The rockefeller university

Long non-coding RNAs (lncRNAs) have recently been found to widely exist in eukaryotes and play important roles in key biological processes. To extend our knowledge of lncRNAs in crop plants we performed both non-directional and strand-specific RNA-sequencing experiments to profile non-coding transcriptomes of various rice and maize organs at different developmental stages. Analysis of more than 3 billion reads identified 22334 long intergenic non-coding RNAs (lincRNAs) and 6673 pairs of sense and natural antisense transcript (NAT). Many lincRNA genes were associated with epigenetic marks. Expression of rice lincRNA genes was significantly correlated with that of nearby protein-coding genes. A set of NAT genes also showed expression correlation with their sense genes. More than 200 rice lincRNA genes had homologous non-coding sequences in the maize genome. Much more lincRNA and NAT genes were derived from conserved genomic regions between the two cereals presenting positional conservation. Protein-coding genes flanking or having a sense-antisense relationship to these conserved lncRNA genes were mainly involved in development and stress responses, suggesting that the associated lncRNAs might have similar functions. Integrating previous genome-wide association studies (GWAS), we found that hundreds of lincRNAs contain trait-associated SNPs (single nucleotide polymorphisms [SNPs]) suggesting their putative contributions to developmental and agriculture traits. Significance Statement Long noncoding RNAs (lncRNAs) play key roles in numerous biological processes. Here we sequenced and characterized lncRNAs from many rice and maize tissues.Hundreds of the lncRNAs have single nucleotide polymorphisms associated with agricultural traits, suggesting that they may play roles in controlling such traits.

Constraints on the lifetime and width of the Higgs boson are obtained from H -> ZZ -> 4l events using data recorded by the CMS experiment during the LHC run 1 with an integrated luminosity of 5.1 and 19.7 fb(-1) at a center-of-mass energy of 7 and 8 TeV, respectively. The measurement of the Higgs boson lifetime is derived from its flight distance in the CMS detector with an upper bound of tau(H) < 1.9 x 10(-13) s at the 95% confidence level (C.L.), corresponding to a lower bound on the width of Gamma(H) > 3.5 x 10(-9) MeV. The measurement of the width is obtained from an off-shell production technique, generalized to include anomalous couplings of the Higgs boson to two electroweak bosons. From this measurement, a joint constraint is set on the Higgs boson width and a parameter f(Lambda Q) that expresses an anomalous coupling contribution as an on-shell cross-section fraction. The limit on the Higgs boson width is Gamma(H) < 46 MeV with f(Lambda Q) unconstrained and Gamma(H) < 26 MeV for f(Lambda Q) = 0 at the 95% C.L. The constraint f(Lambda Q) < 3.8 x 10(-3) at the 95% C.L. is obtained for the expected standard model Higgs boson width.

Objective The natural course of chronic hepatitis C varies widely. To improve the profiling of patients at risk of developing advanced liver disease, we assessed the relative contribution of factors for liver fibrosis progression in hepatitis C. Design We analysed 1461 patients with chronic hepatitis C with an estimated date of infection and at least one liver biopsy. Risk factors for accelerated fibrosis progression rate (FPR), defined as >= 0.13 Metavir fibrosis units per year, were identified by logistic regression. Examined factors included age at infection, sex, route of infection, HCV genotype, body mass index (BMI), significant alcohol drinking (>= 20 g/day for >= 5 years), HIV coinfection and diabetes. In a subgroup of 575 patients, we assessed the impact of single nucleotide polymorphisms previously associated with fibrosis progression in genome-wide association studies. Results were expressed as attributable fraction (AF) of risk for accelerated FPR. Results Age at infection (AF 28.7%), sex (AF 8.2%), route of infection (AF 16.5%) and HCV genotype (AF 7.9%) contributed to accelerated FPR in the Swiss Hepatitis C Cohort Study, whereas significant alcohol drinking, anti-HIV, diabetes and BMI did not. In genotyped patients, variants at rs9380516 (TULP1), rs738409 (PNPLA3), rs4374383 (MERTK) (AF 19.2%) and rs910049 (major histocompatibility complex region) significantly added to the risk of accelerated FPR. Results were replicated in three additional independent cohorts, and a meta-analysis confirmed the role of age at infection, sex, route of infection, HCV genotype, rs738409, rs4374383 and rs910049 in accelerating FPR. Conclusions Most factors accelerating liver fibrosis progression in chronic hepatitis C are unmodifiable.

