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"25604": 0.23710809648036957, "25746": 0.6332852244377136, "26285": 0.04674193635582924, "26305": 0.35128939151763916, "26601": 0.23710809648036957, "26741": 0.20818853378295898, "26874": 0.17020416259765625, "26994": 1.1695996522903442, "28290": 0.129004567861557, "28436": 0.4518963396549225, "28488": 0.6482070088386536, "28498": 0.255429208278656, "28911": 0.10291612148284912, "29206": 0.11430477350950241, "29595": 0.09317722171545029} | 13949015 | Highly active (i.e., "hot") long interspersed element-1 (LINE-1 or L1) sequences comprise the bulk of retrotransposition activity in the human genome; however, the abundance of hot L1s in the human population remains largely unexplored. Here, we used a fosmid-based, paired-end DNA sequencing strategy to identify 68 full-length L1s that are differentially present among individuals but are absent from the human genome reference sequence. The majority of these L1s were highly active in a cultured cell retrotransposition assay. Genotyping 26 elements revealed that two L1s are only found in Africa and that two more are absent from the H952 subset of the Human Genome Diversity Panel. Therefore, these results suggest that hot L1s are more abundant in the human population than previously appreciated, and that ongoing L1 retrotransposition continues to be a major source of interindividual genetic variation. | LINE-1 Retrotransposition Activity in Human Genomes |
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Data from mouse models suggest that the recruitment of immunosuppressive cells to tumours protects metastatic cancer cells from surveillance by killer cells, which nullifies the effects of immunotherapy and thus establishes metastasis. Furthermore, in most cases, tumour-infiltrating immune cells differentiate into cells that promote each step of the metastatic cascade and thus are novel targets for therapy. In this Review, we describe how tumour-infiltrating immune cells contribute to the metastatic cascade and we discuss potential therapeutic strategies to target these cells. | Immune cell promotion of metastasis |
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However, very little is known about the function of PICH or how it is recruited to UFBs. Using a combination of microfluidics, fluorescence microscopy, and optical tweezers, we have defined the properties of PICH in an in vitro model of an anaphase bridge. We show that PICH binds with a remarkably high affinity to duplex DNA, resulting in ATP-dependent protein translocation and extension of the DNA. Most strikingly, the affinity of PICH for binding DNA increases with tension-induced DNA stretching, which mimics the effect of the mitotic spindle on a UFB. PICH binding also appears to diminish force-induced DNA melting. We propose a model in which PICH recognizes and stabilizes DNA under tension during anaphase, thereby facilitating the resolution of entangled sister chromatids. | PICH: a DNA translocase specially adapted for processing anaphase bridge DNA. |
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We have carried out whole-genome bisulfite sequencing (BS-Seq) and RNA-Seq across key stages from E6.5 epiblast to E16.5 PGCs. Global loss of methylation takes place during PGC expansion and migration with evidence for passive demethylation, but sequences that carry long-term epigenetic memory (imprints, CpG islands on the X chromosome, germline-specific genes) only become demethylated upon entry of PGCs into the gonads. The transcriptional profile of PGCs is tightly controlled despite global hypomethylation, with transient expression of the pluripotency network, suggesting that reprogramming and pluripotency are inextricably linked. Our results provide a framework for the understanding of the epigenetic ground state of pluripotency in the germline. | The Dynamics of Genome-wide DNA Methylation Reprogramming in Mouse Primordial Germ Cells |
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0.6027565002441406} | 13956305 | Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype. | Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1 |
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0.45994341373443604, "26775": 0.21687394380569458, "26835": 0.8187123537063599, "26994": 0.4400174915790558, "27058": 0.8509185314178467, "27287": 0.0174254160374403, "27642": 0.20739519596099854, "27753": 0.14939609169960022, "27989": 0.4673144817352295, "28466": 1.0298984050750732, "28848": 0.06246116757392883, "28927": 0.08064348995685577, "28940": 0.026025565341114998, "29166": 0.00875066313892603, "29226": 0.12642613053321838, "29290": 0.3248254358768463, "29720": 0.4938860833644867} | 13958154 | Pancreatic β-cell dysfunction and death are central in the pathogenesis of type 2 diabetes (T2D). Saturated fatty acids cause β-cell failure and contribute to diabetes development in genetically predisposed individuals. Here we used RNA sequencing to map transcripts expressed in five palmitate-treated human islet preparations, observing 1,325 modified genes. Palmitate induced fatty acid metabolism and endoplasmic reticulum (ER) stress. Functional studies identified novel mediators of adaptive ER stress signaling. Palmitate modified genes regulating ubiquitin and proteasome function, autophagy, and apoptosis. Inhibition of autophagic flux and lysosome function contributed to lipotoxicity. Palmitate inhibited transcription factors controlling β-cell phenotype, including PAX4 and GATA6. Fifty-nine T2D candidate genes were expressed in human islets, and 11 were modified by palmitate. Palmitate modified expression of 17 splicing factors and shifted alternative splicing of 3,525 transcripts. Ingenuity Pathway Analysis of modified transcripts and genes confirmed that top changed functions related to cell death. Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis of transcription factor binding sites in palmitate-modified transcripts revealed a role for PAX4, GATA, and the ER stress response regulators XBP1 and ATF6. This human islet transcriptome study identified novel mechanisms of palmitate-induced β-cell dysfunction and death. The data point to cross talk between metabolic stress and candidate genes at the β-cell level. | RNA sequencing identifies dysregulation of the human pancreatic islet transcriptome by the saturated fatty acid palmitate. |
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Young children bear the brunt of the disease and though older children and adults suffer relatively fewer clinical attacks, they remain susceptible to asymptomatic P. falciparum infection. A better understanding of the host factors associated with immunity to clinical malaria and the ability to sustain asymptomatic P. falciparum infection will aid the development of improved strategies for disease prevention. METHODS AND FINDINGS Here we investigate whether full differential blood counts can predict susceptibility to clinical malaria among Kenyan children sampled at five annual cross-sectional surveys. We find that the ratio of monocytes to lymphocytes, measured in peripheral blood at the time of survey, directly correlates with risk of clinical malaria during follow-up. This association is evident among children with asymptomatic P. falciparum infection at the time the cell counts are measured (Hazard ratio (HR) = 2.7 (95% CI 1.42, 5.01, P = 0.002) but not in those without detectable parasitaemia (HR = 1.0 (95% CI 0.74, 1.42, P = 0.9). CONCLUSIONS We propose that the monocyte to lymphocyte ratio, which is easily derived from routine full differential blood counts, reflects an individual's capacity to mount an effective immune response to P. falciparum infection. | The Ratio of Monocytes to Lymphocytes in Peripheral Blood Correlates with Increased Susceptibility to Clinical Malaria in Kenyan Children |
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The leading edge epithelial cells express filopodia and fusion is dependent on interdigitation of these filopodia to prime formation of adhesions. Since the opposing epithelia are molecularly patterned there must exist some mechanism for accurately aligning the two sheets across this fusion seam. To address this, we generated a fly in which RFP-Moesin and GFP-Moesin are expressed in mutually exclusive stripes within each segment using the engrailed and patched promoters. We observe mutually exclusive interactions between the filopodia of engrailed and patched cells. Interactions between filopodia from matching cells leads to formation of tethers between them, and these tethers can pull misaligned epithelial sheets into alignment. Filopodial matching also occurs during repair of laser wounds in the ventral epithelium, and so this behaviour is not restricted to leading edge cells during dorsal closure. Finally, we characterise the behaviour of a patched-expressing cell that we observe within the engrailed region of segments A1-A5, and provide evidence that this cell contributes to cell matching. | Dynamic analysis of filopodial interactions during the zippering phase of Drosophila dorsal closure. |
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0.7863243818283081, "26838": 0.4067663550376892, "26872": 0.3034266233444214, "26953": 0.2516399025917053, "27065": 0.07068414986133575, "27144": 0.176772341132164, "27881": 0.016465263441205025, "28086": 0.05970508232712746, "28156": 0.2026219218969345, "28406": 0.007782140281051397, "28424": 0.6704301834106445, "28691": 0.24018502235412598, "28848": 0.9394577741622925, "29206": 0.7286425232887268, "29458": 0.02412080205976963, "29490": 0.14518201351165771} | 13964633 | BACKGROUND Mature microRNAs (miRNAs) are single-stranded RNAs that regulate post-transcriptional gene expression. In our previous study, we have shown that versican 3'UTR, a fragment of non-coding transcript, has the ability to antagonize miR-199a-3p function thereby regulating expression of the matrix proteins versican and fibronectin, and thus resulting in enhanced cell-cell adhesion and organ adhesion. However, the impact of this non-coding fragment on tumorigenesis is yet to be determined. METHODS AND FINDINGS Using computational prediction confirmed with in vitro and in vivo experiments, we report that the expression of versican 3'UTR not only antagonizes miR-199a-3p but can also lower its steady state expression. We found that expression of versican 3'UTR in a mouse breast carcinoma cell line, 4T1, decreased miR-199a-3p levels. The decrease in miRNA activity consequently translated into differences in tumor growth. Computational analysis indicated that both miR-199a-3p and miR-144 targeted a cell cycle regulator, Rb1. In addition, miR-144 and miR-136, which have also been shown to interact with versican 3'UTR, was found to target PTEN. Expression of Rb1 and PTEN were up-regulated synergistically in vitro and in vivo, suggesting that the 3'UTR binds and modulates miRNA activities, freeing Rb1 and PTEN mRNAs for translation. In tumor formation assays, cells transfected with the 3'UTR formed smaller tumors compared with cells transfected with a control vector. CONCLUSION Our results demonstrated that a 3'UTR fragment can be used to modulate miRNA functions. Our study also suggests that miRNAs in the cancer cells are more susceptible to degradation, due to its interaction with a non-coding 3'UTR. This non-coding component of mRNA may be used retrospectively to modulate miRNA activities. | Expression of Versican 3′-Untranslated Region Modulates Endogenous MicroRNA Functions |
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0.4938860833644867, "25714": 0.10291612148284912, "25765": 0.259204238653183, "25916": 1.3695534467697144, "25969": 0.12384103983640671, "26013": 0.06977381557226181, "26243": 0.09850110858678818, "26244": 0.151916041970253, "26402": 0.3177432417869568, "26557": 0.0770333781838417, "26591": 0.1221139207482338, "26651": 0.1734936386346817, "26737": 0.0842406153678894, "26835": 0.2786078155040741, "27441": 0.1913948506116867, "27781": 1.0116009712219238, "28156": 0.16524957120418549, "28352": 0.9084475636482239, "28389": 0.17020416259765625, "28741": 0.2719337046146393, "28748": 0.26146242022514343, "28804": 0.8821197748184204, "28873": 0.9186317324638367, "28896": 1.4339678287506104, "29090": 0.841701865196228, "29490": 0.06246116757392883, "29598": 0.8272887468338013} | 13965483 | Epitope vaccine based on the enzyme urease of Helicobacter pylori is a promising option for prophylactic and therapeutic vaccination against H. pylori infection. In our previous study, the epitope vaccine CTB-UA, which was composed of the mucosal adjuvant cholera toxin B subunit (CTB) and an epitope (UreA183–203) from the H. pylori urease A subunit (UreA) was constructed. This particular vaccine was shown to have good immunogenicity and immunoreactivity and could induce specific neutralizing antibodies, which exhibited effectively inhibitory effects on the enzymatic activity of H. pylori urease. In this study, the prophylactic and therapeutic efficacy of the epitope vaccine CTB-UA was evaluated in a BALB/c mice model. The experimental results indicated that oral prophylactic or therapeutic immunization with CTB-UA significantly decreased H. pylori colonization compared with oral immunization with PBS. The results also revealed that the protection was correlated with antigen-specific IgG, IgA, and mucosal secretory IgA antibody responses. CTB-UA may be a promising vaccine candidate for the control of H. pylori infection. | Prophylactic and therapeutic efficacy of the epitope vaccine CTB-UA against Helicobacter pylori infection in a BALB/c mice model |
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"23041": 0.16110190749168396, "23061": 0.02412080205976963, "23238": 0.8492490649223328, "23760": 0.7028654217720032, "23784": 0.15693697333335876, "23996": 0.4938860833644867, "24004": 0.28670501708984375, "24158": 1.067535400390625, "24393": 0.3464667797088623, "24710": 0.20022670924663544, "24873": 0.25088030099868774, "25064": 0.841701865196228, "25253": 1.1211429834365845, "25969": 0.3656192123889923, "26013": 0.029824240133166313, "26045": 0.5551415085792542, "26305": 0.0752234235405922, "26735": 0.20818853378295898, "26835": 0.5307431221008301, "26957": 0.07793712615966797, "27152": 0.14095009863376617, "27633": 0.03831886500120163, "28032": 0.7701805830001831, "28498": 1.0458102226257324, "28518": 0.11604541540145874, "28756": 0.06795065850019455, "28836": 1.222740888595581} | 13966946 | OBJECTIVE To determine spatial patterns of co-endemicity of schistosomiasis mansoni and the soil-transmitted helminths (STHs) Ascaris lumbricoides, Trichuris trichiura and hookworm in the Great Lakes region of East Africa, to help plan integrated neglected tropical disease programmes in this region. METHOD Parasitological surveys were conducted in Uganda, Tanzania, Kenya and Burundi in 28 213 children in 404 schools. Bayesian geostatistical models were used to interpolate prevalence of these infections across the study area. Interpolated prevalence maps were overlaid to determine areas of co-endemicity. RESULTS In the Great Lakes region, prevalence was 18.1% for Schistosoma mansoni, 50.0% for hookworm, 6.8% for A. lumbricoides and 6.8% for T. trichiura. Hookworm infection was ubiquitous, whereas S. mansoni, A. lumbricoides and T. trichiura were highly focal. Most areas were endemic (prevalence >or=10%) or hyperendemic (prevalence >or=50%) for one or more STHs, whereas endemic areas for schistosomiasis mansoni were restricted to foci adjacent large perennial water bodies. CONCLUSION Because of the ubiquity of hookworm, treatment programmes are required for STH throughout the region but efficient schistosomiasis control should only be targeted at limited high-risk areas. Therefore, integration of schistosomiasis with STH control is only indicated in limited foci in East Africa. | Spatial co-distribution of neglected tropical diseases in the east African great lakes region: revisiting the justification for integrated control. |
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"24590": 0.7755908370018005, "24710": 0.36358460783958435, "24757": 0.083342544734478, "25145": 0.012615402229130268, "25284": 0.5662899017333984, "25478": 0.48670899868011475, "25520": 1.70332670211792, "25551": 0.09672962874174118, "25969": 0.10203468054533005, "26287": 1.1671710014343262, "26290": 0.018384648486971855, "26601": 0.7163142561912537, "26702": 0.4873090982437134, "26835": 0.1221139207482338, "26874": 0.7153595685958862, "27144": 0.06795065850019455, "27166": 0.037378571927547455, "27287": 0.7086513638496399, "27321": 1.0966572761535645, "27642": 0.42353010177612305, "27989": 0.3743882179260254, "28319": 0.16276304423809052, "28466": 0.19782574474811554, "28479": 0.9783848524093628, "28522": 0.9209672808647156, "28625": 1.222740888595581, "28788": 0.4518963396549225, "29090": 0.8788808584213257, "29251": 0.13071982562541962, "29290": 0.151916041970253, "29494": 0.009718249551951885} | 13969173 | Amyotrophic lateral sclerosis (ALS) causes motor neuron degeneration, paralysis, and death. Accurate disease modeling, identifying disease mechanisms, and developing therapeutics is urgently needed. We previously reported motor neuron toxicity through postmortem ALS spinal cord-derived astrocytes. However, these cells can only be harvested after death, and their expansion is limited. We now report a rapid, highly reproducible method to convert adult human fibroblasts from living ALS patients to induced neuronal progenitor cells and subsequent differentiation into astrocytes (i-astrocytes). Non-cell autonomous toxicity to motor neurons is found following coculture of i-astrocytes from familial ALS patients with mutation in superoxide dismutase or hexanucleotide expansion in C9orf72 (ORF 72 on chromosome 9) the two most frequent causes of ALS. Remarkably, i-astrocytes from sporadic ALS patients are as toxic as those with causative mutations, suggesting a common mechanism. Easy production and expansion of i-astrocytes now enables rapid disease modeling and high-throughput drug screening to alleviate astrocyte-derived toxicity. | Direct conversion of patient fibroblasts demonstrates non-cell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS. |
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"28723": 0.04674193635582924, "28788": 0.1619328260421753, "29021": 0.02412080205976963, "29217": 0.055094651877880096, "29299": 0.5336109399795532, "29490": 0.24859806895256042} | 13980338 | Heterogeneity within the self-renewal durability of adult hematopoietic stem cells (HSCs) challenges our understanding of the molecular framework underlying HSC function. Gene expression studies have been hampered by the presence of multiple HSC subtypes and contaminating non-HSCs in bulk HSC populations. To gain deeper insight into the gene expression program of murine HSCs, we combined single-cell functional assays with flow cytometric index sorting and single-cell gene expression assays. Through bioinformatic integration of these datasets, we designed an unbiased sorting strategy that separates non-HSCs away from HSCs, and single-cell transplantation experiments using the enriched population were combined with RNA-seq data to identify key molecules that associate with long-term durable self-renewal, producing a single-cell molecular dataset that is linked to functional stem cell activity. Finally, we demonstrated the broader applicability of this approach for linking key molecules with defined cellular functions in another stem cell system. | Combined Single-Cell Functional and Gene Expression Analysis Resolves Heterogeneity within Stem Cell Populations |
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We used aire- deficient mice to test the hypothesis that this transcription factor regulates autoimmunity by promoting the ectopic expression of peripheral tissue- restricted antigens in medullary epithelial cells of the thymus. This hypothesis proved correct. The mutant animals exhibited a defined profile of autoimmune diseases that depended on the absence of aire in stromal cells of the thymus. Aire-deficient thymic medullary epithelial cells showed a specific reduction in ectopic transcription of genes encoding peripheral antigens. These findings highlight the importance of thymically imposed "central" tolerance in controlling autoimmunity. | Acids: Structures, Properties, and Functions (University Science Books, Sausalito, CA, 2000). |
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0.8682814836502075, "27295": 0.3423145115375519, "27321": 0.5139457583427429, "27381": 0.010684899985790253, "27633": 1.439538836479187, "27777": 0.12384103983640671, "27854": 0.09850110858678818, "28041": 0.08064348995685577, "28353": 1.2721059322357178, "28788": 0.24325250089168549, "29235": 0.011650617234408855, "29290": 0.07159364968538284, "29489": 0.31845372915267944, "29543": 0.25694093108177185} | 13992047 | We have found that epithelial cells engage in a process of cadherin-mediated intercellular adhesion that utilizes calcium and actin polymerization in unexpected ways. Calcium stimulates filopodia, which penetrate and embed into neighboring cells. E-cadherin complexes cluster at filopodia tips, generating a two-rowed zipper of embedded puncta. Opposing cell surfaces are clamped by desmosomes, while vinculin, zyxin, VASP, and Mena are recruited to adhesion zippers by a mechanism that requires alpha-catenin. Actin reorganizes and polymerizes to merge puncta into a single row and seal cell borders. In keratinocytes either null for alpha-catenin or blocked in VASP/Mena function, filopodia embed, but actin reorganization/polymerization is prevented, and membranes cannot seal. Taken together, a dynamic mechanism for intercellular adhesion is unveiled involving calcium-activated filopodia penetration and VASP/Mena-dependent actin reorganization/polymerization. | Directed Actin Polymerization Is the Driving Force for Epithelial Cell–Cell Adhesion |
