Project description:Trichoplein/mitostatin (TpMs) is a keratin-binding protein that partly colocalizes with mitochondria and is often downregulated in epithelial cancers, but its function remains unclear. In this study, we report that TpMs regulates the tethering between mitochondria and endoplasmic reticulum (ER) in a Mitofusin 2 (Mfn2)-dependent manner. Subcellular fractionation and immunostaining show that TpMs is present at the interface between mitochondria and ER. The expression of TpMs leads to mitochondrial fragmentation and loosens tethering with ER, whereas its silencing has opposite effects. Functionally, the reduced tethering by TpMs inhibits apoptosis by Ca(2+)-dependent stimuli that require ER-mitochondria juxtaposition. Biochemical and genetic evidence support a model in which TpMs requires Mfn2 to modulate mitochondrial shape and tethering. Thus, TpMs is a new regulator of mitochondria-ER juxtaposition.
Project description:Juxtaposition kinetics between specific sites in supercoiled DNA is investigated at close to physiological ionic conditions by Brownian dynamics simulations. At such conditions, supercoiled DNA is interwound, and the probability of spatial site juxtaposition is much higher than in relaxed DNA. We find, however, that supercoiling does not correspondingly increase the rate of juxtaposition at these physiological conditions. An explanation to this unexpected finding emerges on analysis of the juxtaposition dynamics. We note that although a particular site i(1) in supercoiled DNA is often in close proximity (juxtaposed) to another site i(2), the change of i(2) occurs very slowly and depends largely on internal slithering of opposite segments of the DNA superhelix. Such slithering results in long correlations between successive values of i(2); these correlations increase the average time of juxtaposition between two DNA sites. Random collisions between sites located on different superhelix branches-although increasing in importance with DNA size-contribute less substantially to site juxtaposition at high salt than slithering for DNA up to 6 kb in length.
Project description:BackgroundResearch commentaries have the potential for evidence appraisal in emphasising, correcting, shaping and disseminating scientific knowledge.ObjectivesTo identify the appropriate bibliographic source for capturing commentary information, this study compares comment data in PubMed and Web of Science (WoS) to assess their applicability in evidence appraisal.MethodsUsing COVID-19 as a case study, with over 27 k COVID-19 papers in PubMed as a baseline, we designed a comparative analysis for commented-commenting relations in two databases from the same dataset pool, making a fair and reliable comparison. We constructed comment networks for each database for network structural analysis and compared the characteristics of commentary materials and commented papers from various facets.ResultsFor network comparison, PubMed surpasses WoS with more closed feedback loops, reaching a deeper six-level network compared with WoS' four levels, making PubMed well-suited for evidence appraisal through argument mining. PubMed excels in identifying specialised comments, displaying significantly lower author count (mean, 3.59) and page count (mean, 1.86) than WoS (authors, 4.31, 95% CI of difference of two means = [0.66, 0.79], p<0.001; pages, 2.80, 95% CI of difference of two means = [0.87, 1.01], p<0.001), attributed to PubMed's CICO comment identification algorithm. Commented papers in PubMed also demonstrate higher citations and stronger sentiments, especially significantly elevated disputed rates (PubMed, 24.54%; WoS, 18.8%; baseline, 8.3%; all p<0.0001). Additionally, commented papers in both sources exhibit superior network centrality metrics compared with WoS-only counterparts.ConclusionConsidering the impact and controversy of commented works, the accuracy of comments and the depth of network interactions, PubMed potentially serves as a valuable resource in evidence appraisal and detection of controversial issues compared with WoS.
Project description:Background: Metabolic dysregulation has been implicated in bronchopulmonary dysplasia development. Taurine is an essential amino acid for neonates and is critically involved in glucose and fatty acid metabolism. Neonatal tissue obtains taurine mainly through the taurine transporter. The biological role of taurine in neonatal lung development has never been explored. As glucose metabolism mechanistically modulates angiogenesis and angiogenesis is the central player for neonatal lung development, we hypothesize that taurine depletion contributes to bronchopulmonary dysplasia development. Results: Although most genes and proteins for oxidative phosphorylation were enriched in hyperoxia pup lungs, the complex-1 activity decreased. The decrease in taurine-dependent complex-1 core subunits, ND5 and ND6, in hyperoxia lungs reasonably explained the discrepancy. Metabolomics analysis demonstrated decreased lung taurine with increased blood taurine of hyperoxia pups, compatible with the decreased taurine transporter expression. Decreased glycosylation and increased degradation explained the decreased taurine transporter expression. The results of the complementary study using tunicamycin and tauroursodeoxycholic acid studies supported that endoplasmic reticulum stress contributes to decreased taurine transporter expression in hyperoxia lungs. The effect of taurine treatment on reducing endoplasmic reticulum stress, increasing ND5 and ND6 expression, angiogenesis, and, most importantly, the alveolar formation is beneficial to hyperoxia rat pups. Conclusion: Hyperoxia exposure causes endoplasmic reticulum stress, increases taurine transporter degradation, and leads to taurine depletion in the neonatal lungs with subsequent metabolic dysregulation, resulting in poor alveolar formation of the neonatal lungs. We provide evidence of the never-being-reported protective role of taurine in neonatal lung development. The fact that taurine attenuates the severity of bronchopulmonary dysplasia by reducing hyperoxia-induced endoplasmic reticulum stress and mitochondrial dysfunction indicates its therapeutic potential for treating bronchopulmonary dysplasia.