spalde-v3-lexical
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In this study, we investigated the interaction of the RNA editing mechanism with the RNA interference (RNAi) machinery and found that ADAR1 forms a complex with Dicer through direct protein-protein interaction. Most importantly, ADAR1 increases the maximum rate (Vmax) of pre-microRNA (miRNA) cleavage by Dicer and facilitates loading of miRNA onto RNA-induced silencing complexes, identifying a new role of ADAR1 in miRNA processing and RNAi mechanisms. ADAR1 differentiates its functions in RNA editing and RNAi by the formation of either ADAR1/ADAR1 homodimer or Dicer/ADAR1 heterodimer complexes, respectively. As expected, the expression of miRNAs is globally inhibited in ADAR1(-/-) mouse embryos, which, in turn, alters the expression of their target genes and might contribute to their embryonic lethal phenotype. | ADAR1 Forms a Complex with Dicer to Promote MicroRNA Processing and RNA-Induced Gene Silencing |
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0.13755162060260773, "27292": 0.5255602598190308, "27597": 0.006812678650021553, "27694": 0.1485546976327896, "27781": 0.3084607720375061, "27841": 0.011650617234408855, "27858": 1.258327841758728, "27887": 0.2160874605178833, "28024": 0.7942996621131897, "28155": 0.11865071207284927, "28309": 0.02412080205976963, "28637": 0.13071982562541962, "28689": 1.0815403461456299, "28695": 0.6512666940689087, "28847": 0.15860503911972046, "28873": 0.23324857652187347, "28896": 0.3464667797088623, "29167": 0.11691460013389587, "29176": 0.31489628553390503, "29491": 0.2223619967699051} | 5956016 | Many of the best-selling ‘blockbuster’ biological medicinal products are, or will soon be, facing competition from similar biological medicinal products (biosimilars) in the EU. Biosimilarity is based on the comparability concept, which has been used successfully for several decades to ensure close similarity of a biological product before and after a manufacturing change. Over the last 10 years, experience with biosimilars has shown that even complex biotechnology-derived proteins can be copied successfully. Most best-selling biologicals are used for chronic treatment. This has triggered intensive discussion on the interchangeability of a biosimilar with its reference product, with the main concern being immunogenicity. We explore the theoretical basis of the presumed risks of switching between a biosimilar and its reference product and the available data on switches. Our conclusion is that a switch between comparable versions of the same active substance approved in accordance with EU legislation is not expected to trigger or enhance immunogenicity. On the basis of current knowledge, it is unlikely and very difficult to substantiate that two products, comparable on a population level, would have different safety or efficacy in individual patients upon a switch. Our conclusion is that biosimilars licensed in the EU are interchangeable. | Interchangeability of Biosimilars: A European Perspective |
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difficult to surgically resect. To determine the genetic and epigenetic landscape of these tumors, we performed exomic sequencing of 14 brainstem gliomas (BSGs) and 12 thalamic gliomas. We also performed targeted mutational analysis of an additional 24 such tumors and genome-wide methylation profiling of 45 gliomas. This study led to the discovery of tumor-specific mutations in PPM1D, encoding wild-type p53-induced protein phosphatase 1D (WIP1), in 37.5% of the BSGs that harbored hallmark H3F3A mutations encoding p. Lys27Met substitutions. PPM1D mutations were mutually exclusive with TP53 mutations in BSG and attenuated p53 activation in vitro. PPM1D mutations were truncating alterations in exon 6 that enhanced the ability of PPM1D to suppress the activation of the DNA damage response checkpoint protein CHK2. These results define PPM1D as a frequent target of somatic mutation and as a potential therapeutic target in brainstem gliomas. | Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas |
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"24854": 0.034552380442619324, "25003": 0.08244366943836212, "25194": 0.16690383851528168, "25206": 0.009718249551951885, "25426": 0.1619328260421753, "25562": 0.2447827309370041, "25761": 0.3019835948944092, "26014": 0.6853039860725403, "26223": 0.18329764902591705, "26236": 0.2493593990802765, "26244": 0.016465263441205025, "26402": 0.13157635927200317, "26601": 0.10818854719400406, "26775": 0.6689305305480957, "26786": 0.1693800985813141, "26874": 0.630689799785614, "27211": 1.2824517488479614, "27574": 0.1221139207482338, "27642": 0.8780695199966431, "27717": 0.18816383183002472, "27854": 0.1677299439907074, "27965": 0.08064348995685577, "28086": 0.07884006202220917, "28433": 0.20102575421333313, "28527": 0.15943801403045654, "28691": 0.1710275560617447, "28848": 0.08782484382390976, "28873": 0.07431721687316895, "29060": 0.8715548515319824, "29226": 0.015504186972975731} | 5966635 | Activation of transcription within chromatin has been correlated with the incorporation of the essential histone variant H2A.Z into nucleosomes. H2A.Z and other histone variants may establish structurally distinct chromosomal domains; however, the molecular mechanism by which they function is largely unknown. Here we report the 2.6 Å crystal structure of a nucleosome core particle containing the histone variant H2A.Z. The overall structure is similar to that of the previously reported 2.8 Å nucleosome structure containing major histone proteins. However, distinct localized changes result in the subtle destabilization of the interaction between the (H2A.Z–H2B) dimer and the (H3–H4)2 tetramer. Moreover, H2A.Z nucleosomes have an altered surface that includes a metal ion. This altered surface may lead to changes in higher order structure, and/or could result in the association of specific nuclear proteins with H2A.Z. Finally, incorporation of H2A.Z and H2A within the same nucleosome is unlikely, due to significant changes in the interface between the two H2A.Z–H2B dimers. | Crystal structure of a nucleosome core particle containing the variant histone H2A.Z |
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"28696": 0.17020416259765625, "28731": 0.8893690705299377, "28788": 0.29619070887565613, "28873": 0.04953393340110779, "29166": 1.0403043031692505, "29537": 0.04113444685935974} | 5979056 | Dendritic cells (DCs) have been implicated as important regulators of innate and adaptive inflammation in many diseases, including atherosclerosis. However, the molecular mechanisms by which DCs mitigate or promote inflammatory pathogenesis are only partially understood. Previous studies have shown an important anti-inflammatory role for the transcription factor Krüppel-like factor 2 (KLF2) in regulating activation of various cell types that participate in atherosclerotic lesion development, including endothelial cells, macrophages, and T cells. We used a pan-DC, CD11c-specific cre-lox gene knockout mouse model to assess the role of KLF2 in DC activation, function, and control of inflammation in the context of hypercholesterolemia and atherosclerosis. We found that KLF2 deficiency enhanced surface expression of costimulatory molecules CD40 and CD86 in DCs and promoted increased T cell proliferation and apoptosis. Transplant of bone marrow from mice with KLF2-deficient DCs into Ldlr-/- mice aggravated atherosclerosis compared with control mice, most likely due to heightened vascular inflammation evidenced by increased DC presence within lesions, enhanced T cell activation and cytokine production, and increased cell death in atherosclerotic lesions. Taken together, these data indicate that KLF2 governs the degree of DC activation and hence the intensity of proatherogenic T cell responses. | Dendritic Cell KLF2 Expression Regulates T Cell Activation and Proatherogenic Immune Responses. |
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0.07068414986133575, "27781": 0.8813109993934631, "27854": 0.175953671336174, "27881": 0.045809537172317505, "28286": 1.240975022315979, "28518": 0.009718249551951885, "28696": 0.18816383183002472, "28788": 0.1401015669107437, "28873": 0.2247048318386078, "28896": 0.5045560002326965, "29166": 0.9628462791442871, "29290": 0.981317400932312, "29494": 0.0842406153678894, "29514": 0.19220098853111267} | 5991309 | With the success of ipilimumab and promise of programmed death-1 pathway-targeted agents, the field of tumor immunotherapy is expanding rapidly. Newer targets for clinical development include select members of the tumor necrosis factor receptor (TNFR) family. Agonist antibodies to these co-stimulatory molecules target both T and B cells, modulating T-cell activation and enhancing immune responses. In vitro and in vivo preclinical data have provided the basis for continued development of 4-1BB, OX40, glucocorticoid-induced TNFR-related gene, herpes virus entry mediator, and CD27 as potential therapies for patients with cancer. In this review, we summarize the immune response to tumors, consider preclinical and early clinical data on select TNFR family members, discuss potential translational challenges and suggest possible combination therapies with the aim of inducing durable antitumor responses. | Targeting tumor-necrosis factor receptor pathways for tumor immunotherapy |
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0.02792670577764511, "29278": 0.05970508232712746, "29490": 0.9576126337051392} | 5993745 | BACKGROUND Corin is a transmembrane protease that processes natriuretic peptides in the heart. Like many membrane proteins, corin is shed from the cell surface. METHODS AND RESULTS In this study, we obtained plasma samples from healthy controls and patients with heart failure (HF) and acute myocardial infarction. Soluble corin levels in plasma were measured by an ELISA method. In healthy adults (n=198), plasma corin levels were 690 pg/mL (SD, 260 pg/mL). The corin levels did not differ significantly among different age groups. In patients with HF (n=291), plasma corin levels were significantly lower compared with that of healthy controls (365 pg/mL [SD, 259]; P<0.001). The reduction in plasma corin levels seemed to correlate with the severity of HF. In patients of New York Heart Association classes II, III, and IV, plasma corin levels were 450 pg/mL (SD, 281 pg/mL; n=69), 377 pg/mL (SD, 270 pg/mL; n=132), and 282 pg/mL (SD, 194 pg/mL; n=90), respectively (P<0.001 class II vs class IV; P<0.05 class III vs class IV). In contrast, plasma corin levels in patients with acute myocardial infarction (n=73) were similar to that of healthy controls (678 pg/mL [SD, 285 pg/mL]; P>0.05). CONCLUSIONS Soluble corin was detected in human plasma. Plasma corin levels were reduced significantly in patients with HF but not in those with acute myocardial infarction. Our results indicate that corin deficiency may contribute to the pathogenesis of HF and that plasma corin may be used as a biomarker in the diagnosis of HF. | Plasma soluble corin in patients with heart failure. |
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"27179": 0.39367714524269104, "27287": 0.7210738658905029, "27292": 0.8074519634246826, "27295": 0.15442965924739838, "27895": 0.17431432008743286, "28723": 1.3809088468551636, "28835": 0.10203468054533005, "28873": 0.0354953333735466, "29034": 0.9194108247756958, "29170": 0.4537591338157654, "29290": 0.5364705324172974, "29480": 0.12038381397724152, "29720": 0.5690577030181885} | 6000423 | Despite genetic heterogeneity, myelodysplastic syndromes (MDSs) share features of cytological dysplasia and ineffective hematopoiesis. We report that a hallmark of MDSs is activation of the NLRP3 inflammasome, which drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoietic stem and progenitor cells (HSPCs) overexpress inflammasome proteins and manifest activated NLRP3 complexes that direct activation of caspase-1, generation of interleukin-1β (IL-1β) and IL-18, and pyroptotic cell death. Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPCs and bone marrow plasma. Further, like somatic gene mutations, S100A9-induced signaling activates NADPH oxidase (NOX), increasing levels of reactive oxygen species (ROS) that initiate cation influx, cell swelling, and β-catenin activation. Notably, knockdown of NLRP3 or caspase-1, neutralization of S100A9, and pharmacologic inhibition of NLRP3 or NOX suppress pyroptosis, ROS generation, and nuclear β-catenin in MDSs and are sufficient to restore effective hematopoiesis. Thus, alarmins and founder gene mutations in MDSs license a common redox-sensitive inflammasome circuit, which suggests new avenues for therapeutic intervention. | The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype. |
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"26243": 0.259204238653183, "26319": 0.013579257763922215, "26497": 0.011650617234408855, "26721": 0.7028654217720032, "26754": 0.07431721687316895, "26758": 0.16690383851528168, "26786": 0.34508460760116577, "26787": 0.9248477816581726, "26819": 0.9754437208175659, "26994": 0.9591107368469238, "27011": 0.29981520771980286, "27029": 0.19862671196460724, "27090": 0.3070250153541565, "27108": 0.7201237678527832, "27166": 0.011650617234408855, "27651": 0.02412080205976963, "27655": 0.09850110858678818, "27784": 0.14518201351165771, "27790": 0.007782140281051397, "27876": 0.1889725625514984, "28046": 0.3353555500507355, "28141": 0.7086513638496399, "28177": 0.13157635927200317, "28228": 0.6679295301437378, "28309": 0.11778303235769272, "28433": 0.034552380442619324, "28488": 0.5404602885246277, "28687": 0.26146242022514343, "29060": 0.5784112811088562, "29290": 0.5849615335464478, "29577": 0.8039615154266357} | 6036535 | BACKGROUND There is no doubt that good bimanual performance is very important for skilled handball playing. The control of the non-dominant hand is especially demanding since efficient catching and throwing needs both hands. METHODOLOGY/HYPOTHESES We investigated training-induced structural neuroplasticity in professional handball players using several structural neuroimaging techniques and analytic approaches and also provide a review of the literature about sport-induced structural neuroplastic alterations. Structural brain adaptations were expected in regions relevant for motor and somatosensory processing such as the grey matter (GM) of the primary/secondary motor (MI/supplementary motor area, SMA) and somatosensory cortex (SI/SII), basal ganglia, thalamus, and cerebellum and in the white matter (WM) of the corticospinal tract (CST) and corpus callosum, stronger in brain regions controlling the non-dominant left hand. RESULTS Increased GM volume in handball players compared with control subjects were found in the right MI/SI, bilateral SMA/cingulate motor area, and left intraparietal sulcus. Fractional anisotropy (FA) and axial diffusivity were increased within the right CST in handball players compared with control women. Age of handball training commencement correlated inversely with GM volume in the right and left MI/SI and years of handball training experience correlated inversely with radial diffusivity in the right CST. Subcortical structures tended to be larger in handball players. The anatomical measures of the brain regions associated with handball playing were positively correlated in handball players, but not interrelated in control women. DISCUSSION/CONCLUSION Training-induced structural alterations were found in the somatosensory-motor network of handball players, more pronounced in the right hemisphere controlling the non-dominant left hand. Correlations between handball training-related measures and anatomical differences suggest neuroplastic adaptations rather than a genetic predisposition for a ball playing affinity. Investigations of neuroplasticity specifically in sportsmen might help to understand the neural mechanisms of expertise in general. | Structural Brain Correlates Associated with Professional Handball Playing |
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"23067": 0.08961215615272522, "23700": 0.026025565341114998, "23737": 0.015504186972975731, "23924": 0.1212492436170578, "24757": 0.02412080205976963, "25262": 0.06612417846918106, "25524": 0.0752234235405922, "25737": 0.0038986403960734606, "26014": 0.0317181795835495, "26305": 0.12038381397724152, "26435": 0.2478361576795578, "26462": 0.18004031479358673, "26534": 0.10203468054533005, "26906": 0.2741633653640747, "27620": 0.018384648486971855, "28562": 0.06612417846918106, "28767": 0.4002431631088257, "28964": 0.35060185194015503, "29206": 1.426491141319275, "29226": 0.21530038118362427} | 6040392 | The role of epigenetics in aging and age-related diseases is a key issue in molecular physiology and medicine because certain epigenetic factors are thought to mediate, at least in part, the relationship between the genome and the environment. An active role for epigenetics in aging must meet two prior conditions: there must be specific epigenetic changes during aging and they must be functionally associated with the aged phenotype. Assuming that specific epigenetic modifications can have a direct functional outcome in aging, it is also essential to establish whether they depend on genetic, environmental or stochastic factors, and if they can be transmitted from one generation to the next. Here we discuss current knowledge about these matters and future directions in the field. | The role of epigenetics in aging and age-related diseases |
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6042706 | The links between obesity in parents and their offspring and the role of genes and a shared environment are not completely understood. Adipocytokines such as leptin and adiponectin play important roles in glucose and lipid metabolism. Therefore, we examined whether the offspring from dams exposed to a high-fat diet during pregnancy (OH mice) exhibited hypertension, insulin resistance, and hyperlipidemia along with epigenetic changes in the expression of adipocytokine genes. OH mice were significantly heavier than the offspring of dams exposed to a control diet during pregnancy (OC mice) from 14 wk of age after an increased caloric intake from 8 wk. OH mice exhibited higher blood pressure and worse glucose tolerance than the OC mice at 24 wk. Total triglyceride and leptin levels were significantly higher and the adiponectin level was significantly lower in OH compared with OC mice at 12 wk of age. This was associated with changes in leptin and adiponectin expression in white adipose tissue. There were lower acetylation and higher methylation levels of histone H3 at lysine 9 of the promoter of adiponectin in adipose tissues of OH mice at 2 wk of age as well as at 12 and 24 wk of age compared with OC mice. In contrast, methylation of histone 4 at lysine 20 in the leptin promoter was significantly higher in OH compared with OC mice. Thus, exposure to a high-fat diet in utero might cause a metabolic syndrome-like phenomenon through epigenetic modifications of adipocytokine, adiponectin, and leptin gene expression. | Effects of a high-fat diet exposure in utero on the metabolic syndrome-like phenomenon in mouse offspring through epigenetic changes in adipocytokine gene expression. |
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We show here that expression of the miR302/367 cluster rapidly and efficiently reprograms mouse and human somatic cells to an iPSC state without a requirement for exogenous transcription factors. This miRNA-based reprogramming approach is two orders of magnitude more efficient than standard Oct4/Sox2/Klf4/Myc-mediated methods. Mouse and human miR302/367 iPSCs display similar characteristics to Oct4/Sox2/Klf4/Myc-iPSCs, including pluripotency marker expression, teratoma formation, and, for mouse cells, chimera contribution and germline contribution. We found that miR367 expression is required for miR302/367-mediated reprogramming and activates Oct4 gene expression, and that suppression of Hdac2 is also required. Thus, our data show that miRNA and Hdac-mediated pathways can cooperate in a powerful way to reprogram somatic cells to pluripotency. | Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. |
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0.012615402229130268, "25409": 0.8550800085067749, "25468": 0.04394211992621422, "25604": 0.7426811456680298, "25778": 0.19782574474811554, "26224": 0.04113444685935974, "26745": 0.21135559678077698, "27001": 0.38308101892471313, "27144": 0.40806588530540466, "27195": 0.007782140281051397, "27348": 0.04113444685935974, "27484": 0.5805994272232056, "27615": 0.009718249551951885, "27776": 0.28082266449928284, "27794": 0.38174858689308167, "28120": 0.036437395960092545, "28207": 0.1011524572968483, "28281": 0.08603433519601822, "28309": 0.21372433006763458, "28321": 0.7009293437004089, "28767": 0.17759032547473907, "28771": 0.13157635927200317, "29277": 0.09317722171545029, "29353": 0.17840765416622162} | 6057195 | AIMS The aims of this analysis were to examine levels of unmet needs and depression among carers of people newly diagnosed with cancer and to identify groups who may be at higher risk, by examining relationships with demographic characteristics. METHODS One hundred and fifty dyads of people newly diagnosed with cancer and their carers, aged 18 years and older, were recruited from four Australian hospitals. People with cancer receiving adjuvant cancer treatment with curative intent, were eligible to participate. Carers completed the Supportive Care Needs Survey-Partners & Caregivers (SCNS-P&C45), and both carers and patients completed the Centre of Epidemiologic-Depression Scale (CES-D). RESULTS Overall, 57% of carers reported at least one, 37% at least three, 31% at least five, and 15% at least 10 unmet needs; the most commonly endorsed unmet needs were in the domains of information and health care service needs. Thirty percent of carers and 36% of patients were at risk of clinical depression. A weak to moderate positive relationship was observed between unmet needs and carer depression (r=0.30, p<0.001). Carer levels of unmet needs were significantly associated with carer age, hospital type, treatment type, cancer type, living situation, relationship status (in both uni- and multi-factor analysis); person with cancer age and carer level of education (in unifactor analysis only); but not with carer gender or patient gender (in both uni- and multi-factor analyses). CONCLUSION Findings highlight the importance of developing tailored programmes to systematically assist carers who are supporting patients through the early stages of cancer treatment. | Unmet needs and depression among carers of people newly diagnosed with cancer. |
