spalde-v3-lexical
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"26163": 0.1510767638683319, "26402": 0.030771657824516296, "26520": 0.1011524572968483, "26773": 0.4067663550376892, "27011": 0.3012613356113434, "27045": 0.3170322775840759, "27094": 0.42161011695861816, "27354": 0.007782140281051397, "27487": 0.14349138736724854, "27781": 0.6128603219985962, "27915": 0.5324648022651672, "28489": 0.11604541540145874, "28613": 0.6941232681274414, "28691": 0.21214580535888672, "28696": 0.018384648486971855, "28723": 0.7047978043556213, "28788": 0.18411032855510712, "28835": 0.21214580535888672, "28848": 0.0174254160374403, "28873": 0.2516399025917053, "29129": 0.7018978595733643, "29166": 0.9256220459938049, "29290": 0.39893341064453125, "29490": 0.42225050926208496, "29494": 0.47463157773017883} | 8446259 | Background: Vascular calcification (VC), in which vascular smooth muscle cells (VSMCs) undergo a phenotypic transformation into osteoblast-like cells, is one of the emergent risk factors for the accelerated atherosclerosis process characteristic of chronic kidney disease (CKD). Phosphate is an important regulator of VC. Methods: The expression of different smooth muscle cell or osteogenesis markers in response to high concentrations of phosphate or exogenous bone morphogenetic protein 2 (BMP-2) was examined by qRT-PCR and western blotting in rat VSMCs. Osteocalcin secretion was measured by radioimmunoassay. Differentiation and calcification of VSMCs were examined by alkaline phosphatase (ALP) activity assay and Alizarin staining. Short hairpin RNA-mediated silencing of β-catenin was performed to examine the involvement of Wnt/β-catenin signaling in VSMC calcification and osteoblastic differentiation induced by high phosphate or BMP-2. Apoptosis was determined by TUNEL assay and immunofluorescence imaging. Results: BMP-2 serum levels were significantly higher in CKD patients than in controls. High phosphate concentrations and BMP-2 induced VSMC apoptosis and upregulated the expression of β-catenin, Msx2, Runx2 and the phosphate cotransporter Pit1, whereas a BMP-2 neutralization antibody reversed these effects. Knockdown of β-catenin abolished the effect of high phosphate and BMP-2 on VSMC apoptosis and calcification. Conclusions: BMP-2 plays a crucial role in calcium deposition in VSMCs and VC in CKD patients via a mechanism involving the Wnt/β-catenin pathway. | Vascular Calcification in Chronic Kidney Disease is Induced by Bone Morphogenetic Protein-2 via a Mechanism Involving the Wnt/β-Catenin Pathway |
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"26989": 0.7528522610664368, "27011": 0.997294545173645, "27144": 0.996573805809021, "27159": 0.18816383183002472, "27178": 0.12728634476661682, "27179": 0.6038249135017395, "27312": 0.3519764244556427, "27384": 0.03266380727291107, "27404": 0.6405166387557983, "27495": 1.0073304176330566, "27532": 0.24018502235412598, "27881": 0.3850763738155365, "27892": 0.1710275560617447, "27950": 0.9568626880645752, "28207": 0.11256109178066254, "28415": 0.004870930220931768, "28472": 0.2539152204990387, "28518": 0.129004567861557, "28522": 0.15693697333335876, "28674": 0.15442965924739838, "28767": 0.0797421783208847, "28804": 0.1970241367816925, "28893": 0.13243216276168823, "29068": 0.05139094591140747, "29408": 0.08692999184131622} | 8446324 | Advances in the fields of molecular and translational research, oncology, and surgery have emboldened the medical community to believe that intrinsic brain tumors may be treatable. Intraoperative imaging and brain mapping allow operations adjacent to eloquent cortex and more radical resection of tumors with increased confidence and safety. Despite these advances, the infiltrating edge of a neoplasm and distant microscopic satellite lesions will never be amendable to a surgical cure. Indeed, it is continued research into the delivery of an efficacious chemobiologic agent that will eventually allows us to manage this primary cause of treatment failure. | Advances in brain tumor surgery. |
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"28696": 0.05139094591140747, "28804": 0.18978065252304077, "29035": 0.1229778528213501, "29090": 0.4494072198867798, "29110": 0.10555581003427505, "29180": 0.3656192123889923, "29361": 0.0913962796330452, "29392": 0.05970508232712746, "29596": 0.1221139207482338} | 8447873 | BACKGROUND Organophosphorus pesticide (OP) self-poisoning is a major problem in the developing rural world. There is little clinical trial data to guide therapy, hindering the identification of best therapy. Despite the recognition of adverse effects, gastric lavage is commonly done in Asia. We aimed to identify studies assessing its effectiveness. METHOD We systematically searched the literature for controlled clinical studies that assessed the effect of gastric lavage in OP pesticide self-poisoning. RESULTS All 56 studies identified were Chinese and reported benefit from the intervention studied, including multiple gastric lavages, use of norepinephrine or pralidoxime in the lavage fluid, concurrent treatment with naloxone or scopolamine, insertion of the gastric tube via a laparotomy incision, and lavage later than 12 h post-ingestion. However, only 23 were RCTs and none presented adequate methodology for their quality to be assessed. The patient population and study treatment protocol were not defined - large variation in case fatality in the control arm of the studies (from 4.5 to 93%) suggests marked variation between studies and likely between study arms. No study compared an intervention against a control group receiving no gastric lavage or provided any data to indicate whether a significant quantity of poison was removed. CONCLUSION Despite widespread use of multiple gastric lavages for OP pesticide poisoning across Asia, there is currently no high-quality evidence to support its clinical effectiveness. There is a need for studies to identify in which patients and for what duration gastric lavage is able to remove significant quantities of poison. Following these studies, large clinical trials will be required to address the effectiveness and safety of gastric lavage (either single or multiple) in acute OP pesticide poisoning. | Systematic review of controlled clinical trials of gastric lavage in acute organophosphorus pesticide poisoning. |
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0.49030399322509766, "27058": 0.9944084882736206, "27099": 0.06612417846918106, "27427": 0.2223619967699051, "27814": 0.4462870955467224, "27854": 1.3326339721679688, "28517": 0.020300358533859253, "29107": 0.23864774405956268, "29290": 0.43434104323387146} | 8453819 | The integrin family of heterodimeric cell-surface receptors are fundamental in cell-cell and cell-matrix adhesion. Changes to either integrin-ligand affinity or integrin gene expression are central to a variety of disease processes, including inflammation, cardiovascular disease and cancer. In screening for novel activators of integrin-ligand affinity we identified the previously uncharacterised multi-transmembrane domain protein Fam38A, located at the endoplasmic reticulum (ER). siRNA knockdown of Fam38A in epithelial cells inactivates endogenous beta1 integrin, reducing cell adhesion. Fam38A mediates integrin activation by recruiting the small GTPase R-Ras to the ER, which activates the calcium-activated protease calpain by increasing Ca(2+) release from cytoplasmic stores. Fam38A-induced integrin activation is blocked by inhibition of either R-Ras or calpain activity, or by siRNA knockdown of talin, a well-described calpain substrate. This highlights a novel mechanism for integrin activation by Fam38A, utilising calpain and R-Ras signalling from the ER. These data represent the first description of a novel spatial regulator of R-Ras, of an alternative integrin activation-suppression pathway based on direct relocalisation of R-Ras to the ER, and of a mechanism linking R-Ras and calpain signalling from the ER with modulation of integrin-ligand affinity. | Integrin activation by Fam38A uses a novel mechanism of R-Ras targeting to the endoplasmic reticulum. |
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1 and 2). Amphipathic carboxylates such as clofibric acid have been used in man as hypolipidaemic agents and in rodents they stimulate the proliferation of peroxisomes. These agents, termed peroxisome proliferators, and all-trans retinoic acid activate genes involved in peroxisomal-mediated β-oxidation of fatty acids1–4. Here we show that the receptor activated by peroxisome proliferators5 and the retinoid X receptor-α (ref. 6) form a heterodimer that activates acyl-CoA oxidase gene expression in response to either clofibric acid or the retinoid X receptor-α ligand, 9-cis retinoic acid, an all-trans retinoic acid metabolite7,8; simultaneous exposure to both activators results in a synergistic induction of gene expression. These data demonstrate the coupling of the peroxisome proliferator and retinoid signalling pathways and provide evidence for a physiological role for 9-cis retinoic acid in modulating lipid metabolism. | Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors |
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Recently, Ras-induced macropinocytosis of extracellular proteins was shown to reduce a transformed cell's dependence on extracellular glutamine. Here, we demonstrate that protein macropinocytosis can also serve as an essential amino acid source. Lysosomal degradation of extracellular proteins can sustain cell survival and induce activation of mTORC1 but fails to elicit significant cell accumulation. Unlike its growth-promoting activity under amino-acid-replete conditions, we discovered that mTORC1 activation suppresses proliferation when cells rely on extracellular proteins as an amino acid source. Inhibiting mTORC1 results in increased catabolism of endocytosed proteins and enhances cell proliferation during nutrient-depleted conditions in vitro and within vascularly compromised tumors in vivo. Thus, by preventing nutritional consumption of extracellular proteins, mTORC1 couples growth to availability of free amino acids. These results may have important implications for the use of mTOR inhibitors as therapeutics. | The Utilization of Extracellular Proteins as Nutrients Is Suppressed by mTORC1 |
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"28227": 0.004870930220931768, "28283": 0.8780695199966431, "28290": 1.2313295602798462, "28309": 0.05046287178993225, "28335": 0.026976587250828743, "29125": 0.006812678650021553, "29206": 0.17431432008743286, "29458": 0.5551415085792542, "29532": 0.16690383851528168} | 8476213 | We developed a general model of sporophytic self-incompatibility under negative frequency-dependent selection allowing complex patterns of dominance among alleles. We used this model deterministically to investigate the effects on equilibrium allelic frequencies of the number of dominance classes, the number of alleles per dominance class, the asymmetry in dominance expression between pollen and pistil, and whether selection acts on male fitness only or both on male and on female fitnesses. We show that the so-called "recessive effect" occurs under a wide variety of situations. We found emerging properties of finite population models with several alleles per dominance class such as that higher numbers of alleles are maintained in more dominant classes and that the number of dominance classes can evolve. We also investigated the occurrence of homozygous genotypes and found that substantial proportions of those can occur for the most recessive alleles. We used the model for two species with complex dominance patterns to test whether allelic frequencies in natural populations are in agreement with the distribution predicted by our model. We suggest that the model can be used to test explicitly for additional, allele-specific, selective forces. | A general model to explore complex dominance patterns in plant sporophytic self-incompatibility systems. |
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Macrophages in particular are a good example of this phenomenon. Whether the macrophage obtains its energy through glycolysis or through oxidative metabolism can give rise to different phenotypes. Classically activated or M1 macrophages are key players of the first line of defense against bacterial infections and are known to obtain energy through glycolysis. Alternatively activated or M2 macrophages on the other hand are involved in tissue repair and wound healing and use oxidative metabolism to fuel their longer-term functions. Metabolic intermediates, however, are not just a source of energy but can be directly implicated in a particular macrophage phenotype. In M1 macrophages, the Krebs cycle intermediate succinate regulates HIF1α, which is responsible for driving the sustained production of the pro-inflammatory cytokine IL1β. In M2 macrophages, the sedoheptulose kinase carbohydrate kinase-like protein is critical for regulating the pentose phosphate pathway. The potential to target these events and impact on disease is an exciting prospect. | Metabolic Reprograming in Macrophage Polarization |
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0.07159364968538284, "26524": 0.8366385698318481, "26773": 0.48970574140548706, "26775": 0.24248650670051575, "26874": 0.9485763907432556, "27226": 0.48850810527801514, "27642": 0.6296497583389282, "27854": 0.39367714524269104, "28024": 0.08064348995685577, "29109": 0.03266380727291107, "29206": 0.7258110046386719, "29237": 0.24554696679115295, "29278": 0.06886265426874161} | 8494570 | BACKGROUND Recent studies suggested that human/mammalian genomes are divided into large, discrete domains that are units of chromosome organization. CTCF, a CCCTC binding factor, has a diverse role in genome regulation including transcriptional regulation, chromosome-boundary insulation, DNA replication, and chromatin packaging. It remains unclear whether a subset of CTCF binding sites plays a functional role in establishing/maintaining chromatin topological domains. RESULTS We systematically analysed the genomic, transcriptomic and epigenetic profiles of the CTCF binding sites in 56 human cell lines from ENCODE. We identified ~24,000 CTCF sites (referred to as constitutive sites) that were bound in more than 90% of the cell lines. Our analysis revealed: 1) constitutive CTCF loci were located in constitutive open chromatin and often co-localized with constitutive cohesin loci; 2) most constitutive CTCF loci were distant from transcription start sites and lacked CpG islands but were enriched with the full-spectrum CTCF motifs: a recently reported 33/34-mer and two other potentially novel (22/26-mer); 3) more importantly, most constitutive CTCF loci were present in CTCF-mediated chromatin interactions detected by ChIA-PET and these pair-wise interactions occurred predominantly within, but not between, topological domains identified by Hi-C. CONCLUSIONS Our results suggest that the constitutive CTCF sites may play a role in organizing/maintaining the recently identified topological domains that are common across most human cells. | Characterization of constitutive CTCF/cohesin loci: a possible role in establishing topological domains in mammalian genomes |
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8496132 | Overexpression of the proto-oncogene bcl-2 promotes abnormal cell survival by inhibiting apoptosis. Expression of bcl-2 is determined, in part, by regulatory mechanisms that control the stability of bcl-2 mRNA. Elements in the 3'-untranslated region of bcl-2 mRNA have been shown to play a role in regulating the stability of the message. Previously, it was found that the RNA binding proteins nucleolin and Ebp1 have a role in stabilizing bcl-2 mRNA in HL60 cells. Here, we have identified HuR as a component of bcl-2 messenger ribonucleoprotein (mRNP) complexes. RNA coimmunoprecipitation assays showed that HuR binds to bcl-2 mRNA in vivo. We also observed an RNA-dependent coprecipitation of HuR and nucleolin, suggesting that the two proteins are present in common mRNP complexes. Moreover, nucleolin and HuR bind concurrently to bcl-2 AU-rich element (ARE) RNA in vitro, suggesting separate binding sites for these proteins on bcl-2 mRNA. Knockdown of HuR in A431 cells leads to down-regulation of bcl-2 mRNA and protein levels. Observation of a decreased ratio of bcl-2 mRNA to heterogeneous nuclear RNA in HuR knockdown cells confirmed a positive role for HuR in regulating bcl-2 stability. Recombinant HuR retards exosome-mediated decay of bcl-2 ARE RNA in extracts of HL60 cells. This supports a role for HuR in the regulation of bcl-2 mRNA stability in HL60 cells, as well as in A431 cells. Addition of nucleolin and HuR to HL60 cell extracts produced a synergistic protective effect on decay of bcl-2 ARE RNA. HuR knockdown also leads to redistribution of bcl-2 mRNA from polysomes to monosomes. Thus, HuR seems to play a positive role in both regulation of bcl-2 mRNA translation and mRNA stability. | Regulation of Bcl-2 expression by HuR in HL60 leukemia cells and A431 carcinoma cells. |
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"26786": 0.6654226183891296, "27083": 0.11865071207284927, "27567": 0.12642613053321838, "27691": 0.24631060659885406, "28436": 0.8433839678764343, "28522": 0.6892333030700684, "28892": 0.41389304399490356, "29260": 0.0029254043474793434, "29295": 0.6674286723136902, "29458": 0.6921701431274414, "29497": 1.3570626974105835} | 8502193 | Traits such as clutch size vary markedly across species and environmental gradients but have usually been investigated from either a comparative or a geographic perspective, respectively. We analyzed the global variation in clutch size across 5,290 bird species, excluding brood parasites and pelagic species. We integrated intrinsic (morphological, behavioural), extrinsic (environmental), and phylogenetic effects in a combined model that predicts up to 68% of the interspecific variation in clutch size. We then applied the same species-level model to predict mean clutch size across 2,521 assemblages worldwide and found that it explains the observed eco-geographic pattern very well. Clutches are consistently largest in cavity nesters and in species occupying seasonal environments, highlighting the importance of offspring and adult mortality that is jointly expressed in intrinsic and extrinsic correlates. The findings offer a conceptual bridge between macroecology and comparative biology and provide a global and integrative understanding of the eco-geographic and cross-species variation in a core life-history trait. | The Worldwide Variation in Avian Clutch Size across Species and Space |
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It has traditionally been thought that the pathophysiological cause of heart failure in these patients is an abnormality in the diastolic properties of the left ventricle; however, this hypothesis remains largely unproven. METHODS We prospectively identified 47 patients who met the diagnostic criteria for definite diastolic heart failure; all the patients had signs and symptoms of heart failure, a normal ejection fraction, and an increased left ventricular end-diastolic pressure. Ten patients who had no evidence of cardiovascular disease served as controls. Left ventricular diastolic function was assessed by means of cardiac catheterization and echocardiography. RESULTS The patients with diastolic heart failure had abnormal left ventricular relaxation and increased left ventricular chamber stiffness. The mean (+/-SD) time constant for the isovolumic-pressure decline (tau) was longer in the group with diastolic heart failure than in the control group (59+/-14 msec vs. 35+/-10 msec, P=0.01). The diastolic pressure-volume relation was shifted up and to the left in the patients with diastolic heart failure as compared with the controls. The corrected left ventricular passive-stiffness constant was significantly higher in the group with diastolic heart failure than in the control group (0.03+/-0.01 vs. 0.01+/-0.01, P<0.001). CONCLUSIONS Patients with heart failure and a normal ejection fraction have significant abnormalities in active relaxation and passive stiffness. In these patients, the pathophysiological cause of elevated diastolic pressures and heart failure is abnormal diastolic function. | Diastolic heart failure--abnormalities in active relaxation and passive stiffness of the left ventricle. |
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0.0038986403960734606, "26601": 0.16442140936851501, "26745": 0.6950984001159668, "26835": 0.8682814836502075, "26927": 0.2231435477733612, "27019": 0.03925827145576477, "27794": 0.6853039860725403, "27881": 0.19862671196460724, "28207": 0.037378571927547455, "28848": 0.7800771594047546} | 8512633 | Long noncoding RNAs (IncRNAs) are increasingly implicated in cancer biology, contributing to essential cancer cell functions such as proliferation, invasion, and metastasis. In prostate cancer, several lncRNAs have been nominated as critical actors in disease pathogenesis. Among these, expression of PCGEM1 and PRNCR1 has been identified as a possible component in disease progression through the coordination of androgen receptor (AR) signaling (Yang et al., Nature 2013, see ref. [1]). However, concerns regarding the robustness of these findings have been suggested. Here, we sought to evaluate whether PCGEM1 and PRNCR1 are associated with prostate cancer. Through a comprehensive analysis of RNA-sequencing data (RNA-seq), we find evidence that PCGEM1 but not PRNCR1 is associated with prostate cancer. We employ a large cohort of >230 high-risk prostate cancer patients with long-term outcomes data to show that, in contrast to prior reports, neither gene is associated with poor patient outcomes. We further observe no evidence that PCGEM1 nor PRNCR1 interact with AR, and neither gene is a component of AR signaling. Thus, we conclusively demonstrate that PCGEM1 and PRNCR1 are not prognostic lncRNAs in prostate cancer and we refute suggestions that these lncRNAs interact in AR signaling. | The lncRNAs PCGEM1 and PRNCR1 are not implicated in castration resistant prostate cancer |
