred patients with chronic pain were asked to complete the S-LANSS unaided. A researcher then administered the S-LANSS scale and the Neuropathic Pain Scale (NPS) in interview format. An independent clinician determined the pain type (neuropathic versus nociceptive) and rated his or her certainty about diagnosis. The S-LANSS scale was also incorporated into a chronic pain questionnaire that was sent to 160 community patients and 150 newly referred patients waiting for pain clinic assessment. The S-LANSS scale correctly identified 75% of pain types when self-completed and 80% when used in interview format. Sensitivity for self-completed S-LANSS scores ranged from 74% to 78%, depending on the cutoff score. There were significant associations between NPS items and total score with S-LANSS score. In the postal survey, completed questionnaires were returned by 57% of patients (n = 174). Internal consistency and convergent validity of the survey S-LANSS scores were confirmed. The findings support the S-LANSS scale as a valid and reliable self-report instrument for identifying neuropathic pain and it is also acceptable for use in postal survey research. Establishing valid measures of symptoms and signs in neuropathic pain will allow standardized comparisons with other investigational measures. This might lead to new insights into the relationship between pathophysiologic mechanisms and clinical manifestations of pain. | The S-LANSS score for identifying pain of predominantly neuropathic origin: validation for use in clinical and postal research. |
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0.678390383720398, "27354": 0.2822965085506439, "27605": 0.14602625370025635, "27615": 0.030771657824516296, "27651": 0.021256839856505394, "27833": 0.13499516248703003, "27894": 0.27044451236724854, "28093": 0.4932899475097656, "28436": 0.22157983481884003, "28582": 0.22704219818115234, "29201": 0.8057082891464233, "29361": 0.10555581003427505, "29458": 0.7115318179130554} | 22711954 | OBJECTIVE Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. DESIGN Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30% of the trial); analysis of funnel plots from 37 meta-analyses identified from a hand search of four leading general medicine journals 1993-6 and 38 meta-analyses from the second 1996 issue of the Cochrane Database of Systematic Reviews. MAIN OUTCOME MEASURE Degree of funnel plot asymmetry as measured by the intercept from regression of standard normal deviates against precision. RESULTS In the eight pairs of meta-analysis and large trial that were identified (five from cardiovascular medicine, one from diabetic medicine, one from geriatric medicine, one from perinatal medicine) there were four concordant and four discordant pairs. In all cases discordance was due to meta-analyses showing larger effects. Funnel plot asymmetry was present in three out of four discordant pairs but in none of concordant pairs. In 14 (38%) journal meta-analyses and 5 (13%) Cochrane reviews, funnel plot asymmetry indicated that there was bias. CONCLUSIONS A simple analysis of funnel plots provides a useful test for the likely presence of bias in meta-analyses, but as the capacity to detect bias will be limited when meta-analyses are based on a limited number of small trials the results from such analyses should be treated with considerable caution. | Bias in meta-analysis detected by a simple, graphical test. |
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"28086": 0.02792670577764511, "28252": 0.1930064558982849, "28329": 0.22548456490039825, "28522": 0.9827804565429688, "28788": 0.1011524572968483, "29237": 0.22782009840011597} | 22712546 | Over the past years, plenty of evidence has emerged illustrating how metabolism supports many aspects of cellular function and how metabolic reprogramming can drive cell differentiation and fate. Here, we present a method to assess the metabolic configuration of single cells within their native tissue microenvironment via the visualization and quantification of multiple enzymatic activities measured at saturating substrate conditions combined with subsequent cell type identification. After careful validation of the approach and to demonstrate its potential, we assessed the intracellular metabolic configuration of different human immune cell populations in healthy and tumor colon tissue. Additionally, we analyzed the intercellular metabolic relationship between cancer cells and cancer-associated fibroblasts in a breast cancer tissue array. This study demonstrates that the determination of metabolic configurations in single cells could be a powerful complementary tool for every researcher interested to study metabolic networks in situ. | Exploring Metabolic Configurations of Single Cells within Complex Tissue Microenvironments. |
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22730024 | OBJECTIVE To assess the antihypertensive efficacy of olmesartan medoxomil and ramipril on 24-h ambulatory blood pressure (ABP) in elderly hypertensive patients by pooled data analysis of two studies with identical designs (one Italian, one European). METHODS After a 2-week placebo wash-out 1453 elderly hypertensive patients (65-89 years; sitting office DBP 90-109 mmHg and/or sitting office SBP 140-179 mmHg) were randomized to a 12-week double-blind treatment with olmesartan medoxomil 10 mg or ramipril 2.5 mg once-daily, up-titrated (20 and 40 mg olmesartan medoxomil; 5 and 10 mg ramipril) after 2 and 6 weeks in patients without normalized office BP. 24-h ABP was recorded at randomization and after 12 weeks. RESULTS In 715 patients with valid baseline and end-of-treatment recordings baseline-adjusted 24-h SBP and DBP reductions were greater with olmesartan medoxomil (n = 356) than with ramipril (n = 359) [between-treatment differences and 95% confidence interval (CI), SBP: 2.2 (3.8, 0.6), P = 0.006; DBP: 1.3 (2.2, 0.3), P = 0.009]. Olmesartan medoxomil showed larger BP reductions in the last 6 h from the dosing interval and higher smoothness indices than ramipril. Olmesartan medoxomil reduced the SBP morning rise [-2.8 (-4.9, -0.8) mmHg], whereas ramipril did not [+1.5 (-0.6, +3.6) mmHg; P = 0.004 between-treatments]. Five hundred and eighty-two patients with sustained hypertension (office and 24-h ambulatory hypertension) showed the largest antihypertensive effect, with between-treatment differences still in favor of olmesartan medoxomil [SBP: 2.1 (3.9, 0.4), P = 0.019; DBP: 1.2 (2.3, 0.1), P = 0.032]. CONCLUSIONS Olmesartan medoxomil provides a more effective and sustained 24-h BP control than ramipril in elderly hypertensive patients, particularly in the hours farthest from last intake. | Twenty-four hour and early morning blood pressure control of olmesartan vs. ramipril in elderly hypertensive patients: pooled individual data analysis of two randomized, double-blind, parallel-group studies. |
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Arp2/3 complex, resulting in lamellipodia protrusion. WAVE2 displays Arp2/3-dependent actin nucleation activity in vitro, and does not bind directly to Rac. Instead, it forms macromolecular complexes that have been reported to exert both positive and negative modes of regulation. How these complexes are assembled, localized and activated in vivo remains to be established. Here we use tandem mass spectrometry to identify an Abi1-based complex containing WAVE2, Nap1 (Nck-associated protein) and PIR121. Abi1 interacts directly with the WHD domain of WAVE2, increases WAVE2 actin polymerization activity and mediates the assembly of a WAVE2–Abi1–Nap1–PIR121 complex. The WAVE2–Abi1–Nap1–PIR121 complex is as active as the WAVE2–Abi1 sub-complex in stimulating Arp2/3, and after Rac activation it is re-localized to the leading edge of ruffles in vivo. Consistently, inhibition of Abi1 by RNA interference (RNAi) abrogates Rac-dependent lamellipodia protrusion. Thus, Abi1 orchestrates the proper assembly of the WAVE2 complex and mediates its activation at the leading edge in vivo. | Abi1 is essential for the formation and activation of a WAVE2 signalling complex |
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After four decades of research, we now know that DCs arise from a hematopoietic lineage distinct from other leukocytes, establishing the DC system as a unique hematopoietic branch. Recent work has also established that tissue DCs consist of developmentally and functionally distinct subsets that differentially regulate T lymphocyte function. This review discusses major advances in our understanding of the regulation of DC lineage commitment, differentiation, diversification, and function in situ. | The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. |