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type 2 diabetes. Although GLP-1-based treatments are clinically available, alternative strategies to increase endogenous GLP-1 release from L cells are hampered by our limited physiological understanding of this cell type. By generating transgenic mice with L cell-specific expression of a fluorescent protein, we studied the characteristics of primary L cells by electrophysiology, fluorescence calcium imaging, and expression analysis and show that single L cells are electrically excitable and glucose responsive. Sensitivity to tolbutamide and low-millimolar concentrations of glucose and alpha-methylglucopyranoside, assessed in single L cells and by hormone secretion from primary cultures, suggested that GLP-1 release is regulated by the activity of sodium glucose cotransporter 1 and ATP-sensitive K(+) channels, consistent with their high expression levels in purified L cells by quantitative RT-PCR. These and other pathways identified using this approach will provide exciting opportunities for future physiological and therapeutic exploration. | Glucose Sensing in L Cells: A Primary Cell Study |
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0.030771657824516296, "29166": 0.6533012986183167, "29458": 0.8264343738555908, "29533": 0.3012613356113434} | 6070278 | OBJECTIVE The purpose of the present study was to investigate the relationship between the Total Atherosclerotic Score (TAS), a measurement of the overall atherosclerotic burden of the arterial tree by whole body magnetic resonance angiography (WBMRA), and the risk of major adverse cardiovascular events (MACE), defined as cardiac death, myocardial infarction, stroke and/or coronary revascularization, assuming that TAS predicts MACE. METHODS AND RESULTS 305 randomly selected 70 year-old subjects (47% women) underwent WBMRA. Their atherosclerotic burden was evaluated and TAS > 0, that is atherosclerotic changes, were found in 68% of subjects. During follow-up (mean 4.8 years), MACE occurred in 25 subjects (8.2%). Adjusting for multiple risk factors, TAS was associated with MACE (OR 8.86 for any degree of vessel lumen abnormality, 95%CI 1.14-69.11, p = 0.037). In addition, TAS improved discrimination and reclassification when added to the Framingham risk score (FRS), and ROC (Receiver Operator Curve) increased from 0.681 to 0.750 (p = 0.0421). CONCLUSION In a population-based sample of 70 year old men and women WBMRA, with TAS, predicted MACE independently of major cardiovascular risk factors. | Total atherosclerotic burden by whole body magnetic resonance angiography predicts major adverse cardiovascular events. |
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the ability to self-regulate and regenerate normal structures after being sectioned in half. How is such a morphogenetic field established? We discovered that quadruple knockdown of ADMP and BMP2/4/7 in Xenopus embryos eliminates self-regulation, causing ubiquitous neural induction throughout the ectoderm. ADMP transcription in the Spemann organizer is activated at low BMP levels. When ventral BMP2/4/7 signals are depleted, Admp expression increases, allowing for self-regulation. ADMP has BMP-like activity and signals via the ALK-2 receptor. It is unable to signal dorsally because of inhibition by Chordin. The ventral BMP antagonists Sizzled and Bambi further refine the pattern. By transplanting dorsal or ventral wild-type grafts into ADMP/BMP2/4/7-depleted hosts, we demonstrate that both poles serve as signaling centers that can induce histotypic differentiation over considerable distances. We conclude that dorsal and ventral BMP signals and their extracellular antagonists expressed under opposing transcriptional regulation provide a molecular mechanism for embryonic self-regulation. | Regulation of ADMP and BMP2/4/7 at Opposite Embryonic Poles Generates a Self-Regulating Morphogenetic Field |
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Genetic control strategies aim either to suppress target populations or to introduce a harm-reducing novel trait. Different approaches differ considerably in their properties, especially between self-limiting strategies, where the modification has limited persistence, and self-sustaining strategies, which are intended to persist indefinitely in the target population and may invade other populations. Several methods with different molecular biology are under development and the first field trials have been completed successfully. | Genetic control of mosquitoes. |
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"25409": 1.067535400390625, "25524": 0.5063233375549316, "25604": 0.08692999184131622, "25778": 0.18411032855510712, "26014": 0.6624060273170471, "26305": 0.35334911942481995, "26601": 0.21922965347766876, "26741": 0.27934664487838745, "26874": 0.12642613053321838, "26986": 0.04767346754670143, "27144": 0.18329764902591705, "27642": 0.022212404757738113, "27710": 0.03831886500120163, "27881": 0.06520967930555344, "28207": 0.021256839856505394, "28283": 0.7426811456680298, "28290": 0.034552380442619324, "28321": 0.083342544734478, "28436": 0.4093637466430664, "28667": 0.083342544734478, "28828": 0.0354953333735466, "28911": 0.09850110858678818, "29206": 0.2659635543823242, "29264": 0.013579257763922215} | 6078882 | It has been demonstrated for some cancers that the frequency of somatic oncogenic mutations may vary in ancestral populations. To determine whether key driver alterations might occur at different frequencies in colorectal cancer, we applied a high-throughput genotyping platform (OncoMap) to query 385 mutations across 33 known cancer genes in colorectal cancer DNA from 83 Asian, 149 Black and 195 White patients. We found that Asian patients had fewer canonical oncogenic mutations in the genes tested (60% vs Black 79% (P = 0.011) and White 77% (P = 0.015)), and that BRAF mutations occurred at a higher frequency in White patients (17% vs Asian 4% (P = 0.004) and Black 7% (P = 0.014)). These results suggest that the use of genomic approaches to elucidate the different ancestral determinants harbored by patient populations may help to more precisely and effectively treat colorectal cancer. | Colorectal Cancers from Distinct Ancestral Populations Show Variations in BRAF Mutation Frequency |
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development have largely been identified. In this Review, we discuss how this knowledge has been used to successfully reprogramme various cell types into an amazing array of distinct types of functional neurons. We further discuss the extent to which direct neuronal reprogramming recapitulates embryonic development, and examine the particular barriers to reprogramming that may exist given a cell's unique developmental history. We conclude with a recently proposed model for cell specification called the 'Cook Islands' model, and consider whether it is a fitting model for cell specification based on recent results from the direct reprogramming field. | Direct neuronal reprogramming: learning from and for development. |
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Cancer stem cells (CSCs) often represent a rare population in the tumor mass and possess the exclusive ability to initiate the growth of a heterogeneous tumor. The origin of CSCs remains elusive and is likely to be cancer type specific. One possible but under-appreciated potential mechanism for the generation of CSCs is through fusion between stem cells and differentiated cells. The cell fusion hypothesis of CSCs adds an important functional underpinning to the potential multifaceted roles of cell fusion in the initiation and progression of cancer. | Cell fusion hypothesis of the cancer stem cell. |
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Incubation of LMCAT fibroblast cells with antidepressants potentiates glucocorticoid receptor (GR)-mediated gene transcription in the presence of dexamethasone and cortisol, but not of corticosterone. We have shown that antidepressants do so by inhibiting the LMCAT cell membrane steroid transporter (which is virtually identical to the multidrug resistance P-glycoprotein) and thus by increasing dexamethasone or cortisol intracellular concentrations. However, previous experiments with the antidepressant fluoxetine in the presence of dexamethasone have produced negative results (Pariante et al. (2001). Br. J. Pharmacol., 134, 1335-1343). 2. We have since re-examined the effects of fluoxetine on GR-mediated gene transcription in the presence of dexamethasone. Moreover, we have examined the effects of fluoxetine on GR-mediated gene transcription in the presence of cortisol and corticosterone, and on the intracellular accumulation of radioactive cortisol and corticosterone. Finally, we have examined the effects of fluoxetine on inhibition of P-glycoprotein activity in Caco-2 cells. 3. We now find that fluoxetine (1-10 micro M) enhances GR-mediated gene transcription in the presence of dexamethasone and cortisol (+140-170%), but not of corticosterone, and increases the intracellular accumulation of (3)H-cortisol (+5-15%), but not of (3)H-corticosterone. Moreover, fluoxetine (10 micro M) induces approximately 30% inhibition of PGP activity in Caco-2 cells. 4. Our results show that fluoxetine, like other antidepressants, inhibits membrane steroid transporters. | Antidepressant fluoxetine enhances glucocorticoid receptor function in vitro by modulating membrane steroid transporters. |
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0.052318159490823746, "28353": 0.4580921530723572, "29361": 0.1710275560617447, "29392": 0.4337083101272583, "29477": 0.1401015669107437} | 6085365 | BACKGROUND Few studies have examined whether physician knowledge, attitudes, or practice patterns might contribute to gender disparities in the primary prevention of coronary heart disease (CHD), including among physicians caring for the largest number of reproductive-age women, obstetricians and gynecologists (OB/GYNs). We sought to identify barriers affecting the provision of recommended coronary risk factor therapies in women. METHODS We surveyed internists and OB/GYNs who attended Grand Rounds presentations developed for the New York State Women and Heart Disease Physician Education Initiative. This program was designed to improve screening and management of coronary risk factors in women. Attendees were asked to complete a 7-minute questionnaire. RESULTS The mean age of the 529 respondents was 40.3 years (standard deviation = 12.3), 75.1% were internists (n=378), and 42.7% (n=226) were women. Physicians correctly responded to 71.5% of the 13 questions assessing knowledge of coronary risk prevention (range, 4-13). Almost one third of internists and half of the OB/GYNs did not know that tobacco use was the leading cause of myocardial infarction in young women. For patients who smoked tobacco, only two thirds of internists and 55.4% of OB/GYNs reported suggesting a quit date (p=.007). After controlling for covariates, physicians who did not perceive time as a barrier were more likely to discuss smoking cessation (odds ratio=1.7 [1.1-2.7]). CONCLUSIONS Among the internists and OB/GYNs surveyed, time was perceived as a barrier to implementing risk prevention. These physicians also underestimated the impact of tobacco use as a risk factor for CHD in young women. To lessen gender disparities in CHD prevention, both specialties need time-efficient educational programs that reflect specialty differences. | Physician knowledge levels and barriers to coronary risk prevention in women: survey results from the Women and Heart Disease Physician Education Initiative. |
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"25714": 0.19862671196460724, "25972": 0.030771657824516296, "26462": 0.5540198087692261, "26734": 0.9673105478286743, "27000": 0.2652147710323334, "27152": 0.890972912311554, "27283": 0.056018441915512085, "27343": 0.272677481174469, "27467": 0.2493593990802765, "27521": 0.4158279001712799, "27846": 0.013579257763922215, "28024": 0.5133614540100098, "28079": 0.11256109178066254, "28086": 0.16524957120418549, "28121": 0.09672962874174118, "28488": 0.1064341589808464, "28556": 0.4770587682723999, "29297": 1.1971133947372437, "29489": 0.6358738541603088} | 6106004 | Publisher Summary The budding yeast Saccharomyces cerevisiae ( S. cerevisiae ) divides asymmetrically. In vegetative growth, yeast cells reproduce by budding, and the position where the bud forms ultimately determines the plane of cell division. This chapter describes the detailed procedures for the separation and isolation of mothers and daughters. These protocols have been used by investigators studying aging, bud site selection, and other aspects of asymmetric cell division. The chapter describes the procedures for performing life span analysis by micromanipulation and the steps for the large-scale collection of old cells. At the beginning and the end of a life span, it can be difficult to distinguish mothers from daughters. At most points in the life span, daughter cells are smaller than the mothers that produced them. In addition, mother cells will generally bud a second time before their daughter cells form their first bud. One method for effective isolation of virgin daughter cells from mother cells, but not for recovery of old mothers, is called a “baby machine. ” Mother cells are attached to a membrane and allowed to divide. Daughter cells from these attached cells are eluted continuously by washing the membrane. | Separation of mother and daughter cells. |
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"27133": 1.4246132373809814, "27321": 1.034073829650879, "27343": 0.22548456490039825, "27521": 0.06703783571720123, "27697": 0.3346569836139679, "27759": 1.0973093509674072, "27790": 0.4400174915790558, "27870": 0.8981585502624512, "28024": 0.38574060797691345, "28086": 0.34023189544677734, "28156": 0.9546096324920654, "28293": 1.1217793226242065, "28329": 0.08871890604496002, "28517": 0.0842406153678894, "28652": 0.06977381557226181, "28691": 0.24859806895256042, "28788": 0.4286321699619293, "29181": 1.0312920808792114, "29384": 0.1718502640724182, "29533": 0.025073638185858727} | 6108481 | It has been shown by several investigators that adipocyte number is stable in mature human beings and several species of rodents. Although the number of new cells appearing in the adipose depot can be measured histometrically and by Coulter counting of osmium-fixed cells, such methods do not distinguish between "lipid filling" of preexistent adipocytes and synthesis of new adipocytes. The experiments reported here using in vivo injection of [(3)H]thymidine show that synthesis of new adipocytes in the Sprague-Dawley rat continues after birth and ceases before sexual maturity. Furthermore, during the second and third postnatal weeks, a "bed" of preadipocytes is synthesized. Preadipocytes may take as long as 30 days to appear as mature adipocytes. | Postnatal development of adipocyte cellularity in the normal rat. |
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"25022": 0.688742995262146, "25353": 0.14602625370025635, "25456": 1.0423725843429565, "25510": 0.05417001247406006, "25862": 1.1659544706344604, "26113": 1.0116009712219238, "26163": 0.07341018319129944, "26243": 0.7105726003646851, "26402": 0.25088030099868774, "27484": 0.13157635927200317, "28297": 0.987156867980957, "28436": 0.06886265426874161, "28616": 0.6102113127708435, "29251": 0.848413348197937, "29290": 0.5590575933456421, "29441": 0.9673105478286743, "29474": 0.757441520690918, "29486": 0.4974553883075714} | 6112053 | Background: Selective serotonin reuptake inhibitors (SSRI) are widely used in medical practice. They have been associated with a broad range of symptoms, whose clinical meaning has not been fully appreciated. Methods: The PRISMA guidelines were followed to conduct a systematic review of the literature. Titles, abstracts, and topics were searched using the following terms: ‘withdrawal symptoms' OR ‘withdrawal syndrome' OR ‘discontinuation syndrome' OR ‘discontinuation symptoms', AND ‘SSRI' OR ‘serotonin' OR ‘antidepressant' OR ‘paroxetine' OR ‘fluoxetine' OR ‘sertraline' OR ‘fluvoxamine' OR ‘citalopram' OR ‘escitalopram'. The electronic research literature databases included CINAHL, the Cochrane Library, PubMed and Web-of-Science from inception of each database to July 2014. Results: There were 15 randomized controlled studies, 4 open trials, 4 retrospective investigations, and 38 case reports. The prevalence of the syndrome was variable, and its estimation was hindered by a lack of case identification in many studies. Symptoms typically occur within a few days from drug discontinuation and last a few weeks, also with gradual tapering. However, many variations are possible, including late onset and/or longer persistence of disturbances. Symptoms may be easily misidentified as signs of impending relapse. Conclusions: Clinicians need to add SSRI to the list of drugs potentially inducing withdrawal symptoms upon discontinuation, together with benzodiazepines, barbiturates, and other psychotropic drugs. The term ‘discontinuation syndrome' that is currently used minimizes the potential vulnerabilities induced by SSRI and should be replaced by ‘withdrawal syndrome'. | Withdrawal Symptoms after Selective Serotonin Reuptake Inhibitor Discontinuation: A Systematic Review |
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"28032": 0.8281423449516296, "28309": 0.02792670577764511, "28522": 0.44691193103790283, "28696": 0.1064341589808464, "28728": 0.5156965255737305, "28848": 0.14095009863376617, "28976": 0.15359249711036682, "29206": 0.8475768566131592, "29295": 0.6482070088386536, "29480": 0.469759464263916} | 6121555 | The aim of this study was to investigate the mechanism through which Sphingosine kinase-1 (SPHK1) exerts its anti-apoptosis activity in glioma cancer cells. We here report that dysregulation of SPHK1 alters the sensitivity of glioma to apoptosis both in vitro and in vivo. Further mechanistic study examined the expression of Bcl-2 family members, including Bcl-2, Mcl-1, Bax and Bim, in SPHK1-overexpressing glioma cells and revealed that only pro-apoptotic Bim was downregulated by SPHK1. Moreover, the transcriptional level of Bim was also altered by SPHK1 in glioma cells. We next confirmed the correlation between SPHK1 and Bim expression in primary glioma specimens. Importantly, increasing SPHK1 expression in glioma cells markedly elevated Akt activity and phosphorylated inactivation of FOXO3a, which led to downregulation of Bim. A pharmacological approach showed that these effects of SPHK1 were dependent on phosphatidylinositol 3-kinase (PI3K). Furthermore, effects of SPHK1 on Akt/FOXO3a/Bim pathway could be reversed by SPHK1 specific RNA interference or SPHK1 inhibitor. Collectively, our results indicate that regulation of the Akt/FOXO3a/Bim pathway may be a novel mechanism by which SPHK1 protects glioma cells from apoptosis, thereby involved in glioma tumorigenesis. | Sphingosine Kinase 1 Regulates the Akt/FOXO3a/Bim Pathway and Contributes to Apoptosis Resistance in Glioma Cells |
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0.1212492436170578, "29398": 0.05046287178993225, "29461": 0.19622190296649933} | 6121668 | OBJECTIVES To investigate the expressions of survivin and Cyclooxygenase-2 (COX-2), and their possible correlations in the development of endometrial adenocarcinoma (EC). We also looked at their association with classical prognostic factors in EC. To our knowledge, this is the first time survivin expression is investigated in terms of its relation to COX-2 in the developmental pathway of EC. METHODS Archived tissue samples of 50 EC, 30 endometrial hyperplasia and 20 proliferative endometrium were selected and immunohistochemically analyzed for survivin and COX-2 expression. RESULTS Both survivin and COX-2 were overexpressed in hyperplasia and endometrial adenocarcinoma cases compared to proliferative endometrium, which was statistically significant (p=0.01, p=0.02, respectively). Among EC cases, survivin and COX-2 were strongly positive in 38 (76%) and 30 (60%) patients, respectively. Furthermore, we found survivin and COX-2 to be positively correlated, which was also statistically significant (p=0.0001, r=0.46). Neither survivin nor COX-2 expression was correlated with classical prognostic factors of endometrial carcinoma such as myometrial invasion, grade or lymph node metastasis (p>0.05). Neither COX-2 nor survivin had an impact on overall survival (p>0.05). CONCLUSIONS Both survivin and COX-2 are overexpressed, and they seem to be early events in the occurrence of EC. Moreover, protein products of these two genes are positively correlated. COX-2 and survivin might share a common molecular pathway or enhance each other's actions in the developmental pathway of EC. Molecular basis of such a relationship should be further investigated in endometrial carcinogenesis. | COX-2 and survivin are overexpressed and positively correlated in endometrial carcinoma. |
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"27108": 0.8366385698318481, "27144": 0.3897167444229126, "27287": 0.22001366317272186, "27325": 0.25845035910606384, "27484": 0.8022117614746094, "27668": 0.6064908504486084, "27824": 0.2089812457561493, "28228": 0.8074519634246826, "28295": 0.083342544734478, "28466": 0.10555581003427505, "28696": 1.2835346460342407, "29060": 0.029824240133166313, "29129": 0.5773153901100159, "29166": 0.6882523894309998, "29222": 0.006812678650021553, "29458": 0.0019512200960889459} | 6123521 | The brain interprets experiences and translates them into behavioral and physiological responses. Stressful events are those which are threatening or, at the very least, unexpected and surprising, and the physiological and behavioral responses are intended to promote adaptation via a process called "allostasis. " Chemical mediators of allostasis include cortisol and adrenalin from the adrenal glands, other hormones, and neurotransmitters, the parasympathetic and sympathetic nervous systems, and cytokines and chemokines from the immune system. Two brain structures, the amygdala and hippocampus, play key roles in interpreting what is stressful and determining appropriate responses. The hippocampus, a key structure for memories of events and contexts, expresses receptors that enable it to respond to glucocorticoid hormones in the blood, it undergoes atrophy in a number of psychiatric disorders; it also responds to stressors with changes in excitability, decreased dendritic branching, and reduction in number of neurons in the dentate gyrus. The amygdala, which is important for "emotional memories, " becomes hyperactive in posttraumatic stress disorder and depressive illness, in animal models of stress, there is evidence for growth and hypertrophy of nerve cells in the amygdala. Changes in the brain after acute and chronic stressors mirror the pattern seen in the metabolic, cardiovascular, and immune systems, that is, short-term adaptation (allostasis) followed by long-term damage (allostatic load), eg, atherosclerosis, fat deposition obesity, bone demineralization, and impaired immune function. Allostatic load of this kind is seen in major depressive illness and may also be expressed in other chronic anxiety and mood disorders. | Structural plasticity of the adult brain: how animal models help us understand brain changes in depression and systemic disorders related to depression |
