343 research outputs found

    Epigenetic silencing of SOCS3 expression contributes to fibrosis in Crohn’s disease

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    Identified risk polymorphisms affecting the Jak-STAT3 pathway in patients with Crohn’s disease could affect TGF-ÎČ1 and collagen I expression and in the pathway’s negative regulator, SOCS3. Genetic factors, however, account for only ~25% of disease. Epigenetic events also shape gene expression. Recent experiments showed that autocrine IL-6 production in mesenchymal cells, subepithelial myofibroblasts (SEMF) and muscle cells, of patients with fibrostenotic Crohn’s disease causes sustained Jak-STAT3 activity, excess TGF-ÎČ1 and Collagen I production and fibrosis. SOCS3 paradoxically decreased in these cells. We now identify epigenetic mechanisms that silence SOCS3 expression in SEMF of patients with fibrostenotic Crohn’s disease. In a previous experiment, using isolated SEMF of normal ileum and affected ileum from patients with each Crohn’s phenotype, inflammatory (Montreal B1), fibrostenotic (B2) and penetrating (B3), we confirmed decreased SOCS3 protein levels were unique to B2 patients. Expression of miR-19b increased in SEMF of affected ileum. SOCS3 transcriptional activity decreased after transfection of miR-19b mimic and increased when antagomiR-19b was expressed. Epigenetic silencing of SOCS3 in ileal SEMF of patients with fibrostenotic Crohn’s disease occurs by increased miR-19b mediated inhibition of SOCS3

    Feature Improvement and Cost Reduction of Baitcasting Fishing Reels for Emerging Markets

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    Baitcasting fishing reels are a challenging product to sell to new users in emerging markets. Their complex and less-than-intuitive design make them poor candidates for a novice fisherman selecting his or her first fishing reel. Based upon manufacturer constraints and design requirements, our team lowered the price point and improved the usability of the Okuma Cerros baitcasting fishing reel to make it more appealing to a wider range of consumers, especially in emerging markets. This project resulted in a three-phase redesign: reducing cost via alternative materials and replacing bearings with bushings; prototyping a simplified cast control system; and proposing an improved user interface

    First draft genome and transcriptome of \u3ci\u3eCercosporidium personatum\u3c/i\u3e, causal agent of late leaf spot disease of peanut

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    Objective Two main fungal leaf spot diseases occur in peanut, namely early leaf spot (ELS) and late leaf spot (LLS), these cause a yearly average of $44 million losses. Limited genetic information, 3534 bp of sequencing, exists about the causal agent of LLS, Cercosporidium personatum (syn. Nothopassalora personata, syn. Phaeoisariopsis personata). The extremely slow growth of this fungus, approximately 1 cm colony in 6 months, and challenges in nucleic acid extractions have hindered research on LLS. Our goal in this work is to provide a reference genome for research on this pathogen. Results Whole genome and transcriptome sequencing of the LLS fungus were obtained. A total of 233,542,110 reads of the genome were de novo assembled resulting in 1061 scaffolds, and estimated genome size 27,597,787 bp. RNA sequencing resulted in 11,848,198 reads that were de novo assembled into 13,343 contigs. Genome annotation resulted in 10,703 putative genes. BUSCO analysis of the genome and annotation resulted in 91.1% and 89.5% completeness, respectively. Phylogenetic dendrograms for 5442 bp and 4401 bp of RNA Polymerase II largest and second largest subunits, and for 5474 bp of the ribosomal RNA cistron of C. personatum are presented in relation to closely related fungi

    Eight Weeks of Kettlebell Swing Training Does Not Improve Sprint Performance in Recreationally Active Females

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    International Journal of Exercise Science 9(4): 437-444, 2016. The kettlebell swing (KBS), emphasizing cyclical, explosive hip extension in the horizontal plane, aligns with movement- and velocity-specificity of sprinting. The present study examined the effect of an eight-week KBS intervention on sprinting in recreationally-active females, in comparison to an eight-week intervention using the stiff-legged deadlift (SDL). Following a pre-testing session measuring 30 meter sprint and countermovement vertical jump performance, participants were divided evenly by sprint time into KBS (n=8) and SDL (n=10) cohorts. Following familiarization with the exercises, KBS met twice weekly to perform swings using the Tabata interval (20s work, 10s rest, 8 rounds), stressing a rapid, explosive tempo. In contrast, the SDL group performed their Tabata stiff-legged deadlifts at a conventional resistance training tempo (2 seconds concentric, 2 seconds eccentric). Following eight weeks and greater than 95% training adherence, the SDL group only had a slightly greater average training volume (~3%) than KBS. No significant differences in pre-test values, or changes were noted in sprint performance from pre- to post-intervention in either group. An improvement in vertical jump performance was noted across groups. Potential explanations for the lack of sprint improvement compared to previous studies include differences between recreationally-active and athletic females, and low exercise volume (~46% of a comparable study with improvements in vertical jump). Future studies should seek to determine the appropriate volume and intensity for KBS components of sprint programming

    Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial.

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    PURPOSE: Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER)-positive metastatic breast cancers include, among others, ER loss and acquired activating mutations in the ligand-binding domain of the ER gene (ESR1LBDm). ESR1 mutational mediated resistance may be overcome by selective ER degraders (SERD). During the first-in-human study of oral SERD AZD9496, early changes in circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) were explored as potential noninvasive tools, alongside paired tumor biopsies, to assess pharmacodynamics and early efficacy. EXPERIMENTAL DESIGN: CTC were enumerated/phenotyped for ER and Ki67 using CellSearch in serial blood draws. ctDNA was assessed for the most common ESR1LBDm by droplet digital PCR (BioRad). RESULTS: Before starting AZD9496, 11 of 43 (25%) patients had ≄5 CTC/7.5 mL whole blood (WB), none of whom underwent reduction to <5 CTC/7.5 mL WB on C1D15. Five of 11 patients had baseline CTC-ER+, two of whom had CTC-ER+ reduction. CTC-Ki67 status did not change appreciably. Patients with ≄5 CTC/7.5 mL WB before treatment had worse progression-free survival (PFS) than patients with <5 CTC (P = 0.0003). Fourteen of 45 (31%) patients had ESR1LBDm + ctDNA at baseline, five of whom had ≄2 unique mutations. Baseline ESR1LBDm status was not prognostic. Patients with persistently elevated CTC and/or ESR1LBDm + ctDNA at C1D15 had worse PFS than patients who did not (P = 0.0007). CONCLUSIONS: Elevated CTC at baseline was a strong prognostic factor in this cohort. Early on-treatment changes were observed in CTC-ER+ and ESR1LBDm + ctDNA, but not in overall CTC number. Integrating multiple biomarkers in prospective trials may improve outcome prediction and ET resistance mechanisms' identification over a single biomarker

    LSST: from Science Drivers to Reference Design and Anticipated Data Products

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    (Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg2^2 field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5σ\sigma point-source depth in a single visit in rr will be ∌24.5\sim 24.5 (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg2^2 with ÎŽ<+34.5∘\delta<+34.5^\circ, and will be imaged multiple times in six bands, ugrizyugrizy, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg2^2 region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to r∌27.5r\sim27.5. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie
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