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0.4113073945045471, "27929": 0.0029254043474793434, "28046": 0.9463045597076416, "28156": 0.2501201331615448, "28696": 0.23324857652187347, "28848": 0.46608972549438477, "29003": 0.11343330889940262, "29090": 0.35745587944984436, "29290": 0.12814582884311676, "29490": 0.2969166338443756, "29720": 0.5517725944519043, "29721": 0.4349733293056488} | 22800314 | Interleukin-15 (IL-15) is a cytokine produced in the normal brain that acts on its specific receptor IL-15Rα and co-receptors IL-2Rβ and IL-2Rγ in neuronal cells. The functions of the cerebral IL-15 system, however, are not yet clear. To test the hypothesis that IL-15Rα regulates metabolic activity and body temperature, we quantified the specific metabolic phenotype of IL-15Rα knockout mice. These normal-appearing mice were leaner with lower fat composition. During the entire circadian cycle, the knockout mice had a significantly higher acrophase in locomotor activity and heat dissipation. During the light phase, there was significantly greater food intake, oxygen consumption, and carbon dioxide production. The difference in the dark and light phases suggests that IL-15Rα participates in circadian rhythm regulation. The higher oxygen consumption in the light phase indicates adaptive thermogenesis in the knockout mice. The body temperature of the receptor knockout mice was significantly higher than the control in the light phase, and this was mainly caused by a large difference occurring between 0600 and 0900 h. In addition to the metabolic chamber studies and circadian rhythm analyses, qPCR of hypothalamic homogenates indicated higher mRNA expression of orexin and transient receptor potential vanilloid 4 cation channels. Consistent with a direct role of IL-15Rα in the hypothalamus, IL-15 treatment of the wild-type mice induced c-Fos expression in the preoptic area. We conclude that activation of hypothalamic neurons by IL-15 in mice contributes to thermoregulation and modifies the metabolic phenotype. | IL-15 Receptor Deletion Results in Circadian Changes of Locomotor and Metabolic Activity |
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"29207": 0.08064348995685577, "29242": 0.2918238639831543, "29458": 0.129004567861557, "29513": 0.09584271162748337} | 22815457 | OBJECTIVE To compare the outcome of pregnancy in cohorts of women with singleton pregnancy and history of preterm birth and sonographic short cervix managed with different treatment protocols, namely cerclage, vaginal progesterone or cervical pessary. METHODS This was a comparison of three management protocols for women with singleton pregnancy and a high risk of preterm birth because of a prior spontaneous preterm birth before 34 weeks and a shortened cervical length detected by transvaginal ultrasound. The study included 142 women who were initially treated with cerclage (USA), 59 with vaginal progesterone (UK) and 42 with cervical pessary (Spain). Perinatal outcomes were compared between the three cohorts. RESULTS There were no statistically significant differences in perinatal losses, neonatal morbidity and preterm births among the three groups, apart from a higher rate of preterm birth before 34 weeks' gestation after treatment with vaginal progesterone in comparison with treatment with cervical pessary (32% vs 12%; relative risk (RR) = 2.70; 95% CI, 1.10-6.67). When only the subgroups of women with cervical length < 25 mm, irrespective of gestational age, were compared, the difference between these two cohorts was not statistically significant (RR = 2.21; 95% CI, 0.83-5.89). CONCLUSION Cerclage, vaginal progesterone and pessary appear to have similar effectiveness as management strategies in women with singleton pregnancy, previous spontaneous preterm birth and short cervix. Direct randomized comparisons of these strategies, or combinations thereof, are needed to determine optimal management. | Vaginal progesterone, cerclage or cervical pessary for preventing preterm birth in asymptomatic singleton pregnant women with a history of preterm birth and a sonographic short cervix. |
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"28873": 1.0628231763839722, "29025": 0.5909284353256226, "29048": 0.12556517124176025, "29222": 0.21214580535888672, "29443": 0.4855078160762787} | 22820637 | The placental leucine aminopeptidase (P-LAP), adipocyte-derived leucine aminopeptidase (A-LAP) and leukocyte-derived aminopeptidase (L-RAP) belong to one distinct group of the M1 family of amimopeptidases, which we term the "Oxytocinase subfamily". They share HEXXH(X)18E Zn-binding and GAMEN motifs essential for the enzymatic activities. Intracellular localization is the characteristic feature of the subfamily members. While P-LAP is translocated from intracellular vesicles to plasma membrane in a stimulus-dependent manner, both A-LAP and L-RAP are retained in the endoplasmic reticulum. They contain sequences necessary for the specific localization in the cell. It is getting evident that the subfamily members play important roles in the maintenance of homeostasis including maintenance of normal pregnancy, memory retention, blood pressure regulation and antigen presentation. In this review, current situation of this newly identified subfamily is summarized. | The oxytocinase subfamily of M1 aminopeptidases. |
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1.1121915578842163, "28405": 0.2478361576795578, "28522": 0.8169882297515869, "28696": 0.02316705882549286, "28723": 0.04953393340110779, "28788": 0.11951763927936554, "29109": 0.1401015669107437, "29125": 0.11951763927936554, "29217": 0.004870930220931768, "29290": 0.7144040465354919} | 22843616 | The generation of induced pluripotent stem cells (iPSCs) provides a novel method to facilitate investigations into the mechanisms that control stem cell pluripotency and self-renewal. Myc has previously been shown to be critical for murine embryonic stem cell (mESC) maintenance, while also enhancing directed reprogramming of fibroblasts by effecting widespread changes in gene expression. Despite several studies identifying in vivo target genes, the precise mechanism by which Myc regulates pluripotency remains unknown. Here we report that codeletion of c- and N-MYC in iPSCs and ESCs results in their spontaneous differentiation to primitive endoderm. We show that Myc sustains pluripotency through repression of the primitive endoderm master regulator GATA6, while also contributing to cell cycle control by regulation of the mir-17-92 miRNA cluster. Our findings demonstrate the indispensable requirement for c- or N-myc in pluripotency beyond proliferative and metabolic control. | Myc represses primitive endoderm differentiation in pluripotent stem cells. |
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One of the potential factors related to the difference of the prevalence is vitamin D, because the strength of ambient ultraviolet light, which is essential for vitamin D production, decreases with increasing latitude. It is known that vitamin D has immunomodulatory functions and suppresses an animal model of MS. It is also considered that vitamin D-related genes are critical susceptible genes for MS. An approach from environmental and genetic aspects is needed to investigate the association between vitamin D and MS. | [Vitamin D and latitude as environmental factors in multiple sclerosis]. |
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Type 2 immunity promotes antihelminth immunity, suppresses type 1-driven autoimmune disease, neutralizes toxins, maintains metabolic homeostasis, and regulates wound repair and tissue regeneration pathways following infection or injury. Nevertheless, when type 2 responses are dysregulated, they can become important drivers of disease. Type 2 immunity induces a complex inflammatory response characterized by eosinophils, mast cells, basophils, type 2 innate lymphoid cells, IL-4-and/or IL-13-conditioned macrophages and T helper 2 (TH2) cells, which are crucial to the pathogenesis of many allergic and fibrotic disorders. As chronic type 2 immune responses promote disease, the mechanisms that regulate their maintenance are thought to function as crucial disease modifiers. This Review discusses the many endogenous negative regulatory mechanisms that antagonize type 2 immunity and highlights how therapies that target some of these pathways are being developed to treat type 2-mediated disease. | Type 2 cytokines: mechanisms and therapeutic strategies |
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0.03925827145576477, "28086": 0.38441169261932373, "28466": 0.6563454270362854, "28667": 0.0058422754518687725, "28674": 0.0038986403960734606, "28691": 0.0354953333735466, "28817": 0.7500885725021362, "28873": 0.13157635927200317, "28879": 0.05417001247406006, "28915": 0.2969166338443756} | 22867765 | We have previously demonstrated that implanted microvessels form a new microcirculation with minimal host-derived vessel investment. Our objective was to define the vascular phenotypes present during neovascularization in these implants and identify post-angiogenesis events. Morphological, functional and transcriptional assessments identified three distinct vascular phenotypes in the implants: sprouting angiogenesis, neovascular remodeling, and network maturation. A sprouting angiogenic phenotype appeared first, characterized by high proliferation and low mural cell coverage. This was followed by a neovascular remodeling phenotype characterized by a perfused, poorly organized neovascular network, reduced proliferation, and re-associated mural cells. The last phenotype included a vascular network organized into a stereotypical tree structure containing vessels with normal perivascular cell associations. In addition, proliferation was low and was restricted to the walls of larger microvessels. The transition from angiogenesis to neovascular remodeling coincided with the appearance of blood flow in the implant neovasculature. Analysis of vascular-specific and global gene expression indicates that the intermediate, neovascular remodeling phenotype is transcriptionally distinct from the other two phenotypes. Therefore, this vascular phenotype likely is not simply a transitional phenotype but a distinct vascular phenotype involving unique cellular and vascular processes. Furthermore, this neovascular remodeling phase may be a normal aspect of the general neovascularization process. Given that this phenotype is arguably dysfunctional, many of the microvasculatures present within compromised or diseased tissues may not represent a failure to progress appropriately through a normally occurring neovascularization phenotype. | Implanted microvessels progress through distinct neovascularization phenotypes. |