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Despite the importance of rDNA for cellular function, we know virtually nothing about what governs its copy number, stability, and sequence in the mammalian genome due to challenges associated with mapping and analysis. We applied computational and droplet digital PCR approaches to measure rDNA copy number in normal and cancer states in human and mouse genomes. We find that copy number and sequence can change in cancer genomes. Counterintuitively, human cancer genomes show a loss of copies, accompanied by global copy number co-variation. The sequence can also be more variable in the cancer genome. Cancer genomes with lower copies have mutational evidence of mTOR hyperactivity. The PTEN phosphatase is a tumor suppressor that is critical for genome stability and a negative regulator of the mTOR kinase pathway. Surprisingly, but consistent with the human cancer genomes, hematopoietic cancer stem cells from a Pten-/- mouse model for leukemia have lower rDNA copy number than normal tissue, despite increased proliferation, rRNA production, and protein synthesis. Loss of copies occurs early and is associated with hypersensitivity to DNA damage. Therefore, copy loss is a recurrent feature in cancers associated with mTOR activation. Ribosomal DNA copy number may be a simple and useful indicator of whether a cancer will be sensitive to DNA damaging treatments. | Ribosomal DNA copy number loss and sequence variation in cancer |
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0.08064348995685577, "26897": 0.6754127144813538, "26906": 0.10203468054533005, "27354": 0.4624064862728119, "27794": 0.27044451236724854, "28093": 0.1930064558982849, "28353": 0.10906458646059036, "28389": 0.151916041970253, "28436": 0.1229778528213501, "28739": 0.38174858689308167, "28767": 0.14179791510105133, "28788": 0.27786844968795776, "29031": 0.2105647772550583, "29107": 0.1384023278951645, "29300": 0.16276304423809052, "29361": 0.15359249711036682, "29458": 0.7755908370018005, "29466": 0.0019512200960889459, "29602": 0.04953393340110779} | 14021596 | BACKGROUND The objective of the study was to test the hypothesis that elevated red cell distribution width (RDW) at admission increases the risk of mortality in older patients admitted to the emergency department (ED). METHODS We performed a retrospective analysis of patients admitted to the ED between May 2013 and October 2013. We included patients who were older than 65 years who visited the ED with any medical problems. Baseline RDW values were measured at the time of admission to the ED. The primary outcome was all-cause in-hospital mortality. Multivariate logistic analysis was performed. RESULTS A total of 1,990 patients were finally included in this study. The mean age was 75 years (SD 7), and 936 (47 %) subjects were male. The in-hospital mortality rate was 3.76 % (74 patients). RDW values higher in non-survivors than in survivors (15.9 ± 2.5 vs. 13.8 ± 1.7, p < 0.001). Multivariate logistic analysis showed that RDW was associated with all-cause in-hospital mortality after adjusting for other confounding factors. DISCUSSION RDW value at admission is an independent predictor of all-cause in-hospital mortality among patients older than 65 years. After adjustment for multiple confounders, the all-cause in-hospital mortality rate increased by 21.8% for each 1% increase in RDW. CONCLUSION These results show that RDW at admission is associated with in-hospital mortality among patients older than 65. Thus, RDW at admission may represent a surrogate marker of disease severity. We caution against using these findings to aid clinical decision-making process until they are externally validated. | The association of Red cell distribution width and in-hospital mortality in older adults admitted to the emergency department |
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Two important questions are whether all lncRNAs are functional and how they could exert a function. Several lncRNAs have been shown to function through their product, but this is not the only possible mode of action. In this review we focus on a role for the process of lncRNA transcription, independent of the lncRNA product, in regulating protein-coding-gene activity in cis. We discuss examples where lncRNA transcription leads to gene silencing or activation, and describe strategies to determine if the lncRNA product or its transcription causes the regulatory effect. | Gene regulation by the act of long non-coding RNA transcription |
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0.030771657824516296, "28735": 0.026025565341114998, "28788": 0.9005423784255981, "28964": 1.005902886390686, "29101": 0.15275461971759796, "29129": 0.619189441204071, "29147": 0.021256839856505394, "29228": 0.10555581003427505, "29295": 0.603290855884552} | 14060030 | The recognition that myocyte mitosis occurs in the fetal, neonatal, adult, and hypertrophied heart and that a pool of primitive, undifferentiated cells is present in the myocardium has put forward a different view of the biology of the heart. The new paradigm suggests that myocyte formation is preserved during postnatal life, in adulthood or senescence, pointing to a remarkable growth reserve of the heart throughout the course of life of the organism. This article reviews a large body of novel information, which has been obtained in the last 2 decades, in favor of the notion that the mammalian heart has the inherent ability to continuously replace its parenchymal cells and that this unexpected characteristic has important implications in understanding myocardial homeostasis, cardiac aging, and tissue repair. The paradigm that the heart is a postmitotic organ incapable of regenerating parenchymal cells was established in the 1970s, and this dogma has profoundly conditioned basic and clinical research in cardiology for the last 3 decades. On the basis of this paradigm, cardiomyocytes undergo cellular hypertrophy1,2 but cannot be replaced either by entry into the cell cycle of a subpopulation of nonterminally differentiated myocytes or by activation of a pool of primitive cells that become committed to the myocyte lineage. The only response of cardiomyocytes to stress is hypertrophy and/or death. Therefore, a tremendous effort was made to identify the molecular mechanisms of myocyte hypertrophy and their genetic control. A sophisticated knowledge of various signaling pathways has been achieved, and our understanding of the biology of hypertrophic myocyte growth has advanced markedly.3 An array of new technologies has been introduced that has led to a scientific revolution in terms of questions, approaches, and interpretation of experimental results. Despite this enormous progress in our understanding of basic mechanisms of hypertrophy, however, very little … | Life and death of cardiac stem cells: a paradigm shift in cardiac biology. |
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Recent studies suggest that a pathogenic feed back loop may be operative between platelets and tumor cells, with reciprocal interactions between tumor growth/metastasis and thrombocytosis/platelet activation. Specific molecular pathways have been identified in which tumors can stimulate platelet production and activation; activated platelets can, in turn, promote tumor growth and metastasis. Taken together, these findings provide exciting new potential targets for therapeutic intervention. | Paraneoplastic thrombocytosis: the secrets of tumor self-promotion. |
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0.13157635927200317, "28321": 0.13925230503082275, "28329": 0.045809537172317505, "28767": 0.46608972549438477, "28788": 0.36900100111961365, "29076": 0.2478361576795578, "29295": 0.2576959431171417, "29299": 0.1011524572968483, "29427": 0.05046287178993225, "29458": 0.77198725938797} | 14079881 | OBJECTIVE To determine whether perceived age correlates with survival and important age related phenotypes. DESIGN Follow-up study, with survival of twins determined up to January 2008, by which time 675 (37%) had died. SETTING Population based twin cohort in Denmark. PARTICIPANTS 20 nurses, 10 young men, and 11 older women (assessors); 1826 twins aged >or=70. MAIN OUTCOME MEASURES Assessors: perceived age of twins from photographs. Twins: physical and cognitive tests and molecular biomarker of ageing (leucocyte telomere length). RESULTS For all three groups of assessors, perceived age was significantly associated with survival, even after adjustment for chronological age, sex, and rearing environment. Perceived age was still significantly associated with survival after further adjustment for physical and cognitive functioning. The likelihood that the older looking twin of the pair died first increased with increasing discordance in perceived age within the twin pair-that is, the bigger the difference in perceived age within the pair, the more likely that the older looking twin died first. Twin analyses suggested that common genetic factors influence both perceived age and survival. Perceived age, controlled for chronological age and sex, also correlated significantly with physical and cognitive functioning as well as with leucocyte telomere length. CONCLUSION Perceived age-which is widely used by clinicians as a general indication of a patient's health-is a robust biomarker of ageing that predicts survival among those aged >or=70 and correlates with important functional and molecular ageing phenotypes. | Perceived age as clinically useful biomarker of ageing: cohort study. |
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0.9084475636482239, "28644": 0.2852376699447632, "28674": 1.035461664199829, "28715": 0.07159364968538284, "28788": 0.06886265426874161, "28817": 0.10818854719400406, "28873": 0.03831886500120163, "28964": 0.0058422754518687725, "28987": 0.09228714555501938, "29160": 0.12384103983640671, "29278": 0.1485546976327896, "29458": 0.8091925978660583, "29543": 0.9302552938461304} | 14082855 | PURPOSE To investigate and relate the ultrashort-term and long-term courses of determinants for foreign body reaction as biocompatibility predictors for meshes in an animal model. MATERIALS AND METHODS Three different meshes (TVT, UltraPro, and PVDF) were implanted in sheep. Native and plasma coated meshes were placed bilaterally: (a) interaperitoneally, (b) as fascia onlay, and (c) as muscle onlay (fascia sublay). At 5 min, 20 min, 60 min, and 120 min meshes were explanted and histochemically investigated for inflammatory infiltrate, macrophage infiltration, vessel formation, myofibroblast invasion, and connective tissue accumulation. The results were related to long-term values over 24 months. RESULTS Macrophage invasion reached highest extents with up to 60% in short-term and decreased within 24 months to about 30%. Inflammatory infiltrate increased within the first 2 hours, the reached levels and the different extents and ranking among the investigated meshes remained stable during long-term follow up. For myofibroblasts, connective tissue, and CD31+ cells, no activity was detected during the first 120 min. CONCLUSION The local inflammatory reaction is an early and susceptible event after mesh implantation. It cannot be influenced by prior plasma coating and does not depend on the localisation of implantation. | Inflammatory Reaction as Determinant of Foreign Body Reaction Is an Early and Susceptible Event after Mesh Implantation |
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0.05139094591140747, "27400": 0.25239890813827515, "27725": 0.37102460861206055, "27788": 0.2231435477733612, "27830": 0.1718502640724182, "28026": 0.14686977863311768, "28254": 0.07068414986133575, "28304": 0.05417001247406006, "28370": 0.00875066313892603, "28505": 0.0317181795835495, "28570": 0.07612881064414978, "29431": 0.3423145115375519, "29549": 0.2622140049934387} | 14083283 | We present a new compact image pyramid representation, the Riesz pyramid, that can be used for real-time phase-based motion magnification. Our new representation is less overcomplete than even the smallest two orientation, octave-bandwidth complex steerable pyramid, and can be implemented using compact, efficient linear filters in the spatial domain. Motion-magnified videos produced with this new representation are of comparable quality to those produced with the complex steerable pyramid. When used with phase-based video magnification, the Riesz pyramid phase-shifts image features along only their dominant orientation rather than every orientation like the complex steerable pyramid. | Riesz pyramids for fast phase-based video magnification |
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0.17267228662967682, "26874": 0.24859806895256042, "26972": 0.036437395960092545, "27152": 0.2223619967699051, "27295": 0.0019512200960889459, "27598": 0.47402387857437134, "27642": 0.8901712894439697, "27734": 0.5534584522247314, "27895": 0.02792670577764511, "28041": 1.0101795196533203, "28170": 0.18816383183002472, "28426": 0.040196798741817474, "28466": 0.5707147121429443, "28696": 0.1751343309879303, "28767": 0.04487626627087593, "28779": 0.1332872211933136, "28892": 0.043007105588912964, "29090": 0.49864232540130615, "29290": 0.6553317308425903, "29465": 0.1358480453491211} | 14092737 | α-synuclein dysregulation is a critical aspect of Parkinson's disease pathology. Recent studies have observed that α-synuclein aggregates are cytotoxic to cells in culture and that this toxicity can be spread between cells. However, the molecular mechanisms governing this cytotoxicity and spread are poorly characterized. Recent studies of viruses and bacteria, which achieve their cytoplasmic entry by rupturing intracellular vesicles, have utilized the redistribution of galectin proteins as a tool to measure vesicle rupture by these organisms. Using this approach, we demonstrate that α-synuclein aggregates can induce the rupture of lysosomes following their endocytosis in neuronal cell lines. This rupture can be induced by the addition of α-synuclein aggregates directly into cells as well as by cell-to-cell transfer of α-synuclein. We also observe that lysosomal rupture by α-synuclein induces a cathepsin B dependent increase in reactive oxygen species (ROS) in target cells. Finally, we observe that α-synuclein aggregates can induce inflammasome activation in THP-1 cells. Lysosomal rupture is known to induce mitochondrial dysfunction and inflammation, both of which are well established aspects of Parkinson's disease, thus connecting these aspects of Parkinson's disease to the propagation of α-synuclein pathology in cells. | Alpha-Synuclein Induces Lysosomal Rupture and Cathepsin Dependent Reactive Oxygen Species Following Endocytosis |
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0.30558720231056213, "25524": 0.08154398202896118, "25641": 1.033379077911377, "26396": 0.3283478021621704, "26775": 0.777387797832489, "26819": 0.00875066313892603, "27697": 0.021256839856505394, "27846": 0.1751343309879303, "28228": 0.6533012986183167, "28312": 0.13925230503082275, "28751": 0.011650617234408855, "28929": 1.3690568208694458, "29130": 0.49982786178588867, "29458": 0.8057082891464233} | 14103509 | A mechanistic understanding of fracture in human bone is critical to predicting fracture risk associated with age and disease. Despite extensive work, a mechanistic framework for describing how the microstructure affects the failure of bone is lacking. Although micromechanical models incorporating local failure criteria have been developed for metallic and ceramic materials, few such models exist for biological materials. In fact, there is no proof to support the widely held belief that fracture in bone is locally strain-controlled, as for example has been shown for ductile fracture in metallic materials. In the present study, we provide such evidence through a novel series of experiments involving a double-notch-bend geometry, designed to shed light on the nature of the critical failure events in bone. We examine how the propagating crack interacts with the bone microstructure to provide some mechanistic understanding of fracture and to define how properties vary with orientation. It was found that fracture in human cortical bone is consistent with strain-controlled failure, and the influence of microstructure can be described in terms of several toughening mechanisms. We provide estimates of the relative importance of these mechanisms, such as uncracked-ligament bridging. | Mechanistic Fracture Criteria For The Failure Of Human Cortical Bone |
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"28041": 0.8845420479774475, "28086": 0.31560876965522766, "28397": 0.11081436276435852, "28507": 0.08244366943836212, "28667": 0.4286321699619293, "28741": 0.045809537172317505, "28775": 0.00875066313892603, "28922": 0.20102575421333313, "29129": 0.045809537172317505, "29139": 0.0606246218085289, "29197": 1.1959327459335327, "29243": 0.304147332906723, "29333": 0.23864774405956268, "29334": 0.04953393340110779} | 14105446 | In this experiment actinomycin D was used to explore the action of the wound epidermis on underlying tissues during limb regeneration. In axolotl forelimbs the skin was removed from the elbow to the shoulder. Skin from the right limbs was soaked for three hours in actinomycin D (5.0 or 10.0 μg/ml 0.6% NaCl). For controls, skin from left limbs was soaked in 0.6% NaCl for the same period of time. Each piece of skin was orthotopically replanted, and both limbs were amputated through the treated skin, proximal to the elbow. After an initial healing period, the control limbs regenerated normally. Except for a slightly paler color, limbs bearing actinomycin-treated skin were indistinguishable from the controls, both grossly and histologically, during the first week following amputation. While the control limbs formed early blastemas, no grossly visible evidence of regeneration was apparent in the experimental limbs, but histologically some dedifferentiation was occurring. Normally three to four digits were seen in the control regenerates before blastemas appeared on the experimental limbs. By 35–40 days blastemas had appeared on most experimental limbs. These developed very rapidly, and within a short time many of them had attained levels of development close to the controls. Actinomycin D temporarily suppresses formation of the apical epidermal cap and the subsequent aggregation of dedifferentiated cells into a blastema. When the effect wears off, an apical cap forms and the dedifferentiated cells quickly organize into a blastema and begin to differentiate. | Inhibition of limb regeneration in the axolotl after treatment of the skin with actinomycin D. |
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RORα-deficient mice are protected against age- and diet-induced obesity, hepatosteatosis, and insulin resistance. The resistance to hepatosteatosis in RORα-deficient mice is related to the reduced expression of several genes regulating lipid synthesis, transport, and storage. Adipose tissue-associated inflammation, which plays a critical role in the development of insulin resistance, is considerably diminished in RORα-deficient mice as indicated by the reduced infiltration of M1 macrophages and decreased expression of many proinflammatory genes. Deficiency in RORγ also protects against diet-induced insulin resistance by a mechanism that appears different from that in RORα deficiency. Recent studies indicated that RORs provide an important link between the circadian clock machinery and its regulation of metabolic genes and metabolic syndrome. As ligand-dependent transcription factors, RORs may provide novel therapeutic targets in the management of obesity and associated metabolic diseases, including hepatosteatosis, adipose tissue-associated inflammation, and insulin resistance. | Retinoic acid-related orphan receptors α and γ: key regulators of lipid/glucose metabolism, inflammation, and insulin sensitivity |
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"25505": 0.2470736801624298, "25778": 0.3241194784641266, "25918": 0.43875885009765625, "26021": 0.24401791393756866, "26190": 0.012615402229130268, "26206": 0.055094651877880096, "26210": 0.04113444685935974, "26886": 0.5376120805740356, "27011": 0.01934296265244484, "27090": 0.03831886500120163, "27144": 0.9783848524093628, "27348": 0.02887592278420925, "27354": 0.18329764902591705, "27651": 0.15023678541183472, "27777": 0.17431432008743286, "27989": 0.13414156436920166, "28031": 0.13157635927200317, "28105": 0.4624064862728119, "28296": 1.2065086364746094, "28428": 0.4248080551624298, "28472": 0.007782140281051397, "28804": 0.25845035910606384, "28967": 0.03925827145576477, "29031": 0.15693697333335876, "29191": 0.07250232994556427, "29234": 0.036437395960092545, "29439": 0.28670501708984375} | 14118484 | A collaboration of multidisciplinary experts on the functional evaluation of lung cancer patients has been facilitated by the European Respiratory Society (ERS) and the European Society of Thoracic Surgery (ESTS), in order to draw up recommendations and provide clinicians with clear, up-to-date guidelines on fitness for surgery and chemo-radiotherapy. The subject was divided into different topics, which were then assigned to at least two experts. The authors searched the literature according to their own strategies, with no central literature review being performed. The draft reports written by the experts on each topic were reviewed, discussed and voted on by the entire expert panel. The evidence supporting each recommendation was summarised, and graded as described by the Scottish Intercollegiate Guidelines Network Grading Review Group. Clinical practice guidelines were generated and finalized in a functional algorithm for risk stratification of the lung resection candidates, emphasising cardiological evaluation, forced expiratory volume in 1 s, systematic carbon monoxide lung diffusion capacity and exercise testing. Contrary to lung resection, for which the scientific evidences are more robust, we were unable to recommend any specific test, cut-off value, or algorithm before chemo-radiotherapy due to the lack of data. We recommend that lung cancer patients should be managed in specialised settings by multidisciplinary teams. | ERS/ESTS clinical guidelines on fitness for radical therapy in lung cancer patients (surgery and chemo-radiotherapy). |
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"26874": 0.14602625370025635, "27059": 0.48430517315864563, "27295": 0.08871890604496002, "27781": 0.04953393340110779, "27822": 0.4412745535373688, "27854": 0.3134697377681732, "28086": 0.1808556467294693, "28251": 0.9287132620811462, "28498": 0.004870930220931768, "28691": 0.18248429894447327, "28873": 0.13755162060260773} | 14119470 | Ran is an abundant nuclear GTPase with a clear role in nuclear transport during interphase but with roles in mitotic regulation that are less well understood. The nucleotide-binding state of Ran is regulated by a GTPase activating protein, RanGAP1, and by a guanine nucleotide exchange factor, RCC1. Ran also interacts with a guanine nucleotide dissociation inhibitor, RanBP1. RanBP1 has a high affinity for GTP-bound Ran, and it acts as a cofactor for RanGAP1, increasing the rate of GAP-mediated GTP hydrolysis on Ran approximately tenfold. RanBP1 levels oscillate during the cell cycle [4], and increased concentrations of RanBP1 prolong mitosis in mammalian cells and in Xenopus egg extracts (our unpublished observations). We investigated how increased concentrations of RanBP1 disturb mitosis. We found that spindle assembly is dramatically disrupted when exogenous RanBP1 is added to M phase Xenopus egg extracts. We present evidence that the role of Ran in spindle assembly is independent of nuclear transport and is probably mediated through changes in microtubule dynamics. | The Ran GTPase regulates mitotic spindle assembly |
