1,734 research outputs found

    Negative Feedback Regulation of the Yeast Cth1 and Cth2 mRNA Binding Proteins Is Required for Adaptation to Iron Deficiency and Iron Supplementation

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    Iron (Fe) is an essential element for all eukaryotic organisms because it functions as a cofactor in a wide range of biochemical processes. Cells have developed sophisticated mechanisms to tightly control Fe utilization in response to alterations in cellular demands and bioavailability. In response to Fe deficiency, the yeast Saccharomyces cerevisiae activates transcription of the CTH1 and CTH2 genes, which encode proteins that bind to AU-rich elements (AREs) within the 3′ untranslated regions (3′UTRs) of many mRNAs, leading to metabolic reprogramming of Fe-dependent pathways and decreased Fe storage. The precise mechanisms underlying Cth1 and Cth2 function and regulation are incompletely understood. We report here that the Cth1 and Cth2 proteins specifically bind in vivo to AREs located at the 3′UTRs of their own transcripts in an auto- and cross-regulated mechanism that limits their expression. By mutagenesis of the AREs within the CTH2 transcript, we demonstrate that a Cth2 negative-feedback loop is required for the efficient decline in Cth2 protein levels observed upon a rapid rise in Fe availability. Importantly, Cth2 autoregulation is critical for the appropriate recovery of Fe-dependent processes and resumption of growth in response to a change from Fe deficiency to Fe supplementation

    Oral chondroitin sulfate and prebiotics for the treatment of canine Inflammatory Bowel Disease: a randomized, controlled clinical trial

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    BACKGROUND Canine inflammatory bowel disease (IBD) is a chronic enteropathy of unknown etiology, although microbiome dysbiosis, genetic susceptibility, and dietary and/or environmental factors are hypothesized to be involved in its pathogenesis. Since some of the current therapies are associated with severe side effects, novel therapeutic modalities are needed. A new oral supplement for long-term management of canine IBD containing chondroitin sulfate (CS) and prebiotics (resistant starch, β-glucans and mannaoligosaccharides) was developed to target intestinal inflammation and oxidative stress, and restore normobiosis, without exhibiting any side effects. This double-blinded, randomized, placebo-controlled trial in dogs with IBD aims to evaluate the effects of 180 days administration of this supplement together with a hydrolyzed diet on clinical signs, intestinal histology, gut microbiota, and serum biomarkers of inflammation and oxidative stress. RESULTS Twenty-seven client-owned biopsy-confirmed IBD dogs were included in the study, switched to the same hydrolyzed diet and classified into one of two groups: supplement and placebo. Initially, there were no significant differences between groups (p > 0.05) for any of the studied parameters. Final data analysis (supplement: n = 9; placebo: n = 10) showed a significant decrease in canine IBD activity index (CIBDAI) score in both groups after treatment (p < 0.001). After treatment, a significant decrease (1.53-fold; p < 0.01) in histologic score was seen only in the supplement group. When groups were compared, the supplement group showed significantly higher serum cholesterol (p < 0.05) and paraoxonase-1 (PON1) levels after 60 days of treatment (p < 0.01), and the placebo group showed significantly reduced serum total antioxidant capacity (TAC) levels after 120 days (p < 0.05). No significant differences were found between groups at any time point for CIBDAI, WSAVA histologic score and fecal microbiota evaluated by PCR-restriction fragment length polymorphism (PCR-RFLP). No side effects were reported in any group. CONCLUSIONS The combined administration of the supplement with hydrolyzed diet over 180 days was safe and induced improvements in selected serum biomarkers, possibly suggesting a reduction in disease activity. This study was likely underpowered, therefore larger studies are warranted in order to demonstrate a supplemental effect to dietary treatment of this supplement on intestinal histology and CIBDAI

    Phenotypic, transcriptomic, and genomic features of clonal plasma cells in light-chain amyloidosis