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We present evidence that a spliced, capped, and polyadenylated primary transcript spans this entire Early Embryonic microRNA Cluster (EEmiRC). Partial Drosha processing yields additional large nuclear RNA intermediates. A conserved promoter element containing a TATA-box directs EEmiRC transcription. Sequence analysis shows that the EEmiRC transcription unit is remarkably variable and can only be identified bioinformatically in placental (eutherian) mammals. Consistent with eutherian-specific function, EEmiRC is expressed in trophoblastic stem (TS) cells. When analyzing evolutionary and functional relationships, the organization of the entire miRNA loci should be considered in addition to the mature miRNA sequences. Application of this concept suggests that EEmiRC is a recently acquired rapidly evolving gene important for eutherian development. | Characterization of a highly variable eutherian microRNA gene. |
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How follicular helper T cells (TFH cells) differentiate to regulate B cell immunity is critical for effective protein vaccination. Here we define three transcription factor T-bet–expressing antigen-specific effector helper T cell subsets with distinguishable function, migratory properties and developmental programming in vivo. Expression of the transcriptional repressor Blimp-1 distinguished T zone 'lymphoid' effector helper T cells (CD62LhiCCR7hi) from CXCR5lo 'emigrant' effector helper T cells and CXCR5hi 'resident' TFH cells expressing the transcriptional repressor Bcl-6 (CD62LloCCR7lo). We then show by adoptive transfer and intact polyclonal responses that helper T cells with the highest specific binding of peptide–major histocompatibility complex class II and the most restricted T cell antigen receptor junctional diversity 'preferentially' developed into the antigen-specific effector TFH compartment. Our studies demonstrate a central function for differences in the binding strength of the T cell antigen receptor in the antigen-specific mechanisms that 'program' specialized effector TFH function in vivo. | The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding |
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However, the precise role of TNF-alpha in atherogenesis is still unclear. To examine the effect of TNF-alpha on atherogenesis, we generated compound-deficient mice in apolipoprotein E (apoE) and TNF-alpha (apoE-/-/TNF-alpha-/-) and compared them with apoE-/- mice. Although serum total cholesterol levels were markedly elevated in both apoE-/-/TNF-alpha-/- and apoE-/- mice compared to wild-type mice, no differences were observed between apoE-/-/TNF-alpha-/- and apoE-/- mice. The atherosclerotic plaque area in the aortic luminal surface of apoE-/-/TNF-alpha-/- mice (n=8, 3.1+/-0.4%) was significantly smaller than that of apoE-/- mice (n=7, 4.7+/-0.4%, p<0.001) despite the lack of difference in serum cholesterol levels. The atherosclerotic lesion size in the aortic sinus of apoE-/-/TNF-alpha-/- mice (n=10, 5.1+/-0.3 x 10(5)microm(2)) was also significantly smaller than that of apoE-/- mice (n=11, 7.0+/-0.3 x 10(5)microm(2), p<0.0001). RT-PCR analysis indicated that the expression levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) were significantly higher in apoE-/- than apoE-/-/TNF-alpha-/- mice. Macrophages from apoE(-/-) mice showed higher uptake level of oxidized LDL and increased expression level of scavenger receptor class A (SRA) compared to those from apoE-/-/TNF-alpha-/- mice. These results indicate that TNF-alpha plays an atherogenic role by upregulating the expressions of ICAM-1, VCAM-1 and MCP-1 in the vascular wall, and by inducing SRA expression and oxidized LDL uptake in macrophages. | Disruption of tumor necrosis factor-alpha gene diminishes the development of atherosclerosis in ApoE-deficient mice. |
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0.4356052577495575, "25468": 0.29109421372413635, "25499": 0.5145297050476074, "25610": 0.25088030099868774, "25714": 0.9635916948318481, "25950": 1.263861894607544, "26208": 0.347847044467926, "26394": 0.03831886500120163, "26402": 0.9591107368469238, "26651": 0.2105647772550583, "27321": 0.7960633039474487, "27781": 1.2555493116378784, "28788": 0.7647408246994019, "28873": 1.486563801765442, "29129": 0.45623743534088135, "29290": 0.8264343738555908, "29490": 0.36494144797325134, "29494": 0.6338034868240356} | 22890091 | The recently identified Fas antigen (Ag) is a cell surface molecule that can mediate apoptosis. The cytoplasmic product of proto-oncogene bcl-2 has been shown to prolong the cellular survival by inhibiting apoptosis. To elucidate the physiologic significance of expression of both molecules, we examined the expression of Fas Ag and bcl-2 on blood leukocyte populations and evaluated their sensitivity to the cytolytic action of anti-Fas antibody. Although Fas Ag was expressed on a fraction of lymphocytes, both neutrophils and monocytes expressed Fas Ag constitutively. In contrast, there was marked difference among these leukocytes regarding bcl-2 expression. Lymphocytes expressed bcl-2 intensely, but monocytes showed weaker bcl-2 expression, and neutrophils were essentially absent for bcl-2 expression. Seemingly reflecting this lack of bcl-2-expression, neutrophils more easily underwent apoptotic cell death in vitro as compared with monocytes and lymphocytes. We showed that anti-Fas antibody affectively accelerated apoptotic cell death in neutrophils. However, the apoptosis-inducing effect of anti-Fas antibody was minimal on monocytes, and lymphocytes were resistant to this antibody. These results suggest that anti-Fas-mediated cell death may, in part, be determined by bcl-2 expression status in Fas+ lymphoid and hematopoietic cells. | Differential expression of bcl-2 and susceptibility to anti-Fas-mediated cell death in peripheral blood lymphocytes, monocytes, and neutrophils. |
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0.011650617234408855, "29516": 0.09850110858678818} | 22896384 | The airways of the lung develop through a reiterative process of branching morphogenesis that gives rise to the intricate and extensive surface area required for postnatal respiration. The forkhead transcription factors Foxp2 and Foxp1 are expressed in multiple foregut-derived tissues including the lung and intestine. In this report, we show that loss of Foxp2 in mouse leads to defective postnatal lung alveolarization, contributing to postnatal lethality. Using in vitro and in vivo assays, we show that T1alpha, a lung alveolar epithelial type 1 cell-restricted gene crucial for lung development and function, is a direct target of Foxp2 and Foxp1. Remarkably, loss of a single Foxp1 allele in addition to complete loss of Foxp2 results in increased severity of morphological defects in mutant lungs and leads to perinatal loss of all Foxp2(-/-);Foxp1(+/-) mice. Expression of N-myc and Hop, crucial regulators of lung development, is compromised in Foxp2(-/-);Foxp1(+/-) mutants. In addition to the defects in lung development, esophageal muscle development is disrupted in Foxp2(-/-);Foxp1(+/-) embryos, a tissue where Foxp2 and Foxp1 are co-expressed. These data identify Foxp2 and Foxp1 as crucial regulators of lung and esophageal development, underscoring the necessity of these transcription factors in the development of anterior foregut-derived tissues and demonstrating functional cooperativity between members of the Foxp1/2/4 family in tissues where they are co-expressed. | Foxp2 and Foxp1 cooperatively regulate lung and esophagus development. |