Ectopic calcification is associated with various human diseases, including atherosclerosis, cancer, chronic kidney disease, and diabetes mellitus. Although mineral nanoparticles have been detected in calcified blood vessels, the nature and role of these particles in the human body remain unclear. Here we show for the first time that human kidney tissues obtained from end-stage chronic kidney disease or renal cancer patients contain round, multilamellar mineral particles of 50 to 1,500 nm, whereas no particles are observed in healthy controls. The mineral particles are found mainly in the extracellular matrix surrounding the convoluted tubules, collecting ducts and loops of Henle as well as within the cytoplasm of tubule-delineating cells, and consist of polycrystalline calcium phosphate similar to the mineral found in bones and ectopic calcifications. The kidney mineral nanoparticles contain several serum proteins that inhibit ectopic calcification in body fluids, including albumin, fetuin-A, and apolipoprotein A1. Since the mineralo-organic nanoparticles are found not only within calcified deposits but also in areas devoid of microscopic calcifications, our observations indicate that the nanoparticles may represent precursors of calcification and renal stones in humans.

Protein noise measurements are increasingly used to elucidate biophysical parameters. Unfortunately noise analyses are often at odds with directly measured parameters. Here we show that these inconsistencies arise from two problematic analytical choices: (i) the assumption that protein translation rate is invariant for different proteins of different abundances, which has inadvertently led to (ii) the assumption that a large constitutive extrinsic noise sets the low noise limit in gene expression. While growing evidence suggests that transcriptional bursting may set the low noise limit, variability in translational bursting has been largely ignored. We show that genome-wide systematic variation in translational efficiency can-and in the case of E. coli does-control the low noise limit in gene expression. Therefore constitutive extrinsic noise is small and only plays a role in the absence of a systematic variation in translational efficiency. These results show the existence of two distinct expression noise patterns: (1) a global noise floor uniformly imposed on all genes by expression bursting; and (2) high noise distributed to only a select group of genes.

Different dendritic cell (DC) subsets co-exist in humans and coordinate the immune response. Having a short life, DCs must be constantly replenished from their progenitors in the bone marrow through hematopoiesis. Identification of a DC-restricted progenitor in mouse has improved our understanding of how DC lineage diverges from myeloid and lymphoid lineages. However, identification of the DC-restricted progenitor in humans has not been possible because a system that simultaneously nurtures differentiation of human DCs, myeloid and lymphoid cells, is lacking. Here we report a cytokine and stromal cell culture that allows evaluation of CD34(+) progenitor potential to all three DC subsets as well as other myeloid and lymphoid cells, at a single cell level. Using this system, we show that human granulocyte macrophage progenitors are heterogeneous and contain restricted progenitors to DCs. (C) 2015 Published by Elsevier B.V.

Background: CCR5-using (r5) HIV-1 predominates during asymptomatic disease followed by occasional emergence of CXCR4-using (x4) or dual tropic (r5x4) virus. We examined the contribution of the x4 and r5 components to replicative fitness of HIV-1 isolates. Methods: Dual tropic r5x4 viruses were predicted from average HIV-1 env sequences of two primary subtype C HIV-1 isolates (C19 and C27) and from two patient plasma samples (B12 and B19). Chimeric Env viruses with an NL4-3 backbone were constructed from the B12 and B19 env sequences. To determine replicative fitness, these primary and chimeric dual tropic HIV-1 were then competed against HIV-1 reference isolates in U87. CD4 cells expressing CXCR4 or CCR5 or in PBMCs +/- entry inhibitors. Contribution of the x4 and r5 clones within the quasispecies of these chimeric or primary HIV-1 isolates were then compared to the frequency of x4, r5, and dual tropic clones within the quasispecies as predicted by phenotypic assays, clonal sequencing, and 454 deep sequencing. Results: In the primary HIV-1 isolates (C19 and C27), subtype C dual tropic clones dominated over x4 clones while pure r5 clones were absent. In two subtype B chimeric viruses (B12 and B19), r5 clones were > 100-fold more abundant than x4 or r5/x4 clones. The dual tropic C19 and C27 HIV-1 isolates outcompeted r5 primary HIV-1 isolates, B2 and C3 in PBMCs. When AMD3100 was added or when only U87. CD4. CCR5 cells were used, the B2 and C3 reference viruses now out-competed the r5 component of the dual tropic C19 and C27. In contrast, the same replicative fitness was observed with dualtropic B12 and B19 HIV-1 isolates relative to x4 HIV-1 A8 and E6 or the r5 B2 and C3 viruses, even when the r5 or x4 component was inhibited by maraviroc (or AMD3100) or in U87. CD4. CXCR4 (or CCR5) cells. Conclusions: In the dual tropic HIV-1 isolates, the x4 replicative fitness is higher than r5 clones but the x4 or x4/r5 clones are typically at low frequency in the intrapatient virus population. Ex vivo HIV propagation promotes outgrowth of the x4 clones and provides an over-estimate of x4 dominance in replicative fitness within dual tropic viruses.