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on blood pressure (BP) is often compromised by the effects of antihypertensive medications. A review of numerous clinical trials that investigated the effects of BP-lowering medications is summarized here. METHODS Published clinical trials, including 137 clinical trials with monodrug therapies and 28 clinical trials of combination drug therapies with a total of 11,739 participants, were reviewed from PubMed. Six major classes/groups of antihypertensive medications were categorized by ethnicity, including angiotensin-converting enzyme (ACE) inhibitors, alpha1-blockers, cardioselective beta-blockers (beta1-blockers), calcium channel blockers, thiazide and thiazide-like diuretics, and loop diuretics. RESULTS Using sitting or supine BP, for ethnic groups combined, monodrug therapy with ACE inhibitors showed a weighted average effect of lowering the systolic and diastolic BP by 12.5/9.5 mm Hg; alpha1-blockers by 15.5/11.7 mm Hg; beta1-blockers by 14.8/12.2 mm Hg; calcium channel blockers by 15.3/10.5 mm Hg; thiazide diuretics by 15.3/9.8 mm Hg; and loop diuretics by 15.8/8.2 mm Hg. However, ACE inhibitors, alpha1-blockers, and beta1-blockers were less effective in African Americans than in non-African Americans, whereas calcium channel blockers, thiazide diuretics, and loop diuretics were more effective in African Americans than in non-African Americans. For two-drug combination therapy with ethnic groups combined, the BP-lowering effect of the second medication, when compared to its effect as monodrug therapy, was 84% and 65% for systolic and diastolic BP, respectively. CONCLUSIONS The BP-lowering effects reported here may be used to impute the pretreatment BP levels, which can improve the information content and hence the power of epidemiologic analysis in studies where use of antihypertensive medications is a confounding factor in the BP measurements. | A summary of the effects of antihypertensive medications on measured blood pressure. |
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0.319873183965683, "29280": 0.6280876994132996} | 14128314 | The recent derivation of pluripotent stem cell lines from a number of different sources, including reprogrammed adult somatic cells, raises the issue of the developmental equivalence of these different pluripotent states. At least two different states representing the epiblast progenitors in the blastocyst and the pluripotent progenitors of the later gastrulating embryo have been recognized. Understanding the initial developmental status of the different pluripotent lines is critical for defining starting conditions for differentiation toward therapeutically relevant cell types. | Stem Cells and Early Lineage Development |
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The etiology and molecular basis for this 'alternative' treatment-resistant cell state remain incompletely understood. Here, by analyzing whole-exome sequencing data of metastatic biopsies from patients, we observed substantial genomic overlap between castration-resistant tumors that were histologically characterized as prostate adenocarcinomas (CRPC-Adeno) and neuroendocrine prostate cancer (CRPC-NE); analysis of biopsy samples from the same individuals over time points to a model most consistent with divergent clonal evolution. Genome-wide DNA methylation analysis revealed marked epigenetic differences between CRPC-NE tumors and CRPC-Adeno, and also designated samples of CRPC-Adeno with clinical features of AR independence as CRPC-NE, suggesting that epigenetic modifiers may play a role in the induction and/or maintenance of this treatment-resistant state. This study supports the emergence of an alternative, 'AR-indifferent' cell state through divergent clonal evolution as a mechanism of treatment resistance in advanced prostate cancer. | Divergent clonal evolution of castration resistant neuroendocrine prostate cancer |
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"26773": 0.03925827145576477, "26874": 0.013579257763922215, "27099": 0.7845434546470642, "27118": 0.6734226942062378, "27152": 0.12038381397724152, "27171": 0.15860503911972046, "27295": 0.014542185701429844, "27723": 0.7942996621131897, "27777": 0.04860413447022438, "27788": 0.05046287178993225, "27854": 0.040196798741817474, "27895": 0.18573370575904846, "28024": 1.0285027027130127, "28577": 0.058784693479537964, "29129": 0.4462870955467224, "29170": 0.4067663550376892, "29248": 0.015504186972975731, "29290": 0.5860490798950195, "29297": 0.9100211262702942} | 14145440 | BACKGROUND DNA replication and mitosis are triggered by activation of kinase complexes, each made up of a cyclin and a cyclin-dependent kinase (Cdk). It had seemed possible that the association of Cdks with different classes of cyclins specifies whether S phase (replication) or M phase (mitosis) will occur. The recent finding that individual B-type cyclins (encoded by the genes CLB1-CLB6) can have functions in both processes in the budding yeast Saccharomyces cerevisiae casts doubt on this notion. RESULTS S. cerevisiae strains lacking C1b1-C1b4 undergo DNA replication once but fail to enter mitosis. We have isolated mutations in two genes, SIM1 and SIM2 (SIM2 is identical to SEC72), which allow such cells to undergo an extra round of DNA replication without mitosis. The Clb5 kinase, which promotes S phase, remains active during the G2-phase arrest of cells of the parental strain, but its activity declines rapidly in sim mutants. Increased expression of the CLB5 gene prevents re-replication. Thus, a cyclin B-kinase that promotes DNA replication in G1-phase cells can prevent re-replication in G2-phase cells. Inactivation of C1b kinases by expression of the specific C1b-Cdk1 inhibitor p40SIC1 is sufficient to induce a prereplicative state at origins of replication in cells blocked in G2/M phase by nocodazole. Re-activation of C1b-Cdk1 kinases induces a second round of DNA replication. CONCLUSIONS We propose that S-phase-promoting cyclin B--Cdk complexes prevent re-replication during S, G2 and M phases by inhibiting the transition of replication origins to a pre-replicative state. This model can explain both why origins 'fire' only once per S phase and why S phase is dependent on completion of the preceding M phase. | S-phase-promoting cyclin-dependent kinases prevent re-replication by inhibiting the transition of replication origins to a pre-replicative state |
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"27642": 0.02316705882549286, "27854": 0.21293537318706512, "27859": 0.2478361576795578, "28038": 0.15023678541183472, "28041": 0.07612881064414978, "28086": 0.1994270235300064, "28156": 0.40741631388664246, "28314": 0.28743788599967957, "28346": 0.05970508232712746, "28353": 1.3540414571762085, "28427": 0.20421554148197174, "28517": 0.3824150264263153, "28688": 0.15526613593101501, "28696": 0.04860413447022438, "28926": 0.15359249711036682, "29170": 0.3676496744155884, "29290": 0.28082266449928284, "29300": 0.129004567861557, "29347": 0.1685553640127182} | 14149065 | E-cadherin has been linked to the suppression of tumor growth and the inhibition of cell proliferation in culture. We observed that progressively decreasing the seeding density of normal rat kidney-52E (NRK-52E) or MCF-10A epithelial cells from confluence, indeed, released cells from growth arrest. Unexpectedly, a further decrease in seeding density so that cells were isolated from neighboring cells decreased proliferation. Experiments using microengineered substrates showed that E-cadherin engagement stimulated the peak in proliferation at intermediate seeding densities, and that the proliferation arrest at high densities did not involve E-cadherin, but rather resulted from a crowding-dependent decrease in cell spreading against the underlying substrate. Rac1 activity, which was induced by E-cadherin engagement specifically at intermediate seeding densities, was required for the cadherin-stimulated proliferation, and the control of Rac1 activation by E-cadherin was mediated by p120-catenin. Together, these findings demonstrate a stimulatory role for E-cadherin in proliferative regulation, and identify a simple mechanism by which cell–cell contact may trigger or inhibit epithelial cell proliferation in different settings. | E-cadherin engagement stimulates proliferation via Rac1 |
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We report the crystal structure of the INO80 complex subunit Arp8 in its ATP-bound form. Human Arp8 has several insertions in the conserved actin fold that explain its inability to polymerize. Most remarkably, one insertion wraps over the active site cleft and appears to rigidify the domain architecture, while active site features shared with actin suggest an allosterically controlled ATPase activity. Quantitative binding studies with nucleosomes and histone complexes reveal that Arp8 and the Arp8-Arp4-actin-HSA sub-complex of INO80 strongly prefer nucleosomes and H3-H4 tetramers over H2A-H2B dimers, suggesting that Arp8 functions as a nucleosome recognition module. In contrast, Arp4 prefers free (H3-H4)(2) over nucleosomes and may serve remodelers through binding to (dis)assembly intermediates in the remodeling reaction. | Structure of Actin-related protein 8 and its contribution to nucleosome binding |
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"29393": 1.5023398399353027, "29544": 0.12384103983640671, "29607": 0.21765978634357452} | 14171859 | beta-adrenergic receptors (beta-ARs), prototypic G-protein-coupled receptors (GPCRs), play a critical role in regulating numerous physiological processes. The GPCR kinases (GRKs) curtail G-protein signaling and target receptors for internalization. Nitric oxide (NO) and/or S-nitrosothiols (SNOs) can prevent the loss of beta-AR signaling in vivo, but the molecular details are unknown. Here we show in mice that SNOs increase beta-AR expression and prevent agonist-stimulated receptor downregulation; and in cells, SNOs decrease GRK2-mediated beta-AR phosphorylation and subsequent recruitment of beta-arrestin to the receptor, resulting in the attenuation of receptor desensitization and internalization. In both cells and tissues, GRK2 is S-nitrosylated by SNOs as well as by NO synthases, and GRK2 S-nitrosylation increases following stimulation of multiple GPCRs with agonists. Cys340 of GRK2 is identified as a principal locus of inhibition by S-nitrosylation. Our studies thus reveal a central molecular mechanism through which GPCR signaling is regulated. | Regulation of β-Adrenergic Receptor Signaling by S-Nitrosylation of G-Protein-Coupled Receptor Kinase 2 |
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required to produce mutant mice, but the involvement of a time-consuming microinjection step still hampers its application for high-throughput genetic analysis. Here we developed a simple, highly efficient, and large-scale genome editing method, in which the RNAs for the CRISPR/Cas9 system are electroporated into zygotes rather than microinjected. We used this method to perform single-stranded oligodeoxynucleotide (ssODN)-mediated knock-in in mouse embryos. This method facilitates large-scale genetic analysis in the mouse. | Electroporation enables the efficient mRNA delivery into the mouse zygotes and facilitates CRISPR/Cas9-based genome editing |
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"27218": 0.7710843086242676, "27258": 0.14939609169960022, "27363": 0.0174254160374403, "27598": 1.0621482133865356, "27709": 1.0553730726242065, "27795": 0.0797421783208847, "28024": 0.1477125883102417, "28041": 0.40546512603759766, "28227": 0.0038986403960734606, "28297": 0.6548244953155518, "28327": 0.9546096324920654, "28424": 0.06886265426874161, "28522": 0.9455460906028748, "28562": 0.2089812457561493, "28767": 0.013579257763922215, "28828": 0.2837681770324707, "28829": 0.33115679025650024, "28927": 0.14179791510105133, "28964": 0.29109421372413635, "28974": 0.1401015669107437, "29217": 0.018384648486971855, "29370": 0.13157635927200317, "29388": 0.0058422754518687725, "29486": 0.30989447236061096, "29494": 0.9724938273429871, "29533": 0.861702561378479} | 14178995 | The genetic diseases Hutchinson-Gilford progeria syndrome (HGPS) and restrictive dermopathy (RD) arise from accumulation of farnesylated prelamin A because of defects in the lamin A maturation pathway. Both of these diseases exhibit symptoms that can be viewed as accelerated aging. The mechanism by which accumulation of farnesylated prelamin A leads to these accelerated aging phenotypes is not understood. Here we present evidence that in HGPS and RD fibroblasts, DNA damage checkpoints are persistently activated because of the compromise in genomic integrity. Inactivation of checkpoint kinases Ataxia-telangiectasia-mutated (ATM) and ATR (ATM- and Rad3-related) in these patient cells can partially overcome their early replication arrest. Treatment of patient cells with a protein farnesyltransferase inhibitor (FTI) did not result in reduction of DNA double-strand breaks and damage checkpoint signaling, although the treatment significantly reversed the aberrant shape of their nuclei. This suggests that DNA damage accumulation and aberrant nuclear morphology are independent phenotypes arising from prelamin A accumulation in these progeroid syndromes. Since DNA damage accumulation is an important contributor to the symptoms of HGPS, our results call into question the possibility of treatment of HGPS with FTIs alone. | Summary |
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The technique relies on the repeated application of an oriented electron-density likelihood target function to identify likely C(alpha) positions. This function is applied both in the location of a few promising ;seed' positions in the map and to grow those initial C(alpha) positions into extended chain fragments. Techniques for assembling the chain fragments into an initial chain trace are discussed. | The Buccaneer software for automated model building. 1. Tracing protein chains. |
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Hence, approaches have been intensively investigated to targeti specific molecular pathways involved in glioblastoma development and progression. Aloe emodin is believed to modulate the expression of several genes in cancer cells. We aimed to understand the molecular mechanisms underlying the therapeutic effect of Aloe emodin on gene expression profiles in the human U87 glioblastoma cell line utilizing microarray technology. The gene expression analysis revealed that a total of 8,226 gene alterations out of 28,869 genes were detected after treatment with 58.6 μg/ml for 24 hours. Out of this total, 34 genes demonstrated statistically significant change (p<0.05) ranging from 1.07 to 1.87 fold. The results revealed that 22 genes were up-regulated and 12 genes were down-regulated in response to Aloe emodin treatment. These genes were then grouped into several clusters based on their biological functions, revealing induction of expression of genes involved in apoptosis (programmed cell death) and tissue remodelling in U87 cells (p<0.01). Several genes with significant changes of the expression level e.g. SHARPIN, BCAP31, FIS1, RAC1 and TGM2 from the apoptotic cluster were confirmed by quantitative real-time PCR (qRT-PCR). These results could serve as guidance for further studies in order to discover molecular targets for the cancer therapy based on Aloe emodin treatment. | Expression profile of genes modulated by Aloe emodin in human U87 glioblastoma cells. |
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Genlisea aurea (Lentibulariaceae) is a carnivorous plant with unusually small genome size - 63.6 Mb - one of the smallest known among higher plants. Data on the genome sizes and the phylogeny of Genlisea suggest that this is a derived state within the genus. Thus, G. aurea is an excellent model organism for studying evolutionary mechanisms of genome contraction. RESULTS Here we report sequencing and de novo draft assembly of G. aurea genome. The assembly consists of 10,687 contigs of the total length of 43.4 Mb and includes 17,755 complete and partial protein-coding genes. Its comparison with the genome of Mimulus guttatus, another representative of higher core Lamiales clade, reveals striking differences in gene content and length of non-coding regions. CONCLUSIONS Genome contraction was a complex process, which involved gene loss and reduction of lengths of introns and intergenic regions, but not intron loss. The gene loss is more frequent for the genes that belong to multigenic families indicating that genetic redundancy is an important prerequisite for genome size reduction. | The miniature genome of a carnivorous plant Genlisea aurea contains a low number of genes and short non-coding sequences |
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"28828": 0.5232481360435486, "29025": 0.07612881064414978} | 14188138 | In vitro studies indicate a role for the LIM kinase family in the regulation of cofilin phosphorylation and actin dynamics. In addition, abnormal expression of LIMK-1 is associated with Williams syndrome, a mental disorder with profound deficits in visuospatial cognition. However, the in vivo function of this family of kinases remains elusive. Using LIMK-1 knockout mice, we demonstrate a significant role for LIMK-1 in vivo in regulating cofilin and the actin cytoskeleton. Furthermore, we show that the knockout mice exhibited significant abnormalities in spine morphology and in synaptic function, including enhanced hippocampal long-term potentiation. The knockout mice also showed altered fear responses and spatial learning. These results indicate that LIMK-1 plays a critical role in dendritic spine morphogenesis and brain function. | Abnormal Spine Morphology and Enhanced LTP in LIMK-1 Knockout Mice |
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0.12470348179340363} | 14191255 | The embryonic stem (ES) cell transcriptional and chromatin-modifying networks are critical for self-renewal maintenance. However, it remains unclear whether these networks functionally interact and, if so, what factors mediate such interactions. Here, we show that WD repeat domain 5 (Wdr5), a core member of the mammalian Trithorax (trxG) complex, positively correlates with the undifferentiated state and is a regulator of ES cell self-renewal. We demonstrate that Wdr5, an "effector" of H3K4 methylation, interacts with the pluripotency transcription factor Oct4. Genome-wide protein localization and transcriptome analyses demonstrate overlapping gene regulatory functions between Oct4 and Wdr5. The Oct4-Sox2-Nanog circuitry and trxG cooperate in activating transcription of key self-renewal regulators, and furthermore, Wdr5 expression is required for the efficient formation of induced pluripotent stem (iPS) cells. We propose an integrated model of transcriptional and epigenetic control, mediated by select trxG members, for the maintenance of ES cell self-renewal and somatic cell reprogramming. | Wdr5 Mediates Self-Renewal and Reprogramming via the Embryonic Stem Cell Core Transcriptional Network |
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0.48430517315864563, "27343": 0.10818854719400406, "27528": 0.5347557663917542, "27734": 0.0019512200960889459, "28024": 0.14433705806732178, "28086": 0.3560888469219208, "28156": 0.43812891840934753, "28282": 0.9842413663864136, "28405": 0.13499516248703003, "28522": 0.9271688461303711, "28636": 0.37102460861206055, "28667": 0.040196798741817474, "28788": 0.11865071207284927, "29290": 0.5685047507286072} | 14192687 | The long-term goal of nuclear transfer or alternative reprogramming approaches is to create patient-specific donor cells for transplantation therapy, avoiding immunorejection, a major complication in current transplantation medicine. It was recently shown that the four transcription factors Oct4, Sox2, Klf4, and c-Myc induce pluripotency in mouse fibroblasts. However, the therapeutic potential of induced pluripotent stem (iPS) cells for neural cell replacement strategies remained unexplored. Here, we show that iPS cells can be efficiently differentiated into neural precursor cells, giving rise to neuronal and glial cell types in culture. Upon transplantation into the fetal mouse brain, the cells migrate into various brain regions and differentiate into glia and neurons, including glutamatergic, GABAergic, and catecholaminergic subtypes. Electrophysiological recordings and morphological analysis demonstrated that the grafted neurons had mature neuronal activity and were functionally integrated in the host brain. Furthermore, iPS cells were induced to differentiate into dopamine neurons of midbrain character and were able to improve behavior in a rat model of Parkinson's disease upon transplantation into the adult brain. We minimized the risk of tumor formation from the grafted cells by separating contaminating pluripotent cells and committed neural cells using fluorescence-activated cell sorting. Our results demonstrate the therapeutic potential of directly reprogrammed fibroblasts for neuronal cell replacement in the animal model. | Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease. |