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In comparison to their prokaryotic counterparts, eukaryotic ribosomes are considerably larger and are subject to more complex regulation. The large ribosomal subunit (60S) catalyzes peptide bond formation and contains the nascent polypeptide exit tunnel. We present the structure of the 60S ribosomal subunit from Tetrahymena thermophila in complex with eukaryotic initiation factor 6 (eIF6), cocrystallized with the antibiotic cycloheximide (a eukaryotic-specific inhibitor of protein synthesis), at a resolution of 3.5 angstroms. The structure illustrates the complex functional architecture of the eukaryotic 60S subunit, which comprises an intricate network of interactions between eukaryotic-specific ribosomal protein features and RNA expansion segments. It reveals the roles of eukaryotic ribosomal protein elements in the stabilization of the active site and the extent of eukaryotic-specific differences in other functional regions of the subunit. Furthermore, it elucidates the molecular basis of the interaction with eIF6 and provides a structural framework for further studies of ribosome-associated diseases and the role of the 60S subunit in the initiation of protein synthesis. | Crystal structure of the eukaryotic 60S ribosomal subunit in complex with initiation factor 6. |
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"26775": 0.20660123229026794, "27144": 0.2493593990802765, "27295": 0.0752234235405922, "27532": 0.791648268699646, "27854": 0.036437395960092545, "27881": 0.09761575609445572, "27915": 0.4425300657749176, "28086": 0.15442965924739838, "28156": 0.16110190749168396, "28207": 0.025073638185858727, "28227": 0.3982778787612915, "28522": 1.0416836738586426, "28765": 0.77198725938797, "29217": 0.2247048318386078, "29290": 0.36900100111961365, "29441": 0.10555581003427505, "29458": 0.2830325961112976, "29480": 0.4920966327190399} | 22901758 | The identification of brain tumor stem-like cells (BTSCs) has implicated a role of biological self-renewal mechanisms in clinical brain tumor initiation and propagation. The molecular mechanisms underlying the tumor-forming capacity of BTSCs, however, remain unknown. Here, we have generated molecular signatures of glioblastoma multiforme (GBM) using gene expression profiles of BTSCs and have identified both Sonic Hedgehog (SHH) signaling-dependent and -independent BTSCs and their respective glioblastoma surgical specimens. BTSC proliferation could be abrogated in a pathway-dependent fashion in vitro and in an intracranial tumor model in athymic mice. Both SHH-dependent and -independent brain tumor growth required phosphoinositide 3-kinase-mammalian target of rapamycin signaling. In human GBMs, the levels of SHH and PTCH1 expression were significantly higher in PTEN-expressing tumors than in PTEN-deficient tumors. In addition, we show that hyperactive SHH-GLI signaling in PTEN-coexpressing human GBM is associated with reduced survival time. Thus, distinct proliferation signaling dependence may underpin glioblastoma propagation by BTSCs. Modeling these BTSC proliferation mechanisms may provide a rationale for individualized glioblastoma treatment. | Hedgehog signaling regulates brain tumor-initiating cell proliferation and portends shorter survival for patients with PTEN-coexpressing glioblastomas. |
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1.060796856880188, "28268": 0.020300358533859253, "28297": 1.2905446290969849, "28314": 0.020300358533859253, "28964": 0.38041436672210693, "28987": 0.17267228662967682, "29105": 0.8004589080810547, "29251": 1.1198691129684448, "29320": 0.1221139207482338, "29486": 0.8583967685699463} | 22908536 | Nonreplicating and metabolically quiescent bacteria are implicated in latent tuberculosis infections and relapses following "sterilizing" chemotherapy. However, evidence linking bacterial dormancy and persistence in vivo is largely inconclusive. Here we measure the single-cell dynamics of Mycobacterium tuberculosis replication and ribosomal activity using quantitative time-lapse microscopy and a reporter of ribosomal RNA gene expression. Single-cell dynamics exhibit heterogeneity under standard growth conditions, which is amplified by stressful conditions such as nutrient limitation, stationary phase, intracellular replication, and growth in mouse lungs. Additionally, the lungs of chronically infected mice harbor a subpopulation of nongrowing but metabolically active bacteria, which are absent in mice lacking interferon-γ, a cytokine essential for antituberculosis immunity. These cryptic bacterial forms are prominent in mice treated with the antituberculosis drug isoniazid, suggesting a role in postchemotherapeutic relapses. Thus, amplification of bacterial phenotypic heterogeneity in response to host immunity and drug pressure may contribute to tuberculosis persistence. | Stress and host immunity amplify Mycobacterium tuberculosis phenotypic heterogeneity and induce nongrowing metabolically active forms. |
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0.07884006202220917, "24558": 0.1677299439907074, "24755": 0.7665573358535767, "24848": 0.06612417846918106, "25002": 0.28155985474586487, "25117": 0.20739519596099854, "25320": 0.24171993136405945, "25458": 0.609149694442749, "25524": 0.06246116757392883, "25874": 0.175953671336174, "25971": 0.058784693479537964, "26472": 0.2689530849456787, "26601": 0.8013357520103455, "26745": 0.3588210940361023, "26986": 0.2247048318386078, "27144": 0.0009760859538801014, "28282": 0.04207121208310127, "28699": 0.8143964409828186, "28846": 0.13925230503082275, "28847": 0.5584990978240967, "28873": 0.025073638185858727, "29237": 1.0868242979049683, "29490": 0.1718502640724182, "29607": 0.05970508232712746} | 22914228 | In this present work, we characterized the proteomes of pancreatic ductal adenocarcinoma (PDAC) cell line PANC-1 and normal pancreatic duct cells by mass spectrometry using LTQ-Orbitrap and identified more than 1700 proteins from each sample. On the basis of the spectra count label-free quantification approach, we identified a large number of differentially expressed metabolic enzymes and proteins involved in cytoskeleton, cell adhesion, transport, transcription, translation, and cell proliferation as well. The data demonstrated that metabolic pathways were altered in PANC-1, consistent with the Warburg effect. In addition, the comparative MS analysis unveiled anomalous metabolism of glutamine, suggesting that glutamine was largely consumed as a nitrogen donor in nucleotide and amino acid biosynthesis in PANC-1. Our analysis provides a potentially comprehensive picture of metabolism in PANC-1, which may serve as the basis of new diagnostics and treatment of PDAC. | Proteomic analysis reveals Warburg effect and anomalous metabolism of glutamine in pancreatic cancer cells. |
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0.29109421372413635, "28687": 0.04207121208310127, "29050": 0.0354953333735466, "29180": 0.058784693479537964, "29305": 0.006812678650021553, "29361": 0.10026945173740387, "29494": 0.18654440343379974} | 22922353 | CONTEXT Overweight and obesity are increasing in the United States. Changes in diet and physical activity are important for weight control. OBJECTIVES To examine the prevalence of attempting to lose or to maintain weight and to describe weight control strategies among US adults. DESIGN The Behavioral Risk Factor Surveillance System, a random-digit telephone survey conducted in 1996 by state health departments. Setting The 49 states (and the District of Columbia) that participated in the survey. PARTICIPANTS Adults aged 18 years and older (N = 107 804). MAIN OUTCOME MEASURES Reported current weights and goal weights, prevalence of weight loss or maintenance attempts, and strategies used to control weight (eating fewer calories, eating less fat, or using physical activity) by population subgroup. RESULTS The prevalence of attempting to lose and maintain weight was 28.8% and 35.1 % among men and 43.6% and 34.4% among women, respectively. Among those attempting to lose weight, a common strategy was to consume less fat but not fewer calories (34.9% of men and 40.0% of women); only 21.5% of men and 19.4% of women reported using the recommended combination of eating fewer calories and engaging in at least 150 minutes of leisure-time physical activity per week. Among men trying to lose weight, the median weight was 90.4 kg with a goal weight of 81.4 kg. Among women, the median weight was 70.3 kg with a goal weight of 59.0 kg. CONCLUSIONS Weight loss and weight maintenance are common concerns for US men and women. Most persons trying to lose weight are not using the recommended combination of reducing calorie intake and engaging in leisure-time physical activity 150 minutes or more per week. | Prevalence of attempting weight loss and strategies for controlling weight. |
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0.1970241367816925, "29490": 1.34847891330719} | 22937651 | Epstein-Barr virus (EBV) is associated with multiple sclerosis (MS), and antibodies to the EBV nuclear antigen-1 (EBNA-1) are consistently increased in MS patients. The hypothesis of this study is that anti-EBNA-1 antibodies cross-react with a self antigen in MS patients. We affinity purified anti-EBNA-1 antibodies from human plasma, used the anti-EBNA-1 to immunoprecipitate antigens from human brain, and identified bound antigens with mass spectrometry. Anti-EBNA-1 consistently bound heterogeneous nuclear ribonucleoprotein L (HNRNPL). We expressed both the long and short isoforms of this protein, and verified with Western blots and ELISA that the long isoform cross-reacts with EBNA-1. Immunohistochemistry demonstrated that anti-EBNA-1 bound to an antigen in the nucleus of cultured rat central nervous system cells. ELISA demonstrated the presence of antibodies to HNRNPL in the plasma of both healthy controls and MS patients, but anti-HNRNPL was not increased in MS patients. We conclude that HNRNPL is an autoantigen which cross-reacts with EBNA-1. The relevance of this autoantigen to MS and other autoimmune diseases remains to be investigated. | Antibodies specific for Epstein-Barr virus nuclear antigen-1 cross-react with human heterogeneous nuclear ribonucleoprotein L. |