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    Immunoglobulin light-chain amyloidosis (AL) and multiple myeloma (MM) are 2 distinct monoclonal gammopathies that involve the same cellular compartment: clonal plasma cells (PCs). Despite the fact that knowledge about MM PC biology has significantly increased in the last decade, the same does not apply for AL. Here, we used an integrative phenotypic, molecular, and genomic approach to study clonal PCs from 24 newly diagnosed patients with AL. Through principal-component-analysis, we demonstrated highly overlapping phenotypic profiles between AL and both monoclonal gammopathy of undetermined significance and MM PCs. However, in contrast to MM, highly purified fluorescence-activated cell-sorted clonal PCs from AL (n = 9) showed almost normal transcriptome, with only 38 deregulated genes vs normal PCs; these included a few tumor-suppressor (CDH1, RCAN) and proapoptotic (GLIPR1, FAS) genes. Notwithstanding, clonal PCs in AL (n=11) were genomically unstable, with a median of 9 copy number alterations (CNAs) per case, many of such CNAs being similar to those found in MM. Whole-exome sequencing (WES) performed in 5 AL patients revealed a median of 15 nonrecurrent mutations per case. Altogether, our results show that in the absence of a unifying mutation by WES, clonal PCs in AL display phenotypic and CNA profiles similar to MM, but their transcriptome is remarkably similar to that of normal PCs

    Differential branching fraction and angular analysis of the decay B0→K∗0μ+μ−

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    The angular distribution and differential branching fraction of the decay B 0→ K ∗0 μ + μ − are studied using a data sample, collected by the LHCb experiment in pp collisions at s√=7 TeV, corresponding to an integrated luminosity of 1.0 fb−1. Several angular observables are measured in bins of the dimuon invariant mass squared, q 2. A first measurement of the zero-crossing point of the forward-backward asymmetry of the dimuon system is also presented. The zero-crossing point is measured to be q20=4.9±0.9GeV2/c4 , where the uncertainty is the sum of statistical and systematic uncertainties. The results are consistent with the Standard Model predictions

    Study of WW boson production in association with beauty and charm

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    The associated production of a WW boson with a jet originating from either a light parton or heavy-flavor quark is studied in the forward region using proton-proton collisions. The analysis uses data corresponding to integrated luminosities of 1.0 and 2.0fb12.0\,{\rm fb}^{-1} collected with the LHCb detector at center-of-mass energies of 7 and 8 TeV, respectively. The WW bosons are reconstructed using the WμνW\to\mu\nu decay and muons with a transverse momentum, pTp_{\rm T}, larger than 20 GeV in the pseudorapidity range 2.0202.0 20 GeV and 2.2<η<4.22.2 < \eta < 4.2. The sum of the muon and jet momenta must satisfy pT>20p_{\rm T} > 20 GeV. The fraction of W+W+jet events that originate from beauty and charm quarks is measured, along with the charge asymmetries of the W ⁣+ ⁣bW\!+\!b and W ⁣+ ⁣cW\!+\!c production cross-sections. The ratio of the W+W+jet to Z+Z+jet production cross-sections is also measured using the ZμμZ\to\mu\mu decay. All results are in agreement with Standard Model predictions

    Study of BDKπ+πB^{-}\to DK^-\pi^+\pi^- and BDππ+πB^-\to D\pi^-\pi^+\pi^- decays and determination of the CKM angle γ\gamma

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    We report a study of the suppressed BDKπ+πB^-\to DK^-\pi^+\pi^- and favored BDππ+πB^-\to D\pi^-\pi^+\pi^- decays, where the neutral DD meson is detected through its decays to the Kπ±K^{\mp}\pi^{\pm} and CP-even K+KK^+K^- and π+π\pi^+\pi^- final states. The measurement is carried out using a proton-proton collision data sample collected by the LHCb experiment, corresponding to an integrated luminosity of 3.0~fb1^{-1}. We observe the first significant signals in the CP-even final states of the DD meson for both the suppressed BDKπ+πB^-\to DK^-\pi^+\pi^- and favored BDππ+πB^-\to D\pi^-\pi^+\pi^- modes, as well as in the doubly Cabibbo-suppressed DK+πD\to K^+\pi^- final state of the BDππ+πB^-\to D\pi^-\pi^+\pi^- decay. Evidence for the ADS suppressed decay BDKπ+πB^{-}\to DK^-\pi^+\pi^-, with DK+πD\to K^+\pi^-, is also presented. From the observed yields in the BDKπ+πB^-\to DK^-\pi^+\pi^-, BDππ+πB^-\to D\pi^-\pi^+\pi^- and their charge conjugate decay modes, we measure the value of the weak phase to be γ=(7419+20)o\gamma=(74^{+20}_{-19})^{\rm o}. This is one of the most precise single-measurement determinations of γ\gamma to date.Comment: 22 pages, 9 figures; All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2015-020.htm