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However, the homeostatic requirement for IL-2 among specific populations of peripheral T reg cells remains poorly understood. We show that IL-2 selectively maintains a population of quiescent CD44(lo)CD62L(hi) T reg cells that gain access to paracrine IL-2 produced in the T cell zones of secondary lymphoid tissues due to their expression of the chemokine receptor CCR7. In contrast, CD44(hi)CD62L(lo)CCR7(lo) T reg cells that populate nonlymphoid tissues do not access IL-2-prevalent regions in vivo and are insensitive to IL-2 blockade; instead, their maintenance depends on continued signaling through the co-stimulatory receptor ICOS (inducible co-stimulator). Thus, we define a fundamental homeostatic subdivision in T reg cell populations based on their localization and provide an integrated framework for understanding how T reg cell abundance and function are controlled by unique signals in different tissue environments. | CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets |
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"28771": 0.23092569410800934, "29060": 0.037378571927547455, "29458": 0.06795065850019455, "29490": 0.3005385100841522} | 6128334 | Pairwise sequence comparison methods have been assessed using proteins whose relationships are known reliably from their structures and functions, as described in the SCOP database [Murzin, A. G., Brenner, S. E., Hubbard, T. & Chothia C. (1995) J. Mol. Biol. 247, 536-540]. The evaluation tested the programs BLAST [Altschul, S. F., Gish, W., Miller, W., Myers, E. W. & Lipman, D. J. (1990). J. Mol. Biol. 215, 403-410], WU-BLAST2 [Altschul, S. F. & Gish, W. (1996) Methods Enzymol. 266, 460-480], FASTA [Pearson, W. R. & Lipman, D. J. (1988) Proc. Natl. Acad. Sci. USA 85, 2444-2448], and SSEARCH [Smith, T. F. & Waterman, M. S. (1981) J. Mol. Biol. 147, 195-197] and their scoring schemes. The error rate of all algorithms is greatly reduced by using statistical scores to evaluate matches rather than percentage identity or raw scores. The E-value statistical scores of SSEARCH and FASTA are reliable: the number of false positives found in our tests agrees well with the scores reported. However, the P-values reported by BLAST and WU-BLAST2 exaggerate significance by orders of magnitude. SSEARCH, FASTA ktup = 1, and WU-BLAST2 perform best, and they are capable of detecting almost all relationships between proteins whose sequence identities are >30%. For more distantly related proteins, they do much less well; only one-half of the relationships between proteins with 20-30% identity are found. Because many homologs have low sequence similarity, most distant relationships cannot be detected by any pairwise comparison method; however, those which are identified may be used with confidence. | Assessing sequence comparison methods with reliable structurally identified distant evolutionary relationships. |
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"28237": 0.06429435312747955, "28586": 0.3269403576850891, "28767": 0.06886265426874161, "28823": 0.009718249551951885, "29025": 0.07068414986133575, "29061": 0.08513788133859634, "29073": 0.20102575421333313, "29101": 0.02887592278420925, "29458": 0.49626702070236206, "29536": 0.07431721687316895} | 6129301 | AIMS To describe the characteristics of homeless children and families seen by the mental health outreach service (MHOS), to evaluate the impact of this service on the short term psychosocial functioning of children and parents, and to establish perceptions of, and satisfaction with, the service. METHODS Twenty seven children from 23 families who were in receipt of the MHOS and 27 children from 23 families residing in other hostels where no such service was available were studied. The MHOS was delivered by a clinical nurse specialist with expertise in child mental health, who offered the following interventions: assessment and brief treatment of mental health disorders in children; liaison with agencies; and training of homeless centre staff. RESULTS Children in the experimental group had a significantly higher decrease in Strengths and Difficulties Questionnaire (SDQ) total scores. Having received the intervention was the strongest predictor of improvement in SDQ total scores. There was no significant impact on parental mental health (General Health Questionnaire) scores. Homeless families and staff expressed high satisfaction with the MHOS. CONCLUSION This MHOS for homeless families is an innovative intervention which meets the complex and multiple needs of a vulnerable population unable to access mainstream mental health services. The primary objective of the service was to improve child mental health problems; however, the service developed in a responsive way by meeting social and practical needs of families in addition to its clinical role. | Evaluation of a mental health outreach service for homeless families. |
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0.14602625370025635, "26210": 0.5925496220588684, "26243": 0.8715548515319824, "26715": 0.5914691090583801, "26745": 0.12470348179340363, "26778": 0.8425432443618774, "26886": 0.18004031479358673, "27011": 0.6181373596191406, "27312": 0.27712854743003845, "27354": 0.06337817758321762, "27404": 0.3883931338787079, "28136": 0.08782484382390976, "28207": 0.5517725944519043, "28329": 0.011650617234408855, "28472": 0.31489628553390503, "28804": 0.07793712615966797, "29458": 0.06977381557226181} | 6137330 | OBJECTIVES The objective of this article is to update previous evidence-based recommendations for evaluation and management of individuals with solid pulmonary nodules and to generate new recommendations for those with nonsolid nodules. METHODS We updated prior literature reviews, synthesized evidence, and formulated recommendations by using the methods described in the "Methodology for Development of Guidelines for Lung Cancer" in the American College of Chest Physicians Lung Cancer Guidelines, 3rd ed. RESULTS We formulated recommendations for evaluating solid pulmonary nodules that measure > 8 mm in diameter, solid nodules that measure ≤ 8 mm in diameter, and subsolid nodules. The recommendations stress the value of assessing the probability of malignancy, the utility of imaging tests, the need to weigh the benefits and harms of different management strategies (nonsurgical biopsy, surgical resection, and surveillance with chest CT imaging), and the importance of eliciting patient preferences. CONCLUSIONS Individuals with pulmonary nodules should be evaluated and managed by estimating the probability of malignancy, performing imaging tests to better characterize the lesions, evaluating the risks associated with various management alternatives, and eliciting their preferences for management. | Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. |
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0.21372433006763458, "27781": 0.3464667797088623, "28144": 0.16110190749168396, "28727": 1.6875556707382202, "28739": 0.2786078155040741, "28873": 0.5016035437583923, "28896": 0.1734936386346817, "28935": 0.1602703034877777, "29146": 0.8748174905776978, "29290": 0.010684899985790253} | 6144337 | Activation of the insect innate immune system is dependent on a limited number of pattern recognition receptors (PRRs) capable of interacting with pathogen-associated molecular pattern. Here we report a novel role of an alternatively spliced hypervariable immunoglobulin domain-encoding gene, Dscam, in generating a broad range of PRRs implicated in immune defense in the malaria vector Anopheles gambiae. The mosquito Down syndrome cell adhesion molecule gene, AgDscam, has a complex genome organization with 101 exons that can produce over 31,000 potential alternative splice forms with different combinations of adhesive domains and interaction specificities. AgDscam responds to infection by producing pathogen challenge-specific splice form repertoires. Transient silencing of AgDscam compromises the mosquito's resistance to infections with bacteria and the malaria parasite Plasmodium. AgDscam is mediating phagocytosis of bacteria with which it can associate and defend against in a splice form–specific manner. AgDscam is a hypervariable PRR of the A. gambiae innate immune system. | AgDscam, a Hypervariable Immunoglobulin Domain-Containing Receptor of the Anopheles gambiae Innate Immune System |
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"28696": 0.19220098853111267, "28848": 0.09317722171545029, "28873": 0.01934296265244484, "29166": 1.0066169500350952, "29206": 0.9440274834632874, "29290": 0.6430866718292236} | 6144969 | Virally induced inflammatory responses, beta cell destruction and release of beta cell autoantigens may lead to autoimmune reactions culminating in type 1 diabetes. Therefore, viral capability to induce beta cell death and the nature of virus-induced immune responses are among key determinants of diabetogenic viruses. We hypothesised that enterovirus infection induces a specific gene expression pattern that results in islet destruction and that such a host response pattern is not shared among all enterovirus infections but varies between virus strains. The changes in global gene expression and secreted cytokine profiles induced by lytic or benign enterovirus infections were studied in primary human pancreatic islet using DNA microarrays and viral strains either isolated at the clinical onset of type 1 diabetes or capable of causing a diabetes-like condition in mice. The expression of pro-inflammatory cytokine genes (IL-1-α, IL-1-β and TNF-α) that also mediate cytokine-induced beta cell dysfunction correlated with the lytic potential of a virus. Temporally increasing gene expression levels of double-stranded RNA recognition receptors, antiviral molecules, cytokines and chemokines were detected for all studied virus strains. Lytic coxsackievirus B5 (CBV-5)-DS infection also downregulated genes involved in glycolysis and insulin secretion. The results suggest a distinct, virus-strain-specific, gene expression pattern leading to pancreatic islet destruction and pro-inflammatory effects after enterovirus infection. However, neither viral replication nor cytotoxic cytokine production alone are sufficient to induce necrotic cell death. More likely the combined effect of these and possibly cellular energy depletion lie behind the enterovirus-induced necrosis of islets. | Enterovirus-induced gene expression profile is critical for human pancreatic islet destruction |
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"28353": 0.22548456490039825, "28406": 0.1064341589808464, "28667": 0.058784693479537964, "28847": 0.45623743534088135, "28873": 0.4349733293056488, "29217": 0.10906458646059036, "29261": 0.53589928150177, "29280": 0.1485546976327896, "29290": 0.07612881064414978, "29564": 0.012615402229130268} | 6148876 | RATIONALE Islet1 (Isl1) has been proposed as a marker of cardiac progenitor cells derived from the second heart field and is utilized to identify and purify cardiac progenitors from murine and human specimens for ex vivo expansion. The use of Isl1 as a specific second heart field marker is dependent on its exclusion from other cardiac lineages such as neural crest. OBJECTIVE Determine whether Isl1 is expressed by cardiac neural crest. METHODS AND RESULTS We used an intersectional fate-mapping system using the RC::FrePe allele, which reports dual Flpe and Cre recombination. Combining Isl1(Cre/+), a SHF driver, and Wnt1::Flpe, a neural crest driver, with Rc::FrePe reveals that some Isl1 derivatives in the cardiac outflow tract derive from Wnt1-expressing neural crest progenitors. In contrast, no overlap was observed between Wnt1-derived neural crest and an alternative second heart field driver, Mef2c-AHF-Cre. CONCLUSIONS Isl1 is not restricted to second heart field progenitors in the developing heart but also labels cardiac neural crest. The intersection of Isl1 and Wnt1 lineages within the heart provides a caveat to using Isl1 as an exclusive second heart field cardiac progenitor marker and suggests that some Isl1-expressing progenitor cells derived from embryos, embryonic stem cultures, or induced pluripotent stem cultures may be of neural crest lineage. | Islet1 derivatives in the heart are of both neural crest and second heart field origin. |
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"28472": 0.15275461971759796, "28573": 0.3547199070453644, "28696": 0.08692999184131622, "28711": 0.33325836062431335, "28793": 1.0229004621505737, "28817": 0.08782484382390976, "28879": 0.0009760859538801014, "29053": 0.045809537172317505, "29166": 0.9425065517425537, "29278": 0.2493593990802765, "29333": 0.5795059204101562, "29401": 0.08603433519601822, "29458": 0.06520967930555344, "29477": 0.0606246218085289, "29514": 0.5816917419433594, "29516": 0.0174254160374403, "29577": 0.5427330136299133, "29607": 0.020300358533859253} | 6153754 | In patients with spinal cord injury, the primary or mechanical trauma seldom causes total transection, even though the functional loss may be complete. In addition, biochemical and pathological changes in the cord may worsen after injury. To explain these phenomena, the concept of the secondary injury has evolved for which numerous pathophysiological mechanisms have been postulated. This paper reviews the concept of secondary injury with special emphasis on vascular mechanisms. Evidence is presented to support the theory of secondary injury and the hypothesis that a key mechanism is posttraumatic ischemia with resultant infarction of the spinal cord. Evidence for the role of vascular mechanisms has been obtained from a variety of models of acute spinal cord injury in several species. Many different angiographic methods have been used for assessing microcirculation of the cord and for measuring spinal cord blood flow after trauma. With these techniques, the major systemic and local vascular effects of acute spinal cord injury have been identified and implicated in the etiology of secondary injury. The systemic effects of acute spinal cord injury include hypotension and reduced cardiac output. The local effects include loss of autoregulation in the injured segment of the spinal cord and a marked reduction of the microcirculation in both gray and white matter, especially in hemorrhagic regions and in adjacent zones. The microcirculatory loss extends for a considerable distance proximal and distal to the site of injury. Many studies have shown a dose-dependent reduction of spinal cord blood flow varying with the severity of injury, and a reduction of spinal cord blood flow which worsens with time after injury. The functional deficits due to acute spinal cord injury have been measured electrophysiologically with techniques such as motor and somatosensory evoked potentials and have been found proportional to the degree of posttraumatic ischemia. The histological effects include early hemorrhagic necrosis leading to major infarction at the injury site. These posttraumatic vascular effects can be treated. Systemic normotension can be restored with volume expansion or vasopressors, and spinal cord blood flow can be improved with dopamine, steroids, nimodipine, or volume expansion. The combination of nimodipine and volume expansion improves posttraumatic spinal cord blood flow and spinal cord function measured by evoked potentials. These results provide strong evidence that posttraumatic ischemia is an important secondary mechanism of injury, and that it can be counteracted. | Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. |
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key regulatory component, cofilin, are found together in large rod-shaped assemblies in neurons subjected to energy stress. Such inclusions are also enriched in Alzheimer's disease brain, and appear in transgenic models of neurodegeneration. Neuronal insults, such as energy loss and/or oxidative stress, result in rapid dephosphorylation of the cellular cofilin pool prior to its assembly into rod-shaped inclusions. Although these events implicate a role for phosphatases in cofilin rod formation, a mechanism linking energy stress, phosphocofilin turnover, and subsequent rod assembly has been elusive. We demonstrate the ATP-sensitive interaction of the cofilin phosphatase chronophin (CIN) with the chaperone hsp90 to form a biosensor that mediates cofilin/actin rod formation. Our results suggest a model whereby attenuated interactions between CIN and hsp90 during ATP depletion enhance CIN-dependent cofilin dephosphorylation and consequent rod assembly, thereby providing a mechanism for the formation of pathological actin/cofilin aggregates during neurodegenerative energy flux. | Chronophin mediates an ATP-sensing mechanism for cofilin dephosphorylation and neuronal cofilin-actin rod formation. |
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"29458": 0.45994341373443604} | 6157837 | Angiotensin converting enzyme (ACE) inhibitors are now one of the most frequently used classes of antihypertensive drugs. Beyond their utility in the management of hypertension, their use has been extended to the long-term management of patients with congestive heart failure (CHF), as well as diabetic and nondiabetic nephropathies. Although ACE inhibitor therapy usually improves renal blood flow (RBF) and sodium excretion rates in CHF and reduces the rate of progressive renal injury in chronic renal disease, its use can also be associated with a syndrome of “functional renal insufficiency” and/or hyperkalemia. This form of acute renal failure (ARF) most commonly develops shortly after initiation of ACE inhibitor therapy but can be observed after months or years of therapy, even in the absence of prior ill effects. ARF is most likely to occur when renal perfusion pressure cannot be sustained because of substantial decreases in mean arterial pressure (MAP) or when glomerular filtration rate (GFR) is highly angiotensin II (Ang II) dependent. Conditions that predict an adverse hemodynamic effect of ACE inhibitors in patients with CHF are preexisting hypotension and low cardiac filling pressures. The GFR is especially dependent on Ang II during extracellular fluid (ECF) volume depletion, high-grade bilateral renal artery stenosis, or stenosis of a dominant or single kidney, as in a renal transplant recipient. Understanding the pathophysiological mechanisms and the common risk factors for ACE inhibitor–induced functional ARF is critical, because preventive strategies for ARF exist, and if effectively used, they may permit use of these compounds in a less restricted fashion. Under normal physiological conditions, renal autoregulation adjusts renal vascular resistance, so that RBF and GFR remain constant over a wide range of MAPs.1 The intrinsic renal autoregulation mechanism is adjusted by Ang II and the sympathetic nervous system. When renal perfusion pressure falls (as in … | Renal considerations in angiotensin converting enzyme inhibitor therapy: a statement for healthcare professionals from the Council on the Kidney in Cardiovascular Disease and the Council for High Blood Pressure Research of the American Heart Association. |
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0.025073638185858727, "29264": 0.7737906575202942, "29278": 0.045809537172317505, "29327": 0.2822965085506439, "29361": 0.0058422754518687725, "29562": 0.06795065850019455} | 6158879 | BACKGROUND Patients with diabetes mellitus (DM) are at high risk for recurrent cardiovascular events after acute coronary syndromes, in part because of increased platelet reactivity. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) showed an overall reduction in ischemic events with more intensive antiplatelet therapy with prasugrel than with clopidogrel but with more bleeding. We compared prasugrel with clopidogrel among subjects with DM in TRITON-TIMI 38. METHODS AND RESULTS We classified 13 608 subjects on the basis of preexisting history of DM and further according to insulin use. Prespecified analyses of the primary (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and key secondary end points, including net clinical benefit (death, nonfatal myocardial infarction, nonfatal stroke, and nonfatal TIMI major bleeding) were compared by use of the log-rank test. We found that 3146 subjects had a preexisting history of DM, including 776 receiving insulin. The primary end point was reduced significantly with prasugrel among subjects without DM (9.2% versus 10.6%; hazard ratio [HR], 0.86; P=0.02) and with DM (12.2% versus 17.0%; HR, 0.70; P<0.001, P(interaction)=0.09). A benefit for prasugrel was observed among DM subjects on insulin (14.3% versus 22.2%; HR, 0.63; P=0.009) and those not on insulin (11.5% versus 15.3%; HR, 0.74; P=0.009). Myocardial infarction was reduced with prasugrel by 18% among subjects without DM (7.2% versus 8.7%; HR, 0.82; P=0.006) and by 40% among subjects with DM (8.2% versus 13.2%; HR, 0.60; P<0.001, P(interaction)=0.02). Although TIMI major hemorrhage was increased among subjects without DM on prasugrel (1.6% versus 2.4%; HR, 1.43; P=0.02), the rates were similar among subjects with DM for clopidogrel and prasugrel (2.6% versus 2.5%; HR, 1.06; P=0.81, P(interaction)=0.29). Net clinical benefit with prasugrel was greater for subjects with DM (14.6% versus 19.2%; HR, 0.74; P=0.001) than for subjects without DM (11.5% versus 12.3%; HR, 0.92; P=0.16, P(interaction)=0.05). CONCLUSIONS Subjects with DM tended to have a greater reduction in ischemic events without an observed increase in TIMI major bleeding and therefore a greater net treatment benefit with prasugrel compared with clopidogrel. These data demonstrate that the more intensive oral antiplatelet therapy provided with prasugrel is of particular benefit to patients with DM. | Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-Thrombolysis in Myocardial Infarction 38. |