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0.49864232540130615, "29290": 0.2231435477733612, "29292": 0.05046287178993225, "29455": 0.3883931338787079} | 22937815 | Now that we have a good understanding of the DNA double strand break (DSB) repair mechanisms and DSB-induced damage signalling, attention is focusing on the changes to the chromatin environment needed for efficient DSB repair. Mutations in chromatin remodelling complexes have been identified in cancers, making it important to evaluate how they impact upon genomic stability. Our current understanding of the DSB repair pathways suggests that each one has distinct requirements for chromatin remodelling. Moreover, restricting the extent of chromatin modifications could be a significant factor regulating the decision of pathway usage. In this review, we evaluate the distinct DSB repair pathways for their potential need for chromatin remodelling and review the roles of ATP-driven chromatin remodellers in the pathways. | Roles of chromatin remodellers in DNA double strand break repair. |
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0.24248650670051575, "28820": 0.12814582884311676, "28873": 0.13243216276168823, "29261": 0.04394211992621422, "29486": 0.26146242022514343} | 22938539 | A comprehensive mapping of interactions among Epstein-Barr virus (EBV) proteins and interactions of EBV proteins with human proteins should provide specific hypotheses and a broad perspective on EBV strategies for replication and persistence. Interactions of EBV proteins with each other and with human proteins were assessed by using a stringent high-throughput yeast two-hybrid system. Overall, 43 interactions between EBV proteins and 173 interactions between EBV and human proteins were identified. EBV-EBV and EBV-human protein interaction, or "interactome" maps provided a framework for hypotheses of protein function. For example, LF2, an EBV protein of unknown function interacted with the EBV immediate early R transactivator (Rta) and was found to inhibit Rta transactivation. From a broader perspective, EBV genes can be divided into two evolutionary classes, "core" genes, which are conserved across all herpesviruses and subfamily specific, or "noncore" genes. Our EBV-EBV interactome map is enriched for interactions among proteins in the same evolutionary class. Furthermore, human proteins targeted by EBV proteins were enriched for highly connected or "hub" proteins and for proteins with relatively short paths to all other proteins in the human interactome network. Targeting of hubs might be an efficient mechanism for EBV reorganization of cellular processes. | Epstein-Barr virus and virus human protein interaction maps. |
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"27265": 0.043007105588912964, "27615": 1.3799264430999756, "27891": 0.08603433519601822, "28139": 0.17840765416622162, "28207": 0.022212404757738113, "28393": 0.9084475636482239, "28436": 0.011650617234408855, "28472": 0.013579257763922215, "28689": 0.006812678650021553, "28739": 0.15359249711036682, "29333": 0.7755908370018005} | 22942787 | CONTEXT Medicare's reimbursement policy was changed in 1998 to provide coverage for screening colonoscopies for patients with increased colon cancer risk, and expanded further in 2001 to cover screening colonoscopies for all individuals. OBJECTIVE To determine whether the Medicare reimbursement policy changes were associated with an increase in either colonoscopy use or early stage colon cancer diagnosis. DESIGN, SETTING, AND PARTICIPANTS Patients in the Surveillance, Epidemiology, and End Results Medicare linked database who were 67 years of age and older and had a primary diagnosis of colon cancer during 1992-2002, as well as a group of Medicare beneficiaries who resided in Surveillance, Epidemiology, and End Results areas but who were not diagnosed with cancer. MAIN OUTCOME MEASURES Trends in colonoscopy and sigmoidoscopy use among Medicare beneficiaries without cancer were assessed using multivariate Poisson regression. Among the patients with cancer, stage was classified as early (stage I) vs all other (stages II-IV). Time was categorized as period 1 (no screening coverage, 1992-1997), period 2 (limited coverage, January 1998-June 2001), and period 3 (universal coverage, July 2001-December 2002). A multivariate logistic regression (outcome = early stage) was used to assess temporal trends in stage at diagnosis; an interaction term between tumor site and time was included. RESULTS Colonoscopy use increased from an average rate of 285/100,000 per quarter in period 1 to 889 and 1919/100,000 per quarter in periods 2 (P<.001) and 3 (P vs 2<.001), respectively. During the study period, 44,924 eligible patients were diagnosed with colorectal cancer. The proportion of patients diagnosed at an early stage increased from 22.5% in period 1 to 25.5% in period 2 and 26.3% in period 3 (P<.001 for each pairwise comparison). The changes in Medicare coverage were strongly associated with early stage at diagnosis for patients with proximal colon lesions (adjusted relative risk period 2 vs 1, 1.19; 95% confidence interval, 1.13-1.26; adjusted relative risk period 3 vs 2, 1.10; 95% confidence interval, 1.02-1.17) but weakly associated, if at all, for patients with distal colon lesions (adjusted relative risk period 2 vs 1, 1.07; 95% confidence interval, 1.01-1.13; adjusted relative risk period 3 vs 2, 0.97; 95% confidence interval, 0.90-1.05). CONCLUSIONS Expansion of Medicare reimbursement to cover colon cancer screening was associated with an increased use of colonoscopy for Medicare beneficiaries, and for those who were diagnosed with colon cancer, an increased probability of being diagnosed at an early stage. The selective effect of the coverage change on proximal colon lesions suggests that increased use of whole-colon screening modalities such as colonoscopy may have played a pivotal role. | Relation between Medicare screening reimbursement and stage at diagnosis for older patients with colon cancer. |
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However, chromosomal dynamics have never been observed in living MKs. We developed a new transgenic mouse model in which the expression of human histone H2B fused in-frame to green fluorescent protein is targeted to MKs. Ex vivo time-lapse microscopy analysis indicated that chromosomal condensation occurs at early mitosis in all MKs. In high ploidy MKs (>or=8N), late anaphase was marked by a ring-type alignment of chromosomes with multiple territories formed between them. By contrast, in low ploidy MKs mitotic chromosomes segregated to form two groups separated by a clear space before re-joining to one cluster. This is the first study to document chromosomal segregation patterns during endomitosis ex vivo and to indicate their potential differential regulation in low and high ploidy cells. | Direct visualization of the endomitotic cell cycle in living megakaryocytes: differential patterns in low and high ploidy cells. |
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"27179": 0.5092619061470032, "27711": 0.6931471824645996, "27717": 0.9417452812194824, "27881": 0.35060185194015503, "28086": 0.06337817758321762, "28327": 0.9240728616714478, "28424": 0.12814582884311676, "28873": 0.16607704758644104, "29290": 0.14602625370025635, "29477": 0.9045027494430542, "29484": 0.1994270235300064, "29489": 0.0019512200960889459, "29516": 0.0354953333735466} | 22963769 | Disruption of cell adhesion plays a central role in dedifferentiation, invasion, and metastasis of various cancers. The desmosome and hemidesmosome are anchoring junctions that control cell-cell and cell-matrix adhesion, respectively. To clarify their contributions in mediating the biological properties of oral cancer, we immunohistochemically examined the expression of desmoglein 1 (DSG1), DSG2, DSG3, desmocollin 2 (DSC2), integrin beta 4 (ITGB4), laminin gamma chain 2 (LAMC2), and collagen type 17 alpha 1 (COL17A1) in 51 cases of oral squamous cell carcinoma. On normal oral epithelial cells, DSG1, DSG3, DSC2, and COL17A1 were expressed on the plasma membrane, while ITGB4 and mature LAMC2 were present at the basement membrane. In cancer, the expression of DSG1, DSG3, DSC2, and COL17A1 decreased and internalized to the cytoplasm. Cytoplasmic expression of DSG2, ITGB4, and LAMC2 was induced in the cancer cells facing to the stroma. We scored immunohistochemical expression and correlated this to clinicopathological parameters including histologic differentiation, pattern of invasion, and presence of lymph node metastasis. Decrease of DSG3 and DSC2 expression correlated with a more aggressive cancer phenotype: less differentiated and more invasive histologic features and a higher incidence of nodal metastasis. Lower COL17A1 and higher LAMC2 expression were also associated with a more aggressive phenotype. The present study demonstrates that aberrant expression and altered cellular localization of desmosomal and hemidesmosomal proteins are associated with aggressive clinicopathological features of oral cancer. This reinforces the notion that disturbance of the keratin-associated anchoring junctions confers aggressive features to cancer cells. | Aberrant expression and altered cellular localization of desmosomal and hemidesmosomal proteins are associated with aggressive clinicopathological features of oral squamous cell carcinoma |
