Lykkegaardnikolajsen5492

Further exploration into the relevance of NCS1 in breast cancer progression showed that knockout of NCS1 (NCS1 KO) caused decreased cell survival and motility, increased baseline intracellular Ca2+ levels, and decreased inositol 1,4,5-trisphosphate (InsP3)-mediated Ca2+ responses. Protein kinase B (Akt) activity was decreased in NCS1 KO cells, which could be rescued by buffering intracellular Ca2+ . Conversely, Akt activity was increased in cells over-expressing NCS1 (NCS1 OE). We therefore conclude that NCS1 acts as cellular stress response protein up-regulated by stress-induced NFκB signaling, and that NCS1 influences cell survival and motility through effects on Ca2+ signaling and Akt pathway activation. This article is protected by copyright. All rights reserved.Progenitor cells at the basal layer of skin epidermis play an essential role in maintaining tissue homeostasis and enhancing wound repair in skin. The proliferation, differentiation, and cell death of epidermal progenitor cells have to be delicately regulated, as deregulation of this process can lead to many skin diseases, including skin cancers. However, the underlying molecular mechanisms involved in skin homeostasis remain poorly defined. In this study, with quantitative proteomics approach, we identified an important interaction between KDF1 (keratinocyte differentiation factor 1) and IKKα (IκB kinase α) in differentiating skin keratinocytes. Ablation of either KDF1 or IKKα in mice leads to similar but striking abnormalities in skin development, particularly in skin epidermal differentiation. With biochemical and mouse genetics approach, we further demonstrate that the interaction of IKKα and KDF1 is essential for epidermal differentiation. To probe deeper into the mechanisms, we find that KDF1 associates with a deubiquitinating protease USP7 (ubiquitin-specific peptidase 7), and KDF1 can regulate skin differentiation through deubiquitination and stabilization of IKKα. Taken together, our study unravels an important molecular mechanism underlying epidermal differentiation and skin tissue homeostasis. © 2020 The Authors.Tropical forest disturbance is a key driver of global biodiversity decline. On continents, the effects of logging are greatest on endemic species, presumably because disturbance is more likely to cover narrower distributions (the "cookie cutter" model). Islands hold disproportionate biodiversity, and are subject to accelerating biotic homogenization, where specialist endemics are lost while generalists persist. We tested responses of tropical island mammals to logging at multiple spatial scales, using a long-term experimental test in a Pacific archipelago. The most widely distributed ecological generalists did not decline after logging, and we detected no overall changes in relative abundance or species diversity. However, endemics with small ranges did decline in response to logging. The least mobile and most range-restricted species declined even at the smallest spatial scale, supporting the cookie cutter model for sedentary species, and suggesting that habitat change due to selective logging is contributing to biotic homogenization on islands. © 2020 John Wiley & Sons Ltd.OBJECTIVES Despite previous literature on comorbid alcohol use disorders (AUDs) in bipolar disorder (BD), little is known about patterns of alcohol use more widely in this population. We have examined lifetime heaviest average weekly alcohol consumption levels in a large well-characterised UK sample including lifetime clinical correlates of increasing levels of alcohol use. METHODS Participants were 1203 women and 673 men with bipolar I disorder interviewed by semi-structured interview who had consumed alcohol regularly at any point in their life. RESULTS Over half of both women (52.3%) and men (73.6%) had regularly consumed over double the current UK recommended guideline for alcohol consumption. In women and men increasing levels of lifetime alcohol consumption were significantly associated with the presence of suicide attempts (women OR 1.82, P  less then  .001; men OR 1.48, P = .005) and rapid cycling (women OR 1.89, P  less then  .001; men OR 1.88, P  less then  .001). In women only, increasing levels of alcohol consumption were significantly associated with more episodes of depression (OR 1.35, P  less then  .001) and mania (OR 1.30, P  less then  .004) per illness year, less impairment in functioning during the worst episode of mania (OR 1.02, P  less then  .001), fewer psychiatric admissions (OR 0.51, P  less then  .001), comorbid panic disorder (OR 2.16, P  less then  .001) and eating disorder (OR 2.37, P  less then  .001). CONCLUSIONS Our results highlight the clinical importance of obtaining detailed information on levels of alcohol consumption among patients with BD. Increased levels of alcohol use, not necessarily reaching criteria for AUD, may be helpful in predicting BD illness course, in particular eating disorders comorbidity in women. © 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.AIMS The risk of developing type 2 diabetes (T2D) when using inhaled corticosteroids (ICS) is unclear. Previous studies were limited by lack of data regarding important confounders and too short follow-up periods. The aim of this study was to determine the risk of T2D onset associated with accumulated ICS dose during the previous year in patients with chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS We conducted a nationwide observational cohort study based on data from patients with COPD between 1 January 2010 and 31 December 2017 extracted from Danish health databases. Patients were followed for seven years, until death or a T2D event. A propensity-matched Cox model and an adjusted Cox proportional hazards model (stratified on body mass index (BMI)) were used to estimate the hazard ratio (HR) for new-onset T2D. RESULTS A total of 50,148 patients with COPD were included, 3,566 (7.1%) of whom had a T2D event. 35,368 patients (70.5%) used ICS during the previous year before study entry. The propensity-matched Cox model (N=33,466) showed an increased risk of T2D which progressed with increasing accumulated ICS dose (low-ICS HR 1.076, confidence interval [CI] 1.075-1.077, p less then 0.0001; medium-ICS HR 1.106, CI 1.105-1.108, p less then 0.0001; high-ICS HR 1.150, CI 1.148-1.151, p less then 0.0001), compared to no ICS use. Results were confirmed in the adjusted Cox analysis on the entire study population, but only for patients with BMI less then 30 kg/m2 . CONCLUSIONS In patients with COPD, ICS use was associated with a moderate dose-dependent increase in the occurrence of T2D. This article is protected by copyright. Beta-Guttiferrin All rights reserved. This article is protected by copyright. All rights reserved.