Keratinocyte Adherens Junctions Initiate Nuclear Signaling byTranslocation of Plakoglobin from the Membrane to the Nucleus

Because changes in cell-cell adhesion have profound effects on cellular behavior, we hypothesized a link between the adhesion and signaling functions of plakoglobin and beta-catenin. To investigate the existence of adherens-junction-mediated signaling, we used peroxovanadate to tyrosine phosphorylate plakoglobin and beta-catenin and to dissociate adherens junctions. The distribution of plakoglobin and beta-catenin was determined by immunofluorescence, western blot analysis, pulse-chase radiolabeling, and biochemical subcellular fractionation. Coimmunoprecipitation studies from nuclear fractions, gel-shift assays, and transient transfections with T cell factor (TCF)/lymphoid enhancer factor (LEF) optimized promoter reporter constructs were used to investigate the ability of plakoglobin and beta-catenin that had redistributed from the membrane to the nucleus to form functional transcriptional regulatory complexes with TCF/LEF family member transcription factors. Tyrosine phosphorylation of plakoglobin and beta-catenin resulted in their rapid translocation from the cell membrane to the nucleus. Nuclear translocation was associated with increased plakoglobin and decreased beta-catenin binding to nuclear TCF/LEF and downregulation of gene transcription from TCF/LEF reporter constructs. These results are consistent with a signaling pathway initiated by structural changes in the adherens junction in which adherens-junction-derived plakoglobin regulates nuclear transcription by antagonizing the binding of beta-catenin to TCF/LEF proteins

Long-term yogurt consumption and risk of incident hypertension in adults

The Nurses' Health Study and Health Professionals Follow-up Study cohorts are supported by grants UM1 CA186107, UM1 CA176726, and UM1 CA167552 from the National Institutes of Health. The current analyses were supported by small grants from the National Dairy Council, the General Mills Bell Institute for Health and Nutrition, and the Boston Nutrition and Obesity Research Center. The Boston Nutrition Obesity Research Center is administratively based at Boston Medical Center and is funded by the National Institutes of Health (NIH/NIDDK) grant P30DK046200. (UM1 CA186107 - National Institutes of Health; UM1 CA176726 - National Institutes of Health; UM1 CA167552 - National Institutes of Health; small grants from the National Dairy Council; General Mills Bell Institute for Health and Nutrition; Boston Nutrition and Obesity Research Center; P30DK046200 - National Institutes of Health (NIH/NIDDK))Accepted manuscrip

Noise-induced energy excitation by a general environment

We analyze the effects that general environments, namely ohmic and non-ohmic, at zero and high temperature induce over a quantum Brownian particle. We state that the evolution of the system can be summarized in terms of two main environmental induced physical phenomena: decoherence and energy activation. In this article we show that the latter is a post-decoherence phenomenon. As the energy is an observable, the excitation process is a direct indication of the system-environment entanglement particularly useful at zero temperature.Comment: 14 pages; 7 figures. Version to appear in Phys Lett.

Improving band gap prediction in density functional theory from molecules to solids

A novel nonempirical scaling correction method is developed to tackle the challenge of band gap prediction in density functional theory. For finite systems the scaling correction largely restores the straight-line behavior of electronic energy at fractional electron numbers. The scaling correction can be generally applied to a variety of mainstream density functional approximations, leading to significant improvement in the band gap prediction. In particular, the scaled version of a modified local density approximation predicts band gaps with an accuracy consistent for systems of all sizes, ranging from atoms and molecules to solids. The scaled modified local density approximation thus provides a useful tool to quantitatively characterize the size-dependent effect on the energy gaps of nanostructuresFinancial support from the Naval Research Office (N00014-09-0576) (X. Z. and W.Y.), National Science Foundation (CHE-09-11119) (X. H. and W.Y.), Royal Society (A. J. C.), and Ramón y Cajal (P. M.-S.) is gratefully appreciate

Probing the f(R) formalism through gravitational wave polarizations

The direct observation of gravitational waves (GWs) in the near future, and the corresponding determination of the number of independent polarizations, is a powerful tool to test general relativity and alternative theories of gravity. In the present work we use the Newman-Penrose formalism to characterize GWs in quadratic gravity and in a particular class of f(R) Lagrangians. We find that both quadratic gravity and the f(R) theory belong to the most general invariant class of GWs, i.e., they can present up to six independent polarizations of GWs. For a particular combination of the parameters, we find that quadratic gravity can present up to five polarizations states. On the other hand, if we use the Palatini approach for f(R) theories, GWs present only the usual two transverse-traceless polarizations such as in general relativity. Thus, we conclude that the observation of GWs can strongly constrain the suitable formalism for these theories.Comment: 18 pages, 1 figure, accepted for publication in Physics Letters

Engineering culture environment of human pluripotent stem cells to direct their commitment and maturation towards functional cardiomyocytes: An “-Omics” driven approach

