• Lloyd Lykke posted an update 6 months ago

    Ambulatory and not critically ill patients with COVID-19 treated with hydroxychloroquine, azithromycin and/or antiretrovirals develop a significant, but not relevant, QT interval prolongation.Abiotic and biotic stresses adversely affect plant growth and development and eventually result in less yield and threaten food security worldwide. In plants, several studies have been carried out to understand molecular responses to abiotic and biotic stresses. However, the complete circuitry of stress-responsive genes that plants utilise in response to those environmental stresses are still unknown. The protein phosphatase 2A (PP2A) gene has been known to have a crucial role in abiotic and biotic stresses; but how it regulates the stress response in plants is still not known completely. In this study, we constructed gene co-expression networks of PP2A genes with stress-responsive gene datasets from cold, drought, heat, osmotic, genotoxic, salt, and wounding stresses to unveil their relationships with the PP2A under different conditions of stress. The graph analysis identified 13 hub genes and several influential genes based on closeness centrality score (CCS). Our findings also revealed the count of unique genes present in different settings of stresses and subunits. We also formed clusters of influential genes based on the stress, CCS, and co-expression value. Analysis of cis-regulatory elements (CREs), recurring in promoters of these genes was also performed. Our study has led to the identification of 16 conserved CREs.Hutchinson-Gilford progeria syndrome is a genetic disease caused by an aberrant form of Lamin A resulting in chromatin structure disruption, in particular by interfering with lamina associated domains. Early molecular alterations involved in chromatin remodeling have not been identified thus far. Here, we present SAMMY-seq, a high-throughput sequencing-based method for genome-wide characterization of heterochromatin dynamics. Using SAMMY-seq, we detect early stage alterations of heterochromatin structure in progeria primary fibroblasts. These structural changes do not disrupt the distribution of H3K9me3 in early passage cells, thus suggesting that chromatin rearrangements precede H3K9me3 alterations described at later passages. On the other hand, we observe an interplay between changes in chromatin accessibility and Polycomb regulation, with site-specific H3K27me3 variations and transcriptional dysregulation of bivalent genes. We conclude that the correct assembly of lamina associated domains is functionally connected to the Polycomb repression and rapidly lost in early molecular events of progeria pathogenesis.How circadian rhythms of activity manifest themselves in social life of humans remains one of the most intriguing questions in chronobiology and a major issue for personalized medicine. Over the past years, substantial advances have been made in understanding the personal nature and the robustness-i.e. the persistence-of the circadian rhythms of social activity by the analysis of phone use. At this stage however, the consistency of such advances as their statistical validity remains unclear. The present paper has been specifically designed to address this issue. To this end, we propose a novel statistical procedure for the measurement of the circadian rhythms of social activity which is particularly well-suited for the existing framework of persistence analysis. Furthermore, we illustrate how this procedure works concretely by assessing the persistence of the circadian rhythms of telephone call activity from a 12-month call detail records (CDRs) dataset of adults over than 65 years. The results show the ability of our approach for assessing persistence with a statistical significance. In the field of CDRs analysis, this novel statistical approach can be used for completing the existing methods used to analyze the persistence of the circadian rhythms of a social nature. More importantly, it provides an opportunity to open up the analysis of CDRs for various domains of application in personalized medicine requiring access to statistical significance such as health care monitoring.The central melanocortin system plays a fundamental role in the control of feeding and body weight. Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC) also regulate overall glucose homeostasis via insulin-dependent and -independent pathways. Here, we report that a subset of ARC POMC neurons innervate the liver via preganglionic parasympathetic acetylcholine (ACh) neurons in the dorsal motor nucleus of the vagus (DMV). Optogenetic stimulation of this liver-projecting melanocortinergic pathway elevates blood glucose levels that is associated with increased expression of hepatic gluconeogenic enzymes in female and male mice. Cloperastine fendizoate Pharmacological blockade and knockdown of the melanocortin-4 receptor gene in the DMV abolish this stimulation-induced effect. Activation of melanocortin-4 receptors inhibits DMV cholinergic neurons and optogenetic inhibition of liver-projecting parasympathetic cholinergic fibers increases blood glucose levels. This elevated blood glucose is not due to altered pancreatic hormone release. Interestingly, insulin-induced hypoglycemia increases ARC POMC neuron activity. Hence, this liver-projecting melanocortinergic circuit that we identified may play a critical role in the counterregulatory response to hypoglycemia.White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.

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