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Accumulating evidence supports a role for different cell cycle inhibitors in mammalian aging. Little is known, however, about the upstream signals that induce their expression. Here, we explore the role of p38MAPK by generating a dominant-negative allele (p38(AF)) in which activating phosphorylation sites Thr180 and Tyr182 are mutated. Heterozygous p38(AF) mice show a marked attenuation of p38-dependent signaling and age-induced expression of multiple cell cycle inhibitors in different organs, including pancreatic islets. As a result, aged p38(AF/+) mice show enhanced proliferation and regeneration of islets when compared to wild-type littermates. We further find an age-related reduction in expression of the p38-specific phosphatase Wip1. Wip1-deficient mice demonstrate decreased islet proliferation, while Wip1 overexpression rescues aging-related decline in proliferation and regenerative capacity. We propose that modulation of p38MAPK activity may provide new avenues for treating certain age-related degenerative diseases. | p38MAPK controls expression of multiple cell cycle inhibitors and islet proliferation with advancing age. |
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"28201": 1.013020396232605, "28466": 0.04674193635582924, "28517": 0.007782140281051397, "28767": 0.23633737862110138, "28831": 0.09228714555501938, "29212": 0.3034266233444214, "29234": 0.2026219218969345, "29310": 0.8592242002487183, "29336": 0.12728634476661682, "29398": 0.31845372915267944} | 8520041 | OBJECTIVE We explored the subjective effects associated with olanzapine, risperidone and older antipsychotics. METHOD We conducted a content analysis of an Internet database of comments about prescribed medications. RESULTS We analysed 223 comments on risperidone, 170 on olanzapine and 46 relating to three older antipsychotics. The predominant subjective effects produced by all drugs consisted of sedation, cognitive impairment and emotional flattening or indifference. Connections appeared between these effects and Parkinsonian-like symptoms with the older drugs, sexual impairment with risperidone and metabolic effects with olanzapine. The experience of akathisia was frequently linked to suicidal thoughts. Some respondents described how the drugs' subjective effects helped to reduce symptoms of mania, psychosis and anxiety. CONCLUSION The generalisability of Internet data is uncertain. However, the data suggest that adverse subjective effects play a central role in the experience of taking antipsychotic drugs and may be related to the drugs' desired benefits. | ACTA PSYCHIATRICA |
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0.33605360984802246, "25520": 0.02792670577764511, "25610": 0.6000806093215942, "26163": 0.8366385698318481, "26221": 0.11081436276435852, "26236": 0.48670899868011475, "26237": 1.1720224618911743, "26305": 0.14686977863311768, "26535": 0.10203468054533005, "26691": 0.03831886500120163, "26835": 0.8366385698318481, "27011": 1.248288631439209, "27354": 0.014542185701429844, "27400": 0.09850110858678818, "27404": 0.7258110046386719, "27480": 0.014542185701429844, "27532": 0.014542185701429844, "27673": 0.255429208278656, "27718": 0.41001203656196594, "28163": 0.1710275560617447, "28314": 0.06520967930555344, "28436": 0.07068414986133575, "28487": 0.010684899985790253, "28685": 0.18411032855510712, "28767": 0.9371650815010071, "28828": 0.7144040465354919, "28915": 0.06977381557226181, "29167": 0.956112265586853, "29458": 0.3027053773403168, "29533": 0.06977381557226181, "29750": 0.08513788133859634} | 8524891 | OBJECTIVE White matter hyperintensities (WMHs) are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) scans that most commonly reflect small vessel cerebrovascular disease. Increased WMH volume is associated with risk and progression of Alzheimer's disease (AD). These observations are typically interpreted as evidence that vascular abnormalities play an additive, independent role contributing to symptom presentation, but not core features of AD. We examined the severity and distribution of WMH in presymptomatic PSEN1, PSEN2, and APP mutation carriers to determine the extent to which WMH manifest in individuals genetically determined to develop AD. METHODS The study comprised participants (n = 299; age = 39.03 ± 10.13) from the Dominantly Inherited Alzheimer Network, including 184 (61.5%) with a mutation that results in AD and 115 (38.5%) first-degree relatives who were noncarrier controls. We calculated the estimated years from expected symptom onset (EYO) by subtracting the affected parent's symptom onset age from the participant's age. Baseline MRI data were analyzed for total and regional WMH. Mixed-effects piece-wise linear regression was used to examine WMH differences between carriers and noncarriers with respect to EYO. RESULTS Mutation carriers had greater total WMH volumes, which appeared to increase approximately 6 years before expected symptom onset. Effects were most prominent for the parietal and occipital lobe, which showed divergent effects as early as 22 years before estimated onset. INTERPRETATION Autosomal-dominant AD is associated with increased WMH well before expected symptom onset. The findings suggest the possibility that WMHs are a core feature of AD, a potential therapeutic target, and a factor that should be integrated into pathogenic models of the disease. Ann Neurol 2016;79:929-939. | White matter hyperintensities are a core feature of Alzheimer's disease: Evidence from the dominantly inherited Alzheimer network. |
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0.41065993905067444, "29101": 0.02792670577764511, "29125": 0.21135559678077698, "29172": 0.39762192964553833, "29299": 0.8957691192626953, "29336": 0.0354953333735466, "29458": 0.7210738658905029, "29477": 0.058784693479537964, "29516": 0.1332872211933136} | 8529693 | In this paper we review the associations between maternal and child undernutrition with human capital and risk of adult diseases in low-income and middle-income countries. We analysed data from five long-standing prospective cohort studies from Brazil, Guatemala, India, the Philippines, and South Africa and noted that indices of maternal and child undernutrition (maternal height, birthweight, intrauterine growth restriction, and weight, height, and body-mass index at 2 years according to the new WHO growth standards) were related to adult outcomes (height, schooling, income or assets, offspring birthweight, body-mass index, glucose concentrations, blood pressure). We undertook systematic reviews of studies from low-income and middle-income countries for these outcomes and for indicators related to blood lipids, cardiovascular disease, lung and immune function, cancers, osteoporosis, and mental illness. Undernutrition was strongly associated, both in the review of published work and in new analyses, with shorter adult height, less schooling, reduced economic productivity, and--for women--lower offspring birthweight. Associations with adult disease indicators were not so clear-cut. Increased size at birth and in childhood were positively associated with adult body-mass index and to a lesser extent with blood pressure values, but not with blood glucose concentrations. In our new analyses and in published work, lower birthweight and undernutrition in childhood were risk factors for high glucose concentrations, blood pressure, and harmful lipid profiles once adult body-mass index and height were adjusted for, suggesting that rapid postnatal weight gain--especially after infancy--is linked to these conditions. The review of published works indicates that there is insufficient information about long-term changes in immune function, blood lipids, or osteoporosis indicators. Birthweight is positively associated with lung function and with the incidence of some cancers, and undernutrition could be associated with mental illness. We noted that height-for-age at 2 years was the best predictor of human capital and that undernutrition is associated with lower human capital. We conclude that damage suffered in early life leads to permanent impairment, and might also affect future generations. Its prevention will probably bring about important health, educational, and economic benefits. Chronic diseases are especially common in undernourished children who experience rapid weight gain after infancy. | Maternal and child undernutrition: consequences for adult health and human capital |
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Still, however, little is known about the components mediating ERAD of membrane proteins. Here we show that the evolutionary conserved rhomboid family protein RHBDL4 is a ubiquitin-dependent ER-resident intramembrane protease that is upregulated upon ER stress. RHBDL4 cleaves single-spanning and polytopic membrane proteins with unstable transmembrane helices, leading to their degradation by the canonical ERAD machinery. RHBDL4 specifically binds the AAA+-ATPase p97, suggesting that proteolytic processing and dislocation into the cytosol are functionally linked. The phylogenetic relationship between rhomboids and the ERAD factor derlin suggests that substrates for intramembrane proteolysis and protein dislocation are recruited by a shared mechanism. | Ubiquitin-dependent intramembrane rhomboid protease promotes ERAD of membrane proteins. |
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However, there are many discrepancies in current NO detection assays and the enzymatic pathways responsible for its synthesis have yet to be determined. This has provoked strong debates concerning the function of NO in plants, even questioning its existence in planta. Here we gather data obtained using the model pathosystem Arabidopsis/Pseudomonas, which confirms the production of NO during the hypersensitive response and supports is role as a trigger of hypersensitive cell death and a mediator of defence gene expression. Finally, we discuss potential sources of NO synthesis, focusing on the role of nitrite as major substrate for NO production during incompatible interactions. | Detection and function of nitric oxide during the hypersensitive response in Arabidopsis thaliana: where there's a will there's a way. |
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"22248": 0.12038381397724152, "22330": 0.822151780128479, "23737": 0.38308101892471313, "23900": 0.33605360984802246, "23959": 0.49626702070236206, "24004": 0.0009760859538801014, "24054": 0.012615402229130268, "24110": 0.6265231370925903, "25409": 0.7701805830001831, "25468": 0.20580662786960602, "25502": 0.9591107368469238, "25778": 0.058784693479537964, "26236": 0.512191891670227, "26244": 0.05417001247406006, "26397": 0.3170322775840759, "26435": 0.1477125883102417, "26534": 0.4734157919883728, "26773": 0.05970508232712746, "26786": 0.35745587944984436, "27144": 0.3241194784641266, "27854": 0.15943801403045654, "27881": 0.15023678541183472, "28086": 0.030771657824516296, "28251": 0.20818853378295898, "28696": 1.1115491390228271, "28774": 0.08244366943836212} | 8538916 | The molecular chaperone CCT/TRiC plays a central role in maintaining cellular proteostasis as it mediates the folding of the major cytoskeletal proteins tubulins and actins. CCT/TRiC is also involved in the oncoprotein cyclin E, the Von Hippel-Lindau tumour suppressor protein, cyclin B and p21(ras) folding which strongly suggests that it is involved in cell proliferation and tumor genesis. To assess the involvement of CCT/TRiC in tumor genesis, we quantified its expression levels and activity in 18 cancer, one non-cancer human cell lines and a non-cancer human liver. We show that the expression levels of CCT/TRiC in cancer cell lines are higher than that in normal cells. However, CCT/TRiC activity does not always correlate with its expression levels. We therefore documented the expression levels of CCT/TRiC modulators and partners PhLP3, Hop/P60, prefoldin and Hsc/Hsp70. Our analysis reveals a functional interplay between molecular chaperones that might account for a precise modulation of CCT/TRiC activity in cell proliferation through changes in the cellular levels of prefoldin and/or Hsc/p70 and CCT/TRiC client protein availability. Our observation and approaches bring novel insights in the role of CCT/TRiC-mediated protein folding machinery in cancer cell development. | The Cytosolic Chaperonin CCT/TRiC and Cancer Cell Proliferation |
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However, the recent discovery of histone demethylases has challenged the stable nature of histone methylation. Here we demonstrate that the JARID1 proteins RBP2, PLU1, and SMCX are histone demethylases specific for di- and trimethylated histone 3 lysine 4 (H3K4). Consistent with a role for the JARID1 Drosophila homolog Lid in regulating expression of homeotic genes during development, we show that RBP2 is displaced from Hox genes during embryonic stem (ES) cell differentiation correlating with an increase of their H3K4me3 levels and expression. Furthermore, we show that mutation or RNAi depletion of the C. elegans JARID1 homolog rbr-2 leads to increased levels of H3K4me3 during larval development and defects in vulva formation. Taken together, these results suggest that H3K4me3/me2 demethylation regulated by the JARID1 family plays an important role during development. | RBP2 Belongs to a Family of Demethylases, Specific for Tri-and Dimethylated Lysine 4 on Histone 3 |
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Additionally, they participate in intermediary metabolism, calcium signaling, and apoptosis. Given these well-established functions, it might be expected that mitochondrial dysfunction would give rise to a simple and predictable set of defects in all tissues. However, mitochondrial dysfunction has pleiotropic effects in multicellular organisms. Clearly, much about the basic biology of mitochondria remains to be understood. Here we discuss recent work that suggests that the dynamics (fusion and fission) of these organelles is important in development and disease. | Mitochondria: Dynamic Organelles in Disease, Aging, and Development |
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0.36494144797325134, "27781": 0.3297532796859741, "28297": 0.987156867980957, "28389": 0.4512746334075928, "28577": 0.2531573474407196, "28674": 0.6170841455459595, "28788": 0.3870677351951599, "28873": 0.932563841342926, "29486": 0.5495203733444214, "29543": 0.9754437208175659} | 8563659 | To explore the mechanism by which herpes simplex virus (HSV)-2 infection is related to HIV-1 acquisition, we conducted in situ analysis of the cellular infiltrate from sequential biopsies of HSV-2 lesions from patients on and off antiviral therapy. CD4(+) and CD8(+) T cells and a mixed population of plasmacytoid and myeloid dendritic cells (DCs), including cells expressing the C-type lectin receptor DC-SIGN, persisted at sites of HSV-2 reactivation for months after healing, even with daily antiviral therapy. The CD4(+) T cells that persisted reacted to HSV-2 antigen, were enriched for expression of the chemokine receptor CCR5, and were contiguous to DCs expressing the interleukin-3 receptor CD123 or DC-SIGN. Ex vivo infection with a CCR5-tropic strain of HIV-1 revealed greater concentrations of integrated HIV-1 DNA in cells derived from healed genital lesion biopsies than in cells from control skin biopsies. The persistence and enrichment of HIV receptor-positive inflammatory cells in the genitalia help explain the inability of anti-HSV-2 therapy to reduce HIV acquisition. | Persistence of HIV-1 Receptor-Positive Cells after HSV-2 Reactivation: A Potential Mechanism for Increased HIV-1 Acquisition |
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0.3615458607673645, "28297": 0.6950984001159668, "28321": 0.24631060659885406, "28353": 0.11168810725212097, "28436": 0.3005385100841522, "28489": 0.347847044467926, "28687": 0.02887592278420925, "28767": 0.15442965924739838, "29212": 0.0770333781838417, "29264": 0.1358480453491211, "29458": 0.5209306478500366, "29486": 0.4267219603061676} | 8570317 | We conducted a two-stage population-based headache survey among subjects aged > or = 15 in Taipei, Taiwan. Subjects with chronic daily headache (CDH) in the past year were identified, interviewed and followed-up. CDH was defined as a headache frequency > 15 days/month, with a duration > 4 h/day. Of the 3377 participants, 108 (3.2%) fulfilled the criteria for CDH, with a higher prevalence in women (4.3%) than men (1.9%). TM was the most common subtype (55%), followed by CTTH (44%). Thirty-four per cent of the CDH subjects overused analgesics. At the 2-year follow-up, 35% of the CDH subjects still had CDH. The significant predictors for persistent CDH at follow-up included: older age ( > or = 40 years) (RR = 2.4), CDH onset after 32 years (RR = 1.8), CDH duration > or = 6 years (RR = 2.0), medication overuse (RR = 1.8), and "daily" headache (RR = 2.1). We found that CDH is not uncommon in the community and its prevalence is similar among different populations. Older subjects and those with medication overuse may have a more protracted course of illness. | Chronic daily headache in Taipei, Taiwan: prevalence, follow-up and outcome predictors. |
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| beta-Tubulin is encoded in the genomes of higher animals by a small multigene family comprising approximately seven functional genes. These genes produce a family of closely related, but distinct polypeptide isotypes that are distinguished principally by sequences within the approximately 15 carboxy-terminal amino acid residues. By immunizing rabbits with chemically synthesized peptides corresponding to these variable domain sequences, we have now prepared polyclonal antibodies specific for each of six distinct isotypes. Specificity of each antiserum has been demonstrated unambiguously by antibody binding to bacterially produced, cloned proteins representing each isotype and by the inhibition of such binding by preincubation of each antiserum only with the immunizing peptide and not with heterologous peptides. Protein blotting of known amounts of cloned, isotypically pure polypeptides has permitted accurate quantitative measurement of the amount of each beta-tubulin isotype present in the soluble and polymer forms in various cells, but has not revealed a bias for preferential assembly of any isotype. Localization of each isotype in three different cell types using indirect immunofluorescence has demonstrated that in vivo each class of microtubules distinguishable by light microscopy is assembled as copolymers of all isotypes expressed in a single cell. | In vivo microtubules are copolymers of available beta-tubulin isotypes: localization of each of six vertebrate beta-tubulin isotypes using polyclonal antibodies elicited by synthetic peptide antigens |
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0.319873183965683, "25604": 0.4734157919883728, "25750": 0.30917787551879883, "26402": 0.31204116344451904, "26642": 0.32270604372024536, "26942": 0.053244512528181076, "27290": 0.06795065850019455, "27354": 0.006812678650021553, "27606": 0.11256109178066254, "27777": 0.6011518239974976, "27833": 0.10026945173740387, "27969": 1.1695996522903442, "28282": 0.9470623731613159, "28436": 0.018384648486971855, "29076": 0.8674615025520325, "29461": 0.004870930220931768, "29513": 0.04394211992621422, "29566": 0.25088030099868774} | 8570690 | INTRODUCTION Topiramate (TOP) blocks glutamate receptors and facilitates GABA (γ-aminobutyric acid) neurotransmission, effects that may facilitate smoking cessation. We compared the effects of behavioral counseling combined with (a) TOP, (b) TOP/nicotine patch (TOP/NIC), or (c) placebo (PLC) for smoking cessation. METHODS We conducted a 10-week randomized trial in which subjects and research personnel were blinded to TOP versus PLC but not to the TOP/NIC patch condition. In groups receiving TOP, the medication dosage was titrated gradually up to 200 mg/day. The smoking quit date (QD) was scheduled after 2 weeks of medication treatment. NIC (21 mg) was started on the QD in subjects randomized to the TOP/NIC condition. The main outcome measure was the end-of-treatment, 4-week continuous abstinence rate (CAR; biochemically confirmed). RESULTS Fifty-seven subjects were randomized to treatment. The 4-week CAR was 1 of 19 (5%) in the PLC group, 5 of 19 (26%) in the TOP group, and 7 of 19 (37%) in the TOP/NIC group (p = .056). Pairwise comparisons showed a difference between TOP/NIC and PLC (p = .042) and a nonsignificant difference between TOP and PLC (p = .18). The PLC group gained 0.37 lb/week, the TOP group lost 0.41 lb/week, and the TOP/NIC group lost 0.07 lb/week (p = .004). Pairwise comparisons showed a difference between TOP and PLC (p < .001) and between TOP/NIC and PLC groups (p = .035). Paresthesia was more frequent in subjects on TOP than PLC (p = .011). CONCLUSIONS TOP, alone or in combination with the NIC, resulted in a numerically higher quit rate than PLC and decreased weight. A larger, PLC-controlled trial is needed to confirm these findings. | Topiramate for smoking cessation: a randomized, placebo-controlled pilot study. |