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0.034552380442619324, "25407": 0.06612417846918106, "25502": 0.0752234235405922, "25610": 0.1229778528213501, "25644": 0.1710275560617447, "25950": 0.20818853378295898, "25969": 0.31489628553390503, "26013": 0.08961215615272522, "26394": 0.04394211992621422, "26396": 0.022212404757738113, "26402": 0.18654440343379974, "26419": 0.04207121208310127, "26435": 0.10291612148284912, "26520": 0.14433705806732178, "26651": 0.14264501631259918, "26721": 0.7881022095680237, "26773": 0.7889899015426636, "26835": 0.619189441204071, "27099": 0.06612417846918106, "27250": 0.9363996982574463, "27321": 0.23864774405956268, "27777": 0.12038381397724152, "27854": 0.08961215615272522, "28251": 1.068206787109375, "28696": 0.02412080205976963, "28788": 0.8091925978660583, "28873": 0.09495500475168228, "28938": 0.03266380727291107, "29090": 0.0354953333735466, "29111": 0.012615402229130268, "29290": 0.026976587250828743} | 6163801 | Cytolytic granules mediate killing of virus-infected cells by cytotoxic T lymphocytes. We show here that the granules can take long or short paths to the secretory domain. Both paths utilized the same intracellular molecular events, which have different spatial and temporal arrangements and are regulated by the kinetics of Ca(2+)-mediated signaling. Rapid signaling caused swift granule concentration near the microtubule-organizing center (MTOC) and subsequent delivery by the polarized MTOC directly to the secretory domain-the shortest path. Indolent signaling led to late recruitment of granules that moved along microtubules to the periphery of the synapse and then moved tangentially to fuse at the outer edge of the secretory domain-a longer path. The short pathway is associated with faster granule release and more efficient killing than the long pathway. Thus, the kinetics of early signaling regulates the quality of the T cell cytolytic response. | Kinetics of early T cell receptor signaling regulate the pathway of lytic granule delivery to the secretory domain. |
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0.8869584798812866, "26786": 0.014542185701429844, "26835": 0.7389566898345947, "27133": 0.6989894509315491, "27321": 0.5238267183303833, "28024": 0.36358460783958435, "28064": 0.6744182109832764, "28156": 0.5800528526306152, "28173": 0.3519764244556427, "28268": 0.10818854719400406, "28389": 0.04953393340110779, "28691": 0.15860503911972046, "28835": 0.020300358533859253, "28848": 0.669430673122406, "29166": 0.7701805830001831, "29290": 0.32553088665008545, "29516": 0.07431721687316895, "29726": 0.1970241367816925} | 6171953 | Inflammation accompanies obesity and its comorbidities-type 2 diabetes, non-alcoholic fatty liver disease and atherosclerosis, among others-and may contribute to their pathogenesis. Yet the cellular machinery that links nutrient sensing to inflammation remains incompletely characterized. The protein deacetylase sirtuin-1 (SirT1) is activated by energy depletion and plays a critical role in the mammalian response to fasting. More recently it has been implicated in the repression of inflammation. SirT1 mRNA and protein expression are suppressed in obese rodent and human white adipose tissue, while experimental reduction of SirT1 in adipocytes and macrophages causes low-grade inflammation that mimics that observed in obesity. Thus suppression of SirT1 during overnutrition may be critical to the development of obesity-associated inflammation. This effect is attributable to multiple actions of SirT1, including direct deacetylation of NFκB and chromatin remodeling at inflammatory gene promoters. In this work, we report that SirT1 is also suppressed by diet-induced obesity in macrophages, which are key contributors to the ontogeny of metabolic inflammation. Thus, SirT1 may be a common mechanism by which cells sense nutrient status and modulate inflammatory signaling networks in accordance with organismal energy availability. | Sirtuin-1 is a nutrient-dependent modulator of inflammation |
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"26629": 0.02316705882549286, "26691": 0.11517547070980072, "26702": 0.2607102394104004, "26745": 0.8400169610977173, "26835": 1.243794322013855, "26944": 0.07431721687316895, "26957": 0.1913948506116867, "26989": 0.8022117614746094, "27059": 0.32553088665008545, "27152": 0.42608439922332764, "27177": 0.3956514894962311, "27441": 1.034073829650879, "27605": 0.29400965571403503, "27642": 0.15275461971759796, "27746": 0.2576959431171417, "27965": 0.00875066313892603, "28250": 0.5010119676589966, "28389": 0.319873183965683, "28911": 0.04207121208310127, "29090": 0.8408597707748413, "29110": 0.3601844012737274, "29490": 0.03360854089260101, "29494": 0.1510767638683319} | 6173523 | IMPORTANCE Identification of the bacterium responsible for an outbreak can aid in disease management. However, traditional culture-based diagnosis can be difficult, particularly if no specific diagnostic test is available for an outbreak strain. OBJECTIVE To explore the potential of metagenomics, which is the direct sequencing of DNA extracted from microbiologically complex samples, as an open-ended clinical discovery platform capable of identifying and characterizing bacterial strains from an outbreak without laboratory culture. DESIGN, SETTING, AND PATIENTS In a retrospective investigation, 45 samples were selected from fecal specimens obtained from patients with diarrhea during the 2011 outbreak of Shiga-toxigenic Escherichia coli (STEC) O104:H4 in Germany. Samples were subjected to high-throughput sequencing (August-September 2012), followed by a 3-phase analysis (November 2012-February 2013). In phase 1, a de novo assembly approach was developed to obtain a draft genome of the outbreak strain. In phase 2, the depth of coverage of the outbreak strain genome was determined in each sample. In phase 3, sequences from each sample were compared with sequences from known bacteria to identify pathogens other than the outbreak strain. MAIN OUTCOMES AND MEASURES The recovery of genome sequence data for the purposes of identification and characterization of the outbreak strain and other pathogens from fecal samples. RESULTS During phase 1, a draft genome of the STEC outbreak strain was obtained. During phase 2, the outbreak strain genome was recovered from 10 samples at greater than 10-fold coverage and from 26 samples at greater than 1-fold coverage. Sequences from the Shiga-toxin genes were detected in 27 of 40 STEC-positive samples (67%). In phase 3, sequences from Clostridium difficile, Campylobacter jejuni, Campylobacter concisus, and Salmonella enterica were recovered. CONCLUSIONS AND RELEVANCE These results suggest the potential of metagenomics as a culture-independent approach for the identification of bacterial pathogens during an outbreak of diarrheal disease. Challenges include improving diagnostic sensitivity, speeding up and simplifying workflows, and reducing costs. | A culture-independent sequence-based metagenomics approach to the investigation of an outbreak of Shiga-toxigenic Escherichia coli O104:H4. |
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"27373": 0.5957841277122498, "27989": 0.4873090982437134, "28093": 0.04767346754670143, "28413": 0.009718249551951885, "28436": 0.19782574474811554, "28466": 1.1185935735702515, "28696": 0.26296505331993103, "28727": 0.16276304423809052, "28828": 0.19622190296649933, "28927": 0.1710275560617447, "29248": 0.04860413447022438, "29295": 0.040196798741817474, "29299": 0.45251765847206116, "29300": 0.05694137513637543, "29458": 0.7755908370018005, "29477": 0.6950984001159668, "29513": 0.13414156436920166, "29610": 0.08513788133859634} | 6176498 | CONTEXT Endothelial dysfunction occurs in diagnosed type 2 diabetes mellitus but may also precede development of diabetes. OBJECTIVE To determine whether elevated plasma levels of biomarkers reflecting endothelial dysfunction (E-selectin; intercellular adhesion molecule 1 [ICAM-1]; and vascular cell adhesion molecule 1 [VCAM-1]) predict development of type 2 diabetes in initially nondiabetic women. DESIGN AND SETTING Prospective, nested case-control study within the Nurses' Health Study, an ongoing US study initiated in 1976. PARTICIPANTS Of 121 700 women initially enrolled, 32 826 provided blood samples in 1989-1990; of those free of diabetes, cardiovascular disease, or cancer at baseline, 737 developed incident diabetes by 2000. Controls (n = 785) were selected according to matched age, fasting status, and race. MAIN OUTCOME MEASURE Risk of confirmed clinically diagnosed type 2 diabetes by baseline levels of E-selectin, ICAM-1, and VCAM-1. RESULTS Baseline median levels of the biomarkers were significantly higher among cases than among controls (E-selectin, 61.2 vs 45.4 ng/mL; ICAM-1, 264.9 vs 247.0 ng/mL; VCAM-1, 545.4 vs 526.0 ng/mL [all P values < or =.004]). Elevated E-selectin and ICAM-1 levels predicted incident diabetes in logistic regression models conditioned on matching criteria and adjusted for body mass index (BMI), family history of diabetes, smoking, diet score, alcohol intake, activity index, and postmenopausal hormone use. The adjusted relative risks for incident diabetes in the top quintile vs the bottom quintiles were 5.43 for E-selectin (95% confidence interval [CI], 3.47-8.50), 3.56 for ICAM-1 (95% CI, 2.28-5.58), and 1.12 for VCAM-1 (95% CI, 0.76-1.66). Adjustment for waist circumference instead of BMI or further adjustment for baseline levels of C-reactive protein, fasting insulin, and hemoglobin A(1c) or exclusion of cases diagnosed during the first 4 years of follow-up did not alter these associations. CONCLUSION Endothelial dysfunction predicts type 2 diabetes in women independent of other known risk factors, including obesity and subclinical inflammation. | Biomarkers of endothelial dysfunction and risk of type 2 diabetes mellitus. |
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virus (IAV) infection primarily targets respiratory epithelial cells and produces clinical outcomes ranging from mild upper respiratory infection to severe pneumonia. Recent studies have shown the importance of lung antioxidant defense systems against injury by IAV. Nuclear factor-erythroid 2 related factor 2 (Nrf2) activates the majority of antioxidant genes. METHODS Alveolar type II (ATII) cells and alveolar macrophages (AM) were isolated from human lungs not suitable for transplantation and donated for medical research. In some studies ATII cells were transdifferentiated to alveolar type I-like (ATI-like) cells. Alveolar epithelial cells were infected with A/PR/8/34 (PR8) virus. We analyzed PR8 virus production, influenza A nucleoprotein levels, ROS generation and expression of antiviral genes. Immunocytofluorescence was used to determine Nrf2 translocation and western blotting to detect Nrf2, HO-1 and caspase 1 and 3 cleavage. We also analyzed ingestion of PR8 virus infected apoptotic ATII cells by AM, cytokine levels by ELISA, glutathione levels, necrosis and apoptosis by TUNEL assay. Moreover, we determined the critical importance of Nrf2 using adenovirus Nrf2 (AdNrf2) or Nrf2 siRNA to overexpress or knockdown Nrf2, respectively. RESULTS We found that IAV induced oxidative stress, cytotoxicity and apoptosis in ATI-like and ATII cells. We also found that AM can ingest PR8 virus-induced apoptotic ATII cells (efferocytosis) but not viable cells, whereas ATII cells did not ingest these apoptotic cells. PR8 virus increased ROS production, Nrf2, HO-1, Mx1 and OAS1 expression and Nrf2 translocation to the nucleus. Nrf2 knockdown with siRNA sensitized ATI-like cells and ATII cells to injury induced by IAV and overexpression of Nrf2 with AdNrf2 protected these cells. Furthermore, Nrf2 overexpression followed by infection with PR8 virus decreased virus replication, influenza A nucleoprotein expression, antiviral response and oxidative stress. However, AdNrf2 did not increase IFN-λ1 (IL-29) levels. CONCLUSIONS Our results indicate that IAV induces alveolar epithelial injury and that Nrf2 protects these cells from the cytopathic effects of IAV likely by increasing the expression of antioxidant genes. Identifying the pathways involved in protecting cells from injury during influenza infection may be particularly important for developing new therapeutic strategies. | Nrf2 protects human alveolar epithelial cells against injury induced by influenza A virus |
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Here, it is proposed to review the molecular dynamics and mosaic organization of the plasma membrane, which are thought to have important functional implications. We will first summarize the basic concepts of Brownian diffusion and lipid domain formation in model membranes and then track the development of ideas and tools in this field, outlining key results obtained on the dynamic processes at work in membrane structure and assembly. We will focus in particular on findings made using fluorescent labeling and imaging procedures to record these dynamic processes. We will also discuss a few examples showing the impact of lateral diffusion on cell signal transduction, and outline some future methodological challenges which must be met before we can answer some of the questions arising in this field of research. | Dynamics in the plasma membrane: how to combine fluidity and order. |
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"25331": 0.3723714053630829, "25360": 0.11517547070980072, "25604": 0.5232481360435486, "25775": 0.03925827145576477, "25778": 0.24401791393756866, "26089": 0.05786345899105072, "26445": 0.7647408246994019, "26456": 0.6931471824645996, "26497": 0.35334911942481995, "27292": 0.6228629946708679, "27484": 0.27712854743003845, "27520": 0.7258110046386719, "29299": 0.7473171949386597, "29443": 0.0009760859538801014, "29477": 0.07068414986133575} | 6191684 | CONTEXT Chronic tension-type headaches are characterized by near-daily headaches and often are difficult to manage in primary practice. Behavioral and pharmacological therapies each appear modestly effective, but data are lacking on their separate and combined effects. OBJECTIVE To evaluate the clinical efficacy of behavioral and pharmacological therapies, singly and combined, for chronic tension-type headaches. DESIGN AND SETTING Randomized placebo-controlled trial conducted from August 1995 to January 1998 at 2 outpatient sites in Ohio. PARTICIPANTS Two hundred three adults (mean age, 37 years; 76% women) with diagnosis of chronic tension-type headaches (mean, 26 headache d/mo). INTERVENTIONS Participants were randomly assigned to receive tricyclic antidepressant (amitriptyline hydrochloride, up to 100 mg/d, or nortriptyline hydrochloride, up to 75 mg/d) medication (n = 53), placebo (n = 48), stress management (eg, relaxation, cognitive coping) therapy (3 sessions and 2 telephone contacts) plus placebo (n = 49), or stress management therapy plus antidepressant medication (n = 53). MAIN OUTCOME MEASURES Monthly headache index scores calculated as the mean of pain ratings (0-10 scale) recorded by participants in a daily diary 4 times per day; number of days per month with at least moderate pain (pain rating >/=5), analgesic medication use, and Headache Disability Inventory scores, compared by intervention group. RESULTS Tricyclic antidepressant medication and stress management therapy each produced larger reductions in headache activity, analgesic medication use, and headache-related disability than placebo, but antidepressant medication yielded more rapid improvements in headache activity. Combined therapy was more likely to produce clinically significant (>/=50%) reductions in headache index scores (64% of participants) than antidepressant medication (38% of participants; P =.006), stress management therapy (35%; P =.003), or placebo (29%; P =.001). On other measures the combined therapy and its 2 component therapies produced similar outcomes. CONCLUSIONS Our results indicate that antidepressant medication and stress management therapy are each modestly effective in treating chronic tension-type headaches. Combined therapy may improve outcome relative to monotherapy. | Management of chronic tension-type headache with tricyclic antidepressant medication, stress management therapy, and their combination: a randomized controlled trial. |
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"28184": 0.13925230503082275, "28314": 0.13157635927200317, "28424": 0.11778303235769272, "28436": 0.1751343309879303, "28591": 0.01934296265244484, "28637": 0.1718502640724182, "28699": 0.7342816591262817, "28732": 0.018384648486971855, "28937": 0.4151833653450012, "28964": 1.0298984050750732, "29154": 0.4444103240966797, "29160": 0.40351006388664246, "29458": 0.20739519596099854} | 6202834 | The understanding that gene trees are often in discord with each other and with the species trees that contain them has led researchers to methods that incorporate the inherent stochasticity of genetic processes in the phylogenetic estimation procedure. Recently developed methods for species-tree estimation that not only consider the retention and sorting of ancestral polymorphism but also quantify the actual probabilities of incomplete lineage sorting are expected to provide an improvement over earlier summary-statistic based approaches that discard much of the information content of gene trees. However, these new methods have yet to be tested on truly challenging evolutionary histories such as those marked by recent rapid speciation where high levels of incomplete lineage sorting and discord among gene trees predominate. Here, we test a new maximum-likelihood method that incorporates stochastic models of both nucleotide substitution and lineage sorting for species-tree estimation. Using a simulation approach, we consider a broad range of species-tree topologies under 2 scenarios representing moderate and severe incomplete lineage sorting. We show that the maximum-likelihood method results in more accurate species trees than a summary-statistic based approach, demonstrating that information contained in discordant gene trees can be effectively extracted using a full probabilistic model. Moreover, we demonstrate that the shape of the original species tree (i.e., the relative lengths of internal branches) has a significant impact on whether the species tree is estimated accurately. In the speciation histories explored here, it is not just the recent origin of species that affects the accuracy of the estimates but the variance in relative species divergence times as well. Additionally, we show that sampling effort (number of individuals and/or loci) and sampling design (ratio of individuals to loci) are both important factors affecting the accuracy of species-tree estimates, which is again affected by the relative timing of divergence among species. The inherent difficulties of estimating relationships when species have undergone a recent radiation are discussed, and in particular, the limitations with maximum-likelihood estimates of species trees that do not consider uncertainty in the estimated gene trees of individual loci. Thus, despite substantial improvements over current summary-statistic based approaches, and the increased sophistication of procedures that incorporate the process of gene lineage coalescence, recent radiations still appear to pose daunting challenges for phylogenetics. | Maximum likelihood estimates of species trees: how accuracy of phylogenetic inference depends upon the divergence history and sampling design. |
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0.11081436276435852, "21961": 0.18329764902591705, "22597": 0.3019835948944092, "22835": 0.1970241367816925, "22939": 0.38374659419059753, "23260": 0.0752234235405922, "23444": 0.03360854089260101, "23675": 0.13071982562541962, "23900": 0.6892333030700684, "24155": 0.14433705806732178, "24454": 0.05970508232712746, "24552": 1.3352066278457642, "24658": 0.20102575421333313, "25022": 0.5290185213088989, "25234": 0.5461324453353882, "25643": 0.15860503911972046, "25783": 0.23864774405956268, "26071": 0.8901712894439697, "26237": 1.1369311809539795, "26319": 0.16359257698059082, "26427": 0.010684899985790253, "26786": 0.09584271162748337, "26820": 0.3757305145263672, "27237": 0.014542185701429844, "27287": 0.13670019805431366, "27400": 0.16607704758644104, "27615": 0.0842406153678894, "27833": 0.040196798741817474, "28093": 0.30558720231056213, "28102": 0.056018441915512085, "28739": 0.3134697377681732, "28753": 0.10026945173740387, "29167": 0.02316705882549286} | 6207111 | OBJECTIVES We estimated the relationship between soft drink consumption and obesity and diabetes worldwide. METHODS We used multivariate linear regression to estimate the association between soft drink consumption and overweight, obesity, and diabetes prevalence in 75 countries, controlling for other foods (cereals, meats, fruits and vegetables, oils, and total calories), income, urbanization, and aging. Data were obtained from the Euromonitor Global Market Information Database, the World Health Organization, and the International Diabetes Federation. Bottled water consumption, which increased with per-capita income in parallel to soft drink consumption, served as a natural control group. RESULTS Soft drink consumption increased globally from 9.5 gallons per person per year in 1997 to 11.4 gallons in 2010. A 1% rise in soft drink consumption was associated with an additional 4.8 overweight adults per 100 (adjusted B; 95% confidence interval [CI] = 3.1, 6.5), 2.3 obese adults per 100 (95% CI = 1.1, 3.5), and 0.3 adults with diabetes per 100 (95% CI = 0.1, 0.8). These findings remained robust in low- and middle-income countries. CONCLUSIONS Soft drink consumption is significantly linked to overweight, obesity, and diabetes worldwide, including in low- and middle-income countries. | Relationship of soft drink consumption to global overweight, obesity, and diabetes: a cross-national analysis of 75 countries. |
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However, the biological functions of these circRNAs remain largely unclear. Here we report that N6-methyladenosine (m6A), the most abundant base modification of RNA, promotes efficient initiation of protein translation from circRNAs in human cells. We discover that consensus m6A motifs are enriched in circRNAs and a single m6A site is sufficient to drive translation initiation. This m6A-driven translation requires initiation factor eIF4G2 and m6A reader YTHDF3, and is enhanced by methyltransferase METTL3/14, inhibited by demethylase FTO, and upregulated upon heat shock. Further analyses through polysome profiling, computational prediction and mass spectrometry reveal that m6A-driven translation of circRNAs is widespread, with hundreds of endogenous circRNAs having translation potential. Our study expands the coding landscape of human transcriptome, and suggests a role of circRNA-derived proteins in cellular responses to environmental stress. | Extensive translation of circular RNAs driven by N6-methyladenosine |