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"28873": 0.29255300760269165, "28896": 0.07159364968538284, "29336": 0.0770333781838417, "29461": 1.4515039920806885, "29533": 0.17020416259765625} | 22968257 | Histone/protein deacetylases (HDACs) decrease histone and protein acetylation, typically leading to suppression of gene transcription and modulation of various protein functions. We found significant differences in expression of HDAC before and after stimulation of human T regulatory (Treg) and T effector cells, suggesting the potential for future selective targeting of Tregs with HDAC inhibitors (HDACi). Use of various HDACi small molecules enhanced, by up to 4.5-fold (average 2-fold), the suppressive functions of both freshly isolated and expanded human Tregs, consistent with our previous murine data. HDACi use increased Treg expression of CTLA-4, a key negative regulator of immune response, and we found a direct and significant correlation between CTLA-4 expression and Treg suppression. Hence, HDACi compounds are promising pharmacologic tools to increase Treg suppressive functions, and this action may potentially be of use in patients with autoimmunity or post-transplantation. | Histone/protein deacetylase inhibitors increase suppressive functions of human FOXP3+ Tregs. |
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0.1685553640127182, "26402": 0.9470623731613159, "26721": 0.23247487843036652, "26942": 0.23710809648036957, "26982": 0.18573370575904846, "27144": 0.11951763927936554, "27531": 0.06429435312747955, "27854": 0.37907835841178894, "28086": 0.17267228662967682, "28156": 0.4203280806541443, "28227": 0.5450005531311035, "29107": 0.22548456490039825, "29206": 0.9425065517425537, "29720": 0.8764448165893555} | 22972632 | Inhibition of αvβ3 or αvβ5 integrin function has been reported to suppress neovascularization and tumor growth, suggesting that these integrins are critical modulators of angiogenesis. Here we report that mice lacking β3 integrins or both β3 and β5 integrins not only support tumorigenesis, but have enhanced tumor growth as well. Moreover, the tumors in these integrin-deficient mice display enhanced angiogenesis, strongly suggesting that neither β3 nor β5 integrins are essential for neovascularization. We also observed that angiogenic responses to hypoxia and vascular endothelial growth factor (VEGF) are augmented significantly in the absence of β3 integrins. We found no evidence that the expression or functions of other integrins were altered as a consequence of the β3 deficiency, but we did observe elevated levels of VEGF receptor-2 (also called Flk-1) in β3-null endothelial cells. These data indicate that αvβ3 and αvβ5 integrins are not essential for vascular development or pathological angiogenesis and highlight the need for further evaluation of the mechanisms of action of αv-integrin antagonists in anti-angiogenic therapeutics. | Enhanced pathological angiogenesis in mice lacking β3 integrin or β3 and β5 integrins |
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However, some macrophages develop in the embryo before the appearance of definitive HSCs. We thus reinvestigated macrophage development. We found that the transcription factor Myb was required for development of HSCs and all CD11b(high) monocytes and macrophages, but was dispensable for yolk sac (YS) macrophages and for the development of YS-derived F4/80(bright) macrophages in several tissues, such as liver Kupffer cells, epidermal Langerhans cells, and microglia--cell populations that all can persist in adult mice independently of HSCs. These results define a lineage of tissue macrophages that derive from the YS and are genetically distinct from HSC progeny. | A lineage of myeloid cells independent of Myb and hematopoietic stem cells. |
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"28227": 0.14264501631259918, "28290": 0.23247487843036652, "28621": 0.2561853528022766, "28765": 0.8433839678764343, "28804": 0.9893379211425781, "28873": 0.04767346754670143, "29015": 0.9944084882736206, "29125": 0.8109301924705505, "29206": 0.8357921838760376, "29490": 0.3615458607673645, "29516": 0.13243216276168823, "29598": 0.7153595685958862} | 22975806 | For individuals genetically predisposed to breast and ovarian cancer through inheritance of a mutant BRCA allele, somatic loss of heterozygosity affecting the wild-type allele is considered obligatory for cancer initiation and/or progression. However, several lines of evidence suggest that phenotypic effects may result from BRCA haploinsufficiency. Archival fixed and embedded tissue specimens from women with germ line deleterious mutations in BRCA1 or BRCA2 were identified. After pathologic review, focal areas of normal breast epithelium, atypical ductal hyperplasia, ductal carcinoma-in-situ, and invasive ductal carcinoma were identified from 14 BRCA1-linked and 9 BRCA2-linked breast cancers. Ten BRCA-linked prophylactic mastectomy specimens and 12 BRCA-linked invasive ovarian carcinomas were also studied. Laser catapult microdissection was used to isolate cells from the various pathologic lesions and corresponding normal tissues. After DNA isolation, real-time polymerase chain reaction assays were used to quantitate the proportion of wild-type to mutant BRCA alleles in each tissue sample. Quantitative allelotyping of microdissected cells revealed a high level of heterogeneity in loss of heterozygosity within and between preinvasive lesions and invasive cancers from BRCA1 and BRCA2 heterozygotes with breast cancer. In contrast, all BRCA-associated ovarian cancers displayed complete loss of the wild-type BRCA allele. These data suggest that loss of the wild-type BRCA allele is not required for BRCA-linked breast tumorigenesis, which would have important implications for the genetic mechanism of BRCA tumor suppression and for the clinical management of this patient population. | Heterogenic Loss of the Wild-Type BRCA Allele in Human Breast Tumorigenesis |
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0.7239188551902771, "24471": 1.261651873588562, "24587": 1.182852864265442, "24594": 0.14433705806732178, "24759": 0.15442965924739838, "25086": 0.440646231174469, "25226": 1.0822023153305054, "25409": 0.7028654217720032, "25423": 0.49864232540130615, "25456": 0.3005385100841522, "25708": 1.390192985534668, "25746": 0.04953393340110779, "25778": 0.026025565341114998, "26224": 0.07250232994556427, "26236": 0.9576126337051392, "26563": 0.04487626627087593, "26778": 0.33953672647476196, "27009": 0.24631060659885406, "27144": 1.0855059623718262, "27295": 0.12470348179340363, "27321": 0.08603433519601822, "27531": 0.3423145115375519, "27781": 0.12642613053321838, "27854": 0.21372433006763458, "28032": 0.6902132034301758, "28251": 0.053244512528181076, "28522": 0.7124901413917542, "28696": 0.1946154683828354, "28788": 0.21765978634357452, "28873": 0.8981585502624512, "28879": 0.1751343309879303, "28896": 0.861702561378479} | 22980205 | PURPOSE OF REVIEW Greater understanding of the biology and genetics of urothelial carcinoma is helping to identify and define the role of molecules and pathways appropriate for novel-targeted therapies. Here, we review the targeted therapies that have been reported or are in ongoing urothelial carcinoma clinical trials, and highlight molecular targets characterized in preclinical and clinical studies. RECENT FINDINGS Trials in nonmuscle-invasive bladder cancer are evaluating the role of immunotherapy and agents targeting vascular endothelial growth factor (VEGF) or fibroblast growth factor receptor-3. In muscle-invasive bladder cancer, neoadjuvant studies have focused on combining VEGF agents with chemotherapy; adjuvant studies are testing vaccines and agents targeting the human epidermal growth factor receptor 2, p53, and Hsp27. In the first-line treatment of metastatic urothelial carcinoma, tubulin, cytotoxic T-lymphocyte antigen 4, Hsp27, and p53 are novel targets in clinical trials. The majority of targeted agents studied in urothelial carcinoma are in the second-line setting; new targets include CD105, polo-like kinase-1, phosphatidylinositide 3-kinases (PI3K), transforming growth factor β receptor/activin receptor-like kinase β, estrogen receptor, and the hepatocyte growth factor receptor (HGFR or MET). SUMMARY Development of targeted therapies for urothelial carcinoma is still in early stages, consequently there have been no major therapeutic advances to date. However, greater understanding of urothelial carcinoma and solid tumor biology has resulted in a proliferation of clinical trials that could lead to significant advances in treatment strategies. | Targeted therapies in urothelial carcinoma. |