The immature phenotype of human pluripotent stem cell derived cardiomyocytes (hPSC-CMs) constrains their potential in cell therapy and drug discovery applications. In this study, we aim to overcome this hurdle by devising a novel strategy for generation and maturation of functional hPSC-CM. We relied on the aggregation of hPSC-derived cardiac progenitors to establish a scalable differentiation protocol capable of generating highly pure CM aggregate cultures. Whole-transcriptome analysis and 13C-metabolic flux analysis demonstrate at both molecular and fluxome levels that a 3D culture environment enhances metabolic maturation of hPSC-CMs. When compared to 2D, 3D cultures of hPSC-CMs displayed down-regulation of genes involved in glycolysis and lipid biosynthesis and increased expression of genes involved in OXPHOS. Accordingly, 3D hPSC-CMs had lower fluxes through glycolysis and fatty acid synthesis and increased TCA-cycle activity. We then assessed if alteration of culture medium composition to mimic in vivo substrate usage during cardiac development improves further hPSC-CM maturation in vitro. Our results showed that shifting hPSC-CMs from glucose-containing to galactose- and fatty acid-containing medium promotes their fast maturation into adult-like CMs with higher oxidative metabolism, transcriptional signatures closer to those of adult ventricular tissue, higher myofibril density and alignment, improved calcium handling, enhanced contractility, and more physiological action potential kinetics. Integrated “-Omics” analyses showed that addition of galactose to culture medium improves total oxidative capacity of the cells and ameliorates fatty acid oxidation avoiding the lipotoxicity that results from cell exposure to high fatty acid levels. This study provides an important link between substrate utilization and functional maturation of hPSC-CMs facilitating the application of these cells in preclinical research and regenerative medicine. Funding: This work was supported by FCT-funded projects CardioRegen (HMSP-ICT/0039/2013), CARDIOSTEM (MITPTB/ECE/0013/2013) and Netdiamond (SAICTPAC/0047/2015). iNOVA4Health Research Unit (LISBOA-01-0145-FEDER-007344) is also acknowledged

INTEnsive care bundle with blood pressure reduction in acute cerebral hemorrhage trial (INTERACT3): Study protocol for a pragmatic stepped-wedge cluster-randomized controlled trial

Background: Early intensive blood pressure (BP) lowering remains the most promising treatment for acute intracerebral hemorrhage (ICH), despite discordant results between clinical trials and potential variation in the treatment effects by approach to control BP. As the third in a series of clinical trials on this topic, the INTEnsive care bundle with blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT3) aims to determine the effectiveness of a goal-directed care bundle protocol of early physiological control (intensive BP lowering, glycemic control, and pyrexia treatment) and reversal of anticoagulation, in acute ICH.Methods: INTERACT3 is a pragmatic, international, multicenter, stepped-wedge (4 phases/3 steps), cluster-randomized controlled trial to determine the effectiveness of a multifaceted care package in adult (age ≥ 18 years) patients (target 8360) with acute ICH (\u3c 6 h of onset) recruited from 110 hospitals (average of 19 consecutive patients per phase) in low- and middle-income countries. After a control phase, each hospital implements the intervention (intensive BP lowering, target systolic \u3c 140 mmHg; glucose control, target 6.1-7.8 mmol/L and 7.8-10.0 mmol/L in those without and with diabetes mellitus, respectively; anti-pyrexia treatment to target body temperature ≤ 37.5 °C; and reversal of anticoagulation, target international normalized ratio \u3c 1.5 within 1 h). Information will be obtained on demographic and baseline clinical characteristics, in-hospital management, and 7-day outcomes. Central trained blinded assessors will conduct telephone interviews to assess physical function and health-related quality of life at 6 months. The primary outcome is the modified Rankin scale (mRS) at 6 months analyzed using ordinal logistic regression. The sample size of 8360 subjects provides 90% power (α = 0.05) to detect a 5.6% absolute improvement (shift) in the primary outcome of the intervention versus control standard care, with various assumptions.Discussion: As the largest clinical trial in acute ICH, INTERACT3 is on schedule to provide an assessment of the effectiveness of a widely applicable goal-directed care bundle for a serious condition in which a clearly proven treatment has yet to be established.Trial registration: ClinicalTrials.gov NCT03209258. Registered on 1 July 2017. Chinese Trial Registry ChiCTR-IOC-17011787. Registered on 28 June 2017

FGF23-klotho axis as predictive factors of fractures in type 2 diabetics with early chronic kidney disease

Background: The aim of our study was to evaluate the relevance of FGF23-klotho axis in the predisposition for bone fractures in type 2 diabetic patients with early chronic kidney disease. Methods: In a prospective study we included 126 type 2 diabetic patients with CKD stages 2-3 (from 2010 to 2017). We used descriptive statistics, ANOVA and chi-square test. Our population was divided into two groups according to the occurrence of a bone fracture event or not, and the groups were compared considering several biological and laboratorial parameters. We employed a multiple regression model to identify risk factors for bone fracture events and hazard ratios (HR) were calculated using a backward stepwise likelihood ratio (LR) Cox regression. Results: Patients with a fracture event displayed higher levels of FGF-23, Phosphorus, PTH, TNF-alpha, OxLDL, HOMA-IR, calcium x phosphorus product and ACR and lower levels of Osteocalcin, alpha-Klotho, 25(OH)D3 and eGFR compared with patients without a fracture event (p < 0.001). The number of patients with a fracture event was higher than expected within inclining CKD stages (chi 2, p = 0.06). The occurrence of fracture and the levels of TNF-alpha, klotho, 25(OH)D3 and OxLDL were found to predict patient entry into RRT (p < 0.05). Age, osteocalcin, alpha-Klotho and FGF-23 independently influenced the occurrence of bone fracture (p < 0.05). Conclusions: alpha-Klotho and FGF-23 levels may have a good clinical use as biomarkers to predict the occurrence of fracture events. (C) 2019 Elsevier Inc. All rights reserved.info:eu-repo/semantics/publishedVersio