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"29450": 0.14518201351165771, "29536": 0.19541899859905243, "29577": 0.22704219818115234} | 14195528 | The role of primate frontal cortex in vocal communication and its significance in language evolution have a controversial history. While evidence indicates that vocalization processing occurs in ventrolateral prefrontal cortex neurons, vocal-motor activity has been conjectured to be primarily subcortical and suggestive of a distinctly different neural architecture from humans. Direct evidence of neural activity during natural vocal communication is limited, as previous studies were performed in chair-restrained animals. Here we recorded the activity of single neurons across multiple regions of prefrontal and premotor cortex while freely moving marmosets engaged in a natural vocal behavior known as antiphonal calling. Our aim was to test whether neurons in marmoset frontal cortex exhibited responses during vocal-signal processing and/or vocal-motor production in the context of active, natural communication. We observed motor-related changes in single neuron activity during vocal production, but relatively weak sensory responses for vocalization processing during this natural behavior. Vocal-motor responses occurred both prior to and during call production and were typically coupled to the timing of each vocalization pulse. Despite the relatively weak sensory responses a population classifier was able to distinguish between neural activity that occurred during presentations of vocalization stimuli that elicited an antiphonal response and those that did not. These findings are suggestive of the role that nonhuman primate frontal cortex neurons play in natural communication and provide an important foundation for more explicit tests of the functional contributions of these neocortical areas during vocal behaviors. | Responses of primate frontal cortex neurons during natural vocal communication. |
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"26512": 0.8500841856002808, "26651": 0.8748174905776978, "26773": 0.3519764244556427, "26786": 0.09761575609445572, "27321": 0.823009729385376, "27427": 0.3318578004837036, "27598": 0.6603899002075195, "27753": 0.07068414986133575, "27833": 0.17922431230545044, "27989": 0.012615402229130268, "28041": 0.11343330889940262, "28155": 0.6128603219985962, "28156": 0.4679262638092041, "28389": 0.272677481174469, "28466": 0.7352184057235718} | 14198646 | Obesity and type 2 diabetes are associated with increased lipogenesis in the liver. This results in fat accumulation in hepatocytes, a condition known as hepatic steatosis, which is a form of nonalcoholic fatty liver disease (NAFLD), the most common cause of liver dysfunction in the United States. Carbohydrate-responsive element-binding protein (ChREBP), a transcriptional activator of glycolytic and lipogenic genes, has emerged as a major player in the development of hepatic steatosis in mice. However, the molecular mechanisms enhancing its transcriptional activity remain largely unknown. In this study, we have identified the histone acetyltransferase (HAT) coactivator p300 and serine/threonine kinase salt-inducible kinase 2 (SIK2) as key upstream regulators of ChREBP activity. In cultured mouse hepatocytes, we showed that glucose-activated p300 acetylated ChREBP on Lys672 and increased its transcriptional activity by enhancing its recruitment to its target gene promoters. SIK2 inhibited p300 HAT activity by direct phosphorylation on Ser89, which in turn decreased ChREBP-mediated lipogenesis in hepatocytes and mice overexpressing SIK2. Moreover, both liver-specific SIK2 knockdown and p300 overexpression resulted in hepatic steatosis, insulin resistance, and inflammation, phenotypes reversed by SIK2/p300 co-overexpression. Finally, in mouse models of type 2 diabetes and obesity, low SIK2 activity was associated with increased p300 HAT activity, ChREBP hyperacetylation, and hepatic steatosis. Our findings suggest that inhibition of hepatic p300 activity may be beneficial for treating hepatic steatosis in obesity and type 2 diabetes and identify SIK2 activators and specific p300 inhibitors as potential targets for pharmaceutical intervention. | Salt-inducible kinase 2 links transcriptional coactivator p300 phosphorylation to the prevention of ChREBP-dependent hepatic steatosis in mice. |
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"28715": 0.0009760859538801014, "29398": 0.8641747236251831, "29489": 0.9635916948318481} | 14205246 | The spindle apparatus is a microtubule (MT)-based machinery that attaches to and segregates the chromosomes during mitosis and meiosis. Self-organization of the spindle around chromatin involves the assembly of MTs, their attachment to the chromosomes, and their organization into a bipolar array. One regulator of spindle self-organization is RanGTP. RanGTP is generated at chromatin and activates a set of soluble, Ran-regulated spindle factors such as TPX2, NuMA, and NuSAP . How the spindle factors direct and attach MTs to the chromosomes are key open questions. Nucleolar and Spindle-Associated Protein (NuSAP) was recently identified as an essential MT-stabilizing and bundling protein that is enriched at the central part of the spindle . Here, we show by biochemical reconstitution that NuSAP efficiently adsorbs to isolated chromatin and DNA and that it can directly produce and retain high concentrations of MTs in the immediate vicinity of chromatin or DNA. Moreover, our data reveal that NuSAP-chromatin interaction is subject to Ran regulation and can be suppressed by Importin alpha (Impalpha) and Imp7. We propose that the presence of MT binding agents such as NuSAP, which can be directly immobilized on chromatin, are critical for targeting MT production to vertebrate chromosomes during spindle self-organization. | A Role for NuSAP in Linking Microtubules to Mitotic Chromosomes |
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Early nuclear reprogramming methods, such as somatic cell nuclear transfer (SCNT) and cell fusion, posed significant technical hurdles to precise dissection of the regulatory programmes governing cell identity. However, the discovery of reprogramming by ectopic expression of a defined set of transcription factors, known as direct reprogramming, provided a tractable platform to uncover molecular characteristics of cellular specification and differentiation, cell type stability and pluripotency. We discuss the control and maintenance of cellular identity during developmental transitions as they have been studied using direct reprogramming, with an emphasis on transcriptional and epigenetic regulation. | Molecular features of cellular reprogramming and development |
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0.12814582884311676, "27790": 0.05970508232712746, "27854": 0.0019512200960889459, "28295": 1.1051015853881836, "28300": 0.32199856638908386, "28561": 0.6430866718292236, "28696": 0.05139094591140747, "29010": 0.034552380442619324, "29167": 0.2089812457561493, "29226": 0.9302552938461304} | 14240343 | Circadian clocks orchestrate 24-h oscillations of essential physiological and behavioral processes in response to daily environmental changes. These clocks are remarkably precise under constant conditions yet highly responsive to resetting signals. With the molecular composition of the core oscillator largely established, recent research has increasingly focused on clock-modifying mechanisms/molecules. In particular, small molecule modifiers, intrinsic or extrinsic, are emerging as powerful tools for understanding basic clock biology as well as developing putative therapeutic agents for clock-associated diseases. In this review, we will focus on synthetic compounds capable of modifying the period, phase, or amplitude of circadian clocks, with particular emphasis on the mammalian clock. We will discuss the potential of exploiting these small molecule modifiers in both basic and translational research. | Small molecule modifiers of circadian clocks |
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These hotspot mutations result in oncogenic activity of the enzyme and contribute to therapeutic resistance to the anti-HER2 antibody trastuzumab. The PI3K pathway is, therefore, an attractive target for cancer therapy. We have studied NVP-BEZ235, a dual inhibitor of the PI3K and the downstream mammalian target of rapamycin (mTOR). NVP-BEZ235 inhibited the activation of the downstream effectors Akt, S6 ribosomal protein, and 4EBP1 in breast cancer cells. The antiproliferative activity of NVP-BEZ235 was superior to the allosteric selective mTOR complex inhibitor everolimus in a panel of 21 cancer cell lines of different origin and mutation status. The described Akt activation due to mTOR inhibition was prevented by higher doses of NVP-BEZ235. NVP-BEZ235 reversed the hyperactivation of the PI3K/mTOR pathway caused by the oncogenic mutations of p110-alpha, E545K, and H1047R, and inhibited the proliferation of HER2-amplified BT474 cells exogenously expressing these mutations that render them resistant to trastuzumab. In trastuzumab-resistant BT474 H1047R breast cancer xenografts, NVP-BEZ235 inhibited PI3K signaling and had potent antitumor activity. In treated animals, there was complete inhibition of PI3K signaling in the skin at pharmacologically active doses, suggesting that skin may serve as surrogate tissue for pharmacodynamic studies. In summary, NVP-BEZ235 inhibits the PI3K/mTOR axis and results in antiproliferative and antitumoral activity in cancer cells with both wild-type and mutated p110-alpha. | NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. |
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"27718": 0.08513788133859634, "27781": 0.012615402229130268, "27833": 1.156782865524292, "28093": 0.036437395960092545, "28228": 0.37907835841178894, "28436": 0.4673144817352295, "28530": 0.24325250089168549, "28723": 1.0492360591888428, "29166": 0.32129061222076416, "29290": 0.2470736801624298, "29514": 0.0354953333735466, "29610": 0.43434104323387146} | 14252892 | Osteonecrosis is a severe glucocorticoid-induced complication of acute lymphoblastic leukemia treatment. We prospectively screened children (n = 364) with magnetic resonance imaging of hips and knees, regardless of symptoms; the cumulative incidence of any (grade 1-4) versus symptomatic (grade 2-4) osteonecrosis was 71.8% versus 17.6%, respectively. We investigated whether age, race, sex, acute lymphoblastic leukemia treatment arm, body mass, serum lipids, albumin and cortisol levels, dexamethasone pharmacokinetics, and genome-wide germline genetic polymorphisms were associated with symptomatic osteonecrosis. Age more than 10 years (odds ratio, = 4.85; 95% confidence interval, 2.5-9.2; P = .00001) and more intensive treatment (odds ratio = 2.5; 95% confidence interval, 1.2-4.9; P = .011) were risk factors and included as covariates in all analyses. Lower albumin (P = .05) and elevated cholesterol (P = .02) associated with symptomatic osteonecrosis, and severe (grade 3 or 4) osteonecrosis was linked to poor dexamethasone clearance (P = .0005). Adjusting for clinical features, polymorphisms of ACP1 (eg, rs12714403, P = 1.9 × 10(-6), odds ratio = 5.6; 95% confidence interval, 2.7-11.3), which regulates lipid levels and osteoblast differentiation, were associated with risk of osteonecrosis as well as with lower albumin and higher cholesterol. Overall, older age, lower albumin, higher lipid levels, and dexamethasone exposure were associated with osteonecrosis and may be linked by inherited genomic variation. | Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia. |
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0.02316705882549286, "29598": 0.8853482007980347} | 14260013 | BACKGROUND In the absence of an effective vaccine, HIV continues to spread globally, emphasizing the need for novel strategies to limit its transmission. Pre-exposure prophylaxis (PrEP) with antiretroviral drugs could prove to be an effective intervention strategy if highly efficacious and cost-effective PrEP modalities are identified. We evaluated daily and intermittent PrEP regimens of increasing antiviral activity in a macaque model that closely resembles human transmission. METHODS AND FINDINGS We used a repeat-exposure macaque model with 14 weekly rectal virus challenges. Three drug treatments were given once daily, each to a different group of six rhesus macaques. Group 1 was treated subcutaneously with a human-equivalent dose of emtricitabine (FTC), group 2 received orally the human-equivalent dosing of both FTC and tenofovir-disoproxil fumarate (TDF), and group 3 received subcutaneously a similar dosing of FTC and a higher dose of tenofovir. A fourth group of six rhesus macaques (group 4) received intermittently a PrEP regimen similar to group 3 only 2 h before and 24 h after each weekly virus challenge. Results were compared to 18 control macaques that did not receive any drug treatment. The risk of infection in macaques treated in groups 1 and 2 was 3.8- and 7.8-fold lower than in untreated macaques (p = 0.02 and p = 0.008, respectively). All six macaques in group 3 were protected. Breakthrough infections had blunted acute viremias; drug resistance was seen in two of six animals. All six animals in group 4 that received intermittent PrEP were protected. CONCLUSIONS This model suggests that single drugs for daily PrEP can be protective but a combination of antiretroviral drugs may be required to increase the level of protection. Short but potent intermittent PrEP can provide protection comparable to that of daily PrEP in this SHIV/macaque model. These findings support PrEP trials for HIV prevention in humans and identify promising PrEP modalities. | Prevention of Rectal SHIV Transmission in Macaques by Daily or Intermittent Prophylaxis with Emtricitabine and Tenofovir |
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0.9209672808647156, "27570": 0.13499516248703003, "27777": 0.27934664487838745, "27822": 0.053244512528181076, "27854": 1.0087559223175049, "27898": 0.22548456490039825, "28433": 0.11691460013389587, "28436": 0.9650808572769165, "28667": 0.535327672958374, "28820": 0.33325836062431335, "28937": 1.0506030321121216, "29060": 0.15023678541183472, "29458": 0.9673105478286743} | 14275671 | The similarity in the three-dimensional structures of homologous proteins imposes strong constraints on their sequence variability. It has long been suggested that the resulting correlations among amino acid compositions at different sequence positions can be exploited to infer spatial contacts within the tertiary protein structure. Crucial to this inference is the ability to disentangle direct and indirect correlations, as accomplished by the recently introduced Direct Coupling Analysis (DCA) (Weigt et al. (2009) Proc Natl Acad Sci 106:67). Here we develop a computationally efficient implementation of DCA, which allows us to evaluate the accuracy of contact prediction by DCA for a large number of protein domains, based purely on sequence information. DCA is shown to yield a large number of correctly predicted contacts, recapitulating the global structure of the contact map for the majority of the protein domains examined. Furthermore, our analysis captures clear signals beyond intra- domain residue contacts, arising, e.g., from alternative protein conformations, ligand- mediated residue couplings, and inter-domain interactions in protein oligomers. Our findings suggest that contacts predicted by DCA can be used as a reliable guide to facilitate computational predictions of alternative protein conformations, protein complex formation, and even the de novo prediction of protein domain structures, provided the existence of a large number of homologous sequences which are being rapidly made available due to advances in genome sequencing. | Direct-coupling analysis of residue co-evolution captures native contacts across many protein families |
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"28804": 0.05970508232712746, "28892": 0.10467668622732162, "29234": 0.6476961374282837, "29251": 0.10818854719400406, "29295": 0.21214580535888672, "29598": 0.1889725625514984} | 14290854 | OBJECTIVE To describe variation in antibiotic prescribing for acute cough in contrasting European settings and the impact on recovery. DESIGN Cross sectional observational study with clinicians from 14 primary care research networks in 13 European countries who recorded symptoms on presentation and management. Patients followed up for 28 days with patient diaries. SETTING Primary care. PARTICIPANTS Adults with a new or worsening cough or clinical presentation suggestive of lower respiratory tract infection. MAIN OUTCOME MEASURES Prescribing of antibiotics by clinicians and total symptom severity scores over time. RESULTS 3402 patients were recruited (clinicians completed a case report form for 99% (3368) of participants and 80% (2714) returned a symptom diary). Mean symptom severity scores at presentation ranged from 19 (scale range 0 to 100) in networks based in Spain and Italy to 38 in the network based in Sweden. Antibiotic prescribing by networks ranged from 20% to nearly 90% (53% overall), with wide variation in classes of antibiotics prescribed. Amoxicillin was overall the most common antibiotic prescribed, but this ranged from 3% of antibiotics prescribed in the Norwegian network to 83% in the English network. While fluoroquinolones were not prescribed at all in three networks, they were prescribed for 18% in the Milan network. After adjustment for clinical presentation and demographics, considerable differences remained in antibiotic prescribing, ranging from Norway (odds ratio 0.18, 95% confidence interval 0.11 to 0.30) to Slovakia (11.2, 6.20 to 20.27) compared with the overall mean (proportion prescribed: 0.53). The rate of recovery was similar for patients who were and were not prescribed antibiotics (coefficient -0.01, P<0.01) once clinical presentation was taken into account. CONCLUSIONS Variation in clinical presentation does not explain the considerable variation in antibiotic prescribing for acute cough in Europe. Variation in antibiotic prescribing is not associated with clinically important differences in recovery. TRIAL REGISTRATION Clinicaltrials.gov NCT00353951. | Variation in antibiotic prescribing and its impact on recovery in patients with acute cough in primary care: prospective study in 13 countries. |
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0.6054253578186035, "27777": 0.12986256182193756, "27854": 0.12038381397724152, "28086": 1.2566616535186768, "28156": 0.14686977863311768, "28405": 0.2918238639831543, "28699": 0.3163207769393921, "28723": 0.1602703034877777, "28788": 0.1710275560617447, "29290": 0.40481385588645935} | 14296612 | BACKGROUND Pluripotent embryonic stem (ES) cells, which have the capacity to give rise to all tissue types in the body, show great promise as a versatile source of cells for regenerative therapy. However, the basic mechanisms of lineage specification of pluripotent stem cells are largely unknown, and generating sufficient quantities of desired cell types remains a formidable challenge. Small molecules, particularly those that modulate key developmental pathways like the bone morphogenetic protein (BMP) signaling cascade, hold promise as tools to study in vitro lineage specification and to direct differentiation of stem cells toward particular cell types. METHODOLOGY/ PRINCIPAL FINDINGS We describe the use of dorsomorphin, a selective small molecule inhibitor of BMP signaling, to induce myocardial differentiation in mouse ES cells. Cardiac induction is very robust, increasing the yield of spontaneously beating cardiomyocytes by at least 20 fold. Dorsomorphin, unlike the endogenous BMP antagonist Noggin, robustly induces cardiomyogenesis when treatment is limited to the initial 24-hours of ES cell differentiation. Quantitative-PCR analyses of differentiating ES cells indicate that pharmacological inhibition of BMP signaling during the early critical stage promotes the development of the cardiomyocyte lineage, but reduces the differentiation of endothelial, smooth muscle, and hematopoietic cells. CONCLUSIONS/ SIGNIFICANCE Administration of a selective small molecule BMP inhibitor during the initial stages of ES cell differentiation substantially promotes the differentiation of primitive pluripotent cells toward the cardiomyocytic lineage, apparently at the expense of other mesodermal lineages. Small molecule modulators of developmental pathways like dorsomorphin could become versatile pharmacological tools for stem cell research and regenerative medicine. | Dorsomorphin, a Selective Small Molecule Inhibitor of BMP Signaling, Promotes Cardiomyogenesis in Embryonic Stem Cells |
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"25402": 0.06429435312747955, "25458": 0.11081436276435852, "25476": 0.055094651877880096, "25549": 0.1011524572968483, "25662": 1.202409029006958, "25898": 0.13925230503082275, "26228": 0.23864774405956268, "26308": 0.25995752215385437, "26351": 0.25694093108177185, "26664": 0.0770333781838417, "26837": 0.31845372915267944, "27086": 0.8109301924705505, "27351": 0.31489628553390503, "27354": 0.11081436276435852, "27420": 0.04113444685935974, "27754": 0.5784112811088562, "28032": 0.32553088665008545, "28442": 0.11517547070980072, "28516": 0.1358480453491211, "28550": 0.004870930220931768, "28618": 0.33325836062431335, "29066": 0.21687394380569458} | 14300799 | A key feature of speech is its stereotypical 5 Hz rhythm. One theory posits that this rhythm evolved through the modification of rhythmic facial movements in ancestral primates. If the hypothesis has any validity, then a comparative approach may shed some light. We tested this idea by using cineradiography (X-ray movies) to characterize and quantify the internal dynamics of the macaque monkey vocal tract during lip-smacking (a rhythmic facial expression) versus chewing. Previous human studies showed that speech movements are faster than chewing movements, and the functional coordination between vocal tract structures is different between the two behaviors. If rhythmic speech evolved through a rhythmic ancestral facial movement, then one hypothesis is that monkey lip-smacking versus chewing should also exhibit these differences. We found that the lips, tongue, and hyoid move with a speech-like 5 Hz rhythm during lip-smacking, but not during chewing. Most importantly, the functional coordination between these structures was distinct for each behavior. These data provide empirical support for the idea that the human speech rhythm evolved from the rhythmic facial expressions of ancestral primates. | Cineradiography of Monkey Lip-Smacking Reveals Putative Precursors of Speech Dynamics |