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0.8813109993934631, "25608": 0.11517547070980072, "25654": 0.6538092494010925, "25672": 0.0606246218085289, "25708": 0.1229778528213501, "25714": 1.0655186176300049, "26163": 0.2531573474407196, "26261": 0.4151833653450012, "26402": 0.1221139207482338, "26520": 0.0174254160374403, "26651": 0.32341301441192627, "26773": 0.37102460861206055, "27024": 0.006812678650021553, "27144": 0.010684899985790253, "27292": 0.7333439588546753, "27528": 0.47584590315818787, "27694": 0.1332872211933136, "27854": 0.9635916948318481, "27989": 0.07884006202220917, "28093": 1.3331490755081177, "28155": 0.6911921501159668, "28879": 0.4151833653450012, "28915": 0.8083226680755615, "29048": 0.08154398202896118, "29125": 0.021256839856505394, "29295": 0.03925827145576477, "29336": 1.060796856880188, "29537": 0.5191890001296997} | 6212802 | BACKGROUND Saphenous vein graft (VG) failure occurs more frequently compared with arterial grafts, and graft thrombosis represents the main cause of early occlusion. Because CD40-CD40L pathway CD40 represents a culprit link between local inflammation and coagulation cascade, we investigate the role of CD40 and its soluble ligand (sCD40L) in the immediate in vitro response of VG to arterial pressures, and the potential effects of Simvastatin (Merck Sharp&Dohme, White-house Station, NJ) supplementation. METHODS Samples of saphenous vein and of internal mammary artery (IMA) were obtained from sixteen patients without history of statin therapy. Segments underwent pulsatile pressure distension and culture with or without supplementation of Simvastatin. CD40 and sCD40L were assessed in tissue lysate and in culture supernatant, respectively. sCD40L serum concentrations were also measured. RESULTS During the course of the experiment, the CD40 expression was significantly lower in IMA samples compared with both distended and not distended VG. Pressure distension up-regulated the production of CD40 in VG segments after 24 and 48 h. Statin supplementation significantly reduced the expression of CD40 in both venous (P < 0.001) and arterial samples (P < 0.001). This effect of Simvastatin was not affected by the treatment with L-NAME, but it was reversed by the addition of mevalonic acid. Mean sCD40L content in culture supernatants increased over time, suggesting that not only platelets but also the vessel wall is a source of CD40 and sCD40L. CONCLUSIONS Simvastatin treatment modulates endothelial CD40-sCD40L in both venous and arterial grafts, and therefore may represent a useful tool in the pharmacological prevention of graft failure. | Simvastatin reduces CD40 expression in an experimental model of early arterialization of saphenous vein graft. |
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"24278": 0.42225050926208496, "24314": 0.11604541540145874, "24473": 0.3019835948944092, "24604": 0.034552380442619324, "24797": 0.0174254160374403, "24972": 0.8143964409828186, "25409": 0.8247235417366028, "25468": 0.3141832649707794, "25562": 0.5662899017333984, "25778": 0.1332872211933136, "26096": 0.06886265426874161, "26572": 0.25088030099868774, "26633": 0.4311734735965729, "26642": 0.07068414986133575, "26835": 0.029824240133166313, "27144": 0.6011518239974976, "27216": 0.8583967685699463, "27448": 0.3784096837043762, "27781": 0.4196864068508148, "27881": 0.11256109178066254, "28024": 0.7370892763137817, "28873": 1.0992631912231445, "28896": 0.9568626880645752, "28991": 1.4847954511642456, "29280": 0.19622190296649933} | 6219790 | Cell-derived nanoparticles have been garnering increased attention due to their ability to mimic many of the natural properties displayed by their source cells. This top-down engineering approach can be applied toward the development of novel therapeutic strategies owing to the unique interactions enabled through the retention of complex antigenic information. Herein, we report on the biological functionalization of polymeric nanoparticles with a layer of membrane coating derived from cancer cells. The resulting core-shell nanostructures, which carry the full array of cancer cell membrane antigens, offer a robust platform with applicability toward multiple modes of anticancer therapy. We demonstrate that by coupling the particles with an immunological adjuvant, the resulting formulation can be used to promote a tumor-specific immune response for use in vaccine applications. Moreover, we show that by taking advantage of the inherent homotypic binding phenomenon frequently observed among tumor cells the membrane functionalization allows for a unique cancer targeting strategy that can be utilized for drug delivery applications. | Cancer Cell Membrane-Coated Nanoparticles for Anticancer Vaccination and Drug Delivery |
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"27133": 0.9115922451019287, "27833": 0.2719337046146393, "27989": 0.1685553640127182, "28156": 0.5301685929298401, "28194": 0.960606575012207, "28227": 0.7426811456680298, "28290": 0.05970508232712746, "28466": 0.7537717819213867, "28522": 0.8748174905776978, "28964": 0.04113444685935974, "29107": 0.07431721687316895, "29125": 0.18411032855510712, "29290": 0.46363574266433716, "29516": 0.06246116757392883} | 6227220 | Despite growing interest and a recent surge in papers, the role of autophagy in glucose and lipid metabolism is unclear. We produced mice with skeletal muscle–specific deletion of Atg7 (encoding autophagy-related 7). Unexpectedly, these mice showed decreased fat mass and were protected from diet-induced obesity and insulin resistance; this phenotype was accompanied by increased fatty acid oxidation and browning of white adipose tissue (WAT) owing to induction of fibroblast growth factor 21 (Fgf21). Mitochondrial dysfunction induced by autophagy deficiency increased Fgf21 expression through induction of Atf4, a master regulator of the integrated stress response. Mitochondrial respiratory chain inhibitors also induced Fgf21 in an Atf4-dependent manner. We also observed induction of Fgf21, resistance to diet-induced obesity and amelioration of insulin resistance in mice with autophagy deficiency in the liver, another insulin target tissue. These findings suggest that autophagy deficiency and subsequent mitochondrial dysfunction promote Fgf21 expression, a hormone we consequently term a 'mitokine', and together these processes promote protection from diet-induced obesity and insulin resistance. | Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine |
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"25874": 0.15610189735889435, "26014": 0.00875066313892603, "26163": 0.4400174915790558, "26237": 0.06337817758321762, "26319": 0.05139094591140747, "26387": 0.0797421783208847, "26394": 0.013579257763922215, "26616": 0.1905880719423294, "26745": 0.8161250352859497, "26775": 0.8715548515319824, "26785": 0.857568621635437, "26897": 0.34577593207359314, "26914": 0.21214580535888672, "27010": 0.021256839856505394, "27144": 0.08603433519601822, "27354": 0.04207121208310127, "27703": 0.23479416966438293, "27989": 0.1477125883102417, "28093": 0.15693697333335876, "28389": 0.40546512603759766, "28466": 0.11951763927936554, "28935": 0.14602625370025635, "29125": 0.25694093108177185, "29166": 1.0037577152252197, "29299": 0.8965662121772766, "29391": 0.6218147873878479, "29458": 0.6338034868240356, "29513": 0.05970508232712746, "29607": 0.0913962796330452} | 6250701 | BACKGROUND Acute renal failure is a common complication of severe malaria in adults, and without renal replacement therapy (RRT), it carries a poor prognosis. Even when RRT is available, delaying its initiation may increase mortality. Earlier identification of patients who will need RRT may improve outcomes. METHOD Prospectively collected data from two intervention studies in adults with severe malaria were analysed focusing on laboratory features on presentation and their association with a later requirement for RRT. In particular, laboratory indices of acute tubular necrosis (ATN) and acute kidney injury (AKI) that are used in other settings were examined. RESULTS Data from 163 patients were available for analysis. Whether or not the patients should have received RRT (a retrospective assessment determined by three independent reviewers) was used as the reference. Forty-three (26.4%) patients met criteria for dialysis, but only 19 (44.2%) were able to receive this intervention due to the limited availability of RRT. Patients with impaired renal function on admission (creatinine clearance < 60 ml/min) (n = 84) had their laboratory indices of ATN/AKI analysed. The plasma creatinine level had the greatest area under the ROC curve (AUC): 0.83 (95% confidence interval 0.74-0.92), significantly better than the AUCs for, urinary sodium level, the urea to creatinine ratio (UCR), the fractional excretion of urea (FeUN) and the urinary neutrophil gelatinase-associated lipocalcin (NGAL) level. The AUC for plasma creatinine was also greater than the AUC for blood urea nitrogen level, the fractional excretion of sodium (FeNa), the renal failure index (RFI), the urinary osmolality, the urine to plasma creatinine ratio (UPCR) and the creatinine clearance, although the difference for these variables did not reach statistical significance. CONCLUSIONS In adult patients with severe malaria and impaired renal function on admission, none of the evaluated laboratory indices was superior to the plasma creatinine level when used to predict a later requirement for renal replacement therapy. | Laboratory prediction of the requirement for renal replacement in acute falciparum malaria |
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"26835": 0.20660123229026794, "27094": 0.45499902963638306, "27391": 0.14602625370025635, "27441": 0.22157983481884003, "27781": 1.2198615074157715, "28105": 0.8933739066123962, "28155": 0.055094651877880096, "28389": 0.24018502235412598, "28621": 0.31560876965522766, "28748": 0.04767346754670143, "28788": 0.22392450273036957, "28817": 1.001607894897461, "28873": 1.1935672760009766, "29098": 0.5461324453353882, "29166": 0.010684899985790253, "29490": 1.0953518152236938} | 6251620 | Antineutrophil cytoplasmic antibodies (ANCA) are a sensitive and specific marker for ANCA-associated systemic vasculitis. Using indirect immunofluorescence on ethanol-fixed neutrophils, two major fluoroscopic patterns can be recognised: a diffuse cytoplasmic staining (C-ANCA), and a perinuclear/nuclear staining (P-ANCA). In patients with vasculitis, more of 90% of C-ANCA are directed against proteinase 3 (PR3-ANCA) whereas approximately 80-90% of P-ANCA recognise myelperoxidase (MPO-ANCA). Although C-ANCA (PR3-ANCA) is preferentially associated with Wegener's granulomatosis (WG), and P-ANCA (MPO-ANCA) with microscopic polyangiitis (MPA), idiopathic necrotising crescentic glomerulonephritis (iNCGN) and Churg-Strauss syndrome (CSS), there is not absolute specificity. Between 10-20% of patients with classical WG show P-ANCA (MPO-ANCA), and even a larger percentage of patients with MPA or CSS have C-ANCA (PR3-ANCA). Furthermore, it should be stressed that approximately 10-20% of patients with WG or MPA (and 40-50% of cases of CSS) have negative assay for ANCA. The best diagnostic performance is obtained when indirect immunofluorescence is combined with PR3 and MPO-specific ELISAs. ANCA with different and unknown antigen specificity are found in a variety of conditions other than AASV, including inflammatory bowel diseases, other autoimmune diseases, and infections where their clinical significance is unclear. ANCA levels are useful to monitor disease activity but should not be used by themselves to guide treatment. A significant increase in ANCA titres, or the reappearance of ANCA, should alert the clinicians and lead to a stricter patient control. | Antineutrophil cytoplasmic antibodies (ANCA). |
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of drug detoxifying enzyme gene expression during exposure to environmental electrophiles. Currently, Nrf2 is known to regulate the expression of hundreds of cytoprotective genes to counteract endogenously or exogenously generated oxidative stress. Furthermore, when activated in human tumors by somatic mutations, Nrf2 confers growth advantages and chemoresistance by regulating genes involved in various processes such as the pentose phosphate pathway and nucleotide synthesis in addition to antioxidant proteins. Interestingly, increasing evidence shows that Nrf2 is associated with mitochondrial biogenesis during environmental stresses in certain tissues such as the heart. Furthermore, SKN-1, a functional homolog of Nrf2 in C. elegans, is activated by mitochondrial reactive oxygen species and extends life span by promoting mitochondrial homeostasis (i.e., mitohormesis). Similarly, Nrf2 activation was recently observed in the heart of surfeit locus protein 1 (Surf1) -/- mice in which cellular respiration was decreased due to cytochrome c oxidase defects. In this review, we critically examine the relationship between Nrf2 and mitochondria and argue that the Nrf2 stress pathway intimately communicates with mitochondria to maintain cellular homeostasis during oxidative stress. | Emerging functional cross-talk between the Keap1-Nrf2 system and mitochondria |
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Substantial headway has been made in deciphering many aspects of this elaborate system, particularly with respect to epigenetics, transcription, and noncoding RNAs. Less attention has been paid to posttranscriptional regulatory processes such as alternative splicing, RNA processing and modification, nuclear export, regulation of transcript stability, and translation. Here, we introduce the RNA binding proteins that enable the posttranscriptional regulation of gene expression, summarizing current and ongoing research on their roles at different regulatory points and discussing how they help script the fate of pluripotent stem cells. | Regulation of pluripotency by RNA binding proteins. |
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0.22626367211341858, "29145": 1.1262223720550537, "29290": 0.472198486328125} | 6268106 | The receptor Notch and its ligands of the Delta/Serrate/LAG2 (DSL) family are the central components in the Notch pathway, a fundamental cell signaling system that regulates pattern formation during animal development. Delta is directly ubiquitinated by Drosophila and Xenopus Neuralized, and by zebrafish Mind bomb, two unrelated RING-type E3 ubiquitin ligases with common abilities to promote Delta endocytosis and signaling activity. Although orthologs of both Neuralized and Mind bomb are found in most metazoan organisms, their relative contributions to Notch signaling in any single organism have not yet been assessed. We show here that a Drosophila ortholog of Mind bomb (D-mib) is a positive component of Notch signaling that is required for multiple Neuralized-independent, Notch-dependent developmental processes. Furthermore, we show that D-mib associates physically and functionally with both Serrate and Delta. We find that D-mib uses its ubiquitin ligase activity to promote DSL ligand activity, an activity that is correlated with its ability to induce the endocytosis and degradation of both Delta and Serrate (see also Le Borgne et al., 2005). We further demonstrate that D-mib can functionally replace Neuralized in multiple cell fate decisions that absolutely require endogenous Neuralized, a testament to the highly similar activities of these two unrelated ubiquitin ligases in regulating Notch signaling. We conclude that ubiquitination of Delta and Serrate by Neuralized and D-mib is an obligate feature of DSL ligand activation throughout Drosophila development. | The ubiquitin ligase Drosophila Mind bomb promotes Notch signaling by regulating the localization and activity of Serrate and Delta. |
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activates self-antigen-presenting cells and promotes autoreactive CD4(+) T-cell expansion in experimental autoimmune myocarditis, a mouse model of inflammatory heart disease. OBJECTIVE The aim of this study was to determine the role of MyD88 and IL-1 in the progression of acute myocarditis to an end-stage heart failure. METHODS AND RESULTS Using alpha-myosin heavy chain peptide (MyHC-alpha)-loaded, activated dendritic cells, we induced myocarditis in wild-type and MyD88(-/-) mice with similar distributions of heart-infiltrating cell subsets and comparable CD4(+) T-cell responses. Injection of complete Freund's adjuvant (CFA) or MyHC-alpha/CFA into diseased mice promoted cardiac fibrosis, induced ventricular dilation, and impaired heart function in wild-type but not in MyD88(-/-) mice. Experiments with chimeric mice confirmed the bone marrow origin of the fibroblasts replacing inflammatory infiltrates and showed that MyD88 and IL-1 receptor type I signaling on bone marrow-derived cells was critical for development of cardiac fibrosis during progression to heart failure. CONCLUSIONS Our findings indicate a critical role of MyD88/IL-1 signaling in the bone marrow compartment in postinflammatory cardiac fibrosis and heart failure and point to novel therapeutic strategies against inflammatory cardiomyopathy. | Myeloid differentiation factor-88/interleukin-1 signaling controls cardiac fibrosis and heart failure progression in inflammatory dilated cardiomyopathy. |
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"24848": 0.9613537192344666, "25170": 0.07612881064414978, "25283": 0.2652147710323334, "25456": 0.6989894509315491, "25476": 0.5381823778152466, "25494": 0.00875066313892603, "25662": 0.18004031479358673, "25708": 1.0464962720870972, "25845": 0.5773153901100159, "26014": 0.42799583077430725, "26083": 1.057410478591919, "26402": 0.4831010699272156, "26462": 0.8829278349876404, "26520": 0.2983669638633728, "26524": 0.6317287683486938, "26591": 0.4537591338157654, "26655": 0.12038381397724152, "26773": 0.012615402229130268, "26780": 0.5370414853096008, "26906": 0.9546096324920654, "27258": 0.004870930220931768, "28086": 0.007782140281051397, "28156": 0.025073638185858727, "28518": 0.1064341589808464, "28841": 0.21530038118362427, "29516": 0.02316705882549286} | 6277638 | The target of rapamycin (TOR) pathway is a major nutrient-sensing pathway that, when genetically downregulated, increases life span in evolutionarily diverse organisms including mammals. The central component of this pathway, TOR kinase, is the target of the inhibitory drug rapamycin, a highly specific and well-described drug approved for human use. We show here that feeding rapamycin to adult Drosophila produces the life span extension seen in some TOR mutants. Increase in life span by rapamycin was associated with increased resistance to both starvation and paraquat. Analysis of the underlying mechanisms revealed that rapamycin increased longevity specifically through the TORC1 branch of the TOR pathway, through alterations to both autophagy and translation. Rapamycin could increase life span of weak insulin/Igf signaling (IIS) pathway mutants and of flies with life span maximized by dietary restriction, indicating additional mechanisms. | Mechanisms of Life Span Extension by Rapamycin in the Fruit Fly Drosophila melanogaster |
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usefulness in clinical medicine. Here we show that vascular endothelial cells can transform into multipotent stem-like cells by an activin-like kinase-2 (ALK2) receptor–dependent mechanism. In lesions from individuals with fibrodysplasia ossificans progressiva (FOP), a disease in which heterotopic ossification occurs as a result of activating ALK2 mutations, or from transgenic mice expressing constitutively active ALK2, chondrocytes and osteoblasts expressed endothelial markers. Lineage tracing of heterotopic ossification in mice using a Tie2-Cre construct also suggested an endothelial origin of these cell types. Expression of constitutively active ALK2 in endothelial cells caused endothelial-to-mesenchymal transition and acquisition of a stem cell–like phenotype. Similar results were obtained by treatment of untransfected endothelial cells with the ligands transforming growth factor-β2 (TGF-β2) or bone morphogenetic protein-4 (BMP4) in an ALK2-dependent manner. These stem-like cells could be triggered to differentiate into osteoblasts, chondrocytes or adipocytes. We suggest that conversion of endothelial cells to stem-like cells may provide a new approach to tissue engineering. | Conversion of vascular endothelial cells into multipotent stem-like cells |
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Here, we report that deletion of miR-302a-d in mice results in a fully penetrant late embryonic lethal phenotype. Knockout embryos have an anterior neural tube closure defect associated with a thickened neuroepithelium. The neuroepithelium shows increased progenitor proliferation, decreased cell death, and precocious neuronal differentiation. mRNA profiling at multiple time points during neurulation uncovers a complex pattern of changing targets over time. Overexpression of one of these targets, Fgf15, in the neuroepithelium of the chick embryo induces precocious neuronal differentiation. Compound mutants between mir-302 and the related mir-290 locus have a synthetic lethal phenotype prior to neurulation. Our results show that mir-302 helps regulate neurulation by suppressing neural progenitor expansion and precocious differentiation. Furthermore, these results uncover redundant roles for mir-290 and mir-302 early in development. | miR-302 Is Required for Timing of Neural Differentiation, Neural Tube Closure, and Embryonic Viability |
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"25331": 0.10291612148284912, "25465": 0.1229778528213501, "25524": 0.4752389192581177, "26013": 0.09495500475168228, "26305": 0.5255602598190308, "26308": 1.2499688863754272, "26408": 0.36494144797325134, "26493": 0.1064341589808464, "26741": 0.21214580535888672, "26835": 0.19381128251552582, "26874": 0.09406650811433792, "26986": 0.07612881064414978, "27133": 1.1702059507369995, "27166": 1.3387973308563232, "27226": 0.6038249135017395, "27544": 0.07159364968538284, "28024": 0.7491656541824341, "28436": 0.20818853378295898, "28517": 0.0009760859538801014, "28808": 0.1677299439907074, "28873": 0.18978065252304077, "29206": 0.04860413447022438, "29299": 0.46670228242874146, "29458": 0.025073638185858727} | 6290112 | Common multi-allelic copy number variants (CNVs) appear enriched for phenotypic associations compared to their biallelic counterparts. Here we investigated the influence of gene dosage effects on adiposity through a CNV association study of gene expression levels in adipose tissue. We identified significant association of a multi-allelic CNV encompassing the salivary amylase gene (AMY1) with body mass index (BMI) and obesity, and we replicated this finding in 6,200 subjects. Increased AMY1 copy number was positively associated with both amylase gene expression (P = 2.31 × 10(-14)) and serum enzyme levels (P < 2.20 × 10(-16)), whereas reduced AMY1 copy number was associated with increased BMI (change in BMI per estimated copy = -0.15 (0.02) kg/m(2); P = 6.93 × 10(-10)) and obesity risk (odds ratio (OR) per estimated copy = 1.19, 95% confidence interval (CI) = 1.13-1.26; P = 1.46 × 10(-10)). The OR value of 1.19 per copy of AMY1 translates into about an eightfold difference in risk of obesity between subjects in the top (copy number > 9) and bottom (copy number < 4) 10% of the copy number distribution. Our study provides a first genetic link between carbohydrate metabolism and BMI and demonstrates the power of integrated genomic approaches beyond genome-wide association studies. | Low copy number of the salivary amylase gene predisposes to obesity |
