Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation.

Primary atopic disorders are a group of inborn errors of immunity that skew the immune system toward severe allergic disease. Defining the biology underlying these extreme monogenic phenotypes reveals shared mechanisms underlying common polygenic allergic disease and identifies potential drug targets. Germline gain-of-function (GOF) variants in JAK1 are a cause of severe atopy and eosinophilia. Modeling the JAK1GOF (p.A634D) variant in both zebrafish and human induced pluripotent stem cells (iPSCs) revealed enhanced myelopoiesis. RNA-Seq of JAK1GOF human whole blood, iPSCs, and transgenic zebrafish revealed a shared core set of dysregulated genes involved in IL-4, IL-13, and IFN signaling. Immunophenotypic and transcriptomic analysis of patients carrying a JAK1GOF variant revealed marked Th cell skewing. Moreover, long-term ruxolitinib treatment of 2 children carrying the JAK1GOF (p.A634D) variant remarkably improved their growth, eosinophilia, and clinical features of allergic inflammation. This work highlights the role of JAK1 signaling in atopic immune dysregulation and the clinical impact of JAK1/2 inhibition in treating eosinophilic and allergic disease.

Social and structural factors associated with substance use within the support network of adults living in precarious housing in a socially marginalized neighborhood of Vancouver, Canada.

BACKGROUND: The structure of a social network as well as peer behaviours are thought to affect personal substance use. Where substance use may create health risks, understanding the contribution of social networks to substance use may be valuable for the design and implementation of harm reduction or other interventions. We examined the social support network of people living in precarious housing in a socially marginalized neighborhood of Vancouver, and analysed associations between social network structure, personal substance use, and supporters' substance use. METHODS: An ongoing, longitudinal study recruited 246 participants from four single room occupancy hotels, with 201 providing social network information aligned with a 6-month observation period. Use of tobacco, alcohol, cannabis, cocaine (crack and powder), methamphetamine, and heroin was recorded at monthly visits. Ego- and graph-level measures were calculated; the dispersion and prevalence of substances in the network was described. Logistic mixed effects models were used to estimate the association between ego substance use and peer substance use. Permutation analysis was done to test for randomness of substance use dispersion on the social network. RESULTS: The network topology corresponded to residence (Hotel) with two clusters differing in demographic characteristics (Cluster 1 -Hotel A: 94% of members, Cluster 2 -Hotel B: 95% of members). Dispersion of substance use across the network demonstrated differences according to network topology and specific substance. Methamphetamine use (overall 12%) was almost entirely limited to Cluster 1, and absent from Cluster 2. Different patterns were observed for other substances. Overall, ego substance use did not differ over the six-month period of observation. Ego heroin, cannabis, or crack cocaine use was associated with alter use of the same substances. Ego methamphetamine, powder cocaine, or alcohol use was not associated with alter use, with the exception for methamphetamine in a densely using part of the network. For alters using multiple substances, cannabis use was associated with lower ego heroin use, and lower ego crack cocaine use. Permutation analysis also provided evidence that dispersion of substance use, and the association between ego and alter use was not random for all substances. CONCLUSIONS: In a socially marginalized neighborhood, social network topology was strongly influenced by residence, and in turn was associated with type(s) of substance use. Associations between personal use and supporter's use of a substance differed across substances. These complex associations may merit consideration in the design of interventions to reduce risk and harms associated with substance use in people living in precarious housing.

EvoPipes.net: Bioinformatic Tools for Ecological and Evolutionary Genomics.

Recent increases in the production of genomic data are yielding new opportunities and challenges for biologists. Among the chief problems posed by next-generation sequencing are assembly and analyses of these large data sets. Here we present an online server, http://EvoPipes.net, that provides access to a wide range of tools for bioinformatic analyses of genomic data oriented for ecological and evolutionary biologists. The EvoPipes.net server includes a basic tool kit for analyses of genomic data including a next-generation sequence cleaning pipeline (SnoWhite), scaffolded assembly software (SCARF), a reciprocal best-blast hit ortholog pipeline (RBH Orthologs), a pipeline for reference protein-based translation and identification of reading frame in transcriptome and genomic DNA (TransPipe), a pipeline to identify gene families and summarize the history of gene duplications (DupPipe), and a tool for developing SSRs or microsatellites from a transcriptome or genomic coding sequence collection (findSSR). EvoPipes.net also provides links to other software developed for evolutionary and ecological genomics, including chromEvol and NU-IN, as well as a forum for discussions of issues relating to genomic analyses and interpretation of results. Overall, these applications provide a basic bioinformatic tool kit that will enable ecologists and evolutionary biologists with relatively little experience and computational resources to take advantage of the opportunities provided by next-generation sequencing in their systems.