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0.0913962796330452, "23999": 0.175953671336174, "24004": 0.0019512200960889459, "24054": 0.630689799785614, "24073": 1.0361549854278564, "24269": 0.822151780128479, "24844": 0.4450363218784332, "24848": 1.190008521080017, "25117": 0.018384648486971855, "25194": 0.09850110858678818, "25204": 1.0506030321121216, "25456": 0.3750596046447754, "25502": 0.75193190574646, "25644": 0.2749055027961731, "25714": 0.804835319519043, "26288": 0.058784693479537964, "26402": 0.8633513450622559, "26773": 0.669430673122406, "26838": 0.4337083101272583, "27544": 0.129004567861557, "27756": 0.06886265426874161, "27854": 0.36900100111961365, "27989": 0.9317949414253235, "28156": 0.12556517124176025, "28228": 0.7881022095680237, "28466": 0.28670501708984375, "28517": 0.06886265426874161, "28570": 0.07612881064414978, "28767": 0.36494144797325134, "29300": 0.3683255612850189, "29441": 0.04487626627087593} | 14308244 | Neuregulin-1 (NRG1) and its receptor ErbB4 influence several processes of neurodevelopment, but the mechanisms regulating this signalling in the mature brain are not well known. DISC1 is a multifunctional scaffold protein that mediates many cellular processes. Here we present a functional relationship between DISC1 and NRG1-ErbB4 signalling in mature cortical interneurons. By cell type-specific gene modulation in vitro and in vivo including in a mutant DISC1 mouse model, we demonstrate that DISC1 inhibits NRG1-induced ErbB4 activation and signalling. This effect is likely mediated by competitive inhibition of binding of ErbB4 to PSD95. Finally, we show that interneuronal DISC1 affects NRG1-ErbB4-mediated phenotypes in the fast spiking interneuron-pyramidal neuron circuit. Post-mortem brain analyses and some genetic studies have reported interneuronal deficits and involvement of the DISC1, NRG1 and ErbB4 genes in schizophrenia, respectively. Our results suggest a mechanism by which cross-talk between DISC1 and NRG1-ErbB4 signalling may contribute to these deficits. | Interneuronal DISC1 regulates NRG1-ErbB4 signalling and excitatory-inhibitory synapse formation in the mature cortex. |
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0.9302552938461304, "26534": 0.12038381397724152, "26616": 0.40806588530540466, "26651": 0.04860413447022438, "26773": 0.3683255612850189, "26775": 0.11778303235769272, "27059": 0.19541899859905243, "27099": 0.17840765416622162, "27395": 0.7201237678527832, "27777": 0.013579257763922215, "27854": 0.18411032855510712, "28086": 0.0174254160374403, "28498": 0.009718249551951885, "28788": 0.006812678650021553, "28873": 0.28743788599967957, "29206": 0.14095009863376617, "29248": 0.053244512528181076, "29290": 0.35745587944984436, "29610": 0.04113444685935974} | 14311986 | The molecular basis for the distinctive cytokine expression of CD4+ T helper 1 (Th1) and T helper 2 (Th2) subsets remains elusive. Here, we report that the proto-oncogene c-maf, a basic region/leucine zipper transcription factor, controls tissue-specific expression of IL-4. c-Maf is expressed in Th2 but not Th1 clones and is induced during normal precursor cell differentiation along a Th2 but not Th1 lineage. c-Maf binds to a c-Maf response element (MARE) in the proximal IL-4 promoter adjacent to a site footprinted by extracts from Th2 but not Th1 clones. Ectopic expression of c-Maf transactivates the IL-4 promoter in Th1 cells, B cells, and nonlymphoid cells, a function that maps to the MARE and Th2-specific footprint. Furthermore, c-Maf acts in synergy with the nuclear factor of activated T cells (NF-ATp) to initiate endogeneous IL-4 production by B cells. Manipulation of c-Maf may alter Th subset ratios in human disease. | The Proto-Oncogene c-maf Is Responsible for Tissue-Specific Expression of Interleukin-4 |
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0.32199856638908386, "26773": 0.47827014327049255, "26785": 0.6739205718040466, "26786": 0.0770333781838417, "26886": 0.23324857652187347, "27142": 0.036437395960092545, "27144": 0.10555581003427505, "27184": 0.23092569410800934, "27216": 0.2145126610994339, "27295": 0.3883931338787079, "27400": 0.06612417846918106, "27697": 0.08603433519601822, "27790": 0.1913948506116867, "27881": 0.15359249711036682, "28286": 0.7482418417930603, "28290": 0.11778303235769272, "28309": 0.08692999184131622, "28561": 0.3485364317893982, "28696": 0.1710275560617447, "28828": 0.04860413447022438, "28892": 0.10731173306703568, "29166": 0.9052929878234863, "29206": 0.176772341132164, "29290": 0.08871890604496002, "29295": 0.006812678650021553} | 14315749 | In this study, we aimed to investigate changes in the expression of human Clock (hClock), a gene at the core of the circadian gene family, in colorectal carcinomas (CRCs) and to discuss the possible effects. Previous studies have revealed that the disruption of circadian rhythms is one of the endogenous factors that contribute to the initiation and development of CRCs. However, the underlying molecular changes to the circadian genes associated with CRCs have not been explored. Immunofluorescence and quantitative polymerase chain reaction (qPCR) analysis of the hCLOCK protein and gene expression were performed in 30 cases of CRC. The hCLOCK protein was expressed in all specimens obtained from 30 CRC patients. Higher levels of hCLOCK expression were observed in human CRC tissues compared with the paired non-cancerous tissues. hCLOCK expression was significantly higher in poorly differentiated, or late-stage, Dukes' grade tumors and in 64.3% of tumor cases with lymph node metastasis. The hClock gene was expressed in all specimens. A significantly higher expression of hClock was found in human CRC cases compared with paired non-cancerous tissues. There was a strong positive linear correlation between hClock gene expression and protein expression in human CRCs. A strong positive linear correlation was also found between hClock gene expression and ARNT, HIF-1α and VEGF expression in human CRCs. There was no significant correlation between hClock and Bak, Bax, Bid, tumor necrosis factor receptor I (TNFR I) and TNFR II. The circadian gene hClock was stably expressed in human colorectal mucosa and was important in regulating the expression of downstream clock-controlled genes. hCLOCK may interact with HIF-1α/ARNT and activate VEGF to stimulate tumor angiogenesis and metastasis. | hClock gene expression in human colorectal carcinoma. |
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"26402": 0.23402166366577148, "26462": 0.09406650811433792, "26616": 0.09938567131757736, "26728": 0.25088030099868774, "26745": 0.055094651877880096, "27144": 0.1751343309879303, "27354": 0.025073638185858727, "27794": 0.9842413663864136, "27974": 0.15693697333335876, "28093": 0.2034190446138382, "28196": 0.09850110858678818, "28321": 0.1358480453491211, "28389": 0.28743788599967957, "28436": 0.06520967930555344, "28836": 0.014542185701429844, "28848": 0.13071982562541962} | 14319754 | BACKGROUND Highly active antiretroviral therapy (HAART) is being scaled up in developing countries. We compared baseline characteristics and outcomes during the first year of HAART between HIV-1-infected patients in low-income and high-income settings. METHODS 18 HAART programmes in Africa, Asia, and South America (low-income settings) and 12 HIV cohort studies from Europe and North America (high-income settings) provided data for 4810 and 22,217, respectively, treatment-naïve adult patients starting HAART. All patients from high-income settings and 2725 (57%) patients from low-income settings were actively followed-up and included in survival analyses. FINDINGS Compared with high-income countries, patients starting HAART in low-income settings had lower CD4 cell counts (median 108 cells per muL vs 234 cells per muL), were more likely to be female (51%vs 25%), and more likely to start treatment with a non-nucleoside reverse transcriptase inhibitor (NNRTI) (70%vs 23%). At 6 months, the median number of CD4 cells gained (106 cells per muL vs 103 cells per muL) and the percentage of patients reaching HIV-1 RNA levels lower than 500 copies/mL (76%vs 77%) were similar. Mortality was higher in low-income settings (124 deaths during 2236 person-years of follow-up) than in high-income settings (414 deaths during 20,532 person-years). The adjusted hazard ratio (HR) of mortality comparing low-income with high-income settings fell from 4.3 (95% CI 1.6-11.8) during the first month to 1.5 (0.7-3.0) during months 7-12. The provision of treatment free of charge in low-income settings was associated with lower mortality (adjusted HR 0.23; 95% CI 0.08-0.61). INTERPRETATION Patients starting HAART in resource-poor settings have increased mortality rates in the first months on therapy, compared with those in developed countries. Timely diagnosis and assessment of treatment eligibility, coupled with free provision of HAART, might reduce this excess mortality. | The Antiretroviral Therapy in Lower Income Countries (ART-LINC) Collaboration and ART Cohort Collaboration (ART-CC) groups Summary |
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0.07159364968538284, "27263": 0.07159364968538284, "27531": 1.0250049829483032, "27642": 0.08603433519601822, "27854": 0.22157983481884003, "27896": 0.16110190749168396, "28032": 0.950843095779419, "28048": 0.2607102394104004, "28765": 1.0257055759429932, "28901": 0.083342544734478, "29248": 0.6456501483917236} | 14328288 | BACKGROUND Mammalian phosphoinositide 3-kinases (PI 3-kinases) are involved in receptor-mediated signal transduction and have been implicated in processes such as transformation and mitogenesis through their role in elevating cellular phosphatidylinositol (3,4,5)-trisphosphate. Additionally, a PI 3-kinase activity which generates phosphatidylinositol 3-phosphate has been shown to be required for protein trafficking in yeast. RESULTS We have identified a family of three distinct PI 3-kinases in Drosophila, using an approach based on the polymerase chain reaction to amplify a region corresponding to the conserved catalytic domain of PI 3-kinases. One of these family members, PI3K_92D, is closely related to the prototypical PI 3-kinase, p110 alpha; PI3K_59F is homologous to Vps34p, whereas the third, PI3K_68D, is a novel PI 3-kinase which is widely expressed throughout the Drosophila life cycle. The PI3K_68D cDNA encodes a protein of 210 kDa, which lacks sequences implicated in linking p110 PI 3-kinases to p85 adaptor proteins, but contains an amino-terminal proline-rich sequence, which could bind to SH3 domains, and a carboxy-terminal C2 domain. Biochemical analyses demonstrate that PI3K_68D has a novel substrate specificity in vitro, restricted to phosphatidylinositol and phosphatidylinositol 4-phosphate, and is unable to phosphorylate phosphatidylinositol (4,5)-bisphosphate, the implied in vivo substrate for p110. CONCLUSIONS A family of PI 3-kinases in Drosophila, including a novel class represented by PI3K_68D, is described. PI3K_68D has the potential to bind to signalling molecules containing SH3 domains, lacks p85-adaptor-binding sequences, has a Ca(2+)-independent phospholipid-binding domain and displays a restricted in vitro substrate specificity, so it could define a novel signal transduction pathway. | A family of phosphoinositide 3-kinases in Drosophila identifies a new mediator of signal transduction |
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0.16524957120418549, "25938": 0.8592242002487183, "26296": 0.7925328612327576, "26402": 0.9598589539527893, "26462": 0.6902132034301758, "26520": 0.17020416259765625, "26524": 0.9598589539527893, "26702": 0.29255300760269165, "26874": 0.009718249551951885, "26906": 0.36086538434028625, "26963": 0.1930064558982849, "27009": 0.1619328260421753, "27144": 0.28670501708984375, "27521": 0.09584271162748337, "27777": 0.6980181336402893, "27881": 0.46363574266433716, "28024": 0.8195732831954956, "28086": 0.08603433519601822, "28156": 0.3554046154022217, "28207": 0.2026219218969345, "28424": 0.28890204429626465, "28472": 0.04207121208310127, "28691": 0.0058422754518687725, "29206": 0.30917787551879883, "29290": 0.47827014327049255, "29461": 0.011650617234408855} | 14332945 | Human cancers are characterized by the presence of oncogene-induced DNA replication stress (DRS), making them dependent on repair pathways such as break-induced replication (BIR) for damaged DNA replication forks. To better understand BIR, we performed a targeted siRNA screen for genes whose depletion inhibited G1 to S phase progression when oncogenic cyclin E was overexpressed. RAD52, a gene dispensable for normal development in mice, was among the top hits. In cells in which fork collapse was induced by oncogenes or chemicals, the Rad52 protein localized to DRS foci. Depletion of Rad52 by siRNA or knockout of the gene by CRISPR/Cas9 compromised restart of collapsed forks and led to DNA damage in cells experiencing DRS. Furthermore, in cancer-prone, heterozygous APC mutant mice, homozygous deletion of the Rad52 gene suppressed tumor growth and prolonged lifespan. We therefore propose that mammalian RAD52 facilitates repair of collapsed DNA replication forks in cancer cells. | Mammalian RAD52 Functions in Break-Induced Replication Repair of Collapsed DNA Replication Forks |
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"25930": 0.42161011695861816, "26083": 0.1212492436170578, "26408": 0.09938567131757736, "26417": 0.817850649356842, "26524": 0.10467668622732162, "27166": 0.36086538434028625, "27169": 0.688742995262146, "27287": 0.46853771805763245, "27321": 0.736154317855835, "27531": 0.21687394380569458, "27532": 0.037378571927547455, "27658": 0.12470348179340363, "27969": 0.1401015669107437, "28086": 1.385317325592041, "28105": 0.06703783571720123, "28156": 0.49626702070236206, "28183": 0.17431432008743286, "28228": 0.20102575421333313, "28287": 0.30558720231056213, "28620": 0.025073638185858727, "28636": 0.5729197263717651, "28711": 0.8004589080810547, "28788": 0.35745587944984436, "28991": 0.3070250153541565, "29228": 0.05786345899105072, "29248": 0.1510767638683319} | 14333540 | Neural crest (NC) cells arise in the dorsal neural tube (NT) and migrate into the embryo to develop into many different cell types. A major unresolved question is when and how the fate of NC cells is decided. There is widespread evidence for multipotential NC cells, whose fates are decided during or after migration. There is also some evidence that the NC is already divided into subpopulations of discrete precursors within the NT. We have investigated this question in the mouse embryo. We find that a subpopulation of cells on the most dorsomedial aspect of the NT express the receptor tyrosine kinase Kit (previously known as c-kit), emigrate exclusively into the developing dermis, and then express definitive markers of the melanocyte lineage. These are thus melanocyte progenitor cells. They are generated predominantly at the midbrain-hindbrain junction and cervical trunk, with significant numbers also in lower trunk. Other cells within the dorsal NT are Kit-, migrate ventrally, and, from embryonic day 9.5, express the neurotrophin receptor p75. These cells most likely only give rise to ventral NC derivatives such as neurons and glia. The p75+ cells are located ventrolateral to the Kit+ cells in areas of the NT where these two cell types are found. These data provide direct in vivo evidence for NC lineage segregation within the mouse neural tube. | Neural crest cell lineage segregation in the mouse neural tube. |
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" It is impossible to forecast resource and operational requirements accurately if endpoints have not been defined clearly, yet even during the Global Malaria Eradication Program, debate raged over the precise definition of "eradication. " Analogous deliberations regarding the meaning of "elimination" and "control" are basically nonexistent today despite these terms' core importance to programme planning. To advance the contemporary debate about these issues, this paper presents a historical review of commonly used terms, including control, elimination, and eradication, to help contextualize current understanding of these concepts. The review has been supported by analysis of the underlying mathematical concepts on which these definitions are based through simple branching process models that describe the proliferation of malaria cases following importation. Through this analysis, the importance of pragmatic definitions that are useful for providing malaria control and elimination programmes with a practical set of strategic milestones is emphasized, and it is argued that current conceptions of elimination in particular fail to achieve these requirements. To provide all countries with precise targets, new conceptual definitions are suggested to more precisely describe the old goals of "control" - here more exactly named "controlled low-endemic malaria" - and "elimination. " Additionally, it is argued that a third state, called "controlled non-endemic malaria," is required to describe the epidemiological condition in which endemic transmission has been interrupted, but malaria resulting from onwards transmission from imported infections continues to occur at a sufficiently high level that elimination has not been achieved. Finally, guidelines are discussed for deriving the separate operational definitions and metrics that will be required to make these concepts relevant, measurable, and achievable for a particular environment. | How absolute is zero? An evaluation of historical and current definitions of malaria elimination |
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0.8796916007995605, "28616": 1.1450434923171997, "28691": 0.22704219818115234, "28829": 0.6233867406845093, "28873": 0.04767346754670143, "28927": 0.2478361576795578} | 14338915 | The mechanisms ensuring specific incorporation of CENP-A at centromeres are poorly understood. Mis16 and Mis18 are required for CENP-A localization at centromeres and form a complex that is conserved from fission yeast to human. Fission yeast sim1 mutants that alleviate kinetochore domain silencing are defective in Scm3(Sp), the ortholog of budding yeast Scm3(Sc). Scm3(Sp) depends on Mis16/18 for its centromere localization and like them is recruited to centromeres in late anaphase. Importantly, Scm3(Sp) coaffinity purifies with CENP-A(Cnp1) and associates with CENP-A(Cnp1) in vitro, yet localizes independently of intact CENP-A(Cnp1) chromatin and is differentially released from chromatin. While Scm3(Sc) has been proposed to form a unique hexameric nucleosome with CENP-A(Cse4) and histone H4 at budding yeast point centromeres, we favor a model in which Scm3(Sp) acts as a CENP-A(Cnp1) receptor/assembly factor, cooperating with Mis16 and Mis18 to receive CENP-A(Cnp1) from the Sim3 escort and mediate assembly of CENP-A(Cnp1) into subkinetochore chromatin. | Fission Yeast Scm3: A CENP-A Receptor Required for Integrity of Subkinetochore Chromatin |
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0.5903874635696411, "24868": 0.03831886500120163, "24906": 0.07341018319129944, "24932": 0.24018502235412598, "25117": 0.9936857223510742, "25219": 0.26146242022514343, "25410": 1.0546929836273193, "25622": 0.13670019805431366, "25775": 0.1011524572968483, "26089": 0.02412080205976963, "26163": 0.21293537318706512, "26591": 0.016465263441205025, "26651": 0.21530038118362427, "26709": 0.6420594453811646, "26755": 0.16524957120418549, "26780": 0.5540198087692261, "26835": 0.1994270235300064, "27102": 0.12986256182193756, "27199": 0.08961215615272522, "27325": 0.05417001247406006, "27395": 0.21530038118362427, "27529": 0.1229778528213501, "27781": 0.03266380727291107, "27895": 0.03266380727291107, "28168": 0.36426326632499695, "28177": 0.0009760859538801014, "28227": 0.3241194784641266, "28268": 0.20739519596099854, "28788": 0.1994270235300064, "28873": 0.03831886500120163, "28935": 0.7647408246994019, "29005": 0.0009760859538801014} | 14340571 | Background Celiac disease is a small intestinal inflammatory disorder characterized by malabsorption, nutrient deficiency, and a range of clinical manifestations. It is caused by an inappropriate immune response to dietary gluten and is treated with a gluten-free diet. Recent feeding studies have indicated oats to be safe for celiac disease patients, and oats are now often included in the celiac disease diet. This study aimed to investigate whether oat intolerance exists in celiac disease and to characterize the cells and processes underlying this intolerance. Methods and Findings We selected for study nine adults with celiac disease who had a history of oats exposure. Four of the patients had clinical symptoms on an oats-containing diet, and three of these four patients had intestinal inflammation typical of celiac disease at the time of oats exposure. We established oats-avenin-specific and -reactive intestinal T-cell lines from these three patients, as well as from two other patients who appeared to tolerate oats. The avenin-reactive T-cell lines recognized avenin peptides in the context of HLA-DQ2. These peptides have sequences rich in proline and glutamine residues closely resembling wheat gluten epitopes. Deamidation (glutamine→glutamic acid conversion) by tissue transglutaminase was involved in the avenin epitope formation. Conclusions We conclude that some celiac disease patients have avenin-reactive mucosal T-cells that can cause mucosal inflammation. Oat intolerance may be a reason for villous atrophy and inflammation in patients with celiac disease who are eating oats but otherwise are adhering to a strict gluten-free diet. Clinical follow-up of celiac disease patients eating oats is advisable. | The Molecular Basis for Oat Intolerance in Patients with Celiac Disease |