Neuroinflammation is the response of the central nervous system (CNS) to disturbed homeostasis and typifies all neurological diseases. The main reactive components of the CNS include microglial cells and infiltrating myeloid cells, astrocytes, oligodendrocytes, and the blood-brain barrier, cytokines, and cytokine signaling. Neuroinflammatory responses may be helpful or harmful, as mechanisms associated with neuroinflammation are involved in normal brain development, as well as in neuropathological processes. This review examines the roles of various cell types that contribute to the immune dysregulation associated with neuroinflammation. Microglia enter the CNS very early in embryonic development and, as such, play an essential role in both the healthy and diseased brain. B-cell diversity contributes to CNS disease through both antibody-dependent and antibody-independent mechanisms. The influences of these B-cell mechanisms on other cell types, including myeloid cells and T cells, are reviewed in relationship to antibody-mediated CNS disorders, paraneoplastic neurological diseases, and multiple sclerosis. New insights into neuroinflammation offer exciting opportunities to investigate potential therapeutic targets for debilitating CNS diseases.

A model-independent search for a narrow resonance produced in proton-proton collisions at root s= 8TeV and decaying to a pair of 125GeV Higgs bosons that in turn each decays into a bottom quark-antiquark pair is performed by the CMS experiment at the LHC. The analyzed data correspond to an integrated luminosity of 17.9fb(-1). No evidence for a signal is observed. Upper limits at a 95% confidence level on the production cross section for such a resonance, in the mass range from 270 to 1100 GeV, are reported. Using these results, a radion with decay constant of 1 TeV and mass from 300 to 1100 GeV, and a Kaluza-Klein graviton with mass from 380 to 830 GeV are excluded at a 95% confidence level. (C) 2015 CERN for the benefit of the CMS Collaboration. Published by Elsevier B.V.

MicroRNAs play a crucial role in the regulation of cell growth and differentiation. Mice with genetic deletion of miR-375 exhibit impaired glycemic control due to decreased beta-cell and increased a-cell mass and function. The relative importance of these processes for the overall phenotype of miR375K0 mice is unknown. Here, we show that mice overexpressing miR-375 exhibit noinial beta-cell mass and function. Selective re-expression of miR-375 in beta-cells of miR375K0 mice normalizes both, alpha- and 1 beta-cell phenotypes as well as glucose metabolism. Using this model, we also analyzed the contribution of beta-cells to the total plasma miR-375 levels. Only a small proportion z1 A) of circulating miR-375 originates from beta-cells. Furthermore, acute and profound 3cell destruction is sufficient to detect elevations of miR-375 levels in the blood. These findings are supported by higher miR-375 levels in the circulation of type I diabetes TI D) subjects but not mature onset diabetes of the young MODY) and type 2 diabetes T2D) patients. Together, our data support an essential role for miR-375 in the maintenance of beta-cell mass and provide in vivo evidence for release of miRNAs from pancreatic beta-cells. The small contribution of beta-cells to total plasma miR-375 levels make this miRNA an unlikely biomarker for beta-cell function but suggests a utility for the detection of acute beta-cell death for autoimmune diabetes.