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0.0354953333735466, "27520": 0.841701865196228, "27697": 0.18816383183002472, "27724": 0.3297532796859741, "27755": 0.2983669638633728, "27790": 0.2786078155040741, "28297": 0.40741631388664246, "28442": 1.0116009712219238, "28657": 0.20739519596099854, "28715": 0.011650617234408855, "29101": 0.1332872211933136, "29313": 0.08513788133859634, "29516": 0.24171993136405945} | 6296189 | Many people are exposed to loss or potentially traumatic events at some point in their lives, and yet they continue to have positive emotional experiences and show only minor and transient disruptions in their ability to function. Unfortunately, because much of psychology's knowledge about how adults cope with loss or trauma has come from individuals who sought treatment or exhibited great distress, loss and trauma theorists have often viewed this type of resilience as either rare or pathological. The author challenges these assumptions by reviewing evidence that resilience represents a distinct trajectory from the process of recovery, that resilience in the face of loss or potential trauma is more common than is often believed, and that there are multiple and sometimes unexpected pathways to resilience. | Loss, trauma, and human resilience: have we underestimated the human capacity to thrive after extremely aversive events? |
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1.0512858629226685, "27572": 1.0409941673278809, "28046": 0.23402166366577148, "28105": 0.10203468054533005, "28241": 0.5370414853096008, "28293": 0.058784693479537964, "28424": 0.016465263441205025, "28517": 0.15526613593101501, "28636": 0.8117979168891907, "28674": 0.07612881064414978, "28696": 1.0382318496704102, "28735": 1.005902886390686, "28761": 0.6931471824645996, "28817": 0.24325250089168549, "29290": 0.41840189695358276, "29490": 0.3656192123889923} | 6308416 | Coordinated cell movements in epithelial layers are essential for proper tissue morphogenesis and homeostasis, but our understanding of the mechanisms that coordinate the behavior of multiple cells in these processes is far from complete. Recent experiments with Madin-Darby canine kidney epithelial monolayers revealed a wave-like pattern of injury-induced MAPK activation and showed that it is essential for collective cell migration after wounding. To investigate the effects of the different aspects of wounding on cell sheet migration, we engineered a system that allowed us to dissect the classic wound healing assay. We studied Madin-Darby canine kidney sheet migration under three different conditions: 1) the classic wound healing assay, 2) empty space induction, where a confluent monolayer is grown adjacent to a slab of polydimethylsiloxane and the monolayer is not injured but allowed to migrate upon removal of the slab, and 3) injury via polydimethylsiloxane membrane peel-off, where an injured monolayer migrates onto plain tissue culture surface, as in the case of empty space induction allowing for direct comparison. By tracking the motion of individual cells within the sheet under these three conditions, we show how the dynamics of the individual cells' motion is responsible for the coordinated migration of the sheet and is coordinated with the activation of ERK1/2 MAPK. In addition, we demonstrate that the propagation of the waves of MAPK activation depends on the generation of reactive oxygen species at the wound edge. | Role of boundary conditions in an experimental model of epithelial wound healing. |
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0.1970241367816925, "26462": 0.21530038118362427, "26497": 0.15943801403045654, "26534": 0.010684899985790253, "26563": 0.3662964701652527, "26745": 0.13071982562541962, "26877": 0.24631060659885406, "26906": 0.1229778528213501, "26914": 0.015504186972975731, "27339": 0.04767346754670143, "27794": 0.8796916007995605, "28038": 0.6704301834106445, "28093": 0.23092569410800934, "28687": 0.22782009840011597, "28767": 1.5127204656600952, "29299": 0.009718249551951885, "29427": 0.0019512200960889459, "29458": 0.02792670577764511, "29477": 1.0546929836273193} | 6309659 | CONTEXT Exogenous estrogen use may lower risk of dementia in postmenopausal women. A relationship between long-term exposure to endogenous estrogens and incident dementia has been hypothesized but not studied. OBJECTIVE To determine whether a longer reproductive period, as an indicator of longer exposure to endogenous estrogens, is associated with lower risk of dementia and Alzheimer disease (AD) in women who have natural menopause. DESIGN AND SETTING The Rotterdam Study, a population-based prospective cohort study conducted in the Netherlands. PARTICIPANTS A total of 3601 women aged 55 years or older who did not have dementia at baseline (1990-1993) and had information on age at menarche, age at menopause, and type of menopause. Participants were reexamined in 1993-1994 and 1997-1999 and were continuously monitored for development of dementia. MAIN OUTCOME MEASURES Incidence of dementia, based on Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria, and AD, based on National Institute of Neurological Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria, compared by quartiles of reproductive period among women with natural menopause. RESULTS During 21 046 person-years of follow-up (median follow-up, 6.3 years), 199 women developed dementia, including 159 who developed AD. After adjusting for age, dementia was not clearly associated with length of reproductive period. However, after adjusting for multiple covariates, women with natural menopause and more reproductive years had an increased risk of dementia (adjusted rate ratio [RR] for women with >39 reproductive years [highest quartile] compared with <34 reproductive years [lowest quartile], 1.78; 95% confidence interval [CI], 1.12-2.84). The adjusted RR per year of increase was 1.04 (95% CI, 1.01-1.08). For risk of AD, the adjusted RRs were 1.51 (95% CI, 0.91-2.50) and 1.03 (95% CI, 1.00-1.07), respectively. Risk of dementia associated with a longer reproductive period was most pronounced in APOE epsilon4 carriers (adjusted RR for >39 reproductive years compared with <34 reproductive years, 4.20 [95% CI, 1.97-8.92] for dementia and 3.42 [95% CI, 1.51-7.75] for AD), whereas in noncarriers, no clear association with dementia or AD was observed. CONCLUSION Our findings do not support the hypothesis that a longer reproductive period reduces risk of dementia in women who have natural menopause. | Reproductive period and risk of dementia in postmenopausal women. |
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0.935633659362793, "25708": 1.417065978050232, "25737": 0.1384023278951645, "25937": 0.10467668622732162, "26462": 1.1689931154251099, "26534": 0.026976587250828743, "26657": 0.30989447236061096, "26906": 1.1714173555374146, "27152": 0.630689799785614, "27295": 0.18004031479358673, "27768": 0.014542185701429844, "27989": 0.14095009863376617, "28156": 0.5646255612373352, "28177": 0.5404602885246277, "28179": 0.5209306478500366, "28227": 0.9155091643333435, "28466": 0.15777134895324707, "28562": 0.6348392367362976, "28767": 0.08961215615272522, "28829": 0.04860413447022438, "28927": 0.025073638185858727, "29046": 0.05694137513637543, "29107": 1.036847710609436, "29125": 0.5045560002326965, "29172": 0.0354953333735466, "29494": 0.5952457785606384, "29610": 0.37371641397476196} | 6313547 | Present knowledge on the effects of growth hormone (GH)/insulin-like growth hormone (IGF)1 deficiency on ageing and lifespan are reviewed. Evidence is presented that isolated GH deficiency (IGHD), multiple pituitary hormone deficiencies (MPHD) including GH, as well as primary IGE1 deficiency (GH resistance, Laron syndrome) present signs of early ageing such as thin and wrinkled skin, obesity, hyperglycemia and osteoporosis. These changes do not seem to affect the lifespan, as patients reach old age. Animal models of genetic MPHD (Ames and Snell mice) and GH receptor knockout mice (primary IGF1 deficiency) also have a statistically significant higher longevity compared to normal controls. On the contrary, mice transgenic for GH and acromegalic patients secreting large amounts of GH have premature death. In conclusion longstanding GH/IGF1 deficiency affects several parameters of the ageing process without impairing lifespan, and as shown in animal models prolongs longevity. In contrast high GH/IGF1 levels accelerate death. | Effects of growth hormone and insulin-like growth factor 1 deficiency on ageing and longevity. |
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"27356": 0.055094651877880096, "27480": 1.1153976917266846, "27781": 0.0913962796330452, "27815": 1.0973093509674072, "27969": 0.5336109399795532, "28086": 0.09761575609445572, "28156": 0.27342069149017334, "28290": 0.2689530849456787, "28691": 0.09584271162748337, "28848": 0.14433705806732178, "28873": 0.997294545173645, "28939": 0.17020416259765625, "29058": 0.14686977863311768, "29292": 1.1425544023513794} | 6315132 | We describe a case of severe neonatal anemia with kernicterus caused by compound heterozygosity for null mutations in KLF1, each inherited from asymptomatic parents. One of the mutations is novel. This is the first described case of a KLF1-null human. The phenotype of severe nonspherocytic hemolytic anemia, jaundice, hepatosplenomegaly, and marked erythroblastosis is more severe than that present in congenital dyserythropoietic anemia type IV as a result of dominant mutations in the second zinc-finger of KLF1. There was a very high level of HbF expression into childhood (>70%), consistent with a key role for KLF1 in human hemoglobin switching. We performed RNA-seq on circulating erythroblasts and found that human KLF1 acts like mouse Klf1 to coordinate expression of many genes required to build a red cell including those encoding globins, cytoskeletal components, AHSP, heme synthesis enzymes, cell-cycle regulators, and blood group antigens. We identify novel KLF1 target genes including KIF23 and KIF11 which are required for proper cytokinesis. We also identify new roles for KLF1 in autophagy, global transcriptional control, and RNA splicing. We suggest loss of KLF1 should be considered in otherwise unexplained cases of severe neonatal NSHA or hydrops fetalis. | KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome. |
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0.04487626627087593, "24155": 0.6233867406845093, "24353": 0.3956514894962311, "24497": 0.010684899985790253, "24806": 0.13499516248703003, "24854": 0.567397952079773, "25095": 0.5347557663917542, "25455": 0.603290855884552, "25524": 0.045809537172317505, "25902": 0.23787821829319, "26237": 0.33325836062431335, "26319": 0.5220900774002075, "27144": 0.09584271162748337, "27354": 0.058784693479537964, "28093": 0.7220231294631958, "28329": 0.10467668622732162, "28335": 0.04487626627087593, "28436": 0.5186077356338501, "28648": 0.014542185701429844, "28937": 0.15275461971759796, "29165": 0.14349138736724854, "29206": 0.11256109178066254} | 6319826 | The extent of heterogeneity in a meta-analysis partly determines the difficulty in drawing overall conclusions. This extent may be measured by estimating a between-study variance, but interpretation is then specific to a particular treatment effect metric. A test for the existence of heterogeneity exists, but depends on the number of studies in the meta-analysis. We develop measures of the impact of heterogeneity on a meta-analysis, from mathematical criteria, that are independent of the number of studies and the treatment effect metric. We derive and propose three suitable statistics: H is the square root of the chi2 heterogeneity statistic divided by its degrees of freedom; R is the ratio of the standard error of the underlying mean from a random effects meta-analysis to the standard error of a fixed effect meta-analytic estimate, and I2 is a transformation of (H) that describes the proportion of total variation in study estimates that is due to heterogeneity. We discuss interpretation, interval estimates and other properties of these measures and examine them in five example data sets showing different amounts of heterogeneity. We conclude that H and I2, which can usually be calculated for published meta-analyses, are particularly useful summaries of the impact of heterogeneity. One or both should be presented in published meta-analyses in preference to the test for heterogeneity. | Quantifying heterogeneity in a meta-analysis. |
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(SGA) has increased since the recent approval of growth hormone (GH) therapy in this indication. The objective of GH treatment in SGA children is to provide a symptomatic treatment for growth retardation. From a patient perspective, the ultimate goals of GH therapy are the reduction in the present or future risk of neurocognitive, psychological, social or occupational impairment, not the accompanying improvements in growth velocity and final height per se. Therefore, from a scientific perspective, neurocognitive and psychosocial endpoints become relevant domains of assessment to determine the final treatment benefit experienced by the patient born SGA. This article reviews recent available studies on developmental risks in SGA, and then transforms the empirical findings into an integrated conceptual framework on the sources and mediators of neurocognitive and psychosocial outcomes in intrauterine growth retardation and SGA. This framework depicts two distinct therapeutic pathways by which GH therapy may improve neurocognitive and behavioural outcomes. The first (‘traditional’) pathway is the prevention of exposure to short-stature-related stressors via an improvement in growth velocity and final height. The second pathway refers to potential metabolic, and thus neurotropic and psychotropic, effects of GH binding at receptors in the central nervous system, thus changing neuronal activity. To date, the existence and potential mechanisms of such physiologically and not psychologically mediated effects of GH on neurocognitive functioning in SGA patients remain hypothetical. | Neurocognitive Development in Children Experiencing Intrauterine Growth Retardation and Born Small for Gestational Age: Pathological, Constitutional and Therapeutic Pathways |
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The endothelial G-protein-coupled receptor (GPCR) Gpr124 has been reported to be required for normal forebrain angiogenesis and BBB function in mouse embryos, but the role of this receptor in adult animals is unknown. Here Gpr124 conditional knockout (CKO) in the endothelia of adult mice did not affect homeostatic BBB integrity, but resulted in BBB disruption and microvascular hemorrhage in mouse models of both ischemic stroke and glioblastoma, accompanied by reduced cerebrovascular canonical Wnt–β-catenin signaling. Constitutive activation of Wnt–β-catenin signaling fully corrected the BBB disruption and hemorrhage defects of Gpr124-CKO mice, with rescue of the endothelial gene tight junction, pericyte coverage and extracellular-matrix deficits. We thus identify Gpr124 as an endothelial GPCR specifically required for endothelial Wnt signaling and BBB integrity under pathological conditions in adult mice. This finding implicates Gpr124 as a potential therapeutic target for human CNS disorders characterized by BBB disruption. | Gpr124 is essential for blood–brain barrier integrity in central nervous system disease |
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Soy protein, as well as many other vegan proteins, are higher in non-essential amino acids than most animal-derived food proteins, and as a result should preferentially favor glucagon production. Acting on hepatocytes, glucagon promotes (and insulin inhibits) cAMP-dependent mechanisms that down-regulate lipogenic enzymes and cholesterol synthesis, while up-regulating hepatic LDL receptors and production of the IGF-I antagonist IGFBP-1. The insulin-sensitizing properties of many vegan diets--high in fiber, low in saturated fat--should amplify these effects by down-regulating insulin secretion. Additionally, the relatively low essential amino acid content of some vegan diets may decrease hepatic IGF-I synthesis. Thus, diets featuring vegan proteins can be expected to lower elevated serum lipid levels, promote weight loss, and decrease circulating IGF-I activity. The latter effect should impede cancer induction (as is seen in animal studies with soy protein), lessen neutrophil-mediated inflammatory damage, and slow growth and maturation in children. In fact, vegans tend to have low serum lipids, lean physiques, shorter stature, later puberty, and decreased risk for certain prominent 'Western' cancers; a vegan diet has documented clinical efficacy in rheumatoid arthritis. Low-fat vegan diets may be especially protective in regard to cancers linked to insulin resistance--namely, breast and colon cancer--as well as prostate cancer; conversely, the high IGF-I activity associated with heavy ingestion of animal products may be largely responsible for the epidemic of 'Western' cancers in wealthy societies. Increased phytochemical intake is also likely to contribute to the reduction of cancer risk in vegans. Regression of coronary stenoses has been documented during low-fat vegan diets coupled with exercise training; such regimens also tend to markedly improve diabetic control and lower elevated blood pressure. Risk of many other degenerative disorders may be decreased in vegans, although reduced growth factor activity may be responsible for an increased risk of hemorrhagic stroke. By altering the glucagon/insulin balance, it is conceivable that supplemental intakes of key non-essential amino acids could enable omnivores to enjoy some of the health advantages of a vegan diet. An unnecessarily high intake of essential amino acids--either in the absolute sense or relative to total dietary protein--may prove to be as grave a risk factor for 'Western' degenerative diseases as is excessive fat intake. | Vegan proteins may reduce risk of cancer, obesity, and cardiovascular disease by promoting increased glucagon activity. |
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1.0478670597076416, "25565": 1.202409029006958, "25862": 0.009718249551951885, "25932": 0.11778303235769272, "26083": 1.0920805931091309, "26285": 0.2018241584300995, "26402": 0.03360854089260101, "26520": 0.28670501708984375, "26616": 0.18004031479358673, "26734": 0.48670899868011475, "26838": 0.18167030811309814, "26874": 1.06349778175354, "27094": 0.3346569836139679, "27521": 0.009718249551951885, "27598": 0.8281423449516296, "27642": 0.6563454270362854, "27822": 0.6533012986183167, "28024": 0.7565253376960754, "28086": 1.4037197828292847, "28228": 0.45870962738990784, "28251": 1.1205062866210938, "28297": 0.41840189695358276, "28424": 0.12642613053321838, "28685": 0.1401015669107437, "28691": 1.1312761306762695, "28788": 0.2501201331615448, "28828": 0.1229778528213501, "28829": 0.1970241367816925, "28848": 0.16524957120418549, "28902": 0.1011524572968483, "28976": 0.3325583338737488, "29486": 0.6170841455459595} | 6333347 | An emerging family of kinases related to the Drosophila Aurora and budding yeast Ipl1 proteins has been implicated in chromosome segregation and mitotic spindle formation in a number of organisms. Unlike other Aurora/Ipl1-related kinases, the Caenorhabditis elegans orthologue, AIR-2, is associated with meiotic and mitotic chromosomes. AIR-2 is initially localized to the chromosomes of the most mature prophase I–arrested oocyte residing next to the spermatheca. This localization is dependent on the presence of sperm in the spermatheca. After fertilization, AIR-2 remains associated with chromosomes during each meiotic division. However, during both meiotic anaphases, AIR-2 is present between the separating chromosomes. AIR-2 also remains associated with both extruded polar bodies. In the embryo, AIR-2 is found on metaphase chromosomes, moves to midbody microtubules at anaphase, and then persists at the cytokinesis remnant. Disruption of AIR-2 expression by RNA- mediated interference produces entire broods of one-cell embryos that have executed multiple cell cycles in the complete absence of cytokinesis. The embryos accumulate large amounts of DNA and microtubule asters. Polar bodies are not extruded, but remain in the embryo where they continue to replicate. The cytokinesis defect appears to be late in the cell cycle because transient cleavage furrows initiate at the proper location, but regress before the division is complete. Additionally, staining with a marker of midbody microtubules revealed that at least some of the components of the midbody are not well localized in the absence of AIR-2 activity. Our results suggest that during each meiotic and mitotic division, AIR-2 may coordinate the congression of metaphase chromosomes with the subsequent events of polar body extrusion and cytokinesis. | AIR-2: An Aurora/Ipl1-related Protein Kinase Associated with Chromosomes and Midbody Microtubules Is Required for Polar Body Extrusion and Cytokinesis in Caenorhabditis elegans Embryos |
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0.5707147121429443, "29610": 1.1281205415725708} | 6334188 | BACKGROUND Chemotherapy-induced febrile neutropenia (FN) is a clinically important complication that affects patient outcome by delaying chemotherapy doses or reducing dose intensity. Risk of FN depends on chemotherapy- and patient-level factors. We sought to determine the effects of chronic comorbidities on risk of FN. DESIGN We conducted a cohort study to examine the association between a variety of chronic comorbidities and risk of FN in patients diagnosed with six types of cancer (non-Hodgkin lymphoma and breast, colorectal, lung, ovary, and gastric cancer) from 2000 to 2009 who were treated with chemotherapy at Kaiser Permanente Southern California, a large managed care organization. We excluded those patients who received primary prophylactic granulocyte colony-stimulating factor. History of comorbidities and FN events were identified using electronic medical records. Cox models adjusting for propensity score, stratified by cancer type, were used to determine the association between comorbid conditions and FN. Models that additionally adjusted for cancer stage, baseline neutrophil count, chemotherapy regimen, and dose reduction were also evaluated. RESULTS A total of 19 160 patients with mean age of 60 years were included; 963 (5.0%) developed FN in the first chemotherapy cycle. Chronic obstructive pulmonary disease [hazard ratio (HR) = 1.30 (1.07-1.57)], congestive heart failure [HR = 1.43 (1.00-1.98)], HIV infection [HR = 3.40 (1.90-5.63)], autoimmune disease [HR = 2.01 (1.10-3.33)], peptic ulcer disease [HR = 1.57 (1.05-2.26)], renal disease [HR = 1.60 (1.21-2.09)], and thyroid disorder [HR = 1.32 (1.06-1.64)] were all associated with a significantly increased FN risk. CONCLUSIONS These results provide evidence that history of several chronic comorbidities increases risk of FN, which should be considered when managing patients during chemotherapy. | History of chronic comorbidity and risk of chemotherapy-induced febrile neutropenia in cancer patients not receiving G-CSF prophylaxis. |