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0.04767346754670143, "25775": 0.016465263441205025, "25986": 0.07068414986133575, "25990": 0.8091925978660583, "26180": 0.11168810725212097, "26189": 0.02887592278420925, "26226": 0.35334911942481995, "26419": 0.020300358533859253, "26876": 0.5010119676589966, "27018": 0.46302130818367004, "27065": 0.09317722171545029, "27109": 0.1485546976327896, "27204": 0.014542185701429844, "27222": 0.12728634476661682, "28093": 0.06886265426874161, "28287": 0.18329764902591705, "29048": 0.4974553883075714, "29278": 0.21687394380569458, "29295": 0.22626367211341858, "29329": 0.37304413318634033, "29477": 0.2800849378108978, "29545": 0.16276304423809052} | 14361849 | IntroductionWe conducted the present study to investigate the potential beneficial and adverse effects of continuous positive airway pressure (CPAP) compared with bi-level positive airway pressure (BiPAP) noninvasive ventilation in patients with cardiogenic pulmonary oedema. MethodWe included randomized controlled studies comparing CPAP and BiPAP treatment in patients with cardiogenic pulmonary oedema from the Cochrane Controlled Trials Register (2005 issue 3), and EMBASE and MEDLINE databases (1966 to 1 December 2005), without language restriction. Two reviewers reviewed the quality of the studies and independently performed data extraction. ResultsSeven randomized controlled studies, including a total of 290 patients with cardiogenic pulmonary oedema, were considered. The hospital mortality (relative risk [RR] 0.76, 95% confidence interval [CI] 0.32–1.78; P = 0.52; I2 = 0%) and risk for requiring invasive ventilation (RR 0.80, 95% CI 0.33–1.94; P = 0.62; I2 = 0%) were not significantly different between patients treated with CPAP and those treated with BiPAP. Stratifying studies that used either fixed or titrated pressure during BiPAP treatment and studies involving patients with or without hypercapnia did not change the results. The duration of noninvasive ventilation required until the pulmonary oedema resolved (weighted mean difference [WMD] in hours = 3.65, 95% CI -12.12 to +19.43; P = 0.65, I2 = 0%) and length of hospital stay (WMD in days = -0.04, 95% CI -2.57 to +2.48; P = 0.97, I2 = 0%) were also not significantly different between the two groups. Based on the limited data available, there was an insignificant trend toward an increase in new onset acute myocardial infarction in patients treated with BiPAP (RR 2.10, 95% CI 0.91–4.84; P = 0.08; I2 = 25.3%).ConclusionBiPAP does not offer any significant clinical benefits over CPAP in patients with acute cardiogenic pulmonary oedema. Until a large randomized controlled trial shows significant clinical benefit and cost-effectiveness of BiPAP versus CPAP in patients with acute cardiogenic pulmonary oedema, the choice of modality will depend mainly on the equipment available. | A comparison of continuous and bi-level positive airway pressure non-invasive ventilation in patients with acute cardiogenic pulmonary oedema: a meta-analysis |
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"26288": 0.08782484382390976, "26402": 0.7067264318466187, "26475": 1.1350497007369995, "26773": 0.06703783571720123, "26944": 0.5795059204101562, "27099": 0.010684899985790253, "27295": 0.5098485946655273, "27521": 1.0326838493347168, "27854": 0.12986256182193756, "27989": 0.35403475165367126, "28297": 0.4537591338157654, "28353": 0.1358480453491211, "28424": 0.03266380727291107, "28466": 1.022197961807251, "28691": 0.10818854719400406, "28727": 0.09495500475168228, "28788": 0.11517547070980072, "28965": 0.15693697333335876, "29290": 0.3241194784641266, "29336": 0.7163142561912537, "29486": 0.0913962796330452} | 14362678 | Mitochondrial permeability transition pore (mPTP) is involved in cardiac dysfunction during chronic β-adrenergic receptor (β-AR) stimulation. The mechanism by which chronic β-AR stimulation leads to mPTP openings is elusive. Here, we show that chronic administration of isoproterenol (ISO) persistently increases the frequency of mPTP openings followed by mitochondrial damage and cardiac dysfunction. Mechanistically, this effect is mediated by phosphorylation of mitochondrial fission protein, dynamin-related protein 1 (Drp1), by Ca2+/calmodulin-dependent kinase II (CaMKII) at a serine 616 (S616) site. Mutating this phosphorylation site or inhibiting Drp1 activity blocks CaMKII- or ISO-induced mPTP opening and myocyte death in vitro and rescues heart hypertrophy in vivo. In human failing hearts, Drp1 phosphorylation at S616 is increased. These results uncover a pathway downstream of chronic β-AR stimulation that links CaMKII, Drp1 and mPTP to bridge cytosolic stress signal with mitochondrial dysfunction in the heart. | CaMKII induces permeability transition through Drp1 phosphorylation during chronic β-AR stimulation |
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0.4356052577495575, "25605": 0.8973627090454102, "25714": 0.010684899985790253, "25950": 0.9394577741622925, "25969": 0.6363908052444458, "26013": 0.440646231174469, "26282": 0.11778303235769272, "26358": 0.1994270235300064, "26402": 0.012615402229130268, "26591": 0.16524957120418549, "26632": 0.9987343549728394, "26651": 0.02316705882549286, "26745": 0.41195443272590637, "26773": 0.40546512603759766, "26835": 1.02149498462677, "27152": 0.35677260160446167, "27781": 0.151916041970253, "28848": 0.4158279001712799, "28873": 0.14433705806732178, "28896": 0.11343330889940262, "29110": 0.8666408061981201, "29137": 0.06337817758321762, "29247": 1.0999135971069336} | 14362780 | The role of microRNAs (miRNAs) in infectious diseases is becoming more and more apparent, and the use of miRNAs as a diagnostic tool and their therapeutic application has become the major focus of investigation. The aim of this study was to identify miRNAs involved in the immune signaling of macrophages in response to Arcobacter (A.) butzleri infection, an emerging foodborne pathogen causing gastroenteritis. Therefore, primary human macrophages were isolated and infected, and miRNA expression was studied by means of RNAseq. Analysis of the data revealed the expression of several miRNAs, which were previously associated with bacterial infections such as miR-155, miR-125, and miR-212. They were shown to play a key role in Toll-like receptor signaling where they act as fine-tuners to establish a balanced immune response. In addition, miRNAs which have yet not been identified during bacterial infections such as miR-3613, miR-2116, miR-671, miR-30d, and miR-629 were differentially regulated in A. butzleri-infected cells. Targets of these miRNAs accumulated in pathways such as apoptosis and endocytosis - processes that might be involved in A. butzleri pathogenesis. Our study contributes new findings about the interaction of A. butzleri with human innate immune cells helping to understand underlying regulatory mechanisms in macrophages during infection. | MicroRNA Response of Primary Human Macrophages to Arcobacter Butzleri Infection |
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"26014": 0.5110208988189697, "26236": 0.020300358533859253, "26402": 0.1332872211933136, "26512": 0.08064348995685577, "26520": 1.195341944694519, "26524": 0.009718249551951885, "26534": 0.42608439922332764, "26651": 0.0174254160374403, "26773": 0.6502478122711182, "26775": 0.32341301441192627, "27009": 0.43812891840934753, "27058": 0.9225212931632996, "27697": 0.13755162060260773, "27790": 0.1510767638683319, "27854": 0.12384103983640671, "28696": 0.12384103983640671, "28715": 0.034552380442619324} | 14367469 | Human Period 2 (hPer2) is a transcriptional regulator at the core of the circadian clock mechanism that is responsible for generating the negative feedback loop that sustains the clock. Its relevance to human disease is underlined by alterations in its function that affect numerous biochemical and physiological processes. When absent, it results in the development of various cancers and an increase in the cell's susceptibility to genotoxic stress. Thus we sought to define a yet-uncharacterized checkpoint node in which circadian components integrate environmental stress signals to the DNA-damage response. We found that hPer2 binds the C-terminal half of human p53 (hp53) and forms a stable trimeric complex with hp53's negative regulator, Mdm2. We determined that hPer2 binding to hp53 prevents Mdm2 from being ubiquitinated and targeting hp53 by the proteasome. Down-regulation of hPer2 expression directly affects hp53 levels, whereas its overexpression influences both hp53 protein stability and transcription of targeted genes. Overall our findings place hPer2 directly at the heart of the hp53-mediated response by ensuring that basal levels of hp53 are available to precondition the cell when a rapid, hp53-mediated, transcriptional response is needed. | The circadian factor Period 2 modulates p53 stability and transcriptional activity in unstressed cells |
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0.0752234235405922, "25969": 0.6823468804359436, "26013": 0.848413348197937, "26223": 0.5506471395492554, "26305": 0.417115718126297, "26328": 1.2894693613052368, "26572": 0.9591107368469238, "26601": 0.6704301834106445, "26655": 0.05694137513637543, "26775": 0.19541899859905243, "26835": 0.6054253578186035, "26874": 0.1946154683828354, "26957": 0.020300358533859253, "27058": 1.187628984451294, "27642": 0.030771657824516296, "27663": 0.42990362644195557, "28024": 0.40481385588645935, "29021": 0.2470736801624298, "29050": 0.7836518287658691} | 14376683 | The non-enveloped bacilliform viruses are the second group of plant viruses known to possess a genome consisting of circular double-stranded DNA. We have characterized the viral transcript and determined the complete sequence of the genome of Commelina mellow mottle virus (CoYMV), a member of this group. Analysis of the viral transcript indicates that the virus encodes a single terminally-redundant genome-length plus 120 nucleotide transcript. A fraction of the transcripts is polyadenylated, although the majority of the transcript is not polyadenylated. Analysis of the genome sequence indicates that the genome is 7489 bp in size and that the transcribed strand contains three open reading frames capable of encoding proteins of 23, 15 and 216 kd. The function of the 25 and 15 kd proteins is unknown. Similarities between the 216 kd polypeptide and the cauliflower mosaic virus coat protein and protease/reverse transcriptase polyprotein suggest that the 216 kd polypeptide is a polyprotein that is proteolytically processed to yield the virion coat protein, a protease, and replicase (reverse transcriptase and ribonuclease H). Each strand of the CoYMV genome is interrupted by site-specific discontinuities. The locations of the 5'-ends of these discontinuities, and the presence and location of a region on the CoYMV transcript capable of annealing with the 3'-end of cytosolic initiator methionine tRNA are consistent with replication by reverse transcription. We have demonstrated that a construct containing 1.3 CoYMV genomes is infective when introduced into Commelina diffusa, the host for CoYMV, using Agrobacterium-mediated infection. | Properties of Commelina yellow mottle virus's complete DNA sequence, genomic discontinuities and transcript suggest that it is a pararetrovirus. |
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"28286": 0.8195732831954956, "28516": 0.18816383183002472, "28848": 0.04767346754670143, "28976": 0.4248080551624298, "29098": 1.0788878202438354, "29290": 0.03925827145576477, "29490": 0.4196864068508148, "29514": 0.43053874373435974, "29610": 0.14179791510105133} | 14380875 | Glucocorticoids repress NFkappaB-mediated activation of proinflammatory genes such as interleukin-8 (IL-8) and ICAM-1. Our experiments suggest that the glucocorticoid receptor (GR) confers this effect by associating through protein-protein interactions with NFkappaB bound at each of these genes. That is, we show that the GR zinc binding region (ZBR), which includes the DNA binding and dimerization functions of the receptor, binds directly to the dimerization domain of the RelA subunit of NFkappaB in vitro and that the ZBR is sufficient to associate with RelA bound at NFkappaB response elements in vivo. Moreover, we demonstrate in vivo and in vitro that GR does not disrupt DNA binding by NFkappaB. In transient transfections, we found that the GR ligand binding domain is essential for repression of NFkappaB but not for association with it and that GR can repress an NFkappaB derivative bearing a heterologous activation domain. We used chromatin immunoprecipitation assays in untransfected A549 cells to infer the mechanism by which the tethered GR represses NFkappaB-activated transcription. As expected, we found that the inflammatory signal TNFalpha stimulated preinitiation complex (PIC) assembly at the IL-8 and ICAM-1 promoters and that the largest subunit of RNA polymerase II (pol II) in those complexes became phosphorylated at serines 2 and 5 in its carboxy-terminal domain (CTD) heptapeptide repeats (YSPTSPS); these modifications are required for transcription initiation. Remarkably, GR did not inhibit PIC assembly under repressing conditions, but rather interfered with phosphorylation of serine 2 of the pol II CTD. | The Glucocorticoid Receptor Inhibits |
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0.6808650493621826, "25456": 0.7969439625740051, "25468": 0.5584990978240967, "25526": 0.8332487344741821, "25714": 0.8143964409828186, "25761": 0.004870930220931768, "25778": 0.04207121208310127, "26013": 0.010684899985790253, "26243": 0.08692999184131622, "26402": 1.1005635261535645, "26632": 1.0382318496704102, "26651": 0.14095009863376617, "26835": 0.09495500475168228, "26942": 0.846739649772644, "27144": 0.01934296265244484, "27295": 0.3027053773403168, "27321": 0.5551415085792542, "27781": 0.20580662786960602, "27854": 0.3409265875816345, "28156": 0.1401015669107437, "28309": 0.06246116757392883, "28332": 1.4017986059188843, "28788": 0.15526613593101501, "29109": 0.06429435312747955, "29290": 0.12642613053321838, "29610": 0.0019512200960889459} | 14386505 | Myeloid cells play pivotal roles in chronic inflammatory diseases through their broad proinflammatory, destructive, and remodeling capacities. CD200 is widely expressed on a variety of cell types, while the recently identified CD200R is expressed on myeloid cells and T cells. CD200 deletion in vivo results in myeloid cell dysregulation and enhanced susceptibility to autoimmune inflammation, suggesting that the CD200-CD200R interaction is involved in immune suppression. We demonstrate in this study that CD200R agonists suppress mouse and human myeloid cell function in vitro, and also define a dose relationship between receptor expression and cellular inhibition. IFN-gamma- and IL-17-stimulated cytokine secretion from mouse peritoneal macrophages was inhibited by CD200R engagement. Inhibitory effects were not universal, as LPS-stimulated responses were unaffected. Inhibition of U937 cell cytokine production correlated with CD200R expression levels, and inhibition was only observed in low CD200R expressing cells, if the CD200R agonists were further cross-linked. Tetanus toxoid-induced human PBMC IL-5 and IL-13 secretion was inhibited by CD200R agonists. This inhibition was dependent upon cross-linking the CD200R on monocytes, but not on cross-linking the CD200R on CD4+ T cells. In all, we provide direct evidence that the CD200-CD200R interaction controls monocyte/macrophage function in both murine and human systems, further supporting the potential clinical application of CD200R agonists for the treatment of chronic inflammatory diseases. | Regulation of myeloid cell function through the CD200 receptor. |
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0.056018441915512085, "24757": 0.304147332906723, "24873": 0.40089741349220276, "24978": 0.09761575609445572, "25229": 0.2160874605178833, "25519": 0.5618454217910767, "25714": 0.11865071207284927, "25969": 0.8534175157546997, "26013": 0.12384103983640671, "26236": 0.259204238653183, "26629": 0.04767346754670143, "26835": 0.010684899985790253, "26855": 0.16110190749168396, "26953": 0.6558387279510498, "27152": 0.10731173306703568, "27756": 0.37640097737312317, "27890": 0.15526613593101501, "28321": 0.23864774405956268, "28389": 1.521289587020874, "28466": 0.14095009863376617, "28767": 0.21530038118362427, "29525": 0.7305257320404053} | 14390137 | OBJECTIVE Rates of hepatitis C (HCV) infection, testing, and treatment were compared among patients with schizophrenia, a substance use disorder, or co-occurring schizophrenia or schizoaffective disorder and a substance use disorder and a control group. METHODS Information about 293,445 patients of the Northwest Veterans Healthcare Administration was obtained. RESULTS The substance use disorder group constituted 13.6 percent of the sample; the schizophrenia group, 1.6 percent; and the co-occurring-disorders group, 1.4 percent. Respectively, these groups were approximately four, two, and six times as likely as the control group to receive HCV testing and about seven, two, and eight times as likely to be infected. The rate of interferon (IFN) therapy was significantly lower for the substance use group and the group with co-occurring disorders. However, the magnitude of the differences was not substantial, suggesting that these high-risk groups were not excluded from IFN therapy. | Management of hepatitis C disease among VA patients with schizophrenia and substance use disorders. |
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"26319": 0.16607704758644104, "26453": 0.05139094591140747, "26479": 0.2516399025917053, "26728": 0.32905077934265137, "27293": 0.0058422754518687725, "27322": 0.3903779089450836, "27694": 0.12728634476661682, "27794": 0.129004567861557, "27969": 0.9115922451019287, "28239": 0.6244332790374756, "28298": 0.21922965347766876, "28321": 0.16442140936851501, "28483": 0.732405424118042, "28591": 0.0606246218085289, "29073": 0.37640097737312317, "29101": 0.6573580503463745, "29150": 0.3248254358768463, "29172": 0.04113444685935974, "29234": 0.15526613593101501, "29235": 1.2878543138504028, "29288": 0.08244366943836212, "29299": 0.06612417846918106, "29458": 0.6000806093215942} | 14395738 | Studies from sub-Saharan Africa indicate that children made vulnerable by poverty have been disproportionately affected by HIV with many exposed via mother-to-child transmission. For youth living with HIV, adherence to life-saving treatment regimens are likely to be affected by the complex set of economic and social circumstances that challenge their families and also exacerbate health problems. Using baseline data from the National Institute of Child and Human Development (NICHD) funded Suubi+Adherence study, we examined the extent to which individual and composite measures of equity predict self-reported adherence among Ugandan adolescents aged 10-16 (n = 702) living with HIV. Results showed that greater asset ownership, specifically familial possession of seven or more tangible assets, was associated with greater odds of self-reported adherence (OR 1.69, 95% CI: 1.00-2.85). Our analyses also indicated that distance to the nearest health clinic impacts youth's adherence to an ARV regimen. Youth who reported living nearest to a clinic were significantly more likely to report optimal adherence (OR 1.49, 95% CI: 0.92-2.40). Moreover, applying the composite equity scores, we found that adolescents with greater economic advantage in ownership of household assets, financial savings, and caregiver employment had higher odds of adherence by a factor of 1.70 (95% CI: 1.07-2.70). These findings suggest that interventions addressing economic and social inequities may be beneficial to increase antiretroviral therapy (ART) uptake among economically vulnerable youth, especially in sub-Saharan Africa. This is one of the first studies to address the question of equity in adherence to ART among economically vulnerable youth with HIV. | Equity in adherence to antiretroviral therapy among economically vulnerable adolescents living with HIV in Uganda |
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0.9225212931632996, "29486": 0.27786844968795776, "29516": 0.0058422754518687725} | 14402338 | The pathways that comprise cellular metabolism are highly interconnected, and alterations in individual enzymes can have far-reaching effects. As a result, global profiling methods that measure gene expression are of limited value in predicting how the loss of an individual function will affect the cell. In this work, we employed a new method of global phenotypic profiling to directly define the genes required for the growth of Mycobacterium tuberculosis. A combination of high-density mutagenesis and deep-sequencing was used to characterize the composition of complex mutant libraries exposed to different conditions. This allowed the unambiguous identification of the genes that are essential for Mtb to grow in vitro, and proved to be a significant improvement over previous approaches. To further explore functions that are required for persistence in the host, we defined the pathways necessary for the utilization of cholesterol, a critical carbon source during infection. Few of the genes we identified had previously been implicated in this adaptation by transcriptional profiling, and only a fraction were encoded in the chromosomal region known to encode sterol catabolic functions. These genes comprise an unexpectedly large percentage of those previously shown to be required for bacterial growth in mouse tissue. Thus, this single nutritional change accounts for a significant fraction of the adaption to the host. This work provides the most comprehensive genetic characterization of a sterol catabolic pathway to date, suggests putative roles for uncharacterized virulence genes, and precisely maps genes encoding potential drug targets. | High-Resolution Phenotypic Profiling Defines Genes Essential for Mycobacterial Growth and Cholesterol Catabolism |
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supports synaptic transmission, plasticity, and development. GluN3A (formerly NR3A) is a nonconventional member of the NMDA receptor (NMDAR) subunit family, which endows NMDAR channels with low calcium permeability and reduced magnesium sensitivity compared with NMDARs comprising only GluN1 and GluN2 subunits. Because of these special properties, GluN3A subunits act as a molecular brake to limit the plasticity and maturation of excitatory synapses, pointing toward GluN3A removal as a critical step in the development of neuronal circuitry. However, the molecular signals mediating GluN3A endocytic removal remain unclear. Here we define a novel endocytic motif (YWL), which is located within the cytoplasmic C-terminal tail of GluN3A and mediates its binding to the clathrin adaptor AP2. Alanine mutations within the GluN3A endocytic motif inhibited clathrin-dependent internalization and led to accumulation of GluN3A-containing NMDARs at the cell surface, whereas mimicking phosphorylation of the tyrosine residue promoted internalization and reduced cell-surface expression as shown by immunocytochemical and electrophysiological approaches in recombinant systems and rat neurons in primary culture. We further demonstrate that the tyrosine residue is phosphorylated by Src family kinases, and that Src-activation limits surface GluN3A expression in neurons. Together, our results identify a new molecular signal for GluN3A internalization that couples the functional surface expression of GluN3A-containing receptors to the phosphorylation state of GluN3A subunits, and provides a molecular framework for the regulation of NMDAR subunit composition with implications for synaptic plasticity and neurodevelopment. | Tyrosine phosphorylation regulates the endocytosis and surface expression of GluN3A-containing NMDA receptors. |
