Sensory neurons promote immune homeostasis in the lung

Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK

IL-33 potentiates histaminergic itch

BACKGROUND: Itch is a common symptom that can greatly diminish quality of life. Histamine is a potent endogenous pruritogen, and while antihistamines are often the first-line treatment for itch, in conditions like chronic spontaneous urticaria (CSU), many patients remain symptomatic while receiving maximal doses. Mechanisms that drive resistance to antihistamines are poorly defined. OBJECTIVES: Signaling of the alarmin cytokine IL-33 in sensory neurons is postulated to drive chronic itch by inducing neuronal sensitization to pruritogens. Thus, we sought to determine if IL-33 can augment histamine-induced (histaminergic) itch. METHODS: Itch behavior was assessed in response to histamine after IL-33 or saline administration. Various stimuli and conditional and global knockout mice were utilized to dissect cellular mechanisms. Multiple existing transcriptomic data sets were evaluated, including single-cell RNA sequencing of human and mouse skin, microarrays of isolated mouse mast cells at steady state and after stimulation with IL-33, and microarrays of skin biopsy samples from subjects with CSU and healthy controls. RESULTS: IL-33 amplifies histaminergic itch independent of IL-33 signaling in sensory neurons. Mast cells are the top expressors of the IL-33 receptor in both human and mouse skin. When stimulated by IL-33, mouse mast cells significantly increase IL-13 levels. Enhancement of histaminergic itch by IL-33 relies on a mast cell- and IL-13-dependent mechanism. IL-33 receptor expression is increased in lesional skin of subjects with CSU compared to healthy controls. CONCLUSIONS: Our findings suggest that IL-33 signaling may be a key driver of histaminergic itch in mast cell-associated pruritic conditions such as CSU

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.The Fenland Study is funded by the Medical Research Council (MC_U106179471) and Wellcome Trust

SWIFF : space weather integrated forecasting framework

This research has received funding from the European Commission’s FP7 Program with the grant agreement SWIFF (Project No. 2633430, swiff.eu). The KU Leuven simulations were conducted on the computational resources provided by the PRACE Tier-0 Project No. 2011050747 (Curie supercomputer) and by the Flemish Supercomputer Center (VIC3). Additional computational support is provided at KU Leuven by the NASA NCCS (Discover) and NAS (Pleiades) Divisons, as part of the support to the NASA MMS Mission. UNIPI acknowledges the HPC resources of CINECA made available within the Distributed European Computing Initiative by the PRACE-2IP, receiving funding from the European Community’s Seventh Framework Programme (FP7/ 2007-2013) under Grant Agreement No. nRI-283493. Work at UNIPI was supported by the Italian Supercomputing Center – CINECA under the ISCRA initiative. Work at UNIPI was supported by the HPC-EUROPA2 project (Project No. 228398) with the support of the European Commission – Capacities Area – Research Infrastructures. Work performed at IAP, ASCR was supported also by the Project RVO: 68378289.SWIFF is a project funded by the Seventh Framework Programme of the European Commission to study the mathematical-physics models that form the basis for space weather forecasting. The phenomena of space weather span a tremendous scale of densities and temperature with scales ranging 10 orders of magnitude in space and time. Additionally even in local regions there are concurrent processes developing at the electron, ion and global scales strongly interacting with each other. The fundamental challenge in modelling space weather is the need to address multiple physics and multiple scales. Here we present our approach to take existing expertise in fluid and kinetic models to produce an integrated mathematical approach and software infrastructure that allows fluid and kinetic processes to be modelled together. SWIFF aims also at using this new infrastructure to model specific coupled processes at the Solar Corona, in the interplanetary space and in the interaction at the Earth magnetosphere.Publisher PDFPeer reviewe

A genome‐wide linkage map for the house sparrow (Passer domesticus) provides insights into the evolutionary history of the avian genome

Abstract The house sparrow is an important model species for studying physiological, ecological and evolutionary processes in wild populations. Here, we present a medium density, genome wide linkage map for house sparrow (Passer domesticus) that has aided the assembly of the house sparrow reference genome, and that will provide an important resource for ongoing mapping of genes controlling important traits in the ecology and evolution of this species. Using a custom house sparrow 10 K iSelect Illumina SNP chip we have assigned 6,498 SNPs to 29 autosomal linkage groups, based on a mean of 430 informative meioses per SNP. The map was constructed by combining the information from linkage with that of the physical position of SNPs within scaffold sequences in an iterative process. Averaged between the sexes; the linkage map had a total length of 2,004 cM, with a longer map for females (2,240 cM) than males (1,801 cM). Additionally, recombination rates also varied along the chromosomes. Comparison of the linkage map to the reference genomes of zebra finch, collared flycatcher and chicken, showed a chromosome fusion of the two avian chromosomes 8 and 4A in house sparrow. Lastly, information from the linkage map was utilized to conduct analysis of linkage disequilibrium (LD) in eight populations with different effective population sizes (Ne) in order to quantify the background level LD. Together, these results aid the design of future association studies, facilitate the development of new genomic tools and support the body of research that describes the evolution of the avian genome

Tofacitinib Ameliorates Murine Lupus and Its Associated Vascular Dysfunction

OBJECTIVES: Dysregulation of innate and adaptive immune responses contributes to the pathogenesis of systemic lupus erythematosus (SLE) and its associated premature vascular damage. To date, no drug targets both systemic inflammatory disease and the cardiovascular complications of SLE. Tofacitinib is a Janus kinase (JAK) inhibitor that blocks signaling downstream of multiple cytokines implicated in lupus pathogenesis. While clinical trials have shown that tofacitinib exhibits significant clinical efficacy in various autoimmune diseases, its role in SLE and on its associated vascular pathology remains to be characterized. METHODS: MRL/lpr lupus-prone mice received tofacitinib or vehicle by gavage for 6 weeks (therapeutic arm) or 8 weeks (preventive arm). Nephritis, skin inflammation, serum autoantibody levels and cytokines, mononuclear cell phenotype and gene expression, neutrophil extracellular trap (NET) release, endothelium-dependent vasorelaxation and endothelial differentiation were compared in treated and untreated mice. RESULTS: Treatment with tofacitinib led to significant improvement in measures of disease activity including nephritis, skin inflammation, and autoantibody production. In addition, tofacitinib treatment reduced serum levels of pro-inflammatory cytokines and interferon responses in splenocytes and kidney tissue. Tofacitinib also modulated NET formation and significantly increased endothelium-dependent vasorelaxation and endothelial differentiation. The drug was effective as both preventive and therapeutic strategies. CONCLUSIONS: Tofacitinib modulates the innate and adaptive immune responses, ameliorates murine lupus and improves vascular function. These results indicate that JAK inhibitors have the potential to be beneficial in SLE and its associated vascular damage

SWIFF: Space weather integrated forecasting framework

SWIFF is a project funded by the Seventh Framework Programme of the European Commission to study the mathematical-physics models that form the basis for space weather forecasting. The phenomena of space weather span a tremendous scale of densities and temperature with scales ranging 10 orders of magnitude in space and time. Additionally even in local regions there are concurrent processes developing at the electron, ion and global scales strongly interacting with each other. The fundamental challenge in modelling space weather is the need to address multiple physics and multiple scales. Here we present our approach to take existing expertise in fluid and kinetic models to produce an integrated mathematical approach and software infrastructure that allows fluid and kinetic processes to be modelled together. SWIFF aims also at using this new infrastructure to model specific coupled processes at the Solar Corona, in the interplanetary space and in the interaction at the Earth magnetosphere