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This mechanism appears to be critically important in the restarting of stalled and broken replication forks and in maintaining the integrity of eroded telomeres. Although BIR helps preserve genome integrity during replication, it also promotes genome instability by the production of loss of heterozygosity and the formation of nonreciprocal translocations, as well as in the generation of complex chromosomal rearrangements. | Break-induced DNA replication. |
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"28711": 0.05970508232712746, "28767": 0.6744182109832764, "28817": 0.7295845746994019, "29100": 0.12384103983640671, "29458": 0.06246116757392883} | 8582337 | IMPORTANCE Understanding the major health problems in the United States and how they are changing over time is critical for informing national health policy. OBJECTIVES To measure the burden of diseases, injuries, and leading risk factors in the United States from 1990 to 2010 and to compare these measurements with those of the 34 countries in the Organisation for Economic Co-operation and Development (OECD) countries. DESIGN We used the systematic analysis of descriptive epidemiology of 291 diseases and injuries, 1160 sequelae of these diseases and injuries, and 67 risk factors or clusters of risk factors from 1990 to 2010 for 187 countries developed for the Global Burden of Disease 2010 Study to describe the health status of the United States and to compare US health outcomes with those of 34 OECD countries. Years of life lost due to premature mortality (YLLs) were computed by multiplying the number of deaths at each age by a reference life expectancy at that age. Years lived with disability (YLDs) were calculated by multiplying prevalence (based on systematic reviews) by the disability weight (based on population-based surveys) for each sequela; disability in this study refers to any short- or long-term loss of health. Disability-adjusted life-years (DALYs) were estimated as the sum of YLDs and YLLs. Deaths and DALYs related to risk factors were based on systematic reviews and meta-analyses of exposure data and relative risks for risk-outcome pairs. Healthy life expectancy (HALE) was used to summarize overall population health, accounting for both length of life and levels of ill health experienced at different ages. RESULTS US life expectancy for both sexes combined increased from 75.2 years in 1990 to 78.2 years in 2010; during the same period, HALE increased from 65.8 years to 68.1 years. The diseases and injuries with the largest number of YLLs in 2010 were ischemic heart disease, lung cancer, stroke, chronic obstructive pulmonary disease, and road injury. Age-standardized YLL rates increased for Alzheimer disease, drug use disorders, chronic kidney disease, kidney cancer, and falls. The diseases with the largest number of YLDs in 2010 were low back pain, major depressive disorder, other musculoskeletal disorders, neck pain, and anxiety disorders. As the US population has aged, YLDs have comprised a larger share of DALYs than have YLLs. The leading risk factors related to DALYs were dietary risks, tobacco smoking, high body mass index, high blood pressure, high fasting plasma glucose, physical inactivity, and alcohol use. Among 34 OECD countries between 1990 and 2010, the US rank for the age-standardized death rate changed from 18th to 27th, for the age-standardized YLL rate from 23rd to 28th, for the age-standardized YLD rate from 5th to 6th, for life expectancy at birth from 20th to 27th, and for HALE from 14th to 26th. CONCLUSIONS AND RELEVANCE From 1990 to 2010, the United States made substantial progress in improving health. Life expectancy at birth and HALE increased, all-cause death rates at all ages decreased, and age-specific rates of years lived with disability remained stable. However, morbidity and chronic disability now account for nearly half of the US health burden, and improvements in population health in the United States have not kept pace with advances in population health in other wealthy nations. | The state of US health, 1990-2010: burden of diseases, injuries, and risk factors. |
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"24887": 0.4926934838294983, "24904": 0.34922540187835693, "25094": 0.00875066313892603, "25121": 0.175953671336174, "25276": 0.603290855884552, "25357": 0.2622140049934387, "25553": 0.029824240133166313, "25613": 0.3757305145263672, "25765": 0.16359257698059082, "26031": 0.0058422754518687725, "26046": 0.1510767638683319, "26629": 0.09584271162748337, "26728": 0.35060185194015503, "26770": 0.18492233753204346, "26835": 0.1905880719423294, "26909": 1.0430610179901123, "27135": 0.029824240133166313, "27144": 0.6070231795310974, "27794": 1.2460440397262573, "27830": 0.05694137513637543, "27891": 0.07068414986133575, "28225": 0.06612417846918106, "28321": 0.03831886500120163, "28352": 0.0174254160374403, "28548": 0.3601844012737274, "28679": 0.06795065850019455, "28748": 0.09761575609445572, "28804": 0.11865071207284927, "28805": 0.20977331697940826, "28836": 0.1401015669107437, "28879": 0.4286321699619293, "28896": 1.0822023153305054, "28935": 0.04674193635582924, "29094": 0.1602703034877777, "29207": 0.0317181795835495, "29234": 0.12556517124176025, "29235": 0.997294545173645, "29361": 0.5197699069976807, "29536": 0.1970241367816925, "29598": 0.9724938273429871} | 8593263 | An observational prospective cohort study assessed malaria risk perception, knowledge and prophylaxis practices among individuals of African ethnicity living in Paris and travelling to their country of origin to visit friends or relatives (VFR). The study compared two groups of VFR who had visited a travel clinic (TC; n=122) or a travel agency (TA; n=69) before departure. Of the 47% of VFR citing malaria as a health concern, 75% knew that malaria is mosquito-borne and that bed nets are an effective preventive measure. Perception of high malaria risk was greater in the TA group (33%) than in the TC group (7%). The availability of a malaria vaccine was mentioned by 35% of VFR, with frequent confusion between yellow fever vaccine and malaria prevention. Twenty-nine percent took adequate chemoprophylaxis with complete adherence, which was higher among the TC group (41%) than the TA group (12%). Effective antivector protection measures used were bed nets (16%), wearing long clothes at night (14%) and air conditioning (8%), with no differences between the study groups except in the use of impregnated bed nets (11% of the TC group and none of the TA group). Media coverage, malaria chemoprophylaxis repayment and cultural adaptation of preventive messages should be improved to reduce the high rate of inadequate malaria prophylaxis in VFR. | Malaria risk perception, knowledge and prophylaxis practices among travellers of African ethnicity living in Paris and visiting their country of origin in sub-Saharan Africa. |
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0.10731173306703568, "29564": 0.13414156436920166, "29610": 0.12814582884311676, "30113": 0.06429435312747955} | 8595678 | BACKGROUND The MTHFR 677C→T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke. A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and small-study bias was difficult. A meta-analysis of randomised trials of homocysteine-lowering interventions showed no reduction in coronary heart disease events or stroke, but the trials were generally set in populations with high folate consumption. We aimed to reduce the effect of small-study bias and investigate whether folate status modifies the association between MTHFR 677C→T and stroke in a genetic analysis and meta-analysis of randomised controlled trials. METHODS We established a collaboration of genetic studies consisting of 237 datasets including 59,995 individuals with data for homocysteine and 20,885 stroke events. We compared the genetic findings with a meta-analysis of 13 randomised trials of homocysteine-lowering treatments and stroke risk (45,549 individuals, 2314 stroke events, 269 transient ischaemic attacks). FINDINGS The effect of the MTHFR 677C→T variant on homocysteine concentration was larger in low folate regions (Asia; difference between individuals with TT versus CC genotype, 3·12 μmol/L, 95% CI 2·23 to 4·01) than in areas with folate fortification (America, Australia, and New Zealand, high; 0·13 μmol/L, -0·85 to 1·11). The odds ratio (OR) for stroke was also higher in Asia (1·68, 95% CI 1·44 to 1·97) than in America, Australia, and New Zealand, high (1·03, 0·84 to 1·25). Most randomised trials took place in regions with high or increasing population folate concentrations. The summary relative risk (RR) of stroke in trials of homocysteine-lowering interventions (0·94, 95% CI 0·85 to 1·04) was similar to that predicted for the same extent of homocysteine reduction in large genetic studies in populations with similar folate status (predicted RR 1·00, 95% CI 0·90 to 1·11). Although the predicted effect of homocysteine reduction from large genetic studies in low folate regions (Asia) was larger (RR 0·78, 95% CI 0·68 to 0·90), no trial has evaluated the effect of lowering of homocysteine on stroke risk exclusively in a low folate region. INTERPRETATION In regions with increasing levels or established policies of population folate supplementation, evidence from genetic studies and randomised trials is concordant in suggesting an absence of benefit from lowering of homocysteine for prevention of stroke. Further large-scale genetic studies of the association between MTHFR 677C→T and stroke in low folate settings are needed to distinguish effect modification by folate from small-study bias. If future randomised trials of homocysteine-lowering interventions for stroke prevention are undertaken, they should take place in regions with low folate consumption. FUNDING Full funding sources listed at end of paper (see Acknowledgments). | Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials |
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"27589": 0.06520967930555344, "27781": 0.029824240133166313, "27854": 0.9170717000961304, "28424": 0.3034266233444214, "28691": 0.006812678650021553, "28788": 0.07068414986133575, "28873": 0.03925827145576477, "28896": 0.05694137513637543, "28976": 0.4770587682723999, "29090": 0.04394211992621422, "29105": 0.6931471824645996, "29166": 0.861702561378479, "29290": 0.41389304399490356, "29516": 0.0019512200960889459, "29566": 1.1375575065612793} | 8596357 | Functional disruption of dendritic cells (DC) is an important strategy for viral pathogens to evade host defences. In this context, porcine circovirus type 2 (PCV2), a single-stranded DNA virus, impairs plasmacytoid DC (pDC) and conventional DC activation by certain viruses or Toll-like receptor (TLR) ligands. This inhibitory capacity is associated with the viral DNA, but the impairment does not affect all signalling cascades; TLR7 ligation by small chemical molecules will still induce interleukin-6 (IL-6) and tumour necrosis factor-α secretion, but not interferon-α or IL-12. In this study, the molecular mechanisms by which silencing occurs were investigated. PP2, a potent inhibitor of the Lyn and Hck kinases, produced a similar profile to the PCV2 DNA interference with cytokine secretion by pDC, efficiently inhibiting cell activation induced through TLR9, but not TLR7, ligation. Confocal microscopy and cytometry analysis strongly suggested that PCV2 DNA impairs actin polymerization and endocytosis in pDC and monocyte-derived DC, respectively. Altogether, this study delineates for the first time particular molecular mechanisms involved in PCV2 interference with DC danger recognition, which may be responsible for the virus-induced immunosuppression observed in infected pigs. | Porcine circovirus type 2 DNA influences cytoskeleton rearrangements in plasmacytoid and monocyte-derived dendritic cells. |
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0.07431721687316895, "29477": 0.129004567861557} | 8596837 | Women with a history of hypertensive pregnancy are at greater risk for future cardiovascular events; however, the mechanisms for this increased risk are unknown. Evidence suggests that an exercise stimulus unmasks latent hypertensive tendencies, identifying individuals at the greatest risk for developing cardiovascular disease. The current study examined the hypothesis that women with a hypertensive pregnancy history exhibit an augmented exercise pressor response. Normotensive women with a history of healthy pregnancy (CON; n = 9) and hypertensive pregnancy (HP+; n = 12) were studied during the mid-luteal phase of the menstrual cycle. Heart rate (HR), systolic and diastolic blood pressure (SBP, DBP), and muscle sympathetic nerve activity (MSNA) were measured during a cold pressor test (CPT), and, following a sufficient period of recovery, during static handgrip to fatigue (SHG) and post-exercise circulatory arrest (PECA). The BP, HR, and MSNA responses to the CPT were similar between groups. The SBP response to SHG and PECA was similar between groups, but DBP and HR were significantly greater in HP+ women (both p < 0.05). MSNA burst frequency, but not burst incidence or total activity, tended to be elevated in HP+ women during the stressor (peak Δ from baseline 31 ± 13 vs. 23 ± 13 bursts/min; p for group = 0.06). Despite no clinical signs of cardiovascular disease or hypertension, women with a history of hypertensive pregnancy display an enhanced cardiovascular reactivity to an exercise stimulus compared to women with a healthy pregnancy history. This response may be indicative of impaired cardiovascular control that precedes the clinical manifestation of hypertension or cardiovascular events. | Sympathetic neural and cardiovascular responses during static handgrip exercise in women with a history of hypertensive pregnancy |
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0.6011518239974976, "29610": 0.0038986403960734606} | 8604837 | Stress-induced immunological reactions to exercise have stimulated much research into stress immunology and neuroimmunology. It is suggested that exercise can be employed as a model of temporary immunosuppression that occurs after severe physical stress. The exercise-stress model can be easily manipulated experimentally and allows for the study of interactions between the nervous, the endocrine, and the immune systems. This review focuses on mechanisms underlying exercise-induced immune changes such as neuroendocrinological factors including catecholamines, growth hormone, cortisol, beta-endorphin, and sex steroids. The contribution of a metabolic link between skeletal muscles and the lymphoid system is also reviewed. The mechanisms of exercise-associated muscle damage and the initiation of the inflammatory cytokine cascade are discussed. Given that exercise modulates the immune system in healthy individuals, considerations of the clinical ramifications of exercise in the prevention of diseases for which the immune system has a role is of importance. Accordingly, drawing on the experimental, clinical, and epidemiological literature, we address the interactions between exercise and infectious diseases as well as exercise and neoplasia within the context of both aging and nutrition. | Exercise and the immune system: regulation, integration, and adaptation. |
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0.17759032547473907} | 8610932 | Regulatory gene circuits with positive-feedback loops control stem cell differentiation, but several mechanisms can contribute to positive feedback. Here, we dissect feedback mechanisms through which the transcription factor PU.1 controls lymphoid and myeloid differentiation. Quantitative live-cell imaging revealed that developing B cells decrease PU.1 levels by reducing PU.1 transcription, whereas developing macrophages increase PU.1 levels by lengthening their cell cycles, which causes stable PU.1 accumulation. Exogenous PU.1 expression in progenitors increases endogenous PU.1 levels by inducing cell cycle lengthening, implying positive feedback between a regulatory factor and the cell cycle. Mathematical modeling showed that this cell cycle-coupled feedback architecture effectively stabilizes a slow-dividing differentiated state. These results show that cell cycle duration functions as an integral part of a positive autoregulatory circuit to control cell fate. | Positive feedback between PU.1 and the cell cycle controls myeloid differentiation. |
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"29491": 0.5427330136299133} | 8629328 | Our understanding of the origins and the biological functions of different peripheral B cell subsets continues to evolve. Some understanding has been obtained regarding the synergy between BCR-derived signals and other receptors and signaling pathways that drive the development of follicular, marginal zone, and B-1 B cells, but this remains a complex and poorly understood issue. More recent information regarding the origins of B-1 and B-2 B cells, the ability of follicular B cells to mature both in the bone marrow and the spleen, the existence of a definable precursor for MZ B cells, and the ability of follicular B cells to occupy two distinct niches are all highlighted in this review. | Peripheral B cell subsets. |
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"27216": 0.15526613593101501, "27295": 0.401551216840744, "27781": 0.7629209756851196, "27854": 0.15777134895324707, "27929": 0.1718502640724182, "28329": 0.6011518239974976, "28691": 0.1994270235300064, "28788": 0.026976587250828743, "28848": 0.8500841856002808, "28873": 0.3019835948944092, "29290": 0.41001203656196594, "29295": 0.13243216276168823, "29490": 1.013020396232605, "29610": 0.08154398202896118} | 8639034 | IL-10 gene transcription and IL-10 protein production was assessed in both type 1 (Th1) and type 2 (Th2) CD4+ human T cell clones by polymerase chain reaction and ELISA, respectively. Although Th2 clones apparently showed higher IL-10 mRNA levels, IL-10 mRNA expression was consistently found in Th1 clones, as well. Likewise, measurable IL-10 levels were found in the supernatants of both Th1 and Th2 clones. The effect of human IL-10 (h-IL-10) and viral IL-10 (v-IL-10) on the proliferative response and cytokine production by Th1 and Th2 human clones was also investigated. Addition in culture of h-IL-10 and v-IL-10 significantly reduced the proliferation of both Th1 and Th2 clones in response to the specific Ag and to PHA, but it had no inhibitory effect on the proliferative response of Th1 and Th2 clones to IL-2. h-IL-10 and v-IL-10 also inhibited the Ag-induced production of gamma-interferon (IFN-gamma) by Th1 clones and the production of IL-4 and IL-5 by Th2 clones, whereas they had no effect on the cytokine synthesis by the same clones stimulated with PMA plus anti-CD3 antibody. Preincubation of APC, but not of clonal T blasts, with h-IL-10 resulted in the inhibition of Ag-induced proliferation of both Th1 and Th2 clones, supporting the view that h-IL-10 primarily affects APC. These data demonstrate that, unlike the murine system where IL-10 is a product of Th2 (but not Th1) cells and seems to mainly down-regulate the Th1 response, in the human system, IL-10 is produced by, and down-regulates the function of, both Th1 and Th2 cells. | Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. |
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1.1274882555007935, "25389": 1.04512357711792, "25455": 0.35334911942481995, "25456": 0.006812678650021553, "25613": 0.1602703034877777, "25708": 0.14518201351165771, "25714": 0.46608972549438477, "25937": 0.2689530849456787, "26384": 0.32270604372024536, "26563": 0.1970241367816925, "26616": 0.5483922958374023, "26651": 0.3750596046447754, "26942": 0.42608439922332764, "27058": 1.1665629148483276, "27144": 0.05417001247406006, "27196": 0.14179791510105133, "27354": 0.009718249551951885, "27423": 0.5629584193229675, "28086": 1.0533316135406494, "28155": 0.006812678650021553, "28177": 0.21687394380569458, "28207": 0.0797421783208847, "28228": 0.0913962796330452, "28687": 0.011650617234408855, "28696": 0.10203468054533005, "28788": 0.7163142561912537, "29160": 0.7987030148506165} | 8642784 | OBJECTIVE To assess the efficacy of various controlled ovarian hyperstimulation (COH) regimens in the prior poor-responder patient preparing for assisted reproductive techniques. DESIGN English-language literature review. PATIENT(S) Candidates for assisted reproductive techniques who had been defined as having a prior suboptimal response to standard COH regimens. INTERVENTION(S) A variety of regimes are reviewed, including increased gonadotropin doses, change of gonadotropins, adjunctive growth hormone (GH), luteal phase (long) GnRH agonist (GnRH-a) initiation, early follicular phase (flare) GnRH-a initiation, low-dose luteal phase (ultrashort) GnRH-a initiation, progestin pretreatment, and microdose flare GnRH-a initiation. MAIN OUTCOME MEASURE(S) Maximal serum E(2) levels, follicular development, dose, and duration of gonadotropin therapy, cycle cancellation rates, oocytes retrieved, embryos transferred, and clinical and ongoing pregnancy rates. RESULT(S) A lack of uniformity in definition of the poor responder and of prospective randomized trials make data interpretation somewhat difficult. Of the varied strategies proposed, those that seem to be more uniformly beneficial are microdose GnRH-a flare and late luteal phase initiation of a short course of low-dose GnRH-a discontinued before COH. CONCLUSION(S) No single regimen will benefit all poor responders. General acceptance of uniform definitions and performance of large-scale prospective randomized trials are critical. Development of a reliable precycle screen will allow effective differentiation among normal responders, poor responders, and those who will not conceive with their own oocytes. | Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive techniques. |