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"29235": 0.5220900774002075} | 14407673 | RATIONALE Hemizygous deficiency of the transcription factor Krüppel-like factor 2 (KLF2) has been shown previously to augment atherosclerosis in hypercholesterolemic mice. However, the cell type responsible for the increased atherosclerosis due to KLF2 deficiency has not been identified. This study examined the consequence of myeloid cell-specific KLF2 inactivation in atherosclerosis. METHODS AND RESULTS Cell-specific knockout mice were generated by Cre/loxP recombination. Macrophages isolated from myeloid-specific Klf2 knockout (myeKlf2(-/-)) mice were similar to myeKlf2(+/+) macrophages in response to activation, polarization, and lipid accumulation. However, in comparison to myeKlf2(+/+) macrophages, myeKlf2(-/-) macrophages adhered more robustly to endothelial cells. Neutrophils from myeKlf2(-/-) mice also adhered more robustly to endothelial cells, and fewer myeKlf2(-/-) neutrophils survived in culture over a 24-hour period in comparison with myeKlf2(+/+) neutrophils. When myeKlf2(-/-) mice were mated to Ldlr(-/-) mice and then fed a high fat and high cholesterol diet, significant increase in atherosclerosis was observed in the myeKlf2(-/-)Ldlr(-/-) mice compared with myeKlf2(+/+)Ldlr(-/-) littermates. The increased atherosclerosis in myeKlf2(-/-)Ldlr(-/-) mice was associated with elevated presence of neutrophils and macrophages, with corresponding increase of myeloperoxidase as well as chlorinated and nitrosylated tyrosine epitopes in their lesion areas compared with myeKlf2(+/+)Ldlr(-/-) mice. CONCLUSIONS This study documents a role for myeloid KLF2 expression in modulating atherosclerosis. The increased neutrophil accumulation and atherosclerosis progression with myeloid-specific KLF2 deficiency also underscores the importance of neutrophils in promoting vascular oxidative stress and atherosclerosis. Collectively, these results suggest that elevating KLF2 expression may be a novel strategy for prevention and treatment of atherosclerosis. | Myeloid-specific Krüppel-like factor 2 inactivation increases macrophage and neutrophil adhesion and promotes atherosclerosis. |
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0.14939609169960022, "22955": 0.3084607720375061, "23191": 0.35677260160446167, "23260": 0.1384023278951645, "23446": 1.2381477355957031, "23787": 0.0174254160374403, "23900": 0.678390383720398, "24024": 0.0174254160374403, "24163": 0.5393219590187073, "24479": 0.2711893916130066, "24735": 0.45499902963638306, "25022": 0.5811457633972168, "25481": 0.09761575609445572, "25969": 0.43244171142578125, "26268": 0.31845372915267944, "26445": 0.07068414986133575, "26462": 0.3177432417869568, "26591": 0.15860503911972046, "26629": 0.10467668622732162, "26835": 0.5646255612373352, "26897": 0.20421554148197174, "27152": 0.7809720039367676, "27631": 0.8298473954200745, "28093": 0.17922431230545044, "28436": 0.058784693479537964, "28907": 0.13157635927200317, "29427": 0.755608320236206, "29598": 0.5909284353256226} | 14408200 | CONTEXT Rates of hospital-onset methicillin-resistant Staphylococcus aureus (MRSA) infections are reported as decreasing, but recent rates of community-onset S. aureus infections are less known. OBJECTIVES To characterize the overall and annual incidence rates of community-onset and hospital-onset S. aureus bacteremia and skin and soft tissue infections (SSTIs) in a national health care system and to evaluate trends in the incidence rates of S. aureus bacteremia and SSTIs and the proportion due to MRSA. DESIGN, SETTING, AND PARTICIPANTS Observational study of all Department of Defense TRICARE beneficiaries from January 2005 through December 2010. Medical record databases were used to identify and classify all annual first-positive S. aureus blood and wound or abscess cultures as methicillin-susceptible S. aureus or MRSA, and as community-onset or hospital-onset infections (isolates collected >3 days after hospital admission). MAIN OUTCOME MEASURES Unadjusted incidence rates per 100,000 person-years of observation, the proportion of infections that was due to MRSA, and annual trends for 2005 through 2010 (examined using the Spearman rank correlation test or the Mantel-Haenszel χ2 test for linear trend). RESULTS During 56 million person-years (nonactive duty: 47 million person-years; active duty: 9 million person-years), there were 2643 blood and 80,281 wound or abscess annual first-positive S. aureus cultures. Annual incidence rates varied from 3.6 to 6.0 per 100,000 person-years for S. aureus bacteremia and 122.7 to 168.9 per 100,000 person-years for S. aureus SSTIs. The annual incidence rates for community-onset MRSA bacteremia decreased from 1.7 per 100,000 person-years (95% CI, 1.5-2.0 per 100,000 person-years) in 2005 to 1.2 per 100,000 person-years (95% CI, 0.9-1.4 per 100,000 person-years) in 2010 (P = .005 for trend). The annual incidence rates for hospital-onset MRSA bacteremia also decreased from 0.7 per 100,000 person-years (95% CI, 0.6-0.9 per 100,000 person-years) in 2005 to 0.4 per 100,000 person-years (95% CI, 0.3-0.5 per 100,000 person-years) in 2010 (P = .005 for trend). Concurrently, the proportion of community-onset SSTI due to MRSA peaked at 62% in 2006 before decreasing annually to 52% in 2010 (P < .001 for trend). CONCLUSION In the Department of Defense population consisting of men and women of all ages from across the United States, the rates of both community-onset and hospital-onset MRSA bacteremia decreased in parallel, while the proportion of community-onset SSTIs due to MRSA has more recently declined. | Epidemiology of Staphylococcus aureus blood and skin and soft tissue infections in the US military health system, 2005-2010. |
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"26986": 0.23556606471538544, "27099": 0.02412080205976963, "27166": 0.09584271162748337, "27263": 0.23864774405956268, "27295": 0.14264501631259918, "27391": 1.149384617805481, "27854": 0.319873183965683, "28156": 0.3388410806655884, "28282": 0.10818854719400406, "29170": 0.09850110858678818, "29290": 0.6548244953155518, "29592": 0.09050461649894714} | 14419116 | Whole cell patch-clamp recordings were made from sympathetic preganglionic neurons (SPNs) in the intermediolateral cell column of thoracolumbar spinal cord slices of 12- to 16-day-old rats, and the effects of pituitary adenylate cyclase activating polypeptide (PACAP)-38 on N-methyl-D-aspartate (NMDA)- and kainate (KA)-induced inward currents were examined. PACAP, in concentrations (10-30 nM) that caused no significant change of holding currents, reversibly increased NMDA-induced currents but not KA-induced currents. At higher concentrations (>30 nM), the peptide produced a sustained inward current. The potentiating effect of PACAP was nullified by prior incubation of the slices with the adenylate cyclase inhibitor MDL-12,330A (25 microM). Further, superfusing the slices with the membrane-permeable cyclic AMP analogue N6,2'-O-dibutyryladenosine 3':5'-cyclic monophosphate (100-300 microM) in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (700 microM) increased the NMDA currents. This result suggests that PACAP selectively increases NMDA-receptor-mediated responses in the rat SPNs, probably via a cyclic-AMP-dependent mechanism, providing evidence that the peptide may be involved in synaptic plasticity. | Potentiation of NMDA currents by pituitary adenylate cyclase activating polypeptide in neonatal rat sympathetic preganglionic neurons. |
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"27854": 0.06977381557226181, "28163": 0.22782009840011597, "28327": 0.8433839678764343, "28405": 0.11256109178066254, "28466": 0.38374659419059753, "28487": 0.9302552938461304, "28696": 0.151916041970253, "28767": 1.5058120489120483, "28828": 0.05694137513637543, "29090": 0.012615402229130268, "29222": 0.11865071207284927, "29290": 0.21687394380569458, "29398": 0.07431721687316895, "29516": 0.07793712615966797, "29720": 0.5729197263717651} | 14434123 | AD, a devastating neurodegenerative disorder, is the most common cause of dementia in the elderly. Patients with AD are characterized by three hallmarks of neuropathology including neuritic plaque deposition, neurofibrillary tangle formation, and neuronal loss. Growing evidences indicate that dysregulation of regulator of calcineurin 1 (RCAN1) plays an important role in the pathogenesis of AD. Aberrant RCAN1 expression facilitates neuronal apoptosis and Tau hyperphosphorylation, leading to neuronal loss and neurofibrillary tangle formation. This review aims to describe the recent advances of the regulation of RCAN1 expression and its physiological functions. Moreover, the AD risk factors-induced RCAN1 dysregulation and its role in promoting neuronal loss, synaptic impairments and neurofibrillary tangle formation are summarized. Furthermore, we provide an outlook into the effects of RCAN1 dysregulation on APP processing, Aβ generation and neuritic plaque formation, and the possible underlying mechanisms, as well as the potential of targeting RCAN1 as a new therapeutic approach. | Aberrant Expression of RCAN1 in Alzheimer’s Pathogenesis: A New Molecular Mechanism and a Novel Drug Target |
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When incongruent auditory and visual information is presented concurrently, it can hinder a listener's perception and even cause him or her to perceive information that was not presented in either modality. Efforts to investigate the neural basis of these effects have often focused on the special case of discrete audiovisual syllables that are spatially and temporally congruent, with less work done on the case of natural, continuous speech. Recent electrophysiological studies have demonstrated that cortical response measures to continuous auditory speech can be easily obtained using multivariate analysis methods. Here, we apply such methods to the case of audiovisual speech and, importantly, present a novel framework for indexing multisensory integration in the context of continuous speech. Specifically, we examine how the temporal and contextual congruency of ongoing audiovisual speech affects the cortical encoding of the speech envelope in humans using electroencephalography. We demonstrate that the cortical representation of the speech envelope is enhanced by the presentation of congruent audiovisual speech in noise-free conditions. Furthermore, we show that this is likely attributable to the contribution of neural generators that are not particularly active during unimodal stimulation and that it is most prominent at the temporal scale corresponding to syllabic rate (2-6 Hz). Finally, our data suggest that neural entrainment to the speech envelope is inhibited when the auditory and visual streams are incongruent both temporally and contextually. SIGNIFICANCE STATEMENT Seeing a speaker's face as he or she talks can greatly help in understanding what the speaker is saying. This is because the speaker's facial movements relay information about what the speaker is saying, but also, importantly, when the speaker is saying it. Studying how the brain uses this timing relationship to combine information from continuous auditory and visual speech has traditionally been methodologically difficult. Here we introduce a new approach for doing this using relatively inexpensive and noninvasive scalp recordings. Specifically, we show that the brain's representation of auditory speech is enhanced when the accompanying visual speech signal shares the same timing. Furthermore, we show that this enhancement is most pronounced at a time scale that corresponds to mean syllable length. | Congruent Visual Speech Enhances Cortical Entrainment to Continuous Auditory Speech in Noise-Free Conditions. |
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0.026025565341114998, "23767": 0.5495203733444214, "23934": 0.04767346754670143, "24471": 0.5255602598190308, "24635": 0.8965662121772766, "24674": 1.0655186176300049, "25100": 0.12986256182193756, "25524": 0.026976587250828743, "25562": 0.4926934838294983, "25705": 0.1332872211933136, "26014": 0.04394211992621422, "26228": 0.0038986403960734606, "26296": 0.8450632095336914, "26396": 0.20977331697940826, "26520": 0.12642613053321838, "26874": 0.8039615154266357, "27467": 0.14349138736724854, "27642": 0.4158279001712799, "27790": 0.0770333781838417, "27937": 1.3828705549240112, "27989": 0.09584271162748337, "28024": 0.0770333781838417, "28079": 0.10993985831737518, "29105": 0.9302552938461304, "29109": 0.037378571927547455, "29228": 0.09317722171545029, "29297": 1.1870332956314087, "29489": 0.3963087201118469} | 14446279 | In the yeast Saccharomyces cerevisiae that lacks lamins, the nuclear pore complex (NPC) has been proposed to serve a role in chromatin organization. Here, using fluorescence microscopy in living cells, we show that nuclear pore proteins of the Nup84 core complex, Nup84p, Nup145Cp, Nup120p, and Nup133p, serve to anchor telomere XI-L at the nuclear periphery. The integrity of this complex is shown to be required for repression of a URA3 gene inserted in the subtelomeric region of this chromosome end. Furthermore, altering the integrity of this complex decreases the efficiency of repair of a DNA double-strand break (DSB) only when it is generated in the subtelomeric region, even though the repair machinery is functional. These effects are specific to the Nup84 complex. Our observations thus confirm and extend the role played by the NPC, through the Nup84 complex, in the functional organization of chromatin. They also indicate that anchoring of telomeres is essential for efficient repair of DSBs occurring therein and is important for preserving genome integrity. | Telomere tethering at the nuclear periphery is essential for efficient DNA double strand break repair in subtelomeric region |
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"29101": 0.06246116757392883, "29125": 0.7086513638496399, "29222": 0.20818853378295898, "29516": 0.12986256182193756, "29577": 0.23864774405956268} | 14460402 | The molecular mechanisms that regulate adult neural precursor cell (NPC) survival, and thus maintain adult neurogenesis, are not well defined. Here, we investigate the role of p63, a p53 family member, in adult NPC function in mice. Conditional ablation of p63 in adult NPCs or p63 haploinsufficiency led to reduced numbers of NPCs and newborn neurons in the neurogenic zones of the hippocampus and lateral ventricles and in the olfactory bulb. These reductions were attributable to enhanced apoptosis of NPCs and newborn neurons and were rescued by inhibition of caspase activity, p53, or the p53 apoptotic effector PUMA (p53-upregulated modulator of apoptosis). Moreover, these cellular deficits were functionally important because they led to perturbations in hippocampus-dependent memory formation. These results indicate that p63 regulates the numbers of adult NPCs and adult-born neurons as well as neural stem cell-dependent cognitive functions, and that it does so, at least in part, by inhibiting p53-dependent cell death. | p63 Regulates adult neural precursor and newly born neuron survival to control hippocampal-dependent Behavior. |
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adhesins appear to promote a pathogen's extracellular lifestyle rather than its entry into host cells. However, little is known about the stimuli elicited upon such pathogen host-cell interactions. Here, we report that type IV pili (Tfp)-producing Neisseria gonorrhoeae (P(+)GC) induces an immediate recruitment of caveolin-1 (Cav1) in the host cell, which subsequently prevents bacterial internalization by triggering cytoskeletal rearrangements via downstream phosphotyrosine signaling. A broad and unbiased analysis of potential interaction partners for tyrosine-phosphorylated Cav1 revealed a direct interaction with the Rho-family guanine nucleotide exchange factor Vav2. Both Vav2 and its substrate, the small GTPase RhoA, were found to play a direct role in the Cav1-mediated prevention of bacterial uptake. Our findings, which have been extended to enteropathogenic Escherichia coli, highlight how Tfp-producing bacteria avoid host cell uptake. Further, our data establish a mechanistic link between Cav1 phosphorylation and pathogen-induced cytoskeleton reorganization and advance our understanding of caveolin function. | Tyrosine-Phosphorylated Caveolin-1 Blocks Bacterial Uptake by Inducing Vav2-RhoA-Mediated Cytoskeletal Rearrangements |
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"24576": 1.108330488204956, "24665": 0.09938567131757736, "24949": 0.12642613053321838, "24950": 0.23864774405956268, "25077": 0.15860503911972046, "25202": 0.09584271162748337, "25206": 0.053244512528181076, "25239": 0.16442140936851501, "25352": 1.2910817861557007, "25449": 0.04767346754670143, "25524": 0.812664806842804, "25870": 0.04860413447022438, "25957": 0.08244366943836212, "26001": 0.3077431619167328, "26285": 0.20102575421333313, "26305": 0.16359257698059082, "26601": 0.02792670577764511, "26702": 0.15023678541183472, "26872": 0.8517522215843201, "27142": 0.07884006202220917, "27605": 0.4177590310573578, "27642": 0.15777134895324707, "27694": 0.09672962874174118, "28177": 0.6265231370925903, "28424": 1.301234245300293, "28436": 0.1229778528213501, "29165": 0.0842406153678894, "29172": 0.16359257698059082, "29206": 0.12814582884311676, "29494": 0.10555581003427505} | 14464451 | Next-generation-sequencing (NGS) has revolutionized the field of genome assembly because of its much higher data throughput and much lower cost compared with traditional Sanger sequencing. However, NGS poses new computational challenges to de novo genome assembly. Among the challenges, GC bias in NGS data is known to aggravate genome assembly. However, it is not clear to what extent GC bias affects genome assembly in general. In this work, we conduct a systematic analysis on the effects of GC bias on genome assembly. Our analyses reveal that GC bias only lowers assembly completeness when the degree of GC bias is above a threshold. At a strong GC bias, the assembly fragmentation due to GC bias can be explained by the low coverage of reads in the GC-poor or GC-rich regions of a genome. This effect is observed for all the assemblers under study. Increasing the total amount of NGS data thus rescues the assembly fragmentation because of GC bias. However, the amount of data needed for a full rescue depends on the distribution of GC contents. Both low and high coverage depths due to GC bias lower the accuracy of assembly. These pieces of information provide guidance toward a better de novo genome assembly in the presence of GC bias. | Effects of GC Bias in Next-Generation-Sequencing Data on De Novo Genome Assembly |
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1.0808777809143066, "25714": 0.08603433519601822, "25778": 0.053244512528181076, "26083": 0.08064348995685577, "26236": 0.7163142561912537, "26351": 0.7537717819213867, "26402": 0.8845420479774475, "26534": 0.07159364968538284, "26702": 0.11865071207284927, "26773": 0.04394211992621422, "26775": 0.1401015669107437, "26837": 0.7592713832855225, "26982": 0.1905880719423294, "27144": 0.32270604372024536, "27184": 0.2501201331615448, "27601": 0.04113444685935974, "27673": 0.17020416259765625, "27838": 0.7276995778083801, "27881": 0.3877306580543518, "28156": 0.42608439922332764, "28227": 0.4330752193927765, "28228": 0.7182208299636841, "28314": 0.07159364968538284, "28561": 0.5133614540100098, "28696": 0.2659635543823242, "28848": 0.7276995778083801, "28892": 0.014542185701429844, "29290": 0.41840189695358276, "29458": 0.04487626627087593, "29494": 0.8306987881660461, "29516": 0.13670019805431366, "29610": 0.0029254043474793434} | 14471161 | Circadian disruption accelerates cancer progression, whereas circadian reinforcement could halt it. Mice with P03 pancreatic adenocarcinoma (n = 77) were synchronized and fed ad libitum (AL) or with meal timing (MT) from Zeitgeber time (ZT) 2 to ZT6 with normal or fat diet. Tumor gene expression profiling was determined with DNA microarrays at endogenous circadian time (CT) 4 and CT16. Circadian mRNA expression patterns were determined for clock genes Rev-erbalpha, Per2, and Bmal1, cellular stress genes Hspa8 and Cirbp, and cyclin A2 gene Ccna2 in liver and tumor. The 24-hour patterns in telemetered rest-activity and body temperature and plasma corticosterone and insulin-like growth factor-I (IGF-I) were assessed. We showed that MT inhibited cancer growth by approximately 40% as compared with AL (P = 0.011) irrespective of calorie intake. Clock gene transcription remained arrhythmic in tumors irrespective of feeding schedule or diet. Yet, MT upregulated or downregulated the expression of 423 tumor genes, according to CT. Moreover, 36 genes involved in cellular stress, cell cycle, and metabolism were upregulated at one CT and downregulated 12 h apart. MT induced >10-fold circadian expression of Hspa8, Cirbp, and Ccna2 in tumors. Corticosterone or IGF-I patterns played no role in tumor growth inhibition. In contrast, MT consistently doubled the circadian amplitude of body temperature. Peak and trough respectively corresponded to peak expressions of Hspa8 and Cirbp in tumors. The reinforcement of the host circadian timing system with MT induced 24-hour rhythmic expression of critical genes in clock-deficient tumors, which translated into cancer growth inhibition. Targeting circadian clocks represents a novel potential challenge for cancer therapeutics. | Cancer inhibition through circadian reprogramming of tumor transcriptome with meal timing. |