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"29107": 0.17267228662967682, "29480": 0.6244332790374756} | 6363093 | BACKGROUND Glioblastoma multiforme (GBM) is an umbrella designation that includes a heterogeneous group of primary brain tumors. Several classification strategies of GBM have been reported, some by clinical course and others by resemblance to cell types either in the adult or during development. From a practical and therapeutic standpoint, classifying GBMs by signal transduction pathway activation and by mutation in pathway member genes may be particularly valuable for the development of targeted therapies. METHODOLOGY/PRINCIPAL FINDINGS We performed targeted proteomic analysis of 27 surgical glioma samples to identify patterns of coordinate activation among glioma-relevant signal transduction pathways, then compared these results with integrated analysis of genomic and expression data of 243 GBM samples from The Cancer Genome Atlas (TCGA). In the pattern of signaling, three subclasses of GBM emerge which appear to be associated with predominance of EGFR activation, PDGFR activation, or loss of the RAS regulator NF1. The EGFR signaling class has prominent Notch pathway activation measured by elevated expression of Notch ligands, cleaved Notch receptor, and downstream target Hes1. The PDGF class showed high levels of PDGFB ligand and phosphorylation of PDGFRbeta and NFKB. NF1-loss was associated with lower overall MAPK and PI3K activation and relative overexpression of the mesenchymal marker YKL40. These three signaling classes appear to correspond with distinct transcriptomal subclasses of primary GBM samples from TCGA for which copy number aberration and mutation of EGFR, PDGFRA, and NF1 are signature events. CONCLUSIONS/SIGNIFICANCE Proteomic analysis of GBM samples revealed three patterns of expression and activation of proteins in glioma-relevant signaling pathways. These three classes are comprised of roughly equal numbers showing either EGFR activation associated with amplification and mutation of the receptor, PDGF-pathway activation that is primarily ligand-driven, or loss of NF1 expression. The associated signaling activities correlating with these sentinel alterations provide insight into glioma biology and therapeutic strategies. | Glioblastoma Subclasses Can Be Defined by Activity among Signal Transduction Pathways and Associated Genomic Alterations |
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neuroendocrine changes elicited by pheromonal cues. The molecular mechanisms underlying the sensory response to pheromones and the behavioral repertoire induced through the VNO are not fully characterized. Using the tools of mouse genetics and multielectrode recording, we demonstrate that the sensory activation of VNO neurons requires TRP2, a putative ion channel of the transient receptor potential family that is expressed exclusively in these neurons. Moreover, we show that male mice deficient in TRP2 expression fail to display male-male aggression, and they initiate sexual and courtship behaviors toward both males and females. Our study suggests that, in the mouse, sensory activation of the VNO is essential for sex discrimination of conspecifics and thus ensures gender-specific behavior. | Loss of sex discrimination and male-male aggression in mice deficient for TRP2. |
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"26629": 0.7408206462860107, "26655": 0.07612881064414978, "26718": 0.5069117546081543, "26786": 0.1619328260421753, "26835": 0.969535231590271, "26876": 0.20421554148197174, "26982": 0.4624064862728119, "26989": 1.2336074113845825, "27144": 0.13243216276168823, "27177": 0.0797421783208847, "27233": 0.09672962874174118, "27441": 0.371698260307312, "27512": 1.0229004621505737, "27631": 0.38574060797691345, "27920": 0.5415972471237183, "27950": 0.011650617234408855, "28144": 0.0842406153678894, "28156": 0.7086513638496399, "28297": 0.04767346754670143, "28353": 0.10379679501056671, "28744": 0.16276304423809052, "28775": 0.09672962874174118, "29090": 0.17267228662967682, "29290": 0.3388410806655884, "29486": 0.013579257763922215} | 6372244 | Antibiotics can have significant and long-lasting effects on the gastrointestinal tract microbiota, reducing colonization resistance against pathogens including Clostridium difficile. Here we show that antibiotic treatment induces substantial changes in the gut microbial community and in the metabolome of mice susceptible to C. difficile infection. Levels of secondary bile acids, glucose, free fatty acids and dipeptides decrease, whereas those of primary bile acids and sugar alcohols increase, reflecting the modified metabolic activity of the altered gut microbiome. In vitro and ex vivo analyses demonstrate that C. difficile can exploit specific metabolites that become more abundant in the mouse gut after antibiotics, including the primary bile acid taurocholate for germination, and carbon sources such as mannitol, fructose, sorbitol, raffinose and stachyose for growth. Our results indicate that antibiotic-mediated alteration of the gut microbiome converts the global metabolic profile to one that favours C. difficile germination and growth. | Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection |
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0.043007105588912964, "28965": 0.06612417846918106, "29248": 0.0009760859538801014, "29290": 0.5021947622299194, "29320": 0.9371650815010071} | 6374918 | The CXCR4-SDF-1 axis plays a central role in the trafficking and retention of normal and malignant stem cells in the bone marrow (BM) microenvironment. Here, we used a mouse model of acute promyelocytic leukemia (APL) and a small molecule competitive antagonist of CXCR4, AMD3100, to examine the interaction of mouse APL cells with the BM microenvironment. APL cells from a murine cathepsin G-PML-RARalpha knockin mouse were genetically modified with firefly luciferase (APL(luc)) to allow tracking by bioluminescence imaging. Coculture of APL(luc) cells with M2-10B4 stromal cells protected the leukemia cells from chemotherapy-induced apoptosis in vitro. Upon injection into syngeneic recipients, APL(luc) cells rapidly migrated to the BM followed by egress to the spleen then to the peripheral blood with death due to leukostasis by day 15. Administration of AMD3100 to leukemic mice induced a 1.6-fold increase in total leukocytes and a 9-fold increase of circulating APL blast counts, which peak at 3 hours and return to baseline by 12 hours. Treatment of leukemic mice with chemotherapy plus AMD3100 resulted in decreased tumor burden and improved overall survival compared with mice treated with chemotherapy alone. These studies provide a proof-of-principle for directing therapy to the critical tethers that promote AML-niche interactions. | Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100. |
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been associated with important cellular processes, which should require G-quadruplex-protein interaction. However, the structural basis for specific G-quadruplex recognition by proteins has not been understood. The DEAH (Asp-Glu-Ala-His) box RNA helicase associated with AU-rich element (RHAU) (also named DHX36 or G4R1) specifically binds to and resolves parallel-stranded G-quadruplexes. Here we identified an 18-amino acid G-quadruplex-binding domain of RHAU and determined the structure of this peptide bound to a parallel DNA G-quadruplex. Our structure explains how RHAU specifically recognizes parallel G-quadruplexes. The peptide covers a terminal guanine base tetrad (G-tetrad), and clamps the G-quadruplex using three-anchor-point electrostatic interactions between three positively charged amino acids and negatively charged phosphate groups. This binding mode is strikingly similar to that of most ligands selected for specific G-quadruplex targeting. Binding to an exposed G-tetrad represents a simple and efficient way to specifically target G-quadruplex structures. | Insights into G-quadruplex specific recognition by the DEAH-box helicase RHAU: Solution structure of a peptide-quadruplex complex. |
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0.07159364968538284, "26264": 1.2959036827087402, "26594": 0.3777405619621277, "26698": 0.3443928062915802, "26745": 0.006812678650021553, "26794": 0.026976587250828743, "27010": 0.016465263441205025, "27086": 0.05970508232712746, "27400": 0.4311734735965729, "27718": 0.5010119676589966, "27756": 1.4236729145050049, "27794": 0.6149744987487793, "27890": 0.5707147121429443, "28139": 0.7086513638496399, "28297": 0.0009760859538801014, "28616": 0.49030399322509766, "28767": 0.38574060797691345, "28794": 0.14349138736724854, "28927": 0.06520967930555344, "29004": 0.11081436276435852, "29310": 0.5098485946655273, "29398": 0.10906458646059036} | 6387956 | BACKGROUND Non-clinical psychotic symptoms appear common in children, but it is possible that a proportion of reported symptoms result from misinterpretation. There is a well-established association between pre-morbid low IQ score and schizophrenia. Psychosis-like symptoms in children may also be a risk factor for psychotic disorder but their relationship with IQ is unclear. AIMS To investigate the prevalence, nature and frequency of psychosis-like symptoms in 12-year-old children and study their relationship with IQ. METHOD Longitudinal study using the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. A total of 6455 children completed screening questions for 12 psychotic symptoms followed by a semi-structured clinical assessment. IQ was assessed at 8 years of age using the Wechsler Intelligence Scale for Children (3rd UK edition). RESULTS The 6-month period prevalence for one or more symptoms was 13.7% (95% CI 12.8-14.5). After adjustment for confounding variables, there was a non-linear association between IQ score and psychosis-like symptoms, such that only those with below average IQ score had an increased risk of reporting such symptoms. CONCLUSIONS Non-clinical psychotic symptoms occur in a significant proportion of 12-year-olds. Symptoms are associated with low IQ and also less strongly with a high IQ score. The pattern of association with IQ differs from that observed in schizophrenia. | IQ and non-clinical psychotic symptoms in 12-year-olds: results from the ALSPAC birth cohort |
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0.036437395960092545, "27295": 0.2478361576795578, "27854": 0.02316705882549286, "28517": 0.052318159490823746, "28691": 0.29255300760269165, "28696": 0.25088030099868774, "28848": 0.7881022095680237, "28873": 0.1229778528213501, "28915": 0.4286321699619293, "29166": 0.8091925978660583, "29295": 0.319873183965683, "29454": 0.9493325352668762, "29560": 0.04674193635582924} | 6397191 | Endothelin-1 (ET-1) is the predominant endothelin isopeptide generated by the vascular wall and therefore appears to be the most important peptide involved in regulation of cardiovascular events. Many pathologic conditions are associated with elevations of ET-1 in the blood vessel wall. Because these conditions are often cytokine driven, we examined the effects of a mixture of cytokines on ET-1 production in human vascular smooth muscle cells (VSMCs) derived from internal mammary artery and saphenous vein (SV). Incubation of IMA and SV VSMCs with tumor necrosis factor-alpha (10 ng/ml) and interferon-gamma (1000 U/ml) in combination for up to 48 h markedly elevated the expression of mRNA for prepro-ET-1 and the release of ET-1 into the culture medium. This cytokine-stimulated release of ET-1 was inhibited by a series of dual endothelin-converting enzyme (ECE)/neutral endopeptidase inhibitors, phosphoramidon, CGS 26303, and CGS 26393, with an accompanying increase in big ET-1 release but with no effect on expression of mRNA for prepro-ET-1. These same compounds were 10 times more potent at inhibiting the conversion of exogenously applied big ET-1 to ET-1. ECE-1b/c mRNA is present in SV VSMCs, however no ECE-1a is present in these cells. Thus VSMCs most probably contain, like endothelial cells, an intracellular ECE responsible for the endogenous synthesis of ET-1. Under the influence of pro-inflammatory mediators the vascular smooth muscle can therefore become an important site of ET-1 production, as has already been established for the dilator mediators nitric oxide, prostaglandin I2, and prostaglandin E2. | Endothelin-1 is induced by cytokines in human vascular smooth muscle cells: evidence for intracellular endothelin-converting enzyme. |
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We studied the genome-wide binding locations of three key regulatory proteins (POU5F1, also known as OCT4; NANOG; and CTCF) in human and mouse embryonic stem cells. In contrast to CTCF, we found that the binding profiles of OCT4 and NANOG are markedly different, with only ∼5% of the regions being homologously occupied. We show that transposable elements contributed up to 25% of the bound sites in humans and mice and have wired new genes into the core regulatory network of embryonic stem cells. These data indicate that species-specific transposable elements have substantially altered the transcriptional circuitry of pluripotent stem cells. | Transposable elements have rewired the core regulatory network of human embryonic stem cells |
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"28938": 0.4248080551624298, "29107": 0.8957691192626953, "29486": 0.6989894509315491} | 6404801 | Micro (mi)RNAs are small non-coding RNAs that regulate the expression of their targets' messenger RNAs through both translational inhibition and regulation of target RNA stability. Recently, a number of viruses, particularly of the herpesvirus family, have been shown to express their own miRNAs to control both viral and cellular transcripts. Although some targets of viral miRNAs are known, their function in a physiologically relevant infection remains to be elucidated. As such, no in vivo phenotype of a viral miRNA knock-out mutant has been described so far. Here, we report on the first functional phenotype of a miRNA knock-out virus in vivo. During subacute infection of a mutant mouse cytomegalovirus lacking two viral miRNAs, virus production is selectively reduced in salivary glands, an organ essential for virus persistence and horizontal transmission. This phenotype depends on several parameters including viral load and mouse genetic background, and is abolished by combined but not single depletion of natural killer (NK) and CD4+ T cells. Together, our results point towards a miRNA-based immunoevasion mechanism important for long-term virus persistence. | Cytomegalovirus microRNAs Facilitate Persistent Virus Infection in Salivary Glands |
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0.41195443272590637, "25714": 0.014542185701429844, "25778": 0.03925827145576477, "26226": 0.4624064862728119, "26261": 0.3443928062915802, "26402": 0.8893690705299377, "26591": 0.014542185701429844, "26989": 0.20660123229026794, "27144": 0.7987030148506165, "28139": 0.7182208299636841, "28156": 0.46055975556373596, "29458": 0.38174858689308167} | 6407356 | Coxibs, including celecoxib, and other nonsteroidal anti-inflammatory drugs (NSAID), including aspirin, are among the most promising cancer chemopreventive agents in development today. This article examines the data on the efficacy of these agents in animal model studies of cancer prevention carried out by the authors. The studies evaluated here are restricted to our rodent models of colon/intestinal, bladder, and nonmelanoma skin cancer, in which celecoxib and other NSAIDs were administered as either cancer preventive or therapeutic agents. These studies may shed light on several questions. Is celecoxib unique compared with other NSAIDs, and if so, what implications would this have for human use? Are standard NSAIDs (which inhibit both COX-1 and COX-2) as effective as celecoxib in animal studies? Is the efficacy of celecoxib in particular or NSAIDs in general due to their off-target effects or to their effects on COX-1 and COX-2? What is the likely efficacy of low-dose aspirin? Some questions raised by human trials and epidemiology are discussed and related to our observations in animal model studies. We also discuss the problem of cardiovascular (CV) events associated with coxibs and certain other NSAIDs and whether results in animal models are predictive of efficacy in humans. On the basis of epidemiologic studies and its CV profile, aspirin seems to be the most promising NSAID for preventing human colorectal, bladder, and skin cancer, although the animal data for aspirin are less clear. A comprehensive understanding of the results of coxibs and other NSAIDs in animal studies may help inform and shape human trials of these commonly employed, relatively inexpensive, and highly effective compounds. | Coxibs and other nonsteroidal anti-inflammatory drugs in animal models of cancer chemoprevention. |
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"26835": 0.8433839678764343, "27144": 0.17759032547473907, "27179": 0.31845372915267944, "27292": 0.5523349046707153, "27480": 0.7314660549163818, "27811": 0.28082266449928284, "28389": 0.3346569836139679, "28516": 0.14179791510105133, "28774": 0.13157635927200317, "28788": 0.2105647772550583, "28828": 0.20022670924663544, "28835": 0.034552380442619324, "29238": 0.00875066313892603} | 6415816 | The inborn errors of heme biosynthesis, the porphyrias, are 8 genetically distinct metabolic disorders that can be classified as "acute hepatic," "hepatic cutaneous," and "erythropoietic cutaneous" diseases. Recent advances in understanding their pathogenesis and molecular genetic heterogeneity have led to improved diagnosis and treatment. These advances include DNA-based diagnoses for all the porphyrias, new understanding of the pathogenesis of the acute hepatic porphyrias, identification of the iron overload-induced inhibitor of hepatic uroporphyrin decarboxylase activity that causes the most common porphyria, porphyria cutanea tarda, the identification of an X-linked form of erythropoietic protoporphyria due to gain-of-function mutations in erythroid-specific 5-aminolevulinate synthase (ALAS2), and new and experimental treatments for the erythropoietic porphyrias. Knowledge of these advances is relevant for hematologists because they administer the hematin infusions to treat the acute attacks in patients with the acute hepatic porphyrias, perform the chronic phlebotomies to reduce the iron overload and clear the dermatologic lesions in porphyria cutanea tarda, and diagnose and treat the erythropoietic porphyrias, including chronic erythrocyte transfusions, bone marrow or hematopoietic stem cell transplants, and experimental pharmacologic chaperone and stem cell gene therapies for congenital erythropoietic protoporphyria. These developments are reviewed to update hematologists on the latest advances in these diverse disorders. | The porphyrias: advances in diagnosis and treatment. |
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0.5629584193229675} | 6417632 | BACKGROUND COPD is an inflammatory disorder characterised by chronic airflow limitation, but the extent to which airway inflammation is related to functional abnormalities is still uncertain. The interaction between inflammatory cells and airway smooth muscle may have a crucial role. METHODS To investigate the microlocalisation of inflammatory cells within the airway smooth muscle in COPD, surgical specimens obtained from 26 subjects undergoing thoracotomy (eight smokers with COPD, 10 smokers with normal lung function, and eight non-smoking controls) were examined. Immunohistochemical analysis was used to quantify the number of neutrophils, macrophages, mast cells, CD4+ and CD8+ cells localised within the smooth muscle of peripheral airways. RESULTS Smokers with COPD had an increased number of neutrophils and CD8+ cells in the airway smooth muscle compared with non-smokers. Smokers with normal lung function also had a neutrophilic infiltration in the airway smooth muscle, but to a lesser extent. When all the subjects were analysed as one group, neutrophilic infiltration was inversely related to forced expiratory volume in 1 second (% predicted). CONCLUSIONS Microlocalisation of neutrophils and CD8+ cells in the airway smooth muscle in smokers with COPD suggests a possible role for these cells in the pathogenesis of smoking induced airflow limitation. | Neutrophilic infiltration within the airway smooth muscle in patients with COPD. |
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DESIGN Population based cross sectional postal questionnaire survey. SETTING General Practice Patient Survey 2012-13. MAIN OUTCOME MEASURES Potential associations between sociodemographic factors (including ethnicity and ability to take time away from work during working hours to attend a healthcare consultation) and provider organisation type (not for profit, NHS, or commercial) and service users' experience of out of hours care (timeliness, confidence and trust in the out of hours clinician, and overall experience of the service), rated on a scale of 0-100. Which sociodemographic/provider characteristics were associated with service users' experience, the extent to which any observed differences could be because of clustering of service users of a particular sociodemographic group within poorer scoring providers, and the extent to which observed differences in experience varied across types of provider. RESULTS The overall response rate was 35%; 971,232/2,750,000 patients returned surveys. Data from 902,170 individual service users were mapped through their registered practice to one of 86 providers of out of hours GP care with known organisation type. Commercial providers of out of hours GP care were associated with poorer reports of overall experience of care, with a mean difference of -3.13 (95% confidence interval -4.96 to -1.30) compared with not for profit providers. Asian service users reported lower scores for all three experience outcomes than white service users (mean difference for overall experience of care -3.62, -4.36 to -2.89), as did service users who were unable to take time away from work compared with service users who did not work (mean difference for overall experience of care -4.73, -5.29 to -4.17). CONCLUSIONS Commercial providers of out of hours GP care were associated with poorer experience of care. Targeted interventions aimed at improving experience for patients from ethnic minorities and patients who are unable to take time away from work might be warranted. | Characteristics of service users and provider organisations associated with experience of out of hours general practitioner care in England: population based cross sectional postal questionnaire survey. |