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The relaxation effect was pronouncedly enhanced by H2S- and HS−-donor NaHS (30 μmol/l) at 7.5 pH but not at 6.3 pH. To study molecular mechanism of this effect, we investigated whether NaHS can release NO from NO donors. Using an electron paramagnetic resonance spectroscopy method of spin trap and by measuring the NO oxidation product, which is nitrite, by the Griess reaction, we report that NaHS released NO from nitrosothiols, namely from GSNO, S-nitroso-N-acetyl-dl-penicillamine (SNAP), from metal nitrosyl complex nitroprusside (SNP) and from rat brain homogenate and murine L1210 leukaemia cells. From the observation that the releasing effect was more pronounced at 8.0 pH than 6.0 pH, we suppose that HS−, rather than H2S, is responsible for the NO-releasing effect. Since in mammals, H2S and HS− are produced endogenously, we assume that their effect to release NO from nitrosothiols and from metal nitrosyl complexes are responsible for some of their biological activities and that this mechanism may be involved in S-nitrosothiol-signalling reactions. | H2S and HS− donor NaHS releases nitric oxide from nitrosothiols, metal nitrosyl complex, brain homogenate and murine L1210 leukaemia cells |
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0.11081436276435852, "24901": 1.5144401788711548, "25344": 0.2317005842924118, "26445": 1.360575795173645, "26456": 1.117955207824707, "27405": 0.06886265426874161, "29234": 0.05694137513637543, "29443": 0.14179791510105133, "29566": 0.06520967930555344, "29598": 0.6734226942062378} | 22995579 | The tricyclic antidepressant, amitriptyline, is an effective drug for the treatment of chronic tension-type headache and for other chronic pain syndromes, but it is also effective in the prophylaxis of an episodic type of headache such as migraine. However, its efficacy in episodic tension-type headache has not yet been clarified. We compared the efficacy of amitriptyline (25 mg/day) in 82 nondepressed patients with either chronic or episodic tension-type headache in an open-label study. Amitriptyline significantly reduced (P < 0.05) frequency and duration of headache as well as analgesic consumption in chronic, but not in episodic, tension-type headache. Further placebo-controlled trials, possibly with higher doses of amitriptyline, might confirm if the different pattern of response to amitriptyline can be explained in terms of different involvement of central nociception and of peripheral myofascial factors in the chronic and in the episodic forms of tension-type headache. | Amitriptyline is effective in chronic but not in episodic tension-type headache: pathogenetic implications. |
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"28227": 0.5528968572616577, "28577": 0.21372433006763458, "28788": 0.1477125883102417, "29295": 0.3339579105377197, "29602": 0.06520967930555344, "29610": 0.15023678541183472} | 22997657 | The transcription factor Kruppel-like factor 2 (KLF2) was proposed to regulate genes involved in cell cycle entry and T cell trafficking; however, the physiological role of its expression in postactivated T cells is not well defined. Previous studies suggested that the cytokines IL-2 and IL-15 differentially regulate KLF2 re-expression in postactivation T cells and that these cytokines also influence effector versus memory T cell differentiation. Using conditional and inducible KLF2-knockout model systems, we tested the specific role of KLF2 expression in activated CD8(+) T cells cultured with these cytokines. KLF2 was required for effective transcription of sphingosine-1-phosphate receptor-1 (S1P(1)) and CD62L in postactivation T cells. However, although different cytokines dramatically altered the expression of cell-cycle-related genes, endogenous KLF2 had a minimal impact. Correspondingly, KLF2-deficient T cells showed dysregulated trafficking but not altered proliferative characteristics following in vivo responses to Ag. Thus, our data help to define KLF2-dependent and -independent aspects of activated CD8(+) T cell differentiation and argue against a physiological role in cell cycle regulation. | Kruppel-like factor 2 is required for trafficking but not quiescence in postactivated T cells. |
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0.13925230503082275, "28965": 0.21372433006763458, "29295": 0.05046287178993225, "29458": 0.7610978484153748, "29521": 0.036437395960092545} | 23013317 | OBJECTIVE To determine whether hypoalbuminemia is an independent risk factor for poor outcome in the acutely ill, and to assess the potential of exogenous albumin administration for improving outcomes in hypoalbuminemic patients. SUMMARY BACKGROUND DATA Hypoalbuminemia is associated with poor outcomes in acutely ill patients, but whether this association is causal has remained unclear. Trials investigating albumin therapy to correct hypoalbuminemia have proven inconclusive. METHODS A meta-analysis was conducted of 90 cohort studies with 291,433 total patients evaluating hypoalbuminemia as an outcome predictor by multivariate analysis and, separately, of nine prospective controlled trials with 535 total patients on correcting hypoalbuminemia. RESULTS Hypoalbuminemia was a potent, dose-dependent independent predictor of poor outcome. Each 10-g/L decline in serum albumin concentration significantly raised the odds of mortality by 137%, morbidity by 89%, prolonged intensive care unit and hospital stay respectively by 28% and 71%, and increased resource utilization by 66%. The association between hypoalbuminemia and poor outcome appeared to be independent of both nutritional status and inflammation. Analysis of dose-dependency in controlled trials of albumin therapy suggested that complication rates may be reduced when the serum albumin level attained during albumin administration exceeds 30 g/L. CONCLUSIONS Hypoalbuminemia is strongly associated with poor clinical outcomes. Further well-designed trials are needed to characterize the effects of albumin therapy in hypoalbuminemic patients. In the interim, there is no compelling basis to withhold albumin therapy if it is judged clinically appropriate. | Hypoalbuminemia in acute illness: is there a rationale for intervention? A meta-analysis of cohort studies and controlled trials. |
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"27032": 0.07250232994556427, "27133": 1.167778730392456, "27142": 0.3248254358768463, "27296": 0.11430477350950241, "27364": 0.9754437208175659, "27651": 0.013579257763922215, "27753": 0.39762192964553833, "27794": 0.7674643993377686, "27833": 0.1510767638683319, "28156": 0.5174443125724792, "28212": 0.10026945173740387, "28268": 0.17267228662967682, "28297": 0.052318159490823746, "28517": 0.13755162060260773, "28696": 0.03831886500120163, "29107": 0.0770333781838417, "29295": 0.29473719000816345, "29386": 0.5947071313858032, "29513": 1.0894558429718018, "29516": 0.40806588530540466} | 23017040 | Reduced dietary methionine intake (0.17% methionine, MR) and calorie restriction (CR) prolong lifespan in male Fischer 344 rats. Although the mechanisms are unclear, both regimens feature lower body weight and reductions in adiposity. Reduced fat deposition in CR is linked to preservation of insulin responsiveness in older animals. These studies examine the relationship between insulin responsiveness and visceral fat in MR and test whether, despite lower food intake observed in MR animals, decreased visceral fat accretion and preservation of insulin sensitivity is not secondary to CR. Accordingly, rats pair fed (pf) control diet (0.86% methinone, CF) to match the food intake of MR for 80 weeks exhibit insulin, glucose, and leptin levels similar to control-fed animals and comparable amounts of visceral fat. Conversely, MR rats show significantly reduced visceral fat compared to CF and PF with concomitant decreases in basal insulin, glucose, and leptin, and increased adiponectin and triiodothyronine. Daily energy expenditure in MR animals significantly exceeds that of both PF and CF. In a separate cohort, insulin responses of older MR animals as measured by oral glucose challenge are similar to young animals. Longitudinal assessments of MR and CF through 112 weeks of age reveal that MR prevents age-associated increases in serum lipids. By 16 weeks, MR animals show a 40% reduction in insulin-like growth factor-1 (IGF-1) that is sustained throughout life; CF IGF-1 levels decline much later, beginning at 112 weeks. Collectively, the results indicate that MR reduces visceral fat and preserves insulin activity in aging rats independent of energy restriction. | Methionine restriction decreases visceral fat mass and preserves insulin action in aging male Fischer 344 rats independent of energy restriction. |