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0.2674594223499298} | 8646760 | Protein modifications play a major role for most biological processes in living organisms. Amino-terminal acetylation of proteins is a common modification found throughout the tree of life: the N-terminus of a nascent polypeptide chain becomes co-translationally acetylated, often after the removal of the initiating methionine residue. While the enzymes and protein complexes involved in these processes have been extensively studied, only little is known about the biological function of such N-terminal modification events. To identify common principles of N-terminal acetylation, we analyzed the amino-terminal peptides from proteins extracted from Drosophila Kc167 cells. We detected more than 1,200 mature protein N-termini and could show that N-terminal acetylation occurs in insects with a similar frequency as in humans. As the sole true determinant for N-terminal acetylation we could extract the (X)PX rule that indicates the prevention of acetylation under all circumstances. We could show that this rule can be used to genetically engineer a protein to study the biological relevance of the presence or absence of an acetyl group, thereby generating a generic assay to probe the functional importance of N-terminal acetylation. We applied the assay by expressing mutated proteins as transgenes in cell lines and in flies. Here, we present a straightforward strategy to systematically study the functional relevance of N-terminal acetylations in cells and whole organisms. Since the (X)PX rule seems to be of general validity in lower as well as higher eukaryotes, we propose that it can be used to study the function of N-terminal acetylation in all species. | Identification and Functional Characterization of N-Terminally Acetylated Proteins in Drosophila melanogaster |
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in vivo studies have revealed an association between Helicobacter pylori infection and apoptosis in gastric epithelial cells. Although involvement of the Bcl-2 family of proteins as well as cytochrome c release has been demonstrated in H pylori induced cell death, the exact role of the mitochondria during this type of programmed cell death has not been fully elucidated. Therefore, we sought to determine whether or not Bax translocation and mitochondrial fragmentation occur on exposure of gastric epithelial cells to H pylori, resulting in cell death. METHODS Experiments were performed with human gastric adenocarcinoma (AGS) cells, AGS cells transfected with the HPV-E6 gene (which inactivates p53 function), AGS-neo cells (transfected with the backbone construct), mouse embryonic fibroblasts (MEFs), and p19(ARF) null (ARF(-/-)) MEFs. Cells were incubated with a cag positive H pylori strain for up to 24 hours, lysed, and cytoplasmic and mitochondrial membrane fractions were analysed by western blot for Bax translocation. RESULTS Bax translocation was detected in AGS, AGS-neo, and normal MEF cells after exposure to H pylori for three hours, but not in ARF(-/-) MEFs cells. Translocation of Bax after H pylori incubation was also detected in AGS-E6 cells (inactive p53 gene) but to a lesser degree than in AGS-neo cells. In parallel studies, the mitochondrial morphology of living cells infected with H pylori was assessed by confocal microscopy. Mitochondrial fragmentation was detectable after 10 hours of H pylori incubation with AGS cells and after seven hours with MEF cells. In wild-type MEFs, mitochondrial fragmentation was significantly increased in comparison with ARF null MEFs (43% v 10.4%, respectively). Furthermore, mitochondrial depolarisation and caspase-3 activity were initiated within four hours in cells incubated with H pylori, and these events were inhibited by forced expression of Bcl-2. CONCLUSIONS These data suggest that during H pylori induced apoptosis, Bax translocates to the mitochondria which subsequently undergo depolarisation and profound fragmentation. Functional ARF and p53 proteins may play an important role in H pylori induced mitochondrial modification. | Bax translocation and mitochondrial fragmentation induced by Helicobacter pylori. |
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1.182852864265442, "28207": 0.6317287683486938, "28518": 0.07884006202220917, "28732": 0.06246116757392883, "28804": 0.3870677351951599, "28943": 0.04953393340110779, "28965": 0.3141832649707794, "29234": 0.09584271162748337, "29295": 0.18411032855510712, "29391": 0.3519764244556427, "29458": 0.5805994272232056} | 8659426 | Cancer chemoprevention involves the chronic administration of a synthetic, natural or biological agent to reduce or delay the occurrence of malignancy. The potential value of this approach has been demonstrated with trials in breast, prostate and colon cancer. The paradigm for developing new chemopreventive agents has changed markedly in the last decade and now involves extensive preclinical mechanistic evaluation of agents before clinical trials are instituted and a focus on defining biomarkers of activity that can be used as early predictors of efficacy. This review will summarise the current status of the field of chemoprevention and highlight potential new developments. | Cancer chemoprevention: a rapidly evolving field |
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0.04674193635582924, "25795": 0.66441810131073, "25969": 0.5174443125724792, "26013": 0.4132472574710846, "26305": 1.1629066467285156, "26555": 0.3615458607673645, "26741": 0.2223619967699051, "26805": 0.24401791393756866, "26828": 0.22937409579753876, "26835": 0.4709797203540802, "26957": 1.6656410694122314, "27053": 0.0752234235405922, "27374": 0.04953393340110779, "27633": 0.04207121208310127, "27974": 0.23092569410800934, "28263": 0.12986256182193756, "28389": 0.09672962874174118, "28498": 0.22704219818115234, "28873": 0.15442965924739838, "29110": 0.0317181795835495} | 8665891 | Dengue virus and its four serotypes (DENV 1-4) infect approximately 390 million people worldwide each year, with most cases in tropical and subtropical regions. Because of repeated introduction of DENV from epidemic regions and suitable weather conditions, many regions have shifted from hypo-endemicity to hyper-endemicity over recent decades. Since the first dengue outbreak in 1978, it is crucial to understand the current situation in China over nearly 40 years. The purpose of the study was to examine whether dengue in China was endemic or not, which is essential for relevant dengue control and prevention strategy implementation in China. The study, combining epidemiological characteristics of dengue from the disease notification system, phylogenetic and phylogeographic analyses, showed that all four serotypes had been detected in Guangzhou, China, which was dominated by DENV 1-2. The Maximum Likelihood tree analytic results showed that the virus detected in Guangzhou localized in different clades, except of virus of 2002 and 2003 clustered together. There existed the mutual introductions between Guangzhou and Southeast Asia. Most of the viruses were imported from Southeast Asia and the sources of outbreaks in Guangzhou mainly originated from Thailand, Indonesia, and the Philippines. The study indicates that dengue in China still remains as an imported disease, with the possibility of localization. | Dengue is still an imported disease in China: a case study in Guangzhou. |
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estimating and projecting HIV prevalence levels in countries with generalised epidemics. The paper gives an overall summary of the software and interface. It describes the process of defining and modelling a national epidemic in terms of locally relevant sub-epidemics and the four epidemiological parameters used to fit a curve to produce the prevalence trends in the epidemic. It also provides an example of using the EPP in a country with a generalised epidemic. The paper discusses the strengths and weaknesses of the software and its envisaged future developments. | The UNAIDS Estimation and Projection Package: a software package to estimate and project national HIV epidemics. |
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"26953": 0.053244512528181076, "26986": 0.06977381557226181, "27011": 0.34715715050697327, "27144": 0.37640097737312317, "27166": 1.0108904838562012, "27781": 0.2674594223499298, "27854": 0.25845035910606384, "27881": 0.19862671196460724, "27929": 0.15693697333335876, "28024": 0.9485763907432556, "28156": 0.17922431230545044, "28518": 0.34300774335861206, "28522": 0.861702561378479, "28531": 0.3903779089450836, "28667": 0.5871354341506958, "28873": 0.2969166338443756, "29107": 0.09672962874174118, "29290": 0.5607312321662903, "29490": 0.9546096324920654} | 8671456 | BACKGROUND Interleukin-24 (IL-24) is a cytokine that belongs to the IL-10 family. It can selectively induce cancer cell apoptosis which has been utilized as a cancer gene therapy strategy. METHODS A recombinant type five adenovirus containing IL-24 gene (designated CNHK600-IL24) was constructed, whose replication is activated only in tumor cells. The replication of CNHK600-IL24 in breast tumor cells and fibroblasts were assessed by TCID50 and MTT assay; the secretion of IL-24 was measured by ELISA and western blotting. The in vivo anti-tumor effect of CNHK600-IL24 was investigated in nude mice carrying orthotopic or metastatic breast tumor. RESULTS We observed that CNHK600-IL24 could replicate efficiently and resulted in high level IL-24 expression and massive cell death in human breast cancer cell MDA-MB-231 but not in normal fibroblast cell MRC-5. In addition, orthotopic breast tumor growth in the nude mice model was significantly suppressed when CNHK600-IL24 was administered. In the metastatic model generated by tail vein injection, CNHK600-IL24 virotherapy significantly improved survival compared with the same virus expressing EGFP (median survival CNHK600-IL24, 55 days vs. CNHK600-EGFP, 41 day, p < 0.05 Mantal-Cox test). A similar phenomenon was observed in the metastatic model achieved by left ventricular injection as suggested by in vivo luminescence imaging of tumor growth. CONCLUSION The oncolytic adenovirus armed with IL-24, which exhibited enhanced anti-tumor activity and improved survival, is a promising candidate for virotherapy of breast cancer. | Oncolytic adenovirus armed with IL-24 Inhibits the growth of breast cancer in vitro and in vivo |
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"29171": 0.0770333781838417, "29212": 0.3170322775840759, "29278": 0.020300358533859253, "29469": 0.9929623603820801, "29477": 0.04953393340110779} | 8672737 | BACKGROUND AND PURPOSE Migraineurs are at increased risk of cerebellar infarcts and supratentorial white matter lesions. The prevalence, frequency, and distribution of infratentorial hyperintense lesions in migraine are unknown. METHODS Migraineurs with aura (n=161), without aura (n=134), and controls (n=140) from a population-based sample of adults (30 to 60 years of age) were evaluated with MRI. RESULTS Infratentorial hyperintensities were identified in 13 of 295 (4.4%) migraineurs and in 1 of 140 (0.7%) controls (P=0.04). Twelve cases had hyperintensities, mostly bilaterally, in the dorsal basis pontis. Those with infratentorial hyperintensities also had supratentorial white matter lesions more often. CONCLUSIONS We found an increased prevalence of infratentorial (mostly pontine) hyperintensities in migraineurs from the general population. This extends the knowledge about vulnerable brain regions and type of lesions in migraine brains. A hemodynamic ischemic pathogenesis is likely, but further research is needed. | Brain stem and cerebellar hyperintense lesions in migraine. |
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"28873": 0.10731173306703568, "28896": 0.05046287178993225, "29720": 0.5472630262374878} | 8677721 | The N-myc downstream regulated gene 1 (NDRG1) is significantly associated with advanced tumor stages and poor survival of hepatocellular carcinoma (HCC), thereby implicating it as a potential target for HCC treatment. We aim to further understand its biological roles in hepatocarcinogenesis, as a means to exploit it for therapeutic purposes. By screening using the ProtoArray® Human Protein Microarrays, we identified glycogen synthase kinase 3β (GSK-3β) and the orphan nuclear receptor (Nur77) as potential interaction partners of NDRG1. These interactions were confirmed in HCC cell lines in vitro by co-immunoprecipitation; and co-localizations of NDRG1 with GSK-3β and Nur77 were observed by immunofluorescence staining. Additionally, high levels of NDRG1 competitively bind to GSK-3β and Nur77 to allow β-catenin to escape degradation, with consequent elevated levels of downstream oncogenic genes. In vivo, we consistently observed that NDRG1 suppression in HCC xenografts decreased β-catenin levels and its downstream target Cyclin D1, with concomitant tumor growth inhibition. Clinically, the over-expression of NDRG1 in HCC patient samples is positively correlated with GSK-3β-9ser (| R | = 0.28, p = 0.01), Nur77 (| R | = 0.42, p < 0.001), and β-catenin (| R |= 0.32, p = 0.003) expressions. In conclusion, we identified GSK-3β and Nur77 as novel interaction partners of NDRG1. These protein-protein interactions regulate the turnover of β-catenin and subsequent downstream signaling mediated by β-catenin in HCC cells, and provides potential targets for future therapeutic interventions. | NDRG1 promotes growth of hepatocellular carcinoma cells by directly interacting with GSK-3β and Nur77 to prevent β-catenin degradation |
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"25206": 0.13755162060260773, "25524": 0.2539152204990387, "26237": 0.3191637098789215, "26305": 0.14264501631259918, "26319": 0.8281423449516296, "26521": 0.07612881064414978, "26610": 0.42608439922332764, "26675": 0.14602625370025635, "27354": 0.0797421783208847, "27522": 0.21922965347766876, "28041": 0.28890204429626465, "28093": 0.7370892763137817, "28321": 0.4654768109321594, "28637": 0.016465263441205025, "28937": 0.8829278349876404} | 8690595 | Although genetic association studies have been with us for many years, even for the simplest analyses there is little consensus on the most appropriate statistical procedures. Here I give an overview of statistical approaches to population association studies, including preliminary analyses (Hardy–Weinberg equilibrium testing, inference of phase and missing data, and SNP tagging), and single-SNP and multipoint tests for association. My goal is to outline the key methods with a brief discussion of problems (population structure and multiple testing), avenues for solutions and some ongoing developments. | A tutorial on statistical methods for population association studies |
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0.08871890604496002, "26651": 0.036437395960092545, "26721": 0.5562619566917419, "26773": 0.6823468804359436, "26835": 0.46853771805763245, "26952": 0.7445381283760071, "27226": 0.18573370575904846, "27497": 0.47584590315818787, "27781": 0.012615402229130268, "28389": 1.2313295602798462, "28848": 0.6420594453811646, "28873": 0.7086513638496399} | 8692744 | Tripartite motif (TRIM) proteins constitute a family of over 100 members that share conserved tripartite motifs and exhibit diverse biological functions. Several TRIM proteins have been shown to restrict viral infections and regulate host cellular innate immune responses. In order to identify TRIM proteins that modulate the infection of hepatitis B virus (HBV), we tested 38 human TRIMs for their effects on HBV gene expression, capsid assembly and DNA synthesis in human hepatoma cells (HepG2). The study revealed that ectopic expression of 8 TRIM proteins in HepG2 cells potently reduced the amounts of secreted HBV surface and e antigens as well as intracellular capsid and capsid DNA. Mechanistic analyses further demonstrated that the 8 TRIMs not only reduced the expression of HBV mRNAs, but also inhibited HBV enhancer I and enhancer II activities. Studies focused on TRIM41 revealed that a HBV DNA segment spanning nucleotide 1638 to nucleotide 1763 was essential for TRIM41-mediated inhibition of HBV enhancer II activity and the inhibitory effect depended on the E3 ubiquitin ligase activity of TRIM41 as well as the integrity of TRIM41 C-terminal domain. Moreover, knockdown of endogenous TRIM41 in a HepG2-derived stable cell line significantly increased the level of HBV preC/C RNA, leading to an increase in viral core protein, capsid and capsid DNA. Our studies have thus identified eight TRIM proteins that are able to inhibit HBV transcription and provided strong evidences suggesting the endogenous role of TRIM41 in regulating HBV transcription in human hepatoma cells. | Identification and Characterization of Multiple TRIM Proteins That Inhibit Hepatitis B Virus Transcription |
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Affected females develop normally for 6–18 months, but then lose voluntary movements, including speech and hand skills. Most RTT patients are heterozygous for mutations in the X-linked gene MECP2 (refs. 3–12), encoding a protein that binds to methylated sites in genomic DNA and facilitates gene silencing. Previous work with Mecp2-null embryonic stem cells indicated that MeCP2 is essential for mouse embryogenesis. Here we generate mice lacking Mecp2 using Cre-loxP technology. Both Mecp2-null mice and mice in which Mecp2 was deleted in brain showed severe neurological symptoms at approximately six weeks of age. Compensation for absence of MeCP2 in other tissues by MeCP1 (refs. 19,20) was not apparent in genetic or biochemical tests. After several months, heterozygous female mice also showed behavioral symptoms. The overlapping delay before symptom onset in humans and mice, despite their profoundly different rates of development, raises the possibility that stability of brain function, not brain development per se, is compromised by the absence of MeCP2. | A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome |
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Here, we elucidate the molecular mechanism of phosphorylation-regulated translation of TNF. We demonstrate that translation of the TNF-precursor at the ER requires expression of the ARE-binding and -stabilizing factor human antigen R (HuR) together with either activity of the p38 MAPK/MK2 pathway or the absence of the ARE-binding and -destabilizing factor tristetraprolin (TTP). We show that phosphorylation of TTP by MK2 decreases its affinity to the ARE, inhibits its ability to replace HuR, and permits HuR-mediated initiation of translation of TNF mRNA. Since translation of TTP's own mRNA is also regulated by this mechanism, an intrinsic feedback control of the inflammatory response is ensured. The phosphorylation-regulated TTP/HuR exchange at target mRNAs provides a reversible switch between unstable/non-translatable and stable/efficiently translated mRNAs. | The p38/MK2-Driven Exchange between Tristetraprolin and HuR Regulates AU–Rich Element–Dependent Translation |
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0.3381449282169342, "27295": 0.47827014327049255, "27427": 0.5370414853096008, "27854": 0.25239890813827515, "27881": 0.20022670924663544, "28170": 1.0506030321121216, "28283": 0.9317949414253235, "28522": 1.0087559223175049, "28775": 0.8829278349876404, "28835": 1.0444365739822388, "29206": 1.0229004621505737, "29290": 0.42225050926208496} | 8702697 | AIMS Tumor microenvironment is a strong determinant for the acquisition of metastatic potential of cancer cells. We have recently demonstrated that cancer-associated fibroblasts (CAFs) elicit a redox-dependent epithelial-mesenchymal transition (EMT) in prostate cancer (PCa) cells, driven by cycloxygenase-2/hypoxia-inducible factor-1 (HIF-1)/nuclear factor-κB pathway and enhancing tumor aggressiveness. Here, we investigated the involvement of microRNAs (miRNAs) in tumor-stroma interplay to identify possible tools to counteract oxidative stress and metastasis dissemination. RESULTS We found that miR-205 is the most downmodulated miRNA in PCa cells upon CAF stimulation, due to direct transcriptional repression by HIF-1, a known redox-sensitive transcription factor. Rescue experiments demonstrated that ectopic miR-205 overexpression in PCa cells counteracts CAF-induced EMT, thus impairing enhancement of cell invasion, acquisition of stem cell traits, tumorigenicity, and metastatic dissemination. In addition, miR-205 blocks tumor-driven activation of surrounding fibroblasts by reducing pro-inflammatory cytokine secretion. INNOVATION Overall, such findings suggest miR-205 as a brake against PCa metastasis by blocking both the afferent and efferent arms of the circuit between tumor cells and associated fibroblasts, thus interrupting the pro-oxidant and pro-inflammatory circuitries engaged by reactive stroma. CONCLUSION The evidence that miR-205 replacement in PCa cells is able not only to prevent but also to revert the oxidative/pro-inflammatory axis leading to EMT induced by CAFs sets the rationale for developing miRNA-based approaches to prevent and treat metastatic disease. | miR-205 hinders the malignant interplay between prostate cancer cells and associated fibroblasts. |