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"26013": 0.9878844022750854, "26218": 0.13499516248703003, "26266": 0.1485546976327896, "26305": 0.31204116344451904, "26402": 0.255429208278656, "26534": 0.08603433519601822, "26773": 0.010684899985790253, "26835": 0.630689799785614, "26876": 0.9485763907432556, "26986": 0.022212404757738113, "27009": 0.029824240133166313, "27427": 0.4770587682723999, "27441": 0.1384023278951645, "27531": 0.22392450273036957, "27681": 0.176772341132164, "27781": 0.4041621685028076, "28389": 0.5092619061470032, "28487": 0.7276995778083801, "28518": 0.022212404757738113, "28691": 0.11430477350950241, "28756": 0.0029254043474793434, "28788": 0.2394166737794876, "28815": 0.014542185701429844, "28848": 0.38174858689308167, "28873": 0.5540198087692261, "28896": 0.2409527748823166, "29003": 0.055094651877880096, "29107": 0.23092569410800934, "29290": 0.5557019114494324, "29295": 0.24018502235412598, "29720": 0.49626702070236206} | 14474178 | The objective of the present study was to determine if chicken melanoma-differentiation-associated gene 5 (MDA5) senses infectious bursal disease virus infection to induce innate immunity that bridges to adaptive immunity. During IBDV infection in HD11 cells, IBDV titers and RNA loads increased up to 3.4 × 107 plaque-forming units (PFU)/mL and 1114 ng/µL, respectively, at 24 hours postinfection (hpi). IBDV infection in HD11 cells induced significantly upregulated (p < 0.05) expression levels of chicken MDA5 (59-fold), interferon-β (IFN-β) (693-fold), dsRNA-dependent protein kinase (PKR) (4-fold), 2’, 5’-oligoadenylate synthetase (OAS) (286-fold), myxovirus resistance gene (Mx) (22-fold), interleukin-1β (IL-1β) (5-fold), IL-6 (146-fold), IL-8 (4-fold), IL-10 (4-fold), inducible nitric oxide synthase (iNOS) (15-fold), and major histocompatibility complex class I (MHC class I) (4-fold). Nitric oxide production in the culture supernatants increased significantly (p < 0.05) up to 6.5 μM at 24 hpi. The expressed chMDA5 and IBDV-derived dsRNA were localized in the cytoplasm of HD11 cells during IBDV infection. ChMDA5-knockdown HD11 cells had significantly higher (p < 0.05) IBDV RNA loads at 24 hpi and significantly lower (p < 0.05) nitric oxide production and expression levels of chicken MDA5, IFN-β, PKR, OAS, Mx, IL-1β, IL-6, IL-8, IL-12(p40), IL-18, IL-10, iNOS, MHC class I and CD86 at 24 hpi. In addition, chMDA5 overexpression in HD11 cells resulted in significantly reduced (p < 0.05) IBDV titers and RNA loads and significantly increased (p < 0.05) nitric oxide production at 16 and 24 hpi. It also resulted in significantly higher (p < 0.05) expression levels of chicken MDA5, IFN-β, PKR, OAS, Mx, IL-1β, IL-6, IL-8, IL-12(p40), IL-10 and iNOS at 2 hpi. In conclusion, the results indicate that chMDA5 senses IBDV infection in chicken macrophages, and this is associated with IBDV-induced expression of IFN-β and initiation of an innate immune response that in turn activates the adaptive immune response and limits IBDV replication. | Role of chicken melanoma differentiation-associated gene 5 in induction and activation of innate and adaptive immune responses to infectious bursal disease virus in cultured macrophages |
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0.08244366943836212, "29398": 0.9455460906028748, "29458": 0.043007105588912964, "29598": 0.6441128253936768} | 14475235 | Recent evidence demonstrates a role for paternal aging on offspring disease susceptibility. It is well established that various neuropsychiatric disorders (schizophrenia, autism, etc.), trinucleotide expansion associated diseases (myotonic dystrophy, Huntington's, etc.) and even some forms of cancer have increased incidence in the offspring of older fathers. Despite strong epidemiological evidence that these alterations are more common in offspring sired by older fathers, in most cases the mechanisms that drive these processes are unclear. However, it is commonly believed that epigenetics, and specifically DNA methylation alterations, likely play a role. In this study we have investigated the impact of aging on DNA methylation in mature human sperm. Using a methylation array approach we evaluated changes to sperm DNA methylation patterns in 17 fertile donors by comparing the sperm methylome of 2 samples collected from each individual 9-19 years apart. With this design we have identified 139 regions that are significantly and consistently hypomethylated with age and 8 regions that are significantly hypermethylated with age. A representative subset of these alterations have been confirmed in an independent cohort. A total of 117 genes are associated with these regions of methylation alterations (promoter or gene body). Intriguingly, a portion of the age-related changes in sperm DNA methylation are located at genes previously associated with schizophrenia and bipolar disorder. While our data does not establish a causative relationship, it does raise the possibility that the age-associated methylation of the candidate genes that we observe in sperm might contribute to the increased incidence of neuropsychiatric and other disorders in the offspring of older males. However, further study is required to determine whether, and to what extent, a causative relationship exists. | Age-Associated Sperm DNA Methylation Alterations: Possible Implications in Offspring Disease Susceptibility |
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"28290": 0.3034266233444214, "28297": 0.5990082025527954, "28389": 0.25467249751091003, "28696": 0.9115922451019287, "28712": 0.02887592278420925, "28873": 0.19541899859905243, "29300": 0.09406650811433792, "29336": 0.47036975622177124, "29477": 0.7647408246994019, "29486": 0.25088030099868774, "29533": 0.12728634476661682} | 14479433 | Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection. | Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis |
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"28696": 0.007782140281051397, "29107": 0.07250232994556427, "29264": 0.8195732831954956, "29480": 0.4818955361843109} | 14482051 | BACKGROUND Panobinostat is a histone deacetylase inhibitor with antineoplastic and antiangiogenic effects in glioma that may work synergistically with bevacizumab. We conducted a multicenter phase II trial of panobinostat combined with bevacizumab in patients with recurrent high-grade glioma (HGG). METHODS Patients with recurrent HGG were treated with oral panobinostat 30 mg 3 times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. The primary endpoint was a 6-month progression-fee survival (PFS6) rate for participants with recurrent glioblastoma (GBM). Patients with recurrent anaplastic glioma (AG) were evaluated as an exploratory arm of the study. RESULTS At interim analysis, the GBM arm did not meet criteria for continued accrual, and the GBM arm was closed. A total of 24 patients with GBM were accrued prior to closure. The PFS6 rate was 30.4% (95%, CI 12.4%-50.7%), median PFS was 5 months (range, 3-9 months), and median overall survival (OS) was 9 months (range, 6-19 months). Accrual in the AG arm continued to completion, and a total of 15 patients were enrolled. The PFS6 rate was 46.7% (range, 21%-73%), median PFS was 7 months (range, 2-10 months), and median OS was 17 months (range, 5 months-27 months). CONCLUSIONS This phase II study of panobinostat and bevacizumab in participants with recurrent GBM did not meet criteria for continued accrual, and the GBM cohort of the study was closed. Although it was reasonably well tolerated, the addition of panobinostat to bevacizumab did not significantly improve PFS6 compared with historical controls of bevacizumab monotherapy in either cohort. | Phase II study of panobinostat in combination with bevacizumab for recurrent glioblastoma and anaplastic glioma. |
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Using a murine adoptive transfer system to probe monocyte homing and differentiation in vivo, we identified two functional subsets among murine blood monocytes: a short-lived CX(3)CR1(lo)CCR2(+)Gr1(+) subset that is actively recruited to inflamed tissues and a CX(3)CR1(hi)CCR2(-)Gr1(-) subset characterized by CX(3)CR1-dependent recruitment to noninflamed tissues. Both subsets have the potential to differentiate into dendritic cells in vivo. The level of CX(3)CR1 expression also defines the two major human monocyte subsets, the CD14(+)CD16(-) and CD14(lo)CD16(+) monocytes, which share phenotype and homing potential with the mouse subsets. These findings raise the potential for novel therapeutic strategies in inflammatory diseases. | Blood monocytes consist of two principal subsets with distinct migratory properties |
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0.3012613356113434, "26773": 0.1677299439907074, "27099": 0.20022670924663544, "27295": 0.06154331564903259, "27381": 0.5301685929298401, "27711": 0.0797421783208847, "27790": 0.1229778528213501, "27854": 0.24018502235412598, "27895": 0.056018441915512085, "28024": 0.500420093536377, "28086": 1.1610734462738037, "28228": 0.27934664487838745, "29091": 0.0317181795835495, "29145": 0.08513788133859634, "29290": 0.7463917136192322, "29325": 0.09938567131757736, "29489": 0.06337817758321762} | 14492964 | Signals released by the Spemann organizer of the amphibian gastrula can directly induce neural tissue from ectoderm and can dorsalize ventral mesoderm to form muscle. The secreted polypeptide noggin mimics these activities and is expressed at the appropriate time and place to participate in the organizer signal. Neural induction and mesoderm dorsalization are antagonized by bone morphogenetic proteins (BMPs), which induce epidermis and ventral mesoderm instead. Here we report that noggin protein binds BMP4 with high affinity and can abolish BMP4 activity by blocking binding to cognate cell-surface receptors. These data suggest that noggin secreted by the organizer patterns the embryo by interrupting BMP signaling. | The Spemann Organizer Signal noggin Binds and Inactivates Bone Morphogenetic Protein 4 |
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"27099": 0.09672962874174118, "27768": 0.09584271162748337, "27777": 0.0317181795835495, "28297": 0.08782484382390976, "28696": 1.004473328590393, "28964": 0.28597161173820496, "29290": 0.5098485946655273, "29494": 0.5010119676589966} | 14496749 | Oxidative stress influences cell survival and homeostasis, but the mechanisms underlying the biological effects of oxidative stress remain to be elucidated. Here, we demonstrate that the protein kinase MST1 mediates oxidative-stress-induced cell death in primary mammalian neurons by directly activating the FOXO transcription factors. MST1 phosphorylates FOXO proteins at a conserved site within the forkhead domain that disrupts their interaction with 14-3-3 proteins, promotes FOXO nuclear translocation, and thereby induces cell death in neurons. We also extend the MST-FOXO signaling link to nematodes. Knockdown of the C. elegans MST1 ortholog CST-1 shortens life span and accelerates tissue aging, while overexpression of cst-1 promotes life span and delays aging. The cst-1-induced life-span extension occurs in a daf-16-dependent manner. The identification of the FOXO transcription factors as major and evolutionarily conserved targets of MST1 suggests that MST kinases play important roles in diverse biological processes including cellular responses to oxidative stress and longevity. | A Conserved MST-FOXO Signaling Pathway Mediates Oxidative-Stress Responses and Extends Life Span |
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0.4132472574710846} | 14500725 | BACKGROUND The large-scale emigration of physicians from sub-Saharan Africa (SSA) to high-income nations is a serious development concern. Our objective was to determine current emigration trends of SSA physicians found in the physician workforce of the United States. METHODS AND FINDINGS We analyzed physician data from the World Health Organization (WHO) Global Health Workforce Statistics along with graduation and residency data from the 2011 American Medical Association Physician Masterfile (AMA-PM) on physicians trained or born in SSA countries who currently practice in the US. We estimated emigration proportions, year of US entry, years of practice before emigration, and length of time in the US. According to the 2011 AMA-PM, 10,819 physicians were born or trained in 28 SSA countries. Sixty-eight percent (n = 7,370) were SSA-trained, 20% (n = 2,126) were US-trained, and 12% (n = 1,323) were trained outside both SSA and the US. We estimated active physicians (age ≤ 70 years) to represent 96% (n = 10,377) of the total. Migration trends among SSA-trained physicians increased from 2002 to 2011 for all but one principal source country; the exception was South Africa whose physician migration to the US decreased by 8% (-156). The increase in last-decade migration was >50% in Nigeria (+1,113) and Ghana (+243), >100% in Ethiopia (+274), and >200% (+244) in Sudan. Liberia was the most affected by migration to the US with 77% (n = 175) of its estimated physicians in the 2011 AMA-PM. On average, SSA-trained physicians have been in the US for 18 years. They practiced for 6.5 years before US entry, and nearly half emigrated during the implementation years (1984-1999) of the structural adjustment programs. CONCLUSION Physician emigration from SSA to the US is increasing for most SSA source countries. Unless far-reaching policies are implemented by the US and SSA countries, the current emigration trends will persist, and the US will remain a leading destination for SSA physicians emigrating from the continent of greatest need. Please see later in the article for the Editors' Summary. | Physician Emigration from Sub-Saharan Africa to the United States: Analysis of the 2011 AMA Physician Masterfile |
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pathway of tryptophan metabolism is involved in the pathogenesis of several brain diseases, but its physiological functions remain unclear. We report that kynurenic acid, a metabolite in this pathway, functions as a regulator of food-dependent behavioral plasticity in C. elegans. The experience of fasting in C. elegans alters a variety of behaviors, including feeding rate, when food is encountered post-fast. Levels of neurally produced kynurenic acid are depleted by fasting, leading to activation of NMDA-receptor-expressing interneurons and initiation of a neuropeptide-y-like signaling axis that promotes elevated feeding through enhanced serotonin release when animals re-encounter food. Upon refeeding, kynurenic acid levels are eventually replenished, ending the elevated feeding period. Because tryptophan is an essential amino acid, these findings suggest that a physiological role of kynurenic acid is in directly linking metabolism to activity of NMDA and serotonergic circuits, which regulate a broad range of behaviors and physiologies. | Kynurenic Acid Is a Nutritional Cue that Enables Behavioral Plasticity |
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0.32058215141296387, "25700": 0.02316705882549286, "25708": 0.08871890604496002, "25710": 0.8796916007995605, "25714": 0.10731173306703568, "25778": 0.17759032547473907, "26402": 0.401551216840744, "26512": 0.8433839678764343, "26520": 0.17020416259765625, "26524": 0.010684899985790253, "26773": 0.8658194541931152, "26874": 0.13243216276168823, "27556": 0.2089812457561493, "27642": 0.3325583338737488, "27854": 0.15777134895324707, "28024": 0.07250232994556427, "28295": 0.01934296265244484, "28498": 1.0587663650512695, "28696": 0.055094651877880096, "29109": 0.21530038118362427, "29111": 0.04860413447022438, "29278": 0.17922431230545044} | 14530534 | Chromatin insulators are DNA elements that regulate the level of gene expression either by preventing gene silencing through the maintenance of heterochromatin boundaries or by preventing gene activation by blocking interactions between enhancers and promoters. CCCTC-binding factor (CTCF), a ubiquitously expressed 11-zinc-finger DNA-binding protein, is the only protein implicated in the establishment of insulators in vertebrates. While CTCF has been implicated in diverse regulatory functions, CTCF has only been studied in a limited number of cell types across human genome. Thus, it is not clear whether the identified cell type-specific differences in CTCF-binding sites are functionally significant. Here, we identify and characterize cell type-specific and ubiquitous CTCF-binding sites in the human genome across 38 cell types designated by the Encyclopedia of DNA Elements (ENCODE) consortium. These cell type-specific and ubiquitous CTCF-binding sites show uniquely versatile transcriptional functions and characteristic chromatin features. In addition, we confirm the insulator barrier function of CTCF-binding and explore the novel function of CTCF in DNA replication. These results represent a critical step toward the comprehensive and systematic understanding of CTCF-dependent insulators and their versatile roles in the human genome. | Comprehensive Identification and Annotation of Cell Type-Specific and Ubiquitous CTCF-Binding Sites in the Human Genome |
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0.14179791510105133, "26243": 0.13755162060260773, "26351": 0.9546096324920654, "26563": 0.0606246218085289, "26616": 0.03925827145576477, "26677": 0.520350456237793, "26986": 0.02887592278420925, "27011": 0.00875066313892603, "27109": 0.06246116757392883, "27605": 0.890972912311554, "27756": 0.11951763927936554, "27830": 0.4356052577495575, "27952": 0.4126010537147522, "28102": 0.9493325352668762, "28177": 0.4337083101272583, "28228": 0.8989537954330444, "28322": 0.00875066313892603, "28329": 1.1121915578842163, "28442": 0.036437395960092545, "28488": 0.018384648486971855, "28570": 0.0606246218085289, "28767": 0.03266380727291107, "29076": 0.11517547070980072, "29222": 0.16524957120418549, "29577": 0.18004031479358673, "29602": 0.23710809648036957} | 14535322 | Recent experimental studies and theoretical models have begun to address the challenge of establishing a causal link between subjective conscious experience and measurable neuronal activity. The present review focuses on the well-delimited issue of how an external or internal piece of information goes beyond nonconscious processing and gains access to conscious processing, a transition characterized by the existence of a reportable subjective experience. Converging neuroimaging and neurophysiological data, acquired during minimal experimental contrasts between conscious and nonconscious processing, point to objective neural measures of conscious access: late amplification of relevant sensory activity, long-distance cortico-cortical synchronization at beta and gamma frequencies, and "ignition" of a large-scale prefronto-parietal network. We compare these findings to current theoretical models of conscious processing, including the Global Neuronal Workspace (GNW) model according to which conscious access occurs when incoming information is made globally available to multiple brain systems through a network of neurons with long-range axons densely distributed in prefrontal, parieto-temporal, and cingulate cortices. The clinical implications of these results for general anesthesia, coma, vegetative state, and schizophrenia are discussed. | Experimental and Theoretical Approaches to Conscious Processing |
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"25520": 0.1221139207482338, "25644": 0.7546905279159546, "25708": 0.053244512528181076, "25714": 0.05970508232712746, "25761": 0.20580662786960602, "26402": 0.020300358533859253, "26520": 1.1300151348114014, "26524": 0.4419025182723999, "26534": 0.24859806895256042, "26773": 0.5723689198493958, "26944": 0.08692999184131622, "26986": 0.6563454270362854, "27467": 0.07612881064414978, "27854": 0.04953393340110779, "28079": 0.14939609169960022, "28696": 0.10555581003427505, "28848": 0.5838727951049805} | 14541844 | Highly conserved among eukaryotic cells, the AMP-activated kinase (AMPK) is a central regulator of carbon metabolism. To map the complete network of interactions around AMPK in yeast (Snf1) and to evaluate the role of its regulatory subunit Snf4, we measured global mRNA, protein and metabolite levels in wild type, Deltasnf1, Deltasnf4, and Deltasnf1Deltasnf4 knockout strains. Using four newly developed computational tools, including novel DOGMA sub-network analysis, we showed the benefits of three-level ome-data integration to uncover the global Snf1 kinase role in yeast. We for the first time identified Snf1's global regulation on gene and protein expression levels, and showed that yeast Snf1 has a far more extensive function in controlling energy metabolism than reported earlier. Additionally, we identified complementary roles of Snf1 and Snf4. Similar to the function of AMPK in humans, our findings showed that Snf1 is a low-energy checkpoint and that yeast can be used more extensively as a model system for studying the molecular mechanisms underlying the global regulation of AMPK in mammals, failure of which leads to metabolic diseases. | Reconstruction of the yeast Snf1 kinase regulatory network reveals its role as a global energy regulator |
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0.04674193635582924, "26709": 0.25694093108177185, "26773": 0.5849615335464478, "26775": 0.053244512528181076, "26906": 1.3001704216003418, "27768": 0.2026219218969345, "27777": 0.0797421783208847, "27833": 0.08603433519601822, "27854": 1.162295937538147, "28696": 0.043007105588912964, "28767": 0.08692999184131622, "28848": 0.09495500475168228, "28964": 0.4093637466430664, "29158": 0.13414156436920166, "29290": 0.2689530849456787, "29458": 0.03831886500120163, "29514": 0.6877616047859192, "29610": 0.2539152204990387} | 14544564 | Sterol-sensing nuclear receptors and insulin-like growth factor signaling play evolutionarily conserved roles in the control of aging. In the nematode Caenorhabditis elegans, bile acid-like steroid hormones known as dafachronic acids (DAs) influence longevity by binding to and regulating the activity of the conserved nuclear receptor DAF-12, and the insulin receptor (InsR) ortholog DAF-2 controls life span by inhibiting the FoxO transcription factor DAF-16. How the DA/DAF-12 pathway interacts with DAF-2/InsR signaling to control life span is poorly understood. Here we specifically investigated the roles of liganded and unliganded DAF-12 in life span control in the context of reduced DAF-2/InsR signaling. In animals with reduced daf-2/InsR activity, mutations that either reduce DA biosynthesis or fully abrogate DAF-12 activity shorten life span, suggesting that liganded DAF-12 promotes longevity. In animals with reduced DAF-2/InsR activity induced by daf-2/InsR RNAi, both liganded and unliganded DAF-12 promote longevity. However, in daf-2/InsR mutants, liganded and unliganded DAF-12 act in opposition to control life span. Thus, multiple DAF-12 activities influence life span in distinct ways in contexts of reduced DAF-2/InsR signaling. Our findings establish new roles for a conserved steroid signaling pathway in life span control and elucidate interactions among DA biosynthetic pathways, DAF-12, and DAF-2/InsR signaling in aging. | Influence of Steroid Hormone Signaling on Life Span Control by Caenorhabditis elegans Insulin-Like Signaling |
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