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These Tregs maintained their suppressive properties as well as their phenotype in a highly inflammatory environment. Our findings provide an insight into the mechanisms of Treg reduction in AA. We have identified novel targets with potential for therapeutic interventions. Supplementation of ex vivo expansion cultures of Tregs with high concentrations of IL-2 or delivery of IL-2 directly to patients could improve clinical outcomes in addition to standard immunosuppressive therapy. Copyright © 2020 American Society of Hematology.We recently showed that clotting factor VIIa (FVIIa) binding to endothelial cell protein C receptor (EPCR) induces anti-inflammatory signaling and protects vascular barrier integrity. Inflammation and vascular permeability are thought to be major contributors to the development of hemophilic arthropathy following hemarthrosis. The present study was designed to investigate the potential influence of FVIIa interaction with EPCR in the pathogenesis of hemophilic arthropathy and its treatment with rFVIIa. For this, we first generated hemophilia A (FVIII-/-) mice lacking EPCR (EPCR-/-FVIII-/-) or overexpressing EPCR (EPCR++ FVIII-/-). Joint bleeding was induced in FVIII-/-, EPCR-/-FVIII-/-, and EPCR++FVIII-/- mice by needle puncture injury. Hemophilic synovitis was evaluated by monitoring joint bleeding, change in joint diameter, and histopathological analysis of joint tissue sections. EPCR deficiency in FVIII-/- mice significantly reduced the severity of hemophilic synovitis. EPCR deficiency attenuated the elaboration of IL-6, infiltration of macrophages, and neoangiogenesis in the synovium following hemarthrosis. A single dose of rFVIIa was sufficient to fully prevent the development of milder hemophilic synovitis in EPCR-/-FVIII-/- mice. The development of hemophilic arthropathy in EPCR overexpressing FVIII-/- mice did not significantly differ from that of FVIII-/- mice, and three doses of rFVIIa partly protected against hemophilic synovitis in these mice. Consistent with the data that EPCR deficiency protects against developing hemophilic arthropathy, administration of a single dose of EPCR blocking monoclonal antibodies markedly reduced hemophilic synovitis in FVIII-/- mice subjected to joint bleeding. The present data indicate that EPCR could be an attractive new target to prevent joint damage in hemophilia patients. Copyright © 2020 American Society of Hematology.In this study, Ward et al. (https//doi.org/10.1084/jem.20191689) provide exciting evidence that nucleotide nicotinamide transhydrogenase (NNT), a mitochondrial matrix-located enzyme harnessing the proton gradient to generate NADPH using NADH, markedly contributes to non-small cell lung carcinoma (NSCLC), which is abrogated in the murine C57BL/6J background, a strain known to be deficient in NNT. © 2020 Conrad.Gasdermins (GSDMs) belong to a protein superfamily that is found only in vertebrates and consists of GSDMA, GSDMB, GSDMC, GSDMD, DFNA5 (a.k.a. GSDME) and DFNB59 (a.k.a. Pejvakin (PJVK)) in humans. Except for DFNB59, all members of the GSDM superfamily contain a conserved two-domain structure (N-terminal and C-terminal domains) and share an autoinhibitory mechanism. When the N-terminal domain of these GSDMs is released, it possesses pore-forming activity that causes inflammatory death associated with the loss of cell membrane integrity and release of inflammatory mediators. It has also been found that spontaneous mutations occurring in the genes of GSDMs have been associated with the development of certain autoimmune disorders, as well as cancers. Here, we review the current knowledge of the expression profile and regulation of GSDMs and the important roles of this protein family in inflammatory cell death, tumorigenesis and other related diseases. © The Author(s) 2020. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail [email protected].[This corrects the article DOI 10.1371/journal.pone.0221750.].Opioid addiction is recognized as a chronic relapsing brain disease resulting from repeated exposure to opioid drugs. Cellular and molecular mechanisms underlying the ability of organism to return back to the physiological norm after cessation of drug supply are not fully understood. The aim of this work was to extend our previous studies of morphine-induced alteration of rat forebrain cortex protein composition to the hippocampus. Rats were exposed to morphine for 10 days and sacrificed 24 h (groups +M10 and -M10) or 20 days after the last dose of morphine (groups +M10/-M20 and -M10/-M20). The six altered proteins (≥2-fold) were identified in group (+M10) when compared with group (-M10) by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). The number of differentially expressed proteins was increased to thirteen after 20 days of the drug withdrawal. Noticeably, the altered level of α-synuclein, β-synuclein, α-enolase and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was also determined in both (±M10) and (±M10/-M20) samples of hippocampus. Immunoblot analysis of 2D gels by specific antibodies oriented against α/β-synucleins and GAPDH confirmed the data obtained by 2D-DIGE analysis. Label-free quantification identified nineteen differentially expressed proteins in group (+M10) when compared with group (-M10). After 20 days of morphine withdrawal (±M10/-M20), the number of altered proteins was increased to twenty. We conclude that the morphine-induced alteration of protein composition in rat hippocampus after cessation of drug supply proceeds in a different manner when compared with the forebrain cortex. In forebrain cortex, the total number of altered proteins was decreased after 20 days without morphine, whilst in hippocampus, it was increased.In flea-borne plague, blockage of the flea's foregut by Yersinia pestis hastens transmission to the mammalian host. Based on microscopy observations, we first suggest that flea blockage results from primary infection of the foregut and not from midgut colonization. In this model, flea infection is characterized by the recurrent production of a mass that fills the lumen of the proventriculus and encompasses a large number of Y. pestis. This recurrence phase ends when the proventricular cast is hard enough to block blood ingestion. We further showed that ymt (known to be essential for flea infection) is crucial for cast production, whereas the hmsHFRS operon (known to be essential for the formation of the biofilm that blocks the gut) is needed for cast consolidation. IK-930 in vivo By screening a library of mutants (each lacking a locus previously known to be upregulated in the flea gut) for biofilm formation, we found that rpiA is important for flea blockage but not for colonization of the midgut. This locus may initially be required to resist toxic compounds within the proventricular cast.
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