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0.3883931338787079, "29361": 0.1693800985813141, "29391": 0.42990362644195557, "29610": 0.1011524572968483} | 8708082 | Type 2 diabetes mellitus (T2DM) affects more than 7% of adults in the US and leads to substantial personal and economic burden. In prediabetic states insulin secretion and action—potential targets of preventive interventions—are impaired. In trials lifestyle modification (i.e. weight loss and exercise) has proven effective in preventing incident T2DM in high-risk groups, although weight loss has the greatest effect. Various medications (e.g. metformin, thiazolidinediones and acarbose) can also prevent or delay T2DM. Whether diabetes-prevention strategies also ultimately prevent the development of diabetic vascular complications is unknown, but cardiovascular risk factors are favorably affected. Preventive strategies that can be implemented in routine clinical settings have been developed and evaluated. Widespread application has, however, been limited by local financial considerations, even though cost-effectiveness might be achieved at the population level. | The prevention of type 2 diabetes |
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describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5' and 3' boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development. | The transcriptional landscape of the mammalian genome. |
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(2000), Nucleic Acids Res. 28, 235-242; http://www.pdb.org/] is the single worldwide archive of primary structural data of biological macromolecules. Many secondary sources of information are derived from PDB data. It is the starting point for studies in structural bioinformatics. This article describes the goals of the PDB, the systems in place for data deposition and access, how to obtain further information and plans for the future development of the resource. The reader should come away with an understanding of the scope of the PDB and what is provided by the resource. | The Protein Data Bank |
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0.14939609169960022, "24848": 0.1619328260421753, "24960": 0.3325583338737488, "25002": 0.04487626627087593, "25409": 0.006812678650021553, "25456": 0.5618454217910767, "25468": 1.589713454246521, "25473": 0.034552380442619324, "25499": 0.09317722171545029, "25502": 0.6704301834106445, "25509": 0.0019512200960889459, "25510": 0.987156867980957, "25525": 1.216973900794983, "25761": 0.0913962796330452, "25778": 1.1413075923919678, "25950": 0.129004567861557, "26236": 1.2238903045654297, "26242": 0.4437839686870575, "26305": 0.23402166366577148, "26394": 0.2018241584300995, "26402": 1.0464962720870972, "26616": 0.33115679025650024, "26651": 0.1889725625514984, "26657": 0.21214580535888672, "26741": 0.9598589539527893, "27287": 0.9123768210411072, "28227": 0.5947071313858032, "28788": 0.08961215615272522, "28829": 0.07431721687316895, "28835": 0.966567873954773, "29021": 0.28450319170951843, "29226": 0.08871890604496002} | 8724666 | The balance between oxidative and nonoxidative glucose metabolism is essential for a number of pathophysiological processes. By deleting enzymes that affect aerobic glycolysis with different potencies, we examine how modulating glucose metabolism specifically affects hematopoietic and leukemic cell populations. We find that a deficiency in the M2 pyruvate kinase isoform (PKM2) reduces the levels of metabolic intermediates important for biosynthesis and impairs progenitor function without perturbing hematopoietic stem cells (HSCs), whereas lactate dehydrogenase A (LDHA) deletion significantly inhibits the function of both HSCs and progenitors during hematopoiesis. In contrast, leukemia initiation by transforming alleles putatively affecting either HSCs or progenitors is inhibited in the absence of either PKM2 or LDHA, indicating that the cell-state-specific responses to metabolic manipulation in hematopoiesis do not apply to the setting of leukemia. This finding suggests that fine-tuning the level of glycolysis may be explored therapeutically for treating leukemia while preserving HSC function. | Cell-State-Specific Metabolic Dependency in Hematopoiesis and Leukemogenesis |
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"28688": 0.24018502235412598, "28892": 0.06703783571720123, "29034": 0.007782140281051397, "29083": 0.1229778528213501, "29222": 0.26296505331993103, "29290": 0.49982786178588867, "29440": 0.11517547070980072, "29566": 0.03266380727291107} | 8734695 | Rhythmic oscillations shape cortical dynamics during active behavior, sleep, and general anesthesia. Cross-frequency phase-amplitude coupling is a prominent feature of cortical oscillations, but its role in organizing conscious and unconscious brain states is poorly understood. Using high-density EEG and intracranial electrocorticography during gradual induction of propofol general anesthesia in humans, we discovered a rapid drug-induced transition between distinct states with opposite phase-amplitude coupling and different cortical source distributions. One state occurs during unconsciousness and may be similar to sleep slow oscillations. A second state occurs at the loss or recovery of consciousness and resembles an enhanced slow cortical potential. These results provide objective electrophysiological landmarks of distinct unconscious brain states, and could be used to help improve EEG-based monitoring for general anesthesia. | A transition in brain state during propofol-induced unconsciousness. |
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0.17759032547473907, "27521": 0.09406650811433792, "27642": 1.1063944101333618, "27777": 0.5080875158309937, "27822": 0.4431571960449219, "27846": 0.4873090982437134, "27854": 0.013579257763922215, "28024": 0.4624064862728119, "28184": 0.3485364317893982, "28424": 0.35334911942481995, "28433": 0.09850110858678818, "28667": 0.6086184978485107, "28691": 0.015504186972975731, "28728": 0.12556517124176025, "29060": 0.5051454305648804, "29083": 0.17922431230545044, "29297": 1.09404456615448} | 8747771 | Duplication and segregation of chromosomes involves dynamic reorganization of their internal structure by conserved architectural proteins, including the structural maintenance of chromosomes (SMC) complexes cohesin and condensin. Despite active investigation of the roles of these factors, a genome-wide view of dynamic chromosome architecture at both small and large scale during cell division is still missing. Here, we report the first comprehensive 4D analysis of the higher-order organization of the Saccharomyces cerevisiae genome throughout the cell cycle and investigate the roles of SMC complexes in controlling structural transitions. During replication, cohesion establishment promotes numerous long-range intra-chromosomal contacts and correlates with the individualization of chromosomes, which culminates at metaphase. In anaphase, mitotic chromosomes are abruptly reorganized depending on mechanical forces exerted by the mitotic spindle. Formation of a condensin-dependent loop bridging the centromere cluster with the rDNA loci suggests that condensin-mediated forces may also directly facilitate segregation. This work therefore comprehensively recapitulates cell cycle-dependent chromosome dynamics in a unicellular eukaryote, but also unveils new features of chromosome structural reorganization during highly conserved stages of cell division. | Cohesins and condensins orchestrate the 4D dynamics of yeast chromosomes during the cell cycle |
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"28815": 0.11691460013389587, "29060": 0.1064341589808464} | 8748720 | The Heliconius butterflies are a diverse recent radiation comprising multiple levels of divergence with ongoing gene flow between species. The recently sequenced genome of Heliconius melpomene allowed us to investigate the genomic evolution of this group using dense RAD marker sequencing. Phylogenetic analysis of 54 individuals robustly supported reciprocal monophyly of H. melpomene and Heliconius cydno and refuted previous phylogenetic hypotheses that H. melpomene may be paraphylectic with respect to H. cydno. Heliconius timareta also formed a monophyletic clade closely related but distinct from H. cydno with Heliconius heurippa falling within this clade. We find evidence for genetic admixture between sympatric populations of the sister clades H. melpomene and H. cydno/timareta, particularly between H. cydno and H. melpomene from Central America and between H. timareta and H. melpomene from the eastern slopes of the Andes. Between races, divergence is primarily explained by isolation by distance and there is no detectable genetic population structure between parapatric races, suggesting that hybrid zones between races are not zones of secondary contact. Our results also support previous findings that colour pattern loci are shared between populations and species with similar colour pattern elements. Furthermore, this pattern is almost unique to these genomic regions, with only a very small number of other loci showing significant similarity between populations and species with similar colour patterns. | Genome-wide patterns of divergence and gene flow across a butterfly radiation. |
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0.22548456490039825, "29278": 0.13755162060260773, "29361": 0.10203468054533005, "29477": 0.755608320236206, "29533": 0.2223619967699051, "29598": 0.9650808572769165} | 8756719 | This study represents the first phase III trial of the safety, tolerability, and effectiveness of tafenoquine for malaria prophylaxis. In a randomized (3:1), double-blinded study, Australian soldiers received weekly malaria prophylaxis with 200 mg tafenoquine (492 subjects) or 250 mg mefloquine (162 subjects) for 6 months on a peacekeeping deployment to East Timor. After returning to Australia, tafenoquine-receiving subjects received a placebo and mefloquine-receiving subjects received 30 mg primaquine daily for 14 days. There were no clinically significant differences between hematological and biochemical parameters of the treatment groups. Treatment-related adverse events for the two groups were similar (tafenoquine, 13.4%; mefloquine, 11.7%). Three subjects on tafenoquine (0.6%) and none on mefloquine discontinued prophylaxis because of possible drug-related adverse events. No diagnoses of malaria occurred for either group during deployment, but 4 cases (0.9%) and 1 case (0.7%) of Plasmodium vivax infection occurred among the tafenoquine and mefloquine groups, respectively, up to 20 weeks after discontinuation of medication. In a subset of subjects recruited for detailed safety assessments, treatment-related mild vortex keratopathy was detected in 93% (69 of 74) of tafenoquine subjects but none of the 21 mefloquine subjects. The vortex keratopathy was not associated with any effect on visual acuity and was fully resolved in all subjects by 1 year. Tafenoquine appears to be safe and well tolerated as malaria prophylaxis. Although the volunteers' precise exposure to malaria could not be proven in this study, tafenoquine appears to be a highly efficacious drug for malaria prophylaxis. | Randomized, double-blind study of the safety, tolerability, and efficacy of tafenoquine versus mefloquine for malaria prophylaxis in nonimmune subjects. |
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"25476": 0.47584590315818787, "25524": 0.3588210940361023, "25549": 0.06337817758321762, "25644": 0.08692999184131622, "25662": 0.08513788133859634, "26166": 0.27712854743003845, "26417": 0.18167030811309814, "26524": 0.5800528526306152, "26773": 0.6254787445068359, "26874": 1.0874829292297363, "27642": 0.9394577741622925, "28024": 1.036847710609436, "28086": 0.23633737862110138, "28424": 0.040196798741817474, "28436": 0.2145126610994339, "28892": 0.034552380442619324, "29206": 0.12728634476661682, "29458": 0.07068414986133575} | 8759633 | Studies of replication timing provide a handle into previously impenetrable higher-order levels of chromosome organization and their plasticity during development. Although mechanisms regulating replication timing are not clear, novel genome-wide studies provide a thorough survey of the extent to which replication timing is regulated during most of the early cell fate transitions in mammals, revealing coordinated changes of a defined set of 400–800 kb chromosomal segments that involve at least half the genome. Furthermore, changes in replication time are linked to changes in sub-nuclear organization and domain-wide transcriptional potential, and tissue-specific replication timing profiles are conserved from mouse to human, suggesting that the program has developmental significance. Hence, these studies have provided a solid foundation for linking megabase level chromosome structure to function, and suggest a central role for replication in domain-level genome organization. | Domain-wide regulation of DNA replication timing during mammalian development |
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0.0354953333735466, "27881": 0.09761575609445572, "28086": 0.1229778528213501, "28156": 0.2018241584300995, "28227": 0.5551415085792542, "28723": 0.10731173306703568, "28788": 0.1064341589808464, "29217": 0.14349138736724854, "29290": 0.3956514894962311} | 8764879 | Leukemias and other cancers possess self-renewing stem cells that help to maintain the cancer. Cancer stem cell eradication is thought to be crucial for successful anticancer therapy. Using an acute myeloid leukemia (AML) model induced by the leukemia-associated monocytic leukemia zinc finger (MOZ)-TIF2 fusion protein, we show here that AML can be cured by the ablation of leukemia stem cells. The MOZ fusion proteins MOZ-TIF2 and MOZ-CBP interacted with the transcription factor PU.1 to stimulate the expression of macrophage colony–stimulating factor receptor (CSF1R, also known as M-CSFR, c-FMS or CD115). Studies using PU.1-deficient mice showed that PU.1 is essential for the ability of MOZ-TIF2 to establish and maintain AML stem cells. Cells expressing high amounts of CSF1R (CSF1Rhigh cells), but not those expressing low amounts of CSF1R (CSF1Rlow cells), showed potent leukemia-initiating activity. Using transgenic mice expressing a drug-inducible suicide gene controlled by the CSF1R promoter, we cured AML by ablation of CSF1Rhigh cells. Moreover, induction of AML was suppressed in CSF1R-deficient mice and CSF1R inhibitors slowed the progression of MOZ-TIF2–induced leukemia. Thus, in this subtype of AML, leukemia stem cells are contained within the CSF1Rhigh cell population, and we suggest that targeting of PU.1-mediated upregulation of CSF1R expression might be a useful therapeutic approach. | PU.1-mediated upregulation of CSF1R is crucial for leukemia stem cell potential induced by MOZ-TIF2 |
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transient stage of fibrogenesis characterized by extracellular matrix deposition. While the perpetuation of such phase can lead to permanent tissue scarring, the consequences of its suppression remain to be studied. Using a model of acute muscle damage we were able to determine that pharmacological inhibition of FAP expansion by Nilotinib, a tyrosine kinase inhibitor with potent antifibrotic activity, exerts a detrimental effect on myogenesis during regeneration. We found that Nilotinib inhibits the damage-induced expansion of satellite cells in vivo, but it does not affect in vitro proliferation, suggesting a non cell-autonomous effect. Nilotinib impairs regenerative fibrogenesis by preventing the injury-triggered expansion and differentiation of resident CD45(-):CD31(-):α7integrin(-):Sca1(+) mesenchymal FAPs. Our data support the notion that the expansion of FAPs and transient fibrogenesis observed during regeneration play an important trophic role toward tissue-specific stem cells. | Pharmacological blockage of fibro/adipogenic progenitor expansion and suppression of regenerative fibrogenesis is associated with impaired skeletal muscle regeneration. |
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"25476": 0.6054253578186035, "25662": 0.17267228662967682, "25714": 0.6430866718292236, "25761": 0.034552380442619324, "25950": 0.9687942266464233, "26083": 1.1063944101333618, "26402": 1.179255723953247, "26512": 0.14095009863376617, "26524": 0.7610978484153748, "26982": 0.083342544734478, "27144": 0.045809537172317505, "27169": 0.4574742913246155, "27491": 0.5080875158309937, "27777": 0.055094651877880096, "27854": 0.14433705806732178, "27881": 0.3339579105377197, "28086": 0.16276304423809052, "28156": 0.3269403576850891, "28616": 0.6558387279510498, "28691": 0.014542185701429844, "29107": 0.014542185701429844, "29206": 1.022197961807251, "29290": 0.6734226942062378, "29516": 0.129004567861557} | 8774475 | Loss of cell polarity proteins such as Scribble induces neoplasia in Drosophila by promoting uncontrolled proliferation. In mammals, the role that polarity proteins play during tumorigenesis is not well understood. Here, we demonstrate that depletion of Scribble in mammary epithelia disrupts cell polarity, blocks three-dimensional morphogenesis, inhibits apoptosis, and induces dysplasia in vivo that progress to tumors after long latency. Loss of Scribble cooperates with oncogenes such as c-myc to transform epithelial cells and induce tumors in vivo by blocking activation of an apoptosis pathway. Like depletion, mislocalization of Scribble from cell-cell junction was sufficient to promote cell transformation. Interestingly, spontaneous mammary tumors in mice and humans possess both downregulated and mislocalized Scribble. Thus, we demonstrate that scribble inhibits breast cancer formation and that deregulation of polarity pathways promotes dysplastic and neoplastic growth in mammals by disrupting morphogenesis and inhibiting cell death. | Deregulation of Scribble Promotes Mammary Tumorigenesis and Reveals a Role for Cell Polarity in Carcinoma |
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1.2759300470352173, "26780": 0.1221139207482338, "26906": 0.6332852244377136, "27023": 0.06977381557226181, "27292": 0.5336109399795532, "27613": 0.0354953333735466, "27833": 0.176772341132164, "27896": 0.10906458646059036, "27915": 0.0038986403960734606, "28067": 1.020087480545044, "28093": 0.255429208278656, "28268": 0.11256109178066254, "28353": 0.13157635927200317, "28732": 0.015504186972975731, "29048": 0.083342544734478, "29167": 0.3676496744155884, "29200": 0.11778303235769272, "29513": 0.18654440343379974} | 8780599 | OBJECTIVE Although the Polypill concept (proposed in 2003) is promising in terms of benefits for cardiovascular risk management, the potential costs and adverse effects are its main pitfalls. The objective of this study was to identify a tastier and safer alternative to the Polypill: the Polymeal. METHODS Data on the ingredients of the Polymeal were taken from the literature. The evidence based recipe included wine, fish, dark chocolate, fruits, vegetables, garlic, and almonds. Data from the Framingham heart study and the Framingham offspring study were used to build life tables to model the benefits of the Polymeal in the general population from age 50, assuming multiplicative correlations. RESULTS Combining the ingredients of the Polymeal would reduce cardiovascular disease events by 76%. For men, taking the Polymeal daily represented an increase in total life expectancy of 6.6 years, an increase in life expectancy free from cardiovascular disease of 9.0 years, and a decrease in life expectancy with cardiovascular disease of 2.4 years. The corresponding differences for women were 4.8, 8.1, and 3.3 years. CONCLUSION The Polymeal promises to be an effective, non-pharmacological, safe, cheap, and tasty alternative to reduce cardiovascular morbidity and increase life expectancy in the general population. | The Polymeal: a more natural, safer, and probably tastier (than the Polypill) strategy to reduce cardiovascular disease by more than 75%. |
