Key benefits of dexamethasone and antibody treatment in COVID-19 hamster models revealed by single-cell transcriptomics

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Neurological Manifestations of COVID-19 Feature T Cell Exhaustion and Dedifferentiated Monocytes in Cerebrospinal Fluid

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基于中医药整合药理学和转录组学探究丹栀逍遥散防治焦虑肝郁化火证的作用机制

目的 基于中医药整合药理学和转录组学探究丹栀逍遥散防治焦虑肝郁化火证的作用机制。方法 采用中医药整合药理学研究平台v2.0,检索并获取丹栀逍遥散的活性成分及靶标、焦虑肝郁化火证靶标信息,构建中药-成分-靶点-通路网络。将交集基因导入String数据库,构建交集靶点的蛋白互作网络,以确定最终需要验证的靶标。利用GEO数据库转录组学验证整合网络药理学结果,同时采用动物实验进行验证。结果 共筛选出与焦虑肝郁化火证相关的靶标13个,丹栀逍遥散活性成分430种。整合药理学结果显示,丹栀逍遥散防治焦虑肝郁化火证主要通过调控α-氨基-3-羟基-5-甲基-4-异噁唑丙酸受体（α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor,AMPAR）、蛋白激酶A(protein kinase A,PKA)、N-甲基-D-天冬氨酸（N-methyl-D-aspartic acid,NMDA）受体的激活及磷脂酰肌醇3-激酶（phosphatidylinositide 3-kinases,PI3K）/蛋白激酶B(protein kinase B,...     

Analysis of gene expression profiles of multiple skin diseases identifies a conserved signature of disrupted homeostasis

Triggers of skin disease pathogenesis vary, but events associated with the elicitation of a lesion share many features in common. Our objective was to examine gene expression patterns in skin disease to develop a molecular signature of disruption of cutaneous homeostasis. Gene expression data from common inflammatory skin diseases (eg psoriasis, atopic dermatitis, seborrhoeic dermatitis and acne) and a novel statistical algorithm were used to define a unifying molecular signature referred to as the “unhealthy skin signature” (USS). Using a pattern‐matching algorithm, analysis of public data repositories revealed that the USS is found in diverse epithelial diseases. Studies of milder disruptions of epidermal homeostasis have also shown that these conditions converge, to varying degrees, on the USS and that the degree of convergence is related directly to the severity of homeostatic disruption. The USS contains genes that had no prior published association with skin, but that play important roles in many different disease processes, supporting the importance of the USS to homeostasis. Finally, we show through pattern matching that the USS can be used to discover new potential dermatologic therapeutics. The USS provides a new means to further interrogate epithelial homeostasis and potentially develop novel therapeutics with efficacy across a spectrum of skin conditions.     

From the Cover: An ancient,conserved gene regulatory network led to the rise of oral venom systems

Oral venom systems evolved multiple times in numerous vertebrates enabling the exploitation of unique predatory niches. Yet how and when they evolved remains poorly understood. Up to now, most research on venom evolution has focused strictly on the toxins. However, using toxins present in modern day animals to trace the origin of the venom system is difficult, since they tend to evolve rapidly, show complex patterns of expression, and were incorporated into the venom arsenal relatively recently. Here we focus on gene regulatory networks associated with the production of toxins in snakes, rather than the toxins themselves. We found that overall venom gland gene expression was surprisingly well conserved when compared to salivary glands of other amniotes. We characterized the “metavenom network,” a network of ∼3,000 nonsecreted housekeeping genes that are strongly coexpressed with the toxins, and are primarily involved in protein folding and modification. Conserved across amniotes, this network was coopted for venom evolution by exaptation of existing members and the recruitment of new toxin genes. For instance, starting from this common molecular foundation, Heloderma lizards, shrews, and solenodon, evolved venoms in parallel by overexpression of kallikreins, which were common in ancestral saliva and induce vasodilation when injected, causing circulatory shock. Derived venoms, such as those of snakes, incorporated novel toxins, though still rely on hypotension for prey immobilization. These similarities suggest repeated cooption of shared molecular machinery for the evolution of oral venom in mammals and reptiles, blurring the line between truly venomous animals and their ancestors.

Venoms are proteinaceous mixtures that can be traced and quantified to distinct genomic loci, providing a level of genetic tractability that is rare in other traits (1–4). This advantage of venom systems provides insights into processes of molecular evolution that are otherwise difficult to obtain. For example, studies in cnidarians showed that gene duplication is an effective way to increase protein dosage in tissues where different ecological roles can give rise to different patterns of gene expression (2, 5). Studies of venom in snakes have allowed comparisons of the relative importance of sequence evolution vs. gene expression evolution, as well as how a lack of genetic constraint enables diversity in complex traits (6, 7).Despite the wealth of knowledge venoms have provided about general evolutionary processes, the common molecular basis for the evolution of venom systems themselves is unknown. Even in snakes, which have perhaps the best studied venom systems, very little is known about the molecular architecture of these systems at their origin (8, 9). Using toxin families present in modern snakes to understand evolution at its origin is difficult because toxins evolve rapidly, both in terms of sequence and gene expression (10, 11). Toxins experience varying degrees of selection and drift, complicating interpretations of evolutionary models (12), and estimation of gene family evolution is often inconsistent, varying with which part of the gene (exon or intron) is used to construct the phylogeny (13). Most importantly, present-day toxins became a part of the venom over time; this diminishes their utility in trying to understand events that lead to the rise of venom systems in the nonvenomous ancestors of snakes (14, 15).A gene coexpression network aims to identify genes that interact with one another based on common expression profiles (16). Groups of coexpressed genes that have similar expression patterns across samples are identified using hierarchical clustering and are placed in gene “modules” (17). Constructing a network and comparing expression profiles of modules across taxa can identify key drivers of phenotypic change, as well as aid in identifying initial genetic targets of natural selection (18, 19). Comparative analysis using gene coexpression networks allows us to distinguish between ancient genetic modules representing core cellular processes, evolving modules that give rise to lineage-specific differences, and highly flexible modules that have evolved differently in different taxa (20). Gene coexpression networks are also widely used to construct gene regulatory networks (GRNs) owing to their reliability in capturing biologically relevant interactions between genes, as well as their high power in reproducing known protein–protein interactions (21, 22).Here we focus on gene coexpression networks involved in the production of snake venom, rather than the venom toxins themselves. Using a coexpression network we characterized the genes associated with venom production, which we term the “metavenom network,” and determine its biological role. We traced the origin of this network to the common ancestor of amniotes, which suggests that the venom system originated from a conserved gene regulatory network. The conserved nature of the metavenom network across amniotes suggests that oral venom systems started with a common gene regulatory foundation, and underwent lineage-specific changes to give rise to diverse venom systems in snakes, lizards, and even mammals.