Santossauer8122

Aims Type 1 diabetes (T1D) is a chronic autoimmune disease leading to progressive loss of pancreatic beta cells. Interferon (IFN)-α plays a critical role in the crosstalk between pancreatic beta cells and the immune system in early insulitis. In human beta cells IFNα signals through JAK1 and TYK2, leading to endoplasmic reticulum stress, inflammation and HLA class I overexpression. IFNα, acting synergistically with IL-1β, induces apoptosis. Polymorphisms in TYK2 that decrease its activity are associated with protection against T1D, and we hypothesized that pharmacological inhibitors that specifically target TYK2 could protect human beta cells against the deleterious effects of IFNα. Materials and methods Two TYK2 inhibitors provided by Nimbus Lakshmi Inc, were tested in human insulin-producing EndoC-βH1 cells and human islets to evaluate their effect on IFNα signaling, beta cell function and susceptibility to viral infection using RT-qPCR, western blot, immunofluorescence, ELISA and nuclear dyes. Results The two TYK2 inhibitors tested prevented IFNα-induced human beta cell gene expression in a dose-dependent manner. They also protected human islets against IFNα+IL-1β-induced apoptosis. Importantly, these inhibitors did not modify beta cell function or their survival following infection with the potential diabetogenic coxsackievirus CVB1 and CVB5. Conclusions The two TYK2 inhibitors tested inhibit the IFNα signaling pathway in human beta cells, decreasing its pro-inflammatory and pro-apoptotic effects without sensitizing the cells to viral infection. The pre-clinical findings could pave the way for future clinical trials with TYK2 inhibitors for the prevention and treatment of T1D. This article is protected by copyright. All rights reserved.Chiral aromatic alcohols have received much attention due to their widespread use in pharmaceutical industries. In the asymmetric synthesis processes, the excellent performance of alcohol dehydrogenase makes it a good choice for biocatalysts. In this study, a novel and robust medium-chain alcohol dehydrogenase RhADH from Rhodococcus R6 was discovered and used to catalyse the asymmetric reduction of aromatic ketones to chiral aromatic alcohols. The reduction of 2-hydroxyacetophenone (2-HAP) to (R)-(-)-1-phenyl-1,2-ethanediol ((R)-PED) was chosen as a template to evaluate its catalytic activity. A specific activity of 110 U mg-1 and a 99% purity of e.e. was achieved in the presence of NADH. An efficient bienzyme-coupled catalytic system (RhADH and formate dehydrogenase, CpFDH) was established using a two-phase strategy (dibutyl phthalate and buffer), which highly raised the tolerated substrate concentration (60 g l-1 ). Besides, a broad range of aromatic ketones were enantioselectively reduced to the corresponding chiral alcohols by this enzyme system with highly enantioselectivity. This system is of the potential to be applied at a commercial scale.Aims Sex differences in associations between several risk factors and myocardial infarction (MI), including diabetes, have been found in general populations. Whether similar differences are observed in patients with diabetes is unknown. Materials and methods 11,065 (42% women) participants with type 2 diabetes in the ADVANCE trial and its post-trial follow-up study, ADVANCE-ON, were included. Cox regression models were used to estimate hazard ratios (HRs) for associations between risk factors and MI (fatal and non-fatal) by sex, and the women-to-men ratio of HRs (RHR). Results Over a median of 9.6 years of follow-up, 719 patients experienced MI. Smoking status, smoking intensity, higher systolic blood pressure (SBP), HbA1c , total and LDL cholesterol, duration of diabetes, triglycerides and BMI and lower HDL cholesterol were associated with an increased risk of MI in both sexes. Furthermore, some variables were associated with a greater relative risk of MI in women than men RHRs were 1.75 (95% CI 1.05-2.91) for current smoking, 1.53 (1.00-2.32) for former smoking, 1.18 (1.02-1.37) for SBP, and 1.13 (95% CI, 1.003-1.26) for duration of diabetes. Although incidence rates of MI were higher in men (9.3 per 1,000 person-years) compared with women (5.8 per 1,000 person-years), rate differences associated with risk factors were greater in women than men, except for HDL cholesterol and BMI. Conclusions In patients with type 2 diabetes, smoking, higher SBP and longer duration of diabetes had a greater relative and absolute effect in women than men, highlighting the importance of routine sex-specific approaches and early interventions in women with diabetes. This article is protected by copyright. All rights reserved.Experiments have revealed much about top-down and bottom-up control in ecosystems, but manipulative experiments are limited in spatial and temporal scale. To obtain a more nuanced understanding of trophic control over large scales, we explored long-term time-series data from 13 globally distributed lakes and used empirical dynamic modelling to quantify interaction strengths between zooplankton and phytoplankton over time within and across lakes. Across all lakes, top-down effects were associated with nutrients, switching from negative in mesotrophic lakes to positive in oligotrophic lakes. This result suggests that zooplankton nutrient recycling exceeds grazing pressure in nutrient-limited systems. Within individual lakes, results were consistent with a 'seasonal reset' hypothesis in which top-down and bottom-up interactions varied seasonally and were both strongest at the beginning of the growing season. Thus, trophic control is not static, but varies with abiotic conditions - dynamics that only become evident when observing changes over large spatial and temporal scales.Objectives To describe the characteristics of fibromyalgia among Nigerian patients and assess the sensitivities of the American College of Rheumatology (ACR) criteria of 1990, 2010, 2011, and 2016 for making the diagnosis of fibromyalgia. Methods Consecutive patients diagnosed clinically with fibromyalgia by a rheumatologist were assessed. https://www.selleckchem.com/products/u18666a.html ACR criteria for fibromyalgia of 1990, 2010, 2011, and 2016 were applied to each patient. Polysymptomatic distress scores (PSD) were calculated from the Widespread Pain Index and Symptom Severity Scores. Sleep was assessed using the Pittsburgh Sleep Quality Index; fatigue by the Fatigue Severity Scale and the severity of fibromyalgia was determined using the Revised Fibromyalgia Impact Questionnaire (FIQR). Results A total of 660 new patients were seen out of which a diagnosis of fibromyalgia was made in 114 (17.3%). The mean age of the patients was 44.6 ± 15.6 years and females accounted for 84.2%. Twenty-one (18.4%) patients had changed or quit their jobs due to fibromyalgia.