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"25930": 0.8433839678764343, "26243": 0.03925827145576477, "26261": 0.13243216276168823, "26651": 0.025073638185858727, "26802": 1.0144377946853638, "26838": 0.06337817758321762, "27094": 0.15860503911972046, "27152": 0.6353566646575928, "27226": 0.0354953333735466, "27343": 0.14602625370025635, "27528": 0.04767346754670143, "27572": 0.02792670577764511, "27965": 0.011650617234408855, "28024": 0.11343330889940262, "28086": 0.8600510358810425, "28156": 0.3499138653278351, "28163": 0.083342544734478, "28696": 0.05694137513637543, "28873": 0.007782140281051397, "29105": 0.49686139822006226, "29290": 0.47584590315818787} | 8790729 | BACKGROUND There is a widespread interest in developing renewable sources of islet-replacement tissue for type I diabetes mellitus. Human mesenchymal cells isolated from the Wharton's jelly of the umbilical cord (HUMSCs), which can be easily obtained and processed compared with embryonic and bone marrow stem cells, possess stem cell properties. HUMSCs may be a valuable source for the generation of islets. METHODOLOGY AND PRINCIPAL FINDINGS HUMSCs were induced to transform into islet-like cell clusters in vitro through stepwise culturing in neuron-conditioned medium. To assess the functional stability of the islet-like cell clusters in vivo, these cell clusters were transplanted into the liver of streptozotocin-induced diabetic rats via laparotomy. Glucose tolerance was measured on week 12 after transplantation accompanied with immunohistochemistry and electron microscopy analysis. These islet-like cell clusters were shown to contain human C-peptide and release human insulin in response to physiological glucose levels. Real-time RT-PCR detected the expressions of insulin and other pancreatic beta-cell-related genes (Pdx1, Hlxb9, Nkx2.2, Nkx6.1, and Glut-2) in these islet-like cell clusters. The hyperglycemia and glucose intolerance in streptozotocin-induced diabetic rats was significantly alleviated after xenotransplantation of islet-like cell clusters, without the use of immunosuppressants. In addition to the existence of islet-like cell clusters in the liver, some special fused liver cells were also found, which characterized by human insulin and nuclei-positive staining and possessing secretory granules. CONCLUSIONS AND SIGNIFICANCE In this study, we successfully differentiate HUMSCs into mature islet-like cell clusters, and these islet-like cell clusters possess insulin-producing ability in vitro and in vivo. HUMSCs in Wharton's Jelly of the umbilical cord seem to be the preferential source of stem cells to convert into insulin-producing cells, because of the large potential donor pool, its rapid availability, no risk of discomfort for the donor, and low risk of rejection. | Islet-Like Clusters Derived from Mesenchymal Stem Cells in Wharton's Jelly of the Human Umbilical Cord for Transplantation to Control Type 1 Diabetes |
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"24501": 0.8600510358810425, "24714": 0.1751343309879303, "24735": 0.176772341132164, "24759": 0.06886265426874161, "25002": 0.11691460013389587, "25121": 0.0009760859538801014, "25125": 0.8699195384979248, "25344": 0.0797421783208847, "25918": 0.2034190446138382, "26018": 0.07341018319129944, "26243": 0.6659244894981384, "26557": 0.04860413447022438, "27144": 0.1011524572968483, "27159": 0.48430517315864563, "27531": 0.14264501631259918, "27641": 0.42990362644195557, "27710": 1.1230508089065552, "27794": 0.9440274834632874, "27891": 0.19220098853111267, "28530": 0.10379679501056671, "28715": 0.15442965924739838, "28723": 0.23402166366577148, "28817": 0.0029254043474793434, "29167": 0.14433705806732178, "29361": 0.025073638185858727, "29454": 0.08064348995685577, "29598": 0.04487626627087593} | 8814634 | OBJECTIVE To determine whether the perioperative use of hydroxyethyl starch 6% and albumin 5% in elective joint arthroplasties are associated with an increased risk for perioperative complications. DESIGN Retrospective cohort study of population based data between 2006 and 2013. SETTING Data from 510 different hospitals across the United States participating in the Premier Perspective database. PARTICIPANTS 1,051,441 patients undergoing elective total hip and knee arthroplasties. EXPOSURES Perioperative fluid resuscitation with hydroxyethyl starch 6% or albumin 5%, or neither. MAIN OUTCOME MEASURES Acute renal failure and thromboembolic, cardiac, and pulmonary complications. RESULTS Compared with patients who received neither colloid, perioperative fluid resuscitation with hydroxyethyl starch 6% or albumin 5% was associated with an increased risk of acute renal failure (odds ratios 1.23 (95% confidence interval 1.13 to 1.34) and 1.56 (1.36 to 1.78), respectively) and most other complications. A recent decrease in hydroxyethyl starch 6% use was noted, whereas that of albumin 5% increased. CONCLUSIONS Similar to studies in critically ill patients, we showed that use of hydroxyethyl starch 6% was associated with an increased risk of acute renal failure and other complications in the elective perioperative orthopedic setting. This increased risk also applied to albumin 5%. These findings raise questions regarding the widespread use of these colloids in elective joint arthroplasty procedures. | Use of perioperative hydroxyethyl starch 6% and albumin 5% in elective joint arthroplasty and association with adverse outcomes: a retrospective population based analysis |
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0.7656494975090027, "28268": 0.09495500475168228, "28436": 0.5751199722290039, "28561": 0.5057345628738403, "28696": 1.178053855895996, "28892": 0.16690383851528168, "29226": 0.24859806895256042, "29290": 0.33115679025650024} | 8816869 | Circadian timing is generated through a unique series of autoregulatory interactions termed the molecular clock. Behavioral rhythms subject to the molecular clock are well characterized. We demonstrate a role for Bmal1 and Clock in the regulation of glucose homeostasis. Inactivation of the known clock components Bmal1 (Mop3) and Clock suppress the diurnal variation in glucose and triglycerides. Gluconeogenesis is abolished by deletion of Bmal1 and is depressed in Clock mutants, but the counterregulatory response of corticosterone and glucagon to insulin-induced hypoglycaemia is retained. Furthermore, a high-fat diet modulates carbohydrate metabolism by amplifying circadian variation in glucose tolerance and insulin sensitivity, and mutation of Clock restores the chow-fed phenotype. Bmal1 and Clock, genes that function in the core molecular clock, exert profound control over recovery from insulin-induced hypoglycaemia. Furthermore, asynchronous dietary cues may modify glucose homeostasis via their interactions with peripheral molecular clocks. | BMAL1 and CLOCK, Two Essential Components of the Circadian Clock, Are Involved in Glucose Homeostasis |
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0.7314660549163818, "29494": 0.009718249551951885} | 8839502 | The incidence of chronic kidney diseases is increasing worldwide, and these conditions are emerging as a major public health problem. While genetic factors contribute to susceptibility and progression of renal disease, proteinuria has been claimed as an independent predictor of outcome. Reduction of urinary protein levels by various medications and a low-protein diet limits renal function decline in individuals with nondiabetic and diabetic nephropathies to the point that remission of the disease and regression of renal lesions have been observed in experimental animals and even in humans. In animal models, regression of glomerular structural changes is associated with remodeling of the glomerular architecture. Instrumental to this discovery were 3D reconstruction studies of the glomerular capillary tuft, which allowed the quantification of sclerosis volume reduction and capillary regeneration upon treatment. Regeneration of capillary segments might result from the contribution of resident cells, but progenitor cells of renal or extrarenal origin may also have a role. This review describes recent advances in our understanding of the mechanisms and mediators underlying renal tissue repair ultimately responsible for regression of renal injury. | Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. |
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0.5838727951049805, "28436": 0.16110190749168396, "28739": 0.0354953333735466, "29290": 0.1970241367816925, "29299": 0.31489628553390503, "29458": 0.14179791510105133} | 8842332 | OBJECTIVE To compare contemporary pregnancy outcomes in women with and without type 1 diabetes, and to examine the effects of obesity and glycaemic control on these outcomes. DESIGN AND SETTING Historical cohort study in a specialist diabetes and maternity network in Victoria. PARTICIPANTS All singleton births (at least 20 weeks' gestation), 2010-2013, were analysed: 107 pregnancies to women with type 1 diabetes and 27 075 pregnancies to women without diabetes. Women with type 2 diabetes or gestational diabetes were excluded. METHODS Data were extracted from the Birthing Outcomes System database; associations between type 1 diabetes and pregnancy outcomes were analysed by multivariable regression. MAIN OUTCOME MEASURES Mode of birth; maternal and neonatal outcomes. RESULTS The mean body mass index was higher for women with type 1 diabetes than for women without diabetes (mean, 27.3 kg/m(2) [SD, 5.0] v 25.7 kg/m(2) [SD, 5.9]; P = 0.01); the median gestation period for their babies was shorter (median, 37.3 weeks [IQR, 34.6-38.1] v 39.4 weeks [IQR, 38.4-40.4]; P < 0.001) and they were more likely to be large for gestational age (LGA) (adjusted odds ratio [aOR], 7.9; 95% CI, 5.3-11.8). Women with type 1 diabetes were more likely to have had labour induced (aOR, 3.0; 95% CI, 2.0-4.5), a caesarean delivery (aOR, 4.6; 95% CI, 3.1-7.0), or a pre-term birth (aOR, 6.7; 95% CI, 4.5-10.0); their babies were more likely to have shoulder dystocia (aOR, 8.2; 95% CI, 3.6-18.7), hypoglycaemia (aOR, 10.3; 95% CI, 6.8-15.6), jaundice (aOR, 5.1; 95% CI, 3.3-7.7), respiratory distress (aOR, 2.5; 95% CI, 1.4-4.4) or to suffer perinatal death (aOR, 4.3; 95% CI, 1.9-9.9). In women with type 1 diabetes, greater obesity was associated with increased odds for an LGA baby or congenital malformation, and increased HbA1c levels were associated with pre-term birth and perinatal death. CONCLUSION Women with type 1 diabetes, even when managed in a specialist setting, still experience adverse obstetric and neonatal outcomes. Poor glycaemic control is not wholly responsible for adverse outcomes, reinforcing the importance of other risk factors, such as obesity and weight gain. | Contemporary type 1 diabetes pregnancy outcomes: impact of obesity and glycaemic control. |
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When occupied by 1,25D, VDR interacts with the retinoid X receptor (RXR) to form a heterodimer that binds to vitamin D responsive elements in the region of genes directly controlled by 1,25D. By recruiting complexes of either coactivators or corepressors, ligand-activated VDR-RXR modulates the transcription of genes encoding proteins that promulgate the traditional functions of vitamin D, including signaling intestinal calcium and phosphate absorption to effect skeletal and calcium homeostasis. Thus, vitamin D action in a particular cell depends upon the metabolic production or delivery of sufficient concentrations of the 1,25D ligand, expression of adequate VDR and RXR coreceptor proteins, and cell-specific programming of transcriptional responses to regulate select genes that encode proteins that function in mediating the effects of vitamin D. For example, 1,25D induces RANKL, SPP1 (osteopontin), and BGP (osteocalcin) to govern bone mineral remodeling; TRPV6, CaBP9k, and claudin 2 to promote intestinal calcium absorption; and TRPV5, klotho, and Npt2c to regulate renal calcium and phosphate reabsorption. VDR appears to function unliganded by 1,25D in keratinocytes to drive mammalian hair cycling via regulation of genes such as CASP14, S100A8, SOSTDC1, and others affecting Wnt signaling. Finally, alternative, low-affinity, non-vitamin D VDR ligands, e.g., lithocholic acid, docosahexaenoic acid, and curcumin, have been reported. Combined alternative VDR ligand(s) and 1,25D/VDR control of gene expression may delay chronic disorders of aging such as osteoporosis, type 2 diabetes, cardiovascular disease, and cancer. | Molecular Mechanisms of Vitamin D Action |
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0.3588210940361023} | 8858602 | A systematic quantitative analysis of temporal changes in host and viral proteins throughout the course of a productive infection could provide dynamic insights into virus-host interaction. We developed a proteomic technique called "quantitative temporal viromics" (QTV), which employs multiplexed tandem-mass-tag-based mass spectrometry. Human cytomegalovirus (HCMV) is not only an important pathogen but a paradigm of viral immune evasion. QTV detailed how HCMV orchestrates the expression of >8,000 cellular proteins, including 1,200 cell-surface proteins to manipulate signaling pathways and counterintrinsic, innate, and adaptive immune defenses. QTV predicted natural killer and T cell ligands, as well as 29 viral proteins present at the cell surface, potential therapeutic targets. Temporal profiles of >80% of HCMV canonical genes and 14 noncanonical HCMV open reading frames were defined. QTV is a powerful method that can yield important insights into viral infection and is applicable to any virus with a robust in vitro model. | Quantitative Temporal Viromics: An Approach to Investigate Host-Pathogen Interaction |
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0.9256220459938049, "27989": 0.49864232540130615, "28041": 0.15275461971759796, "28207": 0.14264501631259918, "28227": 0.3381449282169342, "28322": 0.15777134895324707, "28424": 1.4936060905456543, "28466": 0.8450632095336914, "28616": 0.13670019805431366, "28696": 0.053244512528181076, "28828": 0.44753631949424744, "28868": 0.16359257698059082, "28892": 0.37707099318504333, "29083": 0.16524957120418549, "29125": 1.0144377946853638, "29172": 0.09850110858678818, "29440": 0.00875066313892603, "29516": 0.6358738541603088} | 8868863 | Sleep disturbances, including sleep insufficiency and sleep fragmentation, have been linked to abnormal glucose metabolism and increased diabetes risk. Well-controlled laboratory studies have provided insights regarding the underlying mechanisms. Several large prospective studies suggest that these sleep disturbances are associated with an increased risk of incident diabetes. Obstructive sleep apnea, which combines sleep fragmentation and hypoxemia, is a major risk factor for insulin resistance and possibly diabetes. Whether glycemic control in type 2 diabetes patients can be improved by treating sleep apnea remains controversial. Recently, sleep disturbances during pregnancy and their relationship to gestational diabetes and hyperglycemia have received considerable attention owing to potential adverse effects on maternal and fetal health. Additionally, evidence from animal models has identified disruption of the circadian system as a putative risk factor for adverse metabolic outcomes. The purpose of this review is to provide an update on the current state of knowledge linking sleep disturbances, circadian dysfunction, and glucose metabolism. Experimental, prospective, and interventional studies are discussed. | Interactions between sleep, circadian function, and glucose metabolism: implications for risk and severity of diabetes. |
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"25746": 0.04953393340110779, "25761": 0.01934296265244484, "25765": 0.20739519596099854, "26013": 0.07159364968538284, "26243": 1.0485517978668213, "26399": 0.45499902963638306, "26651": 0.37102460861206055, "26835": 0.8117979168891907, "27118": 0.5016035437583923, "27152": 0.9302552938461304, "27325": 0.16110190749168396, "27373": 0.306306391954422, "27391": 0.10993985831737518, "27630": 0.018384648486971855, "27673": 0.05694137513637543, "27781": 1.3175804615020752, "28024": 0.8450632095336914, "28177": 0.01934296265244484, "28389": 0.3554046154022217, "28873": 0.6000806093215942, "28896": 1.3862943649291992, "29237": 0.06429435312747955, "29290": 0.3262358605861664, "29458": 0.7076893448829651, "29490": 0.18329764902591705} | 8883846 | The Global HIV Vaccine Enterprise convened a two-day workshop in May of 2007 to discuss humoral immune responses to HIV and approaches to design vaccines that induce viral neutralizing and other potentially protective antibody responses. The goals of this workshop were to identify key scientific issues, gaps, and opportunities that have emerged since the Enterprise Strategic Plan was first published in 2005 [1], and to make recommendations that Enterprise stakeholders can use to plan new activities. Most effective viral vaccines work, at least in part, by generating antibodies that inactivate or neutralize the invading virus, and the existing data strongly suggest that an optimally effective HIV-1 vaccine should elicit potent antiviral neutralizing antibodies. However, unlike acute viral pathogens, HIV-1 chronically replicates in the host and evades the antibody response. This immune evasion, along with the large genetic variation among HIV-1 strains worldwide, has posed major obstacles to vaccine development. Current HIV vaccine candidates do not elicit neutralizing antibodies against most circulating virus strains, and thus the induction of a protective antibody response remains a major priority for HIV-1 vaccine development. For an antibody-based HIV-1 vaccine, progress in vaccine design is generally gauged by in vitro assays that measure the ability of vaccine-induced antibodies to neutralize a broad spectrum of viral isolates representing the major genetic subtypes (clades) of HIV-1 [2]. Although it is not known what magnitude and breadth of neutralization will predict protection in vaccine recipients, it is clear that current vaccine immunogens elicit antibodies that neutralize only a minority of circulating isolates. Thus, much progress needs to be made in this area. Also, though virus neutralization is considered a critical benchmark for a vaccine, this may not be the only benchmark for predicting success with antibody-based HIV-1 vaccine immunogens. The main targets for neutralizing antibodies to HIV-1 are the surface gp120 and trans-membrane gp41 envelope glycoproteins (Env) that mediate receptor and coreceptor binding and the subsequent membrane fusion events that allow the virus to gain entry into cells [3]. Antibodies neutralize the virus by binding these viral spikes and blocking virus entry into susceptible cells, such as CD4+ T cells [4,5]. In order to chronically replicate in the host, the virus exploits several mechanisms to shield itself against antibody recognition, including a dense outer coating of sugar molecules (N-linked glycans) and the strategic positioning of cysteine–cysteine loop structures on the gp120 molecule [6–8]. These shielding mechanisms, although highly effective, have vulnerabilities imposed by fitness constraints. Information on the precise location and molecular structure of these vulnerable regions could be valuable for the rational design of improved vaccine immunogens. Participants in the workshop identified four areas that, if given proper attention, could provide key information that would bring the field closer to an effective antibody-based HIV-1 vaccine: (1) structure-assisted immunogen design, (2) role of Fc receptors and complement, (3) assay standardization and validation, and (4) immunoregulation of B cell responses. | Antibody-Based HIV-1 Vaccines: Recent Developments and Future Directions |
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"25409": 0.9929623603820801, "25468": 1.1965231895446777, "25634": 0.02792670577764511, "25714": 0.1212492436170578, "25778": 0.013579257763922215, "25840": 0.4518963396549225, "25852": 1.1153976917266846, "25950": 0.7951818704605103, "26296": 0.056018441915512085, "27144": 1.036847710609436, "27881": 0.21293537318706512, "27972": 0.010684899985790253, "28086": 0.9440274834632874, "28207": 0.1734936386346817, "28788": 0.14349138736724854, "29217": 0.21372433006763458} | 8891333 | Data from certain leukemias as well as brain and breast cancer indicate that there is a small population of tumor cells with ‘stem cell’ characteristics and the capacity for self-renewal. The self-renewing cells have many of the properties of normal stem cells and have been termed ‘cancer stem cells’. These cancer stem cells make up as few as 1% of the cells in a tumor, making them difficult to detect and study. Like normal stem cells, cancer stem cells have a number of properties permitting them to survive traditional cancer chemotherapy and radiation therapy. These cells express high levels of ATP-binding cassette (ABC) drug transporters, providing for a level of resistance; are relatively quiescent; have higher levels of DNA repair and a lowered ability to enter apoptosis. Combined cancer therapy approaches targeting the cancer stem cells and the non-stem cells may be developed with increased efficacy. Efforts to target the Hedgehog/Patched pathway, critical to embryonic growth and differentiation, and the ABCG2 drug efflux transporter will be presented. | Targeted therapy for cancer stem cells: the patched pathway and ABC transporters |
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Autosomal dominant AD (ADAD) caused by mutations in the presenilin (PSEN) gene have been postulated to result from increased production of Aβ42 compared to Aβ40 in the central nervous system (CNS). This has been demonstrated in rodent models of ADAD but not in human mutation carriers. We used compartmental modeling of stable isotope labeling kinetic (SILK) studies in human carriers of PSEN mutations and related noncarriers to evaluate the pathophysiological effects of PSEN1 and PSEN2 mutations on the production and turnover of Aβ isoforms. We compared these findings by mutation status and amount of fibrillar amyloid deposition as measured by positron emission tomography (PET) using the amyloid tracer Pittsburgh compound B (PIB). CNS Aβ42 to Aβ40 production rates were 24% higher in mutation carriers compared to noncarriers, and this was independent of fibrillar amyloid deposits quantified by PET PIB imaging. The fractional turnover rate of soluble Aβ42 relative to Aβ40 was 65% faster in mutation carriers and correlated with amyloid deposition, consistent with increased deposition of Aβ42 into plaques, leading to reduced recovery of Aβ42 in cerebrospinal fluid (CSF). Reversible exchange of Aβ42 peptides with preexisting unlabeled peptide was observed in the presence of plaques. These findings support the hypothesis that Aβ42 is overproduced in the CNS of humans with PSEN mutations that cause AD, and demonstrate that soluble Aβ42 turnover and exchange processes are altered in the presence of amyloid plaques, causing a reduction in Aβ42 concentrations in the CSF. | Increased in vivo amyloid-β42 production, exchange, and loss in presenilin mutation carriers. |