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0.08961215615272522, "28873": 0.25239890813827515, "29217": 0.026976587250828743, "29251": 0.9798521995544434} | 6421792 | Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric patients and over 50% of adult patients with ALL do not achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy the most substantial challenge in the treatment of this disease. Using whole-exome sequencing, we identify mutations in the cytosolic 5'-nucleotidase II gene (NT5C2), which encodes a 5'-nucleotidase enzyme that is responsible for the inactivation of nucleoside-analog chemotherapy drugs, in 20/103 (19%) relapse T cell ALLs and 1/35 (3%) relapse B-precursor ALLs. NT5C2 mutant proteins show increased nucleotidase activity in vitro and conferred resistance to chemotherapy with 6-mercaptopurine and 6-thioguanine when expressed in ALL lymphoblasts. These results support a prominent role for activating mutations in NT5C2 and increased nucleoside-analog metabolism in disease progression and chemotherapy resistance in ALL. | Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL |
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"26014": 0.09406650811433792, "26131": 0.7969439625740051, "26147": 0.04674193635582924, "26244": 0.14433705806732178, "26394": 0.45251765847206116, "26520": 0.25088030099868774, "26534": 0.09761575609445572, "26572": 0.9348671436309814, "26601": 0.1905880719423294, "26773": 0.7229714393615723, "26775": 0.04860413447022438, "26874": 0.034552380442619324, "27058": 1.0037577152252197, "27571": 0.0174254160374403, "27776": 0.08154398202896118, "27777": 0.03925827145576477, "27781": 0.14349138736724854, "27854": 0.034552380442619324, "28691": 0.28890204429626465, "28873": 0.8349450826644897, "28901": 0.025073638185858727, "28940": 0.29255300760269165, "29129": 0.026976587250828743, "29226": 0.6080870032310486, "29320": 0.015504186972975731, "29489": 0.43244171142578125} | 6422576 | A growing number of cellular regulatory mechanisms are being linked to protein modification by the polypeptide ubiquitin. These include key transitions in the cell cycle, class I antigen processing, signal transduction pathways, and receptor-mediated endocytosis. In most, but not all, of these examples, ubiquitination of a protein leads to its degradation by the 26S proteasome. Following attachment of ubiquitin to a substrate and binding of the ubiquitinated protein to the proteasome, the bound substrate must be unfolded (and eventually deubiquitinated) and translocated through a narrow set of channels that leads to the proteasome interior, where the polypeptide is cleaved into short peptides. Protein ubiquitination and deubiquitination are both mediated by large enzyme families, and the proteasome itself comprises a family of related but functionally distinct particles. This diversity underlies both the high substrate specificity of the ubiquitin system and the variety of regulatory mechanisms that it serves. | Ubiquitin-dependent protein degradation. |
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"27544": 0.040196798741817474, "27814": 0.04674193635582924, "28154": 0.43875885009765625, "28247": 0.8039615154266357, "28389": 0.08692999184131622, "28691": 1.293763518333435, "28835": 0.04860413447022438, "28848": 0.2822965085506439, "28873": 0.06246116757392883, "29235": 0.03360854089260101, "29300": 0.19782574474811554, "29458": 0.5336109399795532} | 6426919 | Recently, mutations in the connection subdomain (CN) and RNase H domain of HIV-1 reverse transcriptase (RT) were observed to exhibit dual resistance to nucleoside and nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). To elucidate the mechanism by which CN and RH mutations confer resistance to NNRTIs, we hypothesized that these mutations reduce RNase H cleavage and provide more time for the NNRTI to dissociate from the RT, resulting in the resumption of DNA synthesis and enhanced NNRTI resistance. We observed that the effect of the reduction in RNase H cleavage on NNRTI resistance is dependent upon the affinity of each NNRTI to the RT and further influenced by the presence of NNRTI-binding pocket (BP) mutants. D549N, Q475A, and Y501A mutants, which reduce RNase H cleavage, enhance resistance to nevirapine (NVP) and delavirdine (DLV), but not to efavirenz (EFV) and etravirine (ETR), consistent with their increase in affinity for RT. Combining the D549N mutant with NNRTI BP mutants further increases NNRTI resistance from 3- to 30-fold, supporting the role of NNRTI-RT affinity in our NNRTI resistance model. We also demonstrated that CNs from treatment-experienced patients, previously reported to enhance NRTI resistance, also reduce RNase H cleavage and enhance NNRTI resistance in the context of the patient RT pol domain or a wild-type pol domain. Together, these results confirm key predictions of our NNRTI resistance model and provide support for a unifying mechanism by which CN and RH mutations can exhibit dual NRTI and NNRTI resistance. | A novel molecular mechanism of dual resistance to nucleoside and nonnucleoside reverse transcriptase inhibitors. |
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under the assumption of local spatial coding. Most neurons respond maximally to sounds located far to the left or right side, with few neurons tuned to the frontal midline. Paradoxically, psychophysical studies show optimal spatial acuity across the frontal midline. In this paper, we revisit the problem of inhomogeneous spatial sampling in three fields of cat auditory cortex. In each field, we confirm that neural responses tend to be greatest for lateral positions, but show the greatest modulation for near-midline source locations. Moreover, identification of source locations based on cortical responses shows sharp discrimination of left from right but relatively inaccurate discrimination of locations within each half of space. Motivated by these findings, we explore an opponent-process theory in which sound-source locations are represented by differences in the activity of two broadly tuned channels formed by contra- and ipsilaterally preferring neurons. Finally, we demonstrate a simple model, based on spike-count differences across cortical populations, that provides bias-free, level-invariant localization—and thus also a solution to the “binding problem” of associating spatial information with other nonspatial attributes of sounds. | Location Coding by Opponent Neural Populations in the Auditory Cortex |
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However, it is unclear whether intrinsic epigenetic events can drive reprogramming to naive pluripotency or if distinct chromatin states are instead simply a reflection of discrete pluripotent states. Here, we show that blocking histone H3K4 methyltransferase MLL1 activity with the small-molecule inhibitor MM-401 reprograms mouse epiblast stem cells (EpiSCs) to naive pluripotency. This reversion is highly efficient and synchronized, with more than 50% of treated EpiSCs exhibiting features of naive embryonic stem cells (ESCs) within 3 days. Reverted ESCs reactivate the silenced X chromosome and contribute to embryos following blastocyst injection, generating germline-competent chimeras. Importantly, blocking MLL1 leads to global redistribution of H3K4me1 at enhancers and represses lineage determinant factors and EpiSC markers, which indirectly regulate ESC transcription circuitry. These findings show that discrete perturbation of H3K4 methylation is sufficient to drive reprogramming to naive pluripotency. | MLL1 Inhibition Reprograms Epiblast Stem Cells to Naive Pluripotency. |
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Here, we report that combined deficiency for the transcription factors MafB and c-Maf enables extended expansion of mature monocytes and macrophages in culture without loss of differentiated phenotype and function. Upon transplantation, the expanded cells are nontumorigenic and contribute to functional macrophage populations in vivo. Small hairpin RNA inactivation shows that continuous proliferation of MafB/c-Maf deficient macrophages requires concomitant up-regulation of two pluripotent stem cell-inducing factors, KLF4 and c-Myc. Our results indicate that MafB/c-MafB deficiency renders self-renewal compatible with terminal differentiation. It thus appears possible to amplify functional differentiated cells without malignant transformation or stem cell intermediates. | MafB/c-Maf deficiency enables self-renewal of differentiated functional macrophages. |
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"28873": 0.9980146884918213, "29090": 0.045809537172317505, "29111": 0.9240728616714478, "29147": 0.11691460013389587, "29513": 0.2184450328350067} | 6454371 | Macropinocytosis is a regulated form of endocytosis that mediates the non-selective uptake of solute molecules, nutrients and antigens. It is an actin-dependent process initiated from surface membrane ruffles that give rise to large endocytic vacuoles called macropinosomes. Macropinocytosis is important in a range of physiological processes; it is highly active in macrophages and dendritic cells where it is a major pathway for the capture of antigens, it is relevant to cell migration and tumour metastasis and it represents a portal of cell entry exploited by a range of pathogens. The molecular basis for the formation and maturation of macropinosomes has only recently begun to be defined. Here, we review the general characteristics of macropinocytosis, describe some of the regulators of this pathway, which have been identified to date and highlight strategies to explore the relevance of this endocytosis pathway in vivo. | Macropinocytosis: an endocytic pathway for internalising large gulps. |
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"27854": 0.11778303235769272, "28086": 1.2267581224441528, "28835": 0.07612881064414978, "28964": 0.10203468054533005, "28991": 1.2969720363616943, "29206": 0.37640097737312317, "29217": 0.009718249551951885, "29290": 0.11778303235769272} | 6455142 | Although regulation of histone methylation is believed to contribute to embryonic stem cell (ESC) self-renewal, the mechanisms remain obscure. We show here that the histone H3 trimethyl lysine 4 (H3K4me3) demethylase, KDM5B, is a downstream Nanog target and critical for ESC self-renewal. Although KDM5B is believed to function as a promoter-bound repressor, we find that it paradoxically functions as an activator of a gene network associated with self-renewal. ChIP-Seq reveals that KDM5B is predominantly targeted to intragenic regions and that it is recruited to H3K36me3 via an interaction with the chromodomain protein MRG15. Depletion of KDM5B or MRG15 increases intragenic H3K4me3, increases cryptic intragenic transcription, and inhibits transcriptional elongation of KDM5B target genes. We propose that KDM5B activates self-renewal-associated gene expression by repressing cryptic initiation and maintaining an H3K4me3 gradient important for productive transcriptional elongation. | KDM5B regulates embryonic stem cell self-renewal and represses cryptic intragenic transcription. |
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"28251": 1.158010721206665, "28312": 0.083342544734478, "28424": 0.04487626627087593, "28505": 0.029824240133166313, "28691": 0.2026219218969345, "28715": 1.0855059623718262, "28788": 0.46486347913742065, "29391": 0.41195443272590637, "29398": 1.1598494052886963, "29489": 0.7445381283760071} | 6472746 | Chromosome segregation during cell division depends on stable attachment of kinetochores to spindle microtubules. Mitotic spindle formation and kinetochore-microtubule (K-MT) capture typically occur within minutes of nuclear envelope breakdown. In contrast, during meiosis I in mouse oocytes, formation of the acentrosomal bipolar spindle takes 3-4 h, and stabilization of K-MT attachments is delayed an additional 3-4 h. The mechanism responsible for this delay, which likely prevents stabilization of erroneous attachments during spindle formation, is unknown. Here we show that during meiosis I, attachments are regulated by CDK1 activity, which gradually increases through prometaphase and metaphase I. Partial reduction of CDK1 activity delayed formation of stable attachments, whereas a premature increase in CDK1 activity led to precocious formation of stable attachments and eventually lagging chromosomes at anaphase I. These results indicate that the slow increase in CDK1 activity in meiosis I acts as a timing mechanism to allow stable K-MT attachments only after bipolar spindle formation, thus preventing attachment errors. | Increased CDK1 activity determines the timing of kinetochore-microtubule attachments in meiosis I |
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0.22157983481884003, "29401": 0.0770333781838417, "29610": 0.08513788133859634} | 6477536 | OBJECTIVE To determine the rate of early discontinuation and non-publication of randomised controlled trials involving patients undergoing surgery. DESIGN Cross sectional observational study of registered and published trials. SETTING Randomised controlled trials of interventions in patients undergoing a surgical procedure. DATA SOURCES The ClinicalTrials.gov database was searched for interventional trials registered between January 2008 and December 2009 using the keyword "surgery". Recruitment status was extracted from the ClinicalTrials.gov database. A systematic search for studies published in peer reviewed journals was performed; if they were not found, results posted on the ClinicalTrials.gov results database were sought. Email queries were sent to trial investigators of discontinued and unpublished completed trials if no reason for the respective status was disclosed. MAIN OUTCOME MEASURES Trial discontinuation before completion and non-publication after completion. Logistic regression was used to determine the effect of funding source on publication status, with adjustment for intervention type and trial size. RESULTS Of 818 registered trials found using the keyword "surgery", 395 met the inclusion criteria. Of these, 21% (81/395) were discontinued early, most commonly owing to poor recruitment (44%, 36/81). The remaining 314 (79%) trials proceeded to completion, with a publication rate of 66% (208/314) at a median time of 4.9 (interquartile range 4.0-6.0) years from study completion to publication search. A further 6% (20/314) of studies presented results on ClinicalTrials.gov without a corresponding peer reviewed publication. Industry funding did not affect the rate of discontinuation (adjusted odds ratio 0.91, 95% confidence interval 0.54 to 1.55) but was associated with a lower odds of publication for completed trials (0.43, 0.26 to 0.72). Investigators' email addresses for trials with an uncertain fate were identified for 71.4% (10/14) of discontinued trials and 83% (101/122) of unpublished studies. Only 43% (6/14) and 20% (25/122) replies were received. Email responses for completed trials indicated 11 trials in press, five published studies (four in non-indexed peer reviewed journals), and nine trials remaining unpublished. CONCLUSIONS One in five surgical randomised controlled trials are discontinued early, one in three completed trials remain unpublished, and investigators of unpublished studies are frequently not contactable. This represents a waste of research resources and raises ethical concerns regarding hidden clinical data and futile participation by patients with its attendant risks. To promote future efficiency and transparency, changes are proposed to research governance frameworks to overcome these concerns. | Discontinuation and non-publication of surgical randomised controlled trials: observational study |
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human somatic cells into induced pluripotent stem (iPS) cells by defined transcription factors (TFs) provides great potential for regenerative medicine and biomedical research. This procedure has many challenges, including low reprogramming efficiency, many partially reprogrammed colonies, somatic coding mutations in the genome, etc. Here, we describe a simple approach for generating fully reprogrammed human iPS cells by using a single polycistronic retroviral vector expressing four human TFs in a single open reading frame (ORF), combined with a cocktail containing three small molecules (Sodium butyrate, SB431542, and PD0325901). Our results demonstrate that human iPS cells generated by this approach express human ES cells markers and exhibit pluripotency demonstrated by their abilities to differentiate into the three germ layers in vitro and in vivo. Notably, this approach not only provides a much faster reprogramming process but also significantly diminishes partially reprogrammed iPS cell colonies, thus facilitating efficient isolation of desired fully reprogrammed iPS cell colonies. | Efficient Generation of Fully Reprogrammed Human iPS Cells via Polycistronic Retroviral Vector and a New Cocktail of Chemical Compounds |
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0.40546512603759766, "27756": 0.25088030099868774, "27776": 0.1710275560617447, "27805": 0.15442965924739838, "27994": 0.4487839937210083, "28070": 0.2317005842924118, "28093": 0.24171993136405945, "28228": 0.8022117614746094, "28297": 0.10906458646059036, "28321": 0.007782140281051397, "28466": 0.009718249551951885, "28744": 0.9409833550453186, "28767": 0.12986256182193756, "28836": 0.23864774405956268} | 6490571 | CONTEXT Little is known about the extent or severity of untreated mental disorders, especially in less-developed countries. OBJECTIVE To estimate prevalence, severity, and treatment of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) mental disorders in 14 countries (6 less developed, 8 developed) in the World Health Organization (WHO) World Mental Health (WMH) Survey Initiative. DESIGN, SETTING, AND PARTICIPANTS Face-to-face household surveys of 60 463 community adults conducted from 2001-2003 in 14 countries in the Americas, Europe, the Middle East, Africa, and Asia. MAIN OUTCOME MEASURES The DSM-IV disorders, severity, and treatment were assessed with the WMH version of the WHO Composite International Diagnostic Interview (WMH-CIDI), a fully structured, lay-administered psychiatric diagnostic interview. RESULTS The prevalence of having any WMH-CIDI/DSM-IV disorder in the prior year varied widely, from 4.3% in Shanghai to 26.4% in the United States, with an interquartile range (IQR) of 9.1%-16.9%. Between 33.1% (Colombia) and 80.9% (Nigeria) of 12-month cases were mild (IQR, 40.2%-53.3%). Serious disorders were associated with substantial role disability. Although disorder severity was correlated with probability of treatment in almost all countries, 35.5% to 50.3% of serious cases in developed countries and 76.3% to 85.4% in less-developed countries received no treatment in the 12 months before the interview. Due to the high prevalence of mild and subthreshold cases, the number of those who received treatment far exceeds the number of untreated serious cases in every country. CONCLUSIONS Reallocation of treatment resources could substantially decrease the problem of unmet need for treatment of mental disorders among serious cases. Structural barriers exist to this reallocation. Careful consideration needs to be given to the value of treating some mild cases, especially those at risk for progressing to more serious disorders. | Prevalence, severity, and unmet need for treatment of mental disorders in the World Health Organization World Mental Health Surveys. |
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"26835": 0.5381823778152466, "26989": 0.013579257763922215, "27144": 0.4950772523880005, "27276": 0.02316705882549286, "28177": 0.27934664487838745, "28282": 0.2247048318386078, "28283": 0.6719275116920471, "28648": 0.4624064862728119, "29235": 0.12556517124176025, "29251": 0.8989537954330444, "29278": 0.016465263441205025, "29461": 0.0797421783208847} | 6491532 | SETTING Tuberculosis (TB) program, Damien Foundation Projects, Bangladesh. OBJECTIVE To summarize the outcome and its determinants of the first treatment for multidrug-resistant TB using a standardized regimen consisting of a minimum 9 months. DESIGN This was a prospective, observational study of a gatifloxacin (GFX) based directly observed regimen, mainly with initial hospitalization. The 4-month intensive phase was extended until sputum smear conversion. Patients were monitored using culture for up to 2 years after treatment completion. RESULTS Of the 515 patients who met the study inclusion criteria and were successively enrolled from 2005 to 2011, 84.4% had a bacteriologically favorable outcome. Due to extensive disease with delayed sputum conversion, only half of the patients completed treatment within 9 months; however, 95% were able to complete treatment within 12 months. Eleven patients failed or relapsed, and 93.1% of the 435 patients who were successfully treated completed at least 12 months post-treatment follow-up. The strongest risk factor for a bacteriologically unfavorable outcome was high-level fluoroquinolone (FQ) resistance, particularly when compounded by initial pyrazinamide (PZA) resistance. Low-level FQ resistance had no unfavorable effect on treatment outcome. Amplification of drug resistance occurred only once, in a patient strain that was initially only susceptible to kanamycin and clofazimine. CONCLUSION The excellent outcome of the Bangladesh regimen was largely maintained. Bacteriological treatment failures and relapses were rare, except among patients with high-level GFX resistance, notably in the presence of PZA resistance. | Successful '9-month Bangladesh regimen' for multidrug-resistant tuberculosis among over 500 consecutive patients. |
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"28829": 0.3163207769393921, "28835": 0.3923587501049042, "28927": 0.0058422754518687725, "29003": 0.2105647772550583, "29025": 0.1685553640127182, "29516": 0.0058422754518687725} | 6492658 | Weeble mutant mice have severe locomotor instability and significant neuronal loss in the cerebellum and in the hippocampal CA1 field. Genetic mapping was used to localize the mutation to the gene encoding inositol polyphosphate 4-phosphatase type I (Inpp4a), where a single nucleotide deletion results in a likely null allele. The substrates of INPP4A are intermediates in a pathway affecting intracellular Ca(2+) release but are also involved in cell cycle regulation through binding the Akt protooncogene; dysfunction in either may account for the neuronal loss of weeble mice. Although other mutations in phosphoinositide enzymes are associated with synaptic defects without neuronal loss, weeble shows that Inpp4a is critical for the survival of a subset of neurons during postnatal development in mice. | A Null Mutation in Inositol Polyphosphate 4-Phosphatase Type I Causes Selective Neuronal Loss in Weeble Mutant Mice |
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