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0.12556517124176025, "26462": 0.3170322775840759, "26702": 0.04113444685935974, "27159": 0.2478361576795578, "27287": 0.7445381283760071, "27528": 0.6332852244377136, "27710": 0.10467668622732162, "27788": 0.06429435312747955, "28024": 0.4794800877571106, "28086": 0.37640097737312317, "28156": 0.6892333030700684, "28286": 0.014542185701429844, "28667": 0.7755908370018005, "28901": 0.3743882179260254, "29003": 0.026025565341114998, "29206": 0.015504186972975731} | 23032247 | The use of retrogenic mice offers a rapid and flexible approach to T cell receptor (TCR)-transgenic mice. By transducing bone marrow progenitor cells with a retrovirus that encodes a given TCR-α/β subunit, TCR-retrogenic mice can be generated in as few as 4–6 weeks, whereas conventional TCR transgenics can take 6 months or longer. In this updated protocol, we have increased the efficiency of the bone marrow transduction and bone marrow reconstitution compared with our previously published protocol. The main departure from the previous protocol is the implementation of spin transduction with the viral supernatant instead of coculture with the viral producer cell line. The changes in this protocol improve bone marrow viability, increase consistency of the bone marrow transduction and bone marrow engraftment, and they reduce the ratio of bone marrow donor mice to bone marrow recipients. | Generation of T cell receptor–retrogenic mice: improved retroviral-mediated stem cell gene transfer |
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However, telomere extension by nonviral, nonintegrating methods remains inefficient. Here we report that delivery of modified mRNA encoding TERT to human fibroblasts and myoblasts increases telomerase activity transiently (24-48 h) and rapidly extends telomeres, after which telomeres resume shortening. Three successive transfections over a 4 d period extended telomeres up to 0.9 kb in a cell type-specific manner in fibroblasts and myoblasts and conferred an additional 28 ± 1.5 and 3.4 ± 0.4 population doublings (PDs), respectively. Proliferative capacity increased in a dose-dependent manner. The second and third transfections had less effect on proliferative capacity than the first, revealing a refractory period. However, the refractory period was transient as a later fourth transfection increased fibroblast proliferative capacity by an additional 15.2 ± 1.1 PDs, similar to the first transfection. Overall, these treatments led to an increase in absolute cell number of more than 10(12)-fold. Notably, unlike immortalized cells, all treated cell populations eventually stopped increasing in number and expressed senescence markers to the same extent as untreated cells. This rapid method of extending telomeres and increasing cell proliferative capacity without risk of insertional mutagenesis should have broad utility in disease modeling, drug screening, and regenerative medicine. | Transient delivery of modified mRNA encoding TERT rapidly extends telomeres in human cells. |
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However, the final contribution of newborn neurons to neuronal networks is limited. Here we show that in neural stem cells, stimulation of the "death receptor" CD95 does not trigger apoptosis but unexpectedly leads to increased stem cell survival and neuronal specification. These effects are mediated via activation of the Src/PI3K/AKT/mTOR signaling pathway, ultimately leading to a global increase in protein translation. Induction of neurogenesis by CD95 was further confirmed in the ischemic CA1 region, in the naive dentate gyrus, and after forced expression of CD95L in the adult subventricular zone. Lack of hippocampal CD95 resulted in a reduction in neurogenesis and working memory deficits. Following global ischemia, CD95-mediated brain repair rescued behavioral impairment. Thus, we identify the CD95/CD95L system as an instructive signal for ongoing and injury-induced neurogenesis. | The death receptor CD95 activates adult neural stem cells for working memory formation and brain repair. |
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0.6603899002075195, "26709": 0.6430866718292236, "26718": 0.9147270321846008, "27011": 0.4425300657749176, "27144": 0.1677299439907074, "27421": 0.981317400932312, "27790": 0.06977381557226181, "27965": 0.021256839856505394, "28032": 0.7647408246994019, "28043": 0.4974553883075714, "28046": 0.18248429894447327, "28466": 0.7426811456680298, "28578": 0.7978238463401794, "28667": 0.6492279767990112, "28715": 0.0029254043474793434, "28767": 0.29981520771980286, "29060": 0.30558720231056213, "29129": 0.011650617234408855} | 23073816 | Allogeneic umbilical cord blood (UCB) has therapeutic potential for cerebral palsy (CP). Concomitant administration of recombinant human erythropoietin (rhEPO) may boost the efficacy of UCB, as it has neurotrophic effects. The objectives of this study were to assess the safety and efficacy of allogeneic UCB potentiated with rhEPO in children with CP. Children with CP were randomly assigned to one of three parallel groups: the pUCB group, which received allogeneic UCB potentiated with rhEPO; the EPO group, which received rhEPO and placebo UCB; and the Control group, which received placebo UCB and placebo rhEPO. All participants received rehabilitation therapy. The main outcomes were changes in scores on the following measures during the 6 months treatment period: the gross motor performance measure (GMPM), gross motor function measure, and Bayley scales of infant development-II (BSID-II) Mental and Motor scales (18). F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET/CT) and diffusion tensor images (DTI) were acquired at baseline and followed up to detect changes in the brain. In total, 96 subjects completed the study. Compared with the EPO (n = 33) and Control (n = 32) groups, the pUCB (n = 31) group had significantly higher scores on the GMPM and BSID-II Mental and Motor scales at 6 months. DTI revealed significant correlations between the GMPM increment and changes in fractional anisotropy in the pUCB group. 18F-FDG-PET/CT showed differential activation and deactivation patterns between the three groups. The incidence of serious adverse events did not differ between groups. In conclusion, UCB treatment ameliorated motor and cognitive dysfunction in children with CP undergoing active rehabilitation, accompanied by structural and metabolic changes in the brain. | Umbilical Cord Blood Therapy Potentiated with Erythropoietin for Children with Cerebral Palsy: A Double-blind, Randomized, Placebo-Controlled Trial |
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"24054": 0.5773153901100159, "24137": 0.7827593088150024, "24312": 1.0051883459091187, "24363": 0.05694137513637543, "25003": 0.8281423449516296, "25194": 0.3923587501049042, "25456": 0.3622259199619293, "25502": 0.8707374930381775, "25609": 0.8997484445571899, "25761": 0.3676496744155884, "25862": 0.07341018319129944, "26243": 0.013579257763922215, "26402": 0.8957691192626953, "26468": 1.0506030321121216, "26514": 0.7665573358535767, "26520": 0.015504186972975731, "26534": 0.09406650811433792, "26572": 0.45994341373443604, "26773": 0.5882205963134766, "27259": 0.7163142561912537, "27263": 0.015504186972975731, "27544": 0.026025565341114998, "27854": 0.9425065517425537, "27998": 0.5045560002326965, "28228": 0.015504186972975731, "28517": 0.03360854089260101, "29290": 0.5914691090583801, "29441": 0.1401015669107437} | 23076291 | We recently identified a novel mechanism for modulation of the phosphorylation state and function of the N-methyl-d-aspartate (NMDA) receptor via the scaffolding protein RACK1. We found that RACK1 binds both the NR2B subunit of the NMDA receptor and the nonreceptor protein-tyrosine kinase, Fyn. RACK1 inhibits Fyn phosphorylation of NR2B and decreases NMDA receptor-mediated currents in CA1 hippocampal slices (Yaka, R., Thornton, C., Vagts, A. J., Phamluong, K., Bonci, A., and Ron, D. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 5710-5715). Here, we identified the signaling cascade by which RACK1 is released from the NMDA receptor complex and identified the consequences of the dissociation. We found that activation of the cAMP/protein kinase A pathway in hippocampal slices induced the release of RACK1 from NR2B and Fyn. This resulted in the induction of NR2B phosphorylation and the enhancement of NMDA receptor-mediated activity via Fyn. We identified the neuropeptide, pituitary adenylate cyclase activating polypeptide (PACAP(1-38)), as a ligand that induced phosphorylation of NR2B and enhanced NMDA receptor potentials. Finally, we found that activation of the cAMP/protein kinase A pathway induced the movement of RACK1 to the nuclear compartment in dissociated hippocampal neurons. Nuclear RACK1 in turn was found to regulate the expression of brain-derived neurotrophic factor induced by PACAP(1-38). Taken together our results suggest that activation of adenylate cyclase by PACAP(1-38) results in the release of RACK1 from the NMDA receptor and Fyn. This in turn leads to NMDA receptor phosphorylation, enhanced activity mediated by Fyn, and to the induction of brain-derived neurotrophic factor expression by RACK1. | Pituitary adenylate cyclase-activating polypeptide (PACAP(1-38)) enhances N-methyl-D-aspartate receptor function and brain-derived neurotrophic factor expression via RACK1. |
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