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"29170": 0.6649205088615417, "29215": 0.8091925978660583, "29290": 0.2652147710323334, "29333": 0.7352184057235718, "29610": 0.37035053968429565, "29720": 0.5573811531066895, "29721": 0.3588210940361023, "29722": 0.176772341132164, "29723": 0.2837681770324707, "29724": 0.7333439588546753} | 8903143 | The T-cell receptor (TCR) consists of a TCRαβ heterodimer, a TCRζ homodimer, and CD3γε and CD3δε heterodimers. The precise mechanism of T-cell triggering following TCR ligand engagement remains elusive. Previous studies reported that the cytoplasmic tail of CD3ε binds to the plasma membrane through a basic residue-rich stretch (BRS) and proposed that dissociation from the membrane is required for phosphorylation thereof. In this report we show that BRS motifs within the cytoplasmic tail of TCRζ mediate association with the plasma membrane and that TCR engagement results in TCRζ dissociation from the membrane. This dissociation requires phosphorylation of the TCRζ immunoreceptor tyrosine-based activation motifs by lymphocyte cell-specificprotein tyrosine kinase (Lck) but not ζ-chain-associated protein kinase 70 binding. Mutations of the TCRζ BRS motifs that disrupt this membrane association attenuate proximal and distal responses induced by TCR engagement. These mutations appear to alter the localization of TCRζ with respect to Lck as well as the mobility of the TCR complex. This study reveals that tyrosine phosphorylation of the TCRζ cytoplasmic domain regulates its association with the plasma membrane and highlights the functional importance of TCRζ BRS motifs. | Basic residues in the T-cell receptor ζ cytoplasmic domain mediate membrane association and modulate signaling. |
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0.05046287178993225, "27840": 0.21372433006763458, "28283": 0.22392450273036957, "28436": 0.1808556467294693, "28687": 0.0913962796330452, "28731": 0.1602703034877777, "28823": 1.133164644241333, "29131": 0.02316705882549286, "29415": 0.026976587250828743, "29458": 0.009718249551951885} | 8906858 | BACKGROUND Cali, Colombia, has a high incidence of interpersonal violence deaths. Various alcohol control policies have been implemented to reduce alcohol-related problems. The objective of this study was to determine whether different alcohol control policies were associated with changes in the incidence rate of homicides. METHODS Ecologic study conducted during 2004-08 using a time-series design. Policies were implemented with variations in hours of restriction of sales and consumption of alcohol. Most restrictive policies prohibited alcohol between 2 a.m. and 10 a.m. for 446 non-consecutive days. Moderately restrictive policies prohibited alcohol between 3 a.m. and 10 a.m. for 1277 non-consecutive days. Lax policies prohibited alcohol between 4 a.m. and 10 a.m. for 104 non-consecutive days. In conditional autoregressive negative binomial regressions, rates of homicides and unintentional injury deaths (excluding traffic events) were compared between different periods of days when different policies were in effect. RESULTS There was an increased risk of homicides in periods when the moderately restrictive policies were in effect compared with periods when the most restrictive policies were in effect [incidence rate ratio (IRR) 1.15, 90% confidence interval (CI) 1.05-1.26, P = 0.012], and there was an even higher risk of homicides in periods when the lax policies were in effect compared with periods when the most restrictive policies were in effect (IRR 1.42, 90% CI 1.26-1.61, P < 0.001). Less restrictive policies were not associated with increased risk of unintentional injury deaths. CONCLUSION Extended hours of sales and consumption of alcohol were associated with increased risk of homicides. Strong restrictions on alcohol availability could reduce the incidence of interpersonal violence events in communities where homicides are high. | Policies for alcohol restriction and their association with interpersonal violence: a time-series analysis of homicides in Cali, Colombia. |
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0.05694137513637543, "24840": 0.34508460760116577, "24848": 0.026025565341114998, "25002": 0.21293537318706512, "25194": 0.11343330889940262, "25502": 0.015504186972975731, "25714": 0.06977381557226181, "25761": 0.05786345899105072, "25932": 0.3910386264324188, "26305": 0.0009760859538801014, "26402": 0.28963330388069153, "26534": 0.25845035910606384, "26773": 0.014542185701429844, "26775": 0.04487626627087593, "26820": 0.11517547070980072, "26951": 0.4437839686870575, "27060": 0.3339579105377197, "27226": 0.25845035910606384, "27295": 0.15943801403045654, "27467": 0.23710809648036957, "27891": 1.151856780052185, "28517": 0.0354953333735466, "28848": 0.6102113127708435, "29172": 0.1384023278951645, "29297": 1.1018621921539307, "29391": 0.6980181336402893, "29494": 0.24859806895256042} | 8909176 | Maltose metabolism of baker's yeast (Saccharomyces cerevisiae) in lean dough is negatively influenced by glucose repression, thereby delaying the dough fermentation. To improve maltose metabolism and leavening ability, it is necessary to alleviate glucose repression. The Snf1 protein kinase is well known to be essential for the response to glucose repression and required for transcription of glucose-repressed genes including the maltose-utilization genes (MAL). In this study, the SNF1 overexpression and deletion industrial baker's yeast strains were constructed and characterized in terms of maltose utilization, growth and fermentation characteristics, mRNA levels of MAL genes (MAL62 encoding the maltase and MAL61 encoding the maltose permease) and maltase and maltose permease activities. Our results suggest that overexpression of SNF1 was effective to glucose derepression for enhancing MAL expression levels and enzymes (maltase and maltose permease) activities. These enhancements could result in an 18% increase in maltose metabolism of industrial baker's yeast in LSMLD medium (the low sugar model liquid dough fermentation medium) containing glucose and maltose and a 15% increase in leavening ability in lean dough. These findings provide a valuable insight of breeding industrial baker's yeast for rapid fermentation. | Effects of SNF1 on Maltose Metabolism and Leavening Ability of Baker's Yeast in Lean Dough. |
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0.21135559678077698, "28466": 0.2160874605178833, "28685": 0.5860490798950195, "28689": 0.20818853378295898, "28691": 0.15359249711036682, "28723": 0.9613537192344666, "28765": 0.7827593088150024, "28828": 0.9739698171615601, "28829": 0.4400174915790558, "28927": 0.03360854089260101, "29125": 0.47766464948654175, "29461": 0.5313173532485962} | 8925851 | Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes, Schwachman-Diamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome. In addition, the 5q- syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroid phenotype highly similar to Diamond-Blackfan anemia. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases. | Review article |
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"26786": 0.3864043951034546, "26986": 0.15442965924739838, "27094": 0.7258110046386719, "27144": 0.42161011695861816, "27233": 0.05046287178993225, "27354": 0.0058422754518687725, "27373": 0.3683255612850189, "27391": 0.05046287178993225, "27781": 1.0382318496704102, "27881": 0.21922965347766876, "28032": 0.8583967685699463, "28117": 0.043007105588912964, "28207": 0.013579257763922215, "28765": 0.8796916007995605, "28873": 0.7047978043556213, "29299": 0.37974658608436584, "29458": 0.6684301495552063, "29490": 0.1946154683828354} | 8963413 | PD-L1 is an immunoinhibitory molecule that suppresses the activation of T cells, leading to the progression of tumors. Overexpression of PD-L1 in cancers such as gastric cancer, hepatocellular carcinoma, renal cell carcinoma, esophageal cancer, pancreatic cancer, ovarian cancer, and bladder cancer is associated with poor clinical outcomes. In contrast, PD-L1 expression correlates with better clinical outcomes in breast cancer and merkel cell carcinoma. The prognostic value of PD-L1 expression in lung cancer, colorectal cancer, and melanoma is controversial. Blocking antibodies that target PD-1 and PD-L1 have achieved remarkable response rates in cancer patients who have PD-L1-overexpressing tumors. However, using PD-L1 as an exclusive predictive biomarker for cancer immunotherapy is questionable due to the low accuracy of PD-L1 immunohistochemistry staining. Factors that affect the accuracy of PD-L1 immunohistochemistry staining are as follows. First, antibodies used in different studies have different sensitivity. Second, in different studies, the cut-off value of PD-L1 staining positivity is different. Third, PD-L1 expression in tumors is not uniform, and sampling time and location may affect the results of PD-L1 staining. Therefore, better understanding of tumor microenvironment and use of other biomarkers such as gene marker and combined index are necessary to better identify patients who will benefit from PD-1/PD-L1 checkpoint blockade therapy. | PD-L1 expression in human cancers and its association with clinical outcomes |
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0.1930064558982849} | 8979167 | An open reading frame (ORF) with homology to interleukin-10 (IL-10) has been identified in rhesus cytomegalovirus (RhCMV). The IL-10-like protein is generated from a multispliced, polyadenylated early gene transcript encompassing part of the corresponding UL111A ORF of human CMV (HCMV). Immunological analyses confirm expression of the IL-10-like protein both in tissue culture and in RhCMV-infected rhesus macaques. Conserved ORFs were subsequently identified in human, baboon, and African green monkey CMV, and a fully processed transcript has been mapped in fibroblasts infected with the Towne strain of HCMV. The conservation of this previously unrecognized ORF suggests that the protein may play an essential role in primate CMV persistence and pathogenesis. | Primate cytomegaloviruses encode and express an IL-10-like protein. |
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"26835": 0.29109421372413635, "26874": 0.10467668622732162, "27079": 0.03360854089260101, "27642": 0.1889725625514984, "27806": 0.09761575609445572, "27863": 0.13925230503082275, "27881": 0.18411032855510712, "28024": 0.0317181795835495, "28170": 0.05046287178993225, "28297": 0.8400169610977173, "28314": 0.2516399025917053, "28496": 0.24859806895256042, "28774": 0.19220098853111267, "28841": 0.013579257763922215, "29193": 0.4500300884246826, "29246": 0.10906458646059036, "29408": 0.0913962796330452} | 8989616 | The Tasmanian devil (Sarcophilus harrisii), the largest marsupial carnivore, is endangered due to a transmissible facial cancer spread by direct transfer of living cancer cells through biting. Here we describe the sequencing, assembly, and annotation of the Tasmanian devil genome and whole-genome sequences for two geographically distant subclones of the cancer. Genomic analysis suggests that the cancer first arose from a female Tasmanian devil and that the clone has subsequently genetically diverged during its spread across Tasmania. The devil cancer genome contains more than 17,000 somatic base substitution mutations and bears the imprint of a distinct mutational process. Genotyping of somatic mutations in 104 geographically and temporally distributed Tasmanian devil tumors reveals the pattern of evolution and spread of this parasitic clonal lineage, with evidence of a selective sweep in one geographical area and persistence of parallel lineages in other populations. | Genome Sequencing and Analysis of the Tasmanian Devil and Its Transmissible Cancer |
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"24710": 0.022212404757738113, "24759": 0.3723714053630829, "24854": 1.0108904838562012, "24908": 0.11691460013389587, "25067": 0.9348671436309814, "25409": 0.8682814836502075, "25468": 0.23092569410800934, "25690": 0.04674193635582924, "25835": 0.9643365740776062, "26285": 0.11343330889940262, "26305": 0.3304552733898163, "26462": 0.151916041970253, "26520": 0.0019512200960889459, "26773": 0.4337083101272583, "27000": 0.0842406153678894, "27152": 0.6451379656791687, "27373": 0.681853175163269, "27633": 0.04487626627087593, "27711": 0.0019512200960889459, "27794": 0.09584271162748337, "27881": 0.09406650811433792, "28518": 0.025073638185858727, "28522": 0.20977331697940826, "28835": 0.14686977863311768, "28873": 0.4400174915790558, "29206": 0.8780695199966431, "29494": 0.4914994537830353} | 8994465 | Melanomas are highly heterogeneous tumors, but the biological significance of their different subpopulations is not clear. Using the H3K4 demethylase JARID1B (KDM5B/PLU-1/RBP2-H1) as a biomarker, we have characterized a small subpopulation of slow-cycling melanoma cells that cycle with doubling times of >4 weeks within the rapidly proliferating main population. Isolated JARID1B-positive melanoma cells give rise to a highly proliferative progeny. Knockdown of JARID1B leads to an initial acceleration of tumor growth followed by exhaustion which suggests that the JARID1B-positive subpopulation is essential for continuous tumor growth. Expression of JARID1B is dynamically regulated and does not follow a hierarchical cancer stem cell model because JARID1B-negative cells can become positive and even single melanoma cells irrespective of selection are tumorigenic. These results suggest a new understanding of melanoma heterogeneity with tumor maintenance as a dynamic process mediated by a temporarily distinct subpopulation. | A Temporarily Distinct Subpopulation of Slow-Cycling Melanoma Cells Is Required for Continuous Tumor Growth |
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Recently, circRNAs have emerged as a large class of RNA which can function as post-transcriptional regulators. It has also been shown that many circRNAs are tissue- and stage-specifically expressed. Moreover, the unusual stability and expression specificity make circRNAs important candidates for clinical biomarker research. Here, we present a circRNA expression resource of 20 human tissues highly relevant to disease-related research: vascular smooth muscle cells (VSMCs), human umbilical vein cells (HUVECs), artery endothelial cells (HUAECs), atrium, vena cava, neutrophils, platelets, cerebral cortex, placenta, and samples from mesenchymal stem cell differentiation. In eight different samples from a single donor, we found highly tissue-specific circRNA expression. Circular-to-linear RNA ratios revealed that many circRNAs were expressed higher than their linear host transcripts. Among the 71 validated circRNAs, we noticed potential biomarkers. In adenosine deaminase-deficient, severe combined immunodeficiency (ADA-SCID) patients and in Wiskott-Aldrich-Syndrome (WAS) patients' samples, we found evidence for differential circRNA expression of genes that are involved in the molecular pathogenesis of both phenotypes. Our findings underscore the need to assess circRNAs in mechanisms of human disease. KEY MESSAGES: circRNA resource catalog of 20 clinically relevant tissues. circRNA expression is highly tissue-specific. circRNA transcripts are often more abundant than their linear host RNAs. circRNAs can be differentially expressed in disease-associated genes. | A map of human circular RNAs in clinically relevant tissues |
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by experimentally decreasing the activity of the actin filament nucleator and branch former, the Arp2/3 complex. Here we extend these studies via pharmacological inhibition of the Arp2/3 complex in sea urchin coelomocytes, cells that possess an unusually broad LP region and display correspondingly exaggerated centripetal flow. Using light and electron microscopy, we demonstrate that Arp2/3 complex inhibition via the drug CK666 dramatically altered LP actin architecture, slowed centripetal flow, drove a lamellipodial-to-filopodial shape change in suspended cells, and induced a novel actin structural organization during cell spreading. A general feature of the CK666 phenotype in coelomocytes was transverse actin arcs, and arc generation was arrested by a formin inhibitor. We also demonstrate that CK666 treatment produces actin arcs in other cells with broad LP regions, namely fish keratocytes and Drosophila S2 cells. We hypothesize that the actin arcs made visible by Arp2/3 complex inhibition in coelomocytes may represent an exaggerated manifestation of the elongate mother filaments that could possibly serve as the scaffold for the production of the dendritic actin network. | Arp2/3 complex inhibition radically alters lamellipodial actin architecture, suspended cell shape, and the cell spreading process |
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"29295": 0.013579257763922215, "29486": 0.44753631949424744, "29490": 0.306306391954422} | 9021186 | The persistence of transcriptionally silent but replication-competent HIV-1 reservoirs in Highly Active Anti-Retroviral Therapy (HAART)-treated infected individuals, represents a major hurdle to virus eradication. Activation of HIV-1 gene expression in these cells together with an efficient HAART has been proposed as an adjuvant therapy aimed at decreasing the pool of latent viral reservoirs. Using the latently-infected U1 monocytic cell line and latently-infected J-Lat T-cell clones, we here demonstrated a strong synergistic activation of HIV-1 production by clinically used histone deacetylase inhibitors (HDACIs) combined with prostratin, a non-tumor-promoting nuclear factor (NF)- kappaB inducer. In J-Lat cells, we showed that this synergism was due, at least partially, to the synergistic recruitment of unresponsive cells into the expressing cell population. A combination of prostratin+HDACI synergistically activated the 5' Long Terminal Repeat (5'LTR) from HIV-1 Major group subtypes representing the most prevalent viral genetic forms, as shown by transient transfection reporter assays. Mechanistically, HDACIs increased prostratin-induced DNA-binding activity of nuclear NF-kappaB and degradation of cytoplasmic NF-kappaB inhibitor, IkappaBalpha . Moreover, the combined treatment prostratin+HDACI caused a more pronounced nucleosomal remodeling in the U1 viral promoter region than the treatments with the compounds alone. This more pronounced remodeling correlated with a synergistic reactivation of HIV-1 transcription following the combined treatment prostratin+HDACI, as demonstrated by measuring recruitment of RNA polymerase II to the 5'LTR and both initiated and elongated transcripts. The physiological relevance of the prostratin+HDACI synergism was shown in CD8(+)-depleted peripheral blood mononuclear cells from HAART-treated patients with undetectable viral load. Moreover, this combined treatment reactivated viral replication in resting CD4(+) T cells isolated from similar patients. Our results suggest that combinations of different kinds of proviral activators may have important implications for reducing the size of latent HIV-1 reservoirs in HAART-treated patients. | Synergistic Activation of HIV-1 Expression by Deacetylase Inhibitors and Prostratin: Implications for Treatment of Latent Infection |
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Centrosomes organize microtubule arrays throughout the cell cycle, thereby influencing both tissue architecture and the accuracy of chromosome segregation. But what are the origins of centrosomal abnormalities in tumours, and what impact do they have on the generation of invasive, genetically unbalanced cells during cancer progression? | Centrosome aberrations: cause or consequence of cancer progression? |
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intervals were measured over RR intervals ranging from 500 ms to 1000 ms in 13 normal male subjects, 13 male diabetic subjects without and 13 with autonomic neuropathy. There was a close linear relationship between QT and RR in all subjects. The slope of the regression line was significantly greater in the autonomic neuropathy group than the normal group. Thirty-two male diabetic subjects with varying degrees of autonomic dysfunction had repeat QT measurements 3 (range 2–6) years later. QT and QTC lengthened significantly at the second visit, unrelated to age or time between recordings, but which corresponded with changes in autonomic function. Of 71 male diabetic subjects under 60 years followed for 3 years, 13 had died, 8 unexpectedly. Of those with autonomic neuropathy, QT and QTC were significantly longer in those who subsequently died, despite similar ages and duration of diabetes. We conclude that QT/RR interval relationships are altered in diabetic autonomic neuropathy, and that changes in QT length with time parallel changese in autonomic function. There may be an association between QT interval prolongation and the risk of dying unexpectedly in diabetic autonomic neuropathy. | Autonomic neuropathy, QT interval lengthening, and unexpected deaths in male diabetic patients |