    Search for hidden-sector bosons in B0 ⁣K0μ+μB^0 \!\to K^{*0}\mu^+\mu^- decays

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    A search is presented for hidden-sector bosons, χ\chi, produced in the decay B0 ⁣K(892)0χ{B^0\!\to K^*(892)^0\chi}, with K(892)0 ⁣K+πK^*(892)^0\!\to K^{+}\pi^{-} and χ ⁣μ+μ\chi\!\to\mu^+\mu^-. The search is performed using pppp-collision data corresponding to 3.0 fb1^{-1} collected with the LHCb detector. No significant signal is observed in the accessible mass range 214m(χ)4350214 \leq m({\chi}) \leq 4350 MeV, and upper limits are placed on the branching fraction product B(B0 ⁣K(892)0χ)×B(χ ⁣μ+μ)\mathcal{B}(B^0\!\to K^*(892)^0\chi)\times\mathcal{B}(\chi\!\to\mu^+\mu^-) as a function of the mass and lifetime of the χ\chi boson. These limits are of the order of 10910^{-9} for χ\chi lifetimes less than 100 ps over most of the m(χ)m(\chi) range, and place the most stringent constraints to date on many theories that predict the existence of additional low-mass bosons.Comment: All figures and tables, along with supplementary material, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2015-036.htm

    Observation of J/ψpJ/\psi p resonances consistent with pentaquark states in Λb0J/ψKp{\Lambda_b^0\to J/\psi K^-p} decays

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    Observations of exotic structures in the J/ψpJ/\psi p channel, that we refer to as pentaquark-charmonium states, in Λb0J/ψKp\Lambda_b^0\to J/\psi K^- p decays are presented. The data sample corresponds to an integrated luminosity of 3/fb acquired with the LHCb detector from 7 and 8 TeV pp collisions. An amplitude analysis is performed on the three-body final-state that reproduces the two-body mass and angular distributions. To obtain a satisfactory fit of the structures seen in the J/ψpJ/\psi p mass spectrum, it is necessary to include two Breit-Wigner amplitudes that each describe a resonant state. The significance of each of these resonances is more than 9 standard deviations. One has a mass of 4380±8±294380\pm 8\pm 29 MeV and a width of 205±18±86205\pm 18\pm 86 MeV, while the second is narrower, with a mass of 4449.8±1.7±2.54449.8\pm 1.7\pm 2.5 MeV and a width of 39±5±1939\pm 5\pm 19 MeV. The preferred JPJ^P assignments are of opposite parity, with one state having spin 3/2 and the other 5/2.Comment: 48 pages, 18 figures including the supplementary material, v2 after referee's comments, now 19 figure

    Measurement of the branching fraction ratio B(Bc+ψ(2S)π+)/B(Bc+J/ψπ+)\mathcal{B}(B_c^+ \rightarrow \psi(2S)\pi^+)/\mathcal{B}(B_c^+ \rightarrow J/\psi \pi^+)

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    Using pppp collision data collected by LHCb at center-of-mass energies s\sqrt{s} = 7 TeV and 8 TeV, corresponding to an integrated luminosity of 3 fb1^{-1}, the ratio of the branching fraction of the Bc+ψ(2S)π+B_c^+ \rightarrow \psi(2S)\pi^+ decay relative to that of the Bc+J/ψπ+B_c^+ \rightarrow J/\psi\pi^+ decay is measured to be 0.268 ±\pm 0.032 (stat) ±\pm 0.007 (syst) ±\pm 0.006 (BF). The first uncertainty is statistical, the second is systematic, and the third is due to the uncertainties on the branching fractions of the J/ψμ+μJ/\psi \rightarrow \mu^+\mu^- and ψ(2S)μ+μ\psi(2S) \rightarrow \mu^+\mu^- decays. This measurement is consistent with the previous LHCb result, and the statistical uncertainty is halved.Comment: 17 pages including author list, 2 figure
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