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  • Gold Mullins posted an update 1 week, 3 days ago

    ith additional anti-fibrillatory effect beyond adrenergic blockade during sympatho-vagal stimulations. Occupational exposure to silica dust particles was the major cause of pulmonary fibrosis, and many miRNAs have been demonstrated to regulate target mRNAs in silicosis. In the present study, we found that a decreasing level of miR-411-3p in silicosis rats and lung fibroblasts induced by TGF-β1. Enlargement of miR-411-3p could inhibit the cell proliferation and migration in lung fibroblasts with TGF-β1 treatment and attenuate lung fibrosis in silicotic mice. In addition, a mechanistic study showed that miR-411-3p exert its inhibitory effect on Smad ubiquitination regulatory factor 2 (Smurf2) expression and decrease ubiquitination degradation of Smad7 regulated by smurf2, result in blocking of TGF-β/Smad signaling. We proposed that increased expression of miR-411-3p abrogates silicosis by blocking activation of TGF-β/Smad signaling through decreasing ubiquitination degradation effect of smurf2 on Smad7. BACKGROUND Deaths from prescription opioid overdose are dramatically increasing. This study evaluates the incidence, risk factors, and cost of new persistent opioid use after aortic valve replacement (AVR), mitral valve replacement (MVR), and mitral valve repair (MVr). METHODS Insurance claims from commercially insured patients who underwent AVR, MVR, MVr, or AVR and MVR/r from 2014 to 2016 were evaluated. New persistent opioid use was defined as opioid-naïve patients who filled an opioid prescription in the perioperative period and filled opioid prescriptions between 90 and 180 days postoperatively. Multivariable logistic regression identified risk factors for new persistent opioid use. Quantile regression evaluated the impact of new persistent opioid use on total health care payments in the 6 months after discharge. RESULTS Among 3,404 opioid-naïve patients undergoing AVR, MVR or MVr, 188 (5.5%) had new persistent opioid use. Living in the Southern United States (OR 1.89, CI 1.35-2.63, p less then 0.001) and increased opioids prescribed in the perioperative period (OR 1.009, CI 1.006-1.012, p less then 0.001) were independently associated with new persistent opioid use. After risk adjustment, new persistent opioid use was associated with a two-fold higher number of emergency department visits (OR 2.21, CI 1.61-3.03, p less then 0.001) and a $5,422 increase in health care payments in the 6 months after discharge. CONCLUSIONS New persistent opioid use is a significant and costly complication after aortic and mitral valve surgery in privately insured patients. Variation in regional susceptibility and opioid prescribing suggests that standardization may help prevent this complication. Rabies virus (RABV), the etiological agent for the lethal disease of rabies, is a deadly zoonotic pathogen. The RABV glycoprotein (RABV-G) is a key factor mediating virus entry and the major target of neutralizing antibodies. Here, we report the crystal structures of RABV-G solved in the free form at ∼pH-8.0 and in the complex form with a neutralizing antibody 523-11 at ∼pH-6.5, respectively. RABV-G has three domains, and the basic-to-acidic pH change results in large domain re-orientations and concomitant domain-linker re-constructions, switching it from a bent hairpin conformation into an extended conformation. During such low-pH-induced structural transitions, residues located in the domain-linker are found to play important roles in glycoprotein-mediated membrane fusion. Finally, the antibody interacts with RABV-G mainly through its heavy chain and binds to a bipartite conformational epitope in the viral protein for neutralization. These structures provide valuable information for vaccine and drug design.Dietary fibers (DFs) impact the gut microbiome in ways often considered beneficial. However, it is unknown if precise and predictable manipulations of the gut microbiota, and especially its metabolic activity, can be achieved through DFs with discrete chemical structures. Using a dose-response trial with three type-IV resistant starches (RS4s) in healthy humans, we found that crystalline and phosphate cross-linked starch structures induce divergent and highly specific effects on microbiome composition that are linked to directed shifts in the output of either propionate or butyrate. The dominant RS4-induced effects were remarkably consistent within treatment groups, dose-dependent plateauing at 35 g/day, and can be explained by substrate-specific binding and utilization of the RS4s by bacterial taxa with different pathways for starch metabolism. Overall, these findings support the potential of using discrete DF structures to achieve targeted manipulations of the gut microbiome and its metabolic functions relevant to health. BACKGROUND Screen viewing is a sedentary behaviour reported to interfere with sleep and physical activity. However, few longitudinal studies have assessed such associations in children of preschool age (0-6 years) and none have accounted for the compositional nature of these behaviours. We aimed to investigate the associations between total and device-specific screen viewing time at age 2-3 years and accelerometer-measured 24 h movement behaviours, including sleep, sedentary behaviour, light physical activity, and moderate-to-vigorous physical activity (MVPA) at age 5·5 years. METHODS The Growing Up in Singapore Towards healthy Outcomes (GUSTO) study is an ongoing longitudinal birth cohort study in Singapore, which began in June 2009. We recruited pregnant women during their first ultrasound scan visit at two major public maternity units in Singapore. Resiquimod ic50 At clinic visits done at age 2-3 years, we collected parent-reported information about children’s daily total and device-specific screen viewing time (televisiorly childhood might promote healthier behaviours and associated outcomes later in life. FUNDING Singapore National Research Foundation, and Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR). Current CRISPR-targeted single-nucleotide modifications and subsequent isogenic cell line generation in human pluripotent stem cells (hPSCs) require the introduction of deleterious double-stranded DNA breaks followed by inefficient homology-directed repair (HDR). Here, we utilize Cas9 deaminase base-editing technologies to co-target genomic loci and an episomal reporter to enable single-nucleotide genomic changes in hPSCs without HDR. Together, this method entitled base-edited isogenic hPSC line generation using a transient reporter for editing enrichment (BIG-TREE) allows for single-nucleotide editing efficiencies of >80% across multiple hPSC lines. In addition, we show that BIG-TREE allows for efficient generation of loss-of-function hPSC lines via introduction of premature stop codons. Finally, we use BIG-TREE to achieve efficient multiplex editing of hPSCs at several independent loci. This easily adoptable method will allow for the precise and efficient base editing of hPSCs for use in developmental biology, disease modeling, drug screening, and cell-based therapies.

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