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Striking differences in incidence are observed in heart and heart-lung transplant recipients when compared with renal transplant patients. The most significant increase was in the incidence of lymphomas in cardiac versus renal patients. Moreover, a two-fold greater increase of all neoplasms was found in cardiac recipients, with nearly a six-fold increase in visceral tumors. Several factors may account for these differences. In cardiac allograft recipients, intensive immunosuppression is frequently used to reverse acute rejection and the highest number of cardiac transplants was performed in the era of polypharmacy, usually consisting of triple therapy. | Incidence of cancer after immunosuppressive treatment for heart transplantation. |
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Invasive cell migration requires the formation of various structures, such as invadopodia and pseudopodia, which require actin assembly that is regulated by specialized actin nucleation factors. There is a large variety of different actin nucleators in human cells, such as formins, spire and Arp2/3-regulating proteins, and the list is likely to grow. Studies of the mechanisms of various actin nucleation factors that are involved in cancer cell function may ultimately provide new treatments for invasive and metastatic disease. | Nucleating actin for invasion |
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0.5010119676589966, "27287": 1.109619140625, "27321": 0.1229778528213501, "28086": 1.3720329999923706, "28177": 0.04487626627087593, "28227": 0.3381449282169342, "28696": 0.14433705806732178, "28712": 0.056018441915512085, "28788": 0.19622190296649933, "28848": 0.015504186972975731, "29101": 0.004870930220931768, "29129": 0.037378571927547455, "29170": 0.12470348179340363, "29217": 0.030771657824516296, "29290": 0.09672962874174118} | 9076196 | Recent studies have established that during embryonic development, hematopoietic progenitors and stem cells are generated from hemogenic endothelium precursors through a process termed endothelial to hematopoietic transition (EHT). The transcription factor RUNX1 is essential for this process, but its main downstream effectors remain largely unknown. Here, we report the identification of Gfi1 and Gfi1b as direct targets of RUNX1 and critical regulators of EHT. GFI1 and GFI1B are able to trigger, in the absence of RUNX1, the down-regulation of endothelial markers and the formation of round cells, a morphologic change characteristic of EHT. Conversely, blood progenitors in Gfi1- and Gfi1b-deficient embryos maintain the expression of endothelial genes. Moreover, those cells are not released from the yolk sac and disseminated into embryonic tissues. Taken together, our findings demonstrate a critical and specific role of the GFI1 transcription factors in the first steps of the process leading to the generation of hematopoietic progenitors from hemogenic endothelium. | GFI1 and GFI1B control the loss of endothelial identity of hemogenic endothelium during hematopoietic commitment. |
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"27152": 0.06429435312747955, "27226": 0.02316705882549286, "27325": 0.25088030099868774, "27642": 0.2719337046146393, "27774": 0.00875066313892603, "27777": 0.012615402229130268, "28041": 0.030771657824516296, "28079": 0.45623743534088135, "28283": 0.0009760859538801014, "28369": 0.07341018319129944, "28406": 1.072225570678711, "28409": 0.08692999184131622, "28696": 0.010684899985790253, "28848": 0.7907629609107971, "28938": 0.5244048833847046, "28976": 0.5903874635696411} | 9091863 | In a diverse group of organisms that includes Caenorhabditis elegans, Drosophila, planaria, hydra, trypanosomes, fungi and plants, the introduction of double-stranded RNAs inhibits gene expression in a sequence-specific manner. These responses, called RNA interference or post-transcriptional gene silencing, may provide anti-viral defence, modulate transposition or regulate gene expression. We have taken a biochemical approach towards elucidating the mechanisms underlying this genetic phenomenon. Here we show that 'loss-of-function' phenotypes can be created in cultured Drosophila cells by transfection with specific double-stranded RNAs. This coincides with a marked reduction in the level of cognate cellular messenger RNAs. Extracts of transfected cells contain a nuclease activity that specifically degrades exogenous transcripts homologous to transfected double-stranded RNA. This enzyme contains an essential RNA component. After partial purification, the sequence-specific nuclease co-fractionates with a discrete, approximately 25-nucleotide RNA species which may confer specificity to the enzyme through homology to the substrate mRNAs. | An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells. |
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0.817850649356842, "26266": 0.7683706283569336, "26305": 0.3877306580543518, "26308": 0.4764525294303894, "26520": 0.0038986403960734606, "26524": 0.04113444685935974, "26721": 0.5016035437583923, "26745": 0.10906458646059036, "26786": 0.14518201351165771, "26835": 0.981317400932312, "26886": 0.4512746334075928, "27343": 0.03266380727291107, "27711": 0.947819709777832, "27881": 0.15943801403045654, "28436": 0.38308101892471313, "28498": 1.0257055759429932, "28691": 0.10026945173740387, "28815": 0.037378571927547455, "28828": 0.175953671336174, "28873": 0.4938860833644867, "29090": 0.02316705882549286, "29197": 0.03266380727291107, "29484": 0.2034190446138382} | 9095394 | Human epithelium contains keratin, which is expressed during differentiation. Depending on the target cell type, different types of keratin are expressed, and their alterations seem to represent changes in cell properties. The basal cells of oral epithelium express keratin 5 (K5), K14, K15 and K19, but their alterations in tumors are unclear. To address this issue and to seek possible diagnostic application, we examined the expression of these keratins in oral squamous cell carcinoma (OSCC) and squamous intraepithelial neoplasm (SIN). cDNA microarray analysis of 43 OSCC revealed slight upregulation of KRT14, downregulation of KRT15 and KRT19, and unaltered KRT5 expression. There were great variations in KRT15 and KRT19 expression across each cancer. Well-differentiated OSCC tended to express more KRT15 and less KRT19 compared to moderately- or poorly-differentiated OSCC. KRT15 was positively correlated with differentiation-related keratin, KRT13. These observations were further investigated by immunohistochemical examination. K5 and K14 were ubiquitously expressed in all 50 OSCC and 50 SIN examined. K15 and K19 were generally downregulated, but were considerably retained in about half of the cases and showed diverse expression patterns. K15-positive cancers tended to show a well-differentiated phenotype, and K19-positive cancers tended to show more invasive tumor fronts. Most K19-positive cancers appeared to develop with little associating SIN. K19 was consistently downregulated in SIN, while K15 was downregulated mainly in high grade SIN. In summary, K15 and K19, unlike K5 or K14, are expressed variably in both SIN and OSCC, which reflects the differences in their pathogenesis and biological behaviors, suggesting their prospective applications as markers for subclassifying OSCC and SIN. | Expression of basal cell keratin 15 and keratin 19 in oral squamous neoplasms represents diverse pathophysiologies. |
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"25465": 1.3049486875534058, "25468": 0.15860503911972046, "25604": 0.009718249551951885, "25708": 1.070887804031372, "25714": 0.3963087201118469, "25778": 0.06337817758321762, "26163": 0.1212492436170578, "26396": 0.19541899859905243, "26534": 0.013579257763922215, "26651": 0.3554046154022217, "26745": 0.6970458030700684, "26874": 0.43053874373435974, "27144": 1.0158531665802002, "27152": 0.8298473954200745, "27343": 0.09317722171545029, "27354": 0.09317722171545029, "27404": 0.0842406153678894, "27642": 1.2198615074157715, "27673": 0.2516399025917053, "27776": 0.09495500475168228, "27859": 0.07793712615966797, "27881": 0.2145126610994339, "28207": 0.06612417846918106, "28378": 0.8748174905776978, "28406": 0.5010119676589966, "28873": 0.25694093108177185, "29105": 0.7258110046386719, "29458": 0.8861536383628845} | 9095943 | BACKGROUND In patients with Ovarian Cancer (OvCa) exosomes released by tumor cells are present in the plasma and could be involved in tumor progression. This study examines the association between the exosome presence/protein content in plasma of OvCa patients and disease outcome, response to standard therapy and/or tumorresistance to therapies in patients studied at diagnosis and also serially during and after therapy. DESIGN AND METHODS Exosomes were purified from OvCa patients' plasma (n=22), patients with benign tumors (n=10) or (n=10) healthy controls (NC) using ultracentrifugation. Exosomes were visualized by scanning electron microscopy. Their protein content was measured. The presence of MAGE 3/6 and TGF-β1 in exosomes was evaluated in Western blots. RESULTS The OvCa patients' plasma contained higher levels of exosomal proteins (p<0.05) compared to those isolated from plasma of patients with benign tumors or NC. Exosomes isolated from OvCa patients's plasma carried TGF-β1 and MAGE3/6, which distinguished OvCa patients from those with benign tumors and NC. High protein levels of exosomes were seen in newly diagnosed patients; however in advanced stages of OvCa patients the protein content of isolated exosomes was significantly higher than that of early stages. The exosome levels variably changed during/after chemotherapy, and correlations between the changes in exosomal protein levels and clinical data suggested that the protein content of exosomes might be useful in predicting responses to therapy and prognosis in OvCa patients. CONCLUSION Analysis of plasma exosomes levels offers a novel approach to diagnosis and monitoring response to therapies in OvCa patients. | Exosomes in Plasma of Patients with Ovarian Carcinoma: Potential Biomarkers of Tumor Progression and Response to Therapy. |
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DESIGN Cluster randomised controlled trial: household interview survey, observational study of people's behaviour, entomological study with light trap captures of sandflies inside houses. SETTING 14 urban sectors in Trujillo, Venezuela. PARTICIPANTS 2913 inhabitants of 569 houses. INTERVENTION Sectors were paired according to their 12 month cumulative incidence of cutaneous leishmaniasis, one sector in each pair was randomly allocated to receive polyester curtains impregnated with lambdacyhalothrin (intervention group) while the other sector received curtains without insecticide or no curtains (control groups). After 12 months a follow up household survey was conducted. MAIN OUTCOME MEASURES Reduction in abundance of sandflies indoors and 12 month incidence of clinical cases of cutaneous leishmaniasis. RESULTS Transmission of cutaneous leishmaniasis occurred mainly in the domestic setting, with the incidence over 12 months of 4%. The mean number of sandflies per trap per night was 16. After follow up the 12 month incidence of cutaneous leishmaniasis was 0% in the intervention group and 8% in the six pairs in the control group that received unimpregnated curtains (mean difference 8, 95% confidence interval 4.22 to 11.78; P=0.001). There were significantly fewer sandflies in the intervention group (2 v 15, mean difference 13 sandflies per trap; 9 to 17; P<0.001). CONCLUSION Curtains impregnated with insecticide provide a high degree of protection against indoor transmission of cutaneous leishmaniasis. | Insecticide impregnated curtains to control domestic transmission of cutaneous leishmaniasis in Venezuela: cluster randomised trial. |
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We report that selective expression of an endogenous K-Ras(G12V) oncogene in embryonic cells of acinar/centroacinar lineage results in pancreatic intraepithelial neoplasias (PanINs) and invasive PDA, suggesting that PDA originates by differentiation of acinar/centroacinar cells or their precursors into ductal-like cells. Surprisingly, adult mice become refractory to K-Ras(G12V)-induced PanINs and PDA. However, if these mice are challenged with a mild form of chronic pancreatitis, they develop the full spectrum of PanINs and invasive PDA. These observations suggest that, during adulthood, PDA stems from a combination of genetic (e.g., somatic K-Ras mutations) and nongenetic (e.g., tissue damage) events. | Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. |
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"27491": 0.14686977863311768, "27815": 0.3163207769393921, "27921": 0.8796916007995605, "28086": 0.1064341589808464, "28093": 0.2852376699447632, "28156": 0.18329764902591705, "28353": 0.6729245185852051, "28667": 0.16110190749168396, "28728": 0.4093637466430664, "28788": 0.6223390698432922} | 9122283 | RATIONALE Multiple biological mechanisms contribute to the efficacy of cardiac cell therapy. Most prominent among these are direct heart muscle and blood vessel regeneration from transplanted cells, as opposed to paracrine enhancement of tissue preservation and/or recruitment of endogenous repair. OBJECTIVE Human cardiac progenitor cells, cultured as cardiospheres (CSps) or as CSp-derived cells (CDCs), have been shown to be capable of direct cardiac regeneration in vivo. Here we characterized paracrine effects in CDC transplantation and investigated their relative importance versus direct differentiation of surviving transplanted cells. METHODS AND RESULTS In vitro, many growth factors were found in media conditioned by human adult CSps and CDCs; CDC-conditioned media exerted antiapoptotic effects on neonatal rat ventricular myocytes, and proangiogenic effects on human umbilical vein endothelial cells. In vivo, human CDCs secreted vascular endothelial growth factor, hepatocyte growth factor, and insulin-like growth factor 1 when transplanted into the same SCID mouse model of acute myocardial infarction where they were previously shown to improve function and to produce tissue regeneration. Injection of CDCs in the peri-infarct zone increased the expression of Akt, decreased apoptotic rate and caspase 3 level, and increased capillary density, indicating overall higher tissue resilience. Based on the number of human-specific cells relative to overall increases in capillary density and myocardial viability, direct differentiation quantitatively accounted for 20% to 50% of the observed effects. CONCLUSIONS Together with their spontaneous commitment to cardiac and angiogenic differentiation, transplanted CDCs serve as "role models," recruiting endogenous regeneration and improving tissue resistance to ischemic stress. The contribution of the role model effect rivals or exceeds that of direct regeneration. | Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice. |
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1.3377727270126343, "27965": 0.18004031479358673, "28156": 0.3850763738155365, "28282": 0.1477125883102417, "28389": 0.11081436276435852, "28406": 0.40089741349220276, "28518": 0.1485546976327896, "28742": 0.19622190296649933, "28873": 0.7370892763137817, "28896": 1.2198615074157715, "29443": 0.11430477350950241, "29490": 0.5540198087692261} | 9142761 | Plasmodium falciparum surface protein 25 (Pfs25) is a candidate for transmission-blocking vaccines (TBVs). Anti-Pfs25 antibodies block the development of oocysts in membrane-feeding assays and we have shown the activity correlates with antibody titer. In this study, we purified Pfs25-specific IgGs to convert antibody titer to microg/mL and determined the amount of antibody required to inhibit 50% of oocyst development (IC(50)). The IC(50) were, 15.9, 4.2, 41.2, and 85.6microg/mL for mouse, rabbit, monkey and human, respectively, and the differences among species were significant. Anti-Pfs25 sera from rabbit, monkey and human showed different patterns of competition against 6 mouse monoclonal antibodies, and the avidity of antibodies among four species were also different. These data suggests that information obtained from animal studies which assess efficacy of TBV candidates may be difficult to translate to human immunization. | The IC(50) of anti-Pfs25 antibody in membrane-feeding assay varies among species. |
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0.9546096324920654, "28086": 1.227902889251709, "28156": 0.562402069568634, "28290": 0.20421554148197174, "28311": 0.42608439922332764, "28418": 0.9115922451019287, "28436": 0.4537591338157654, "28498": 0.25995752215385437, "28788": 0.06520967930555344, "28873": 0.0842406153678894, "29109": 0.05970508232712746, "29206": 0.3005385100841522} | 9154703 | Expression from both alleles is generally observed in analyses of diploid cell populations, but studies addressing allelic expression patterns genome-wide in single cells are lacking. Here, we present global analyses of allelic expression across individual cells of mouse preimplantation embryos of mixed background (CAST/EiJ × C57BL/6J). We discovered abundant (12 to 24%) monoallelic expression of autosomal genes and that expression of the two alleles occurs independently. The monoallelic expression appeared random and dynamic because there was considerable variation among closely related embryonic cells. Similar patterns of monoallelic expression were observed in mature cells. Our allelic expression analysis also demonstrates the de novo inactivation of the paternal X chromosome. We conclude that independent and stochastic allelic transcription generates abundant random monoallelic expression in the mammalian cell. | Single-Cell RNA-Seq Reveals Dynamic, Random Monoallelic Gene Expression in Mammalian Cells |
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This lipid mediator modulates various immune responses. PGE(2) acts on macrophages and inhibits production of cytokines such as TNF-alpha and IL-12. Membrane-bound glutathione-dependent PGE(2) synthase (mPGES) has been shown to be a terminal enzyme of the cyclooxygenase-2-mediated PGE(2) biosynthesis. Here we identified mPGES as a molecule that is induced by LPS in macrophages. The expression of mPGES was not induced by LPS in mice lacking Toll-like receptor 4 or MyD88. Furthermore, mice deficient in NF-IL6 showed neither induction of mPGES nor biosynthesis of PGE(2) in response to LPS, indicating that mPGES expression in response to LPS is regulated by a Toll-like receptor 4/MyD88/NF-IL6-dependent signaling pathway. We generated mPGES-deficient mice and investigated the role of mPGES in vivo. The mice showed no augmentation of the PGE(2) production in response to LPS. However, they were not impaired in the LPS-induced production of inflammatory cytokines and showed normal response to the LPS-induced shock. Thus, mPGES is critically involved in the biosynthesis of PGE(2) induced by LPS, but is dispensable for the modulation of inflammatory responses. | Lipopolysaccharide-dependent prostaglandin E(2) production is regulated by the glutathione-dependent prostaglandin E(2) synthase gene induced by the Toll-like receptor 4/MyD88/NF-IL6 pathway. |
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"26118": 0.42990362644195557, "26223": 0.01934296265244484, "26282": 0.08244366943836212, "26358": 0.04207121208310127, "26402": 0.30486753582954407, "26451": 0.7898768186569214, "26462": 0.7881022095680237, "26512": 0.11951763927936554, "26534": 0.2674594223499298, "26741": 0.0058422754518687725, "26773": 0.6260011196136475, "26775": 0.01934296265244484, "26906": 0.38308101892471313, "27133": 0.10026945173740387, "27441": 0.0770333781838417, "27598": 0.2145126610994339, "27642": 0.043007105588912964, "27989": 0.06246116757392883, "28436": 0.8057082891464233, "28440": 0.07793712615966797, "28516": 0.08244366943836212, "28562": 0.20739519596099854, "28767": 0.2576959431171417, "28848": 0.7755908370018005, "28892": 0.026025565341114998, "28964": 0.5668440461158752, "29172": 0.2637155055999756, "29206": 0.27044451236724854, "29297": 0.14602625370025635} | 9159495 | Expression levels of many microRNAs (miRNAs) change during aging, notably declining globally in a number of organisms and tissues across taxa. However, little is known about the mechanisms or the biological relevance for this change. We investigated the network of genes that controls miRNA transcription and processing during C. elegans aging. We found that miRNA biogenesis genes are highly networked with transcription factors and aging-associated miRNAs. In particular, miR-71, known to influence life span and itself up-regulated during aging, represses alg-1/Argonaute expression post-transcriptionally during aging. Increased ALG-1 abundance in mir-71 loss-of-function mutants led to globally increased miRNA expression. Interestingly, these mutants demonstrated widespread mRNA expression dysregulation and diminished levels of variability both in gene expression and in overall life span. Thus, the progressive molecular decline often thought to be the result of accumulated damage over an organism's life may be partially explained by a miRNA-directed mechanism of age-associated decline. | A microRNA feedback loop regulates global microRNA abundance during aging. |
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