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During the initiation of thrombosis at 6 hours post-stenosis, Slc44a2-/- mice also had smaller thrombi both in length and weight, with circulating platelets remaining elevated in Slc44a2-/- animals. Platelet activation and aggregation under both static- and venous and arterial shear conditions were normal for blood from Slc44a2-/- mice. CONCLUSIONS These studies corroborate the original GWAS findings and establish a contributing role for SLC44A2 during the initiation of VT, with indications that this may be related to platelet-neutrophil interaction. The precise mechanism however remains elusive and warrants further investigation. This article is protected by copyright. All rights reserved.Solution-state NMR spectroscopy has become a powerful tool to study soluble proteins in cells, provided that they tumble sufficiently fast. In addition, cryo-electron tomography (cryo-ET) has recently displayed a tremendous potential to probe structures of large proteins and assemblies in their native cellular environments. However, challenges remain to obtain atomic-level information in native cell settings for proteins that are small, disordered, or are strongly engaged in intermolecular interactions. In this Minireview, we discuss recent progress in using sensitivity enhanced solid-state NMR spectroscopy methods in the context of cellular structural biology. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.Recent reports have shown that a C-terminal fragment of adhesion protein Fibulin7 (Fbln7-C) could demonstrate both anti-angiogenic and anti-inflammatory activities. The current study investigated the potential of Fbln7-C as a modulator of tumor-associated macrophages (TAMs) and its potential as an anti-cancer therapeutic. Our in vitro data shows that Fbln7-C could inhibit the tumor cell line (MDA-MB-231) supernatant induced reprogramming of human monocytes into immunosuppressive TAMs as indicated by higher expression of pERK1/2, pSTAT1 molecules and reduced expression of CD206 protein and, arg1, ido and vegf transcripts in monocytes cultured in the presence of Fbln7-C compared to controls. Interestingly, Fbln7-C treated macrophages retained their altered phenotype even after the removal of Fbln7-C, and their secretome demonstrated anti-cancer activities. Finally, in a 4T1 induced murine breast tumor model, intravenous administration of Fbln7-C, following the appearance of measurable tumors, significantly reduced the growth and weight of the tumors. Detailed phenotypic analysis of the infiltrated monocyte/macrophage populations (F480+ Ly6G- CD11b+ ) at day 23 post-induction showed a higher percentage of inflammatory monocytes (F480+ Ly6Chi CD11b+ ) and a delayed differentiation into anti-inflammatory TAMs as evident by their reduced levels of CD206 expression. In conclusion, the above data suggest that Fbln7-C could regulate the tumor environment-induced macrophage reprogramming and has the potential for cancer therapeutics. This article is protected by copyright. All rights reserved.Intrahepatic cholangiocarcinoma (iCCA) and mixed hepatocholangiocarcinoma (HCC-CCA) are difficult to diagnose and treat, and generally portend a poor prognosis (1, 2). Surgical resection remains the gold standard, but for unresectable disease, systemic chemotherapy, as well as various adjuncts such as trans-arterial chemoembolization (TACE), stereotactic body radiation (SBRT), and trans-arterial radioembolization (TARE) have demonstrated benefit on overall survival (2, 3). This article is protected by copyright. All rights reserved.AIM Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is an autoimmune disease characterized by necrotizing small vessel vasculitis that can affect various organs and present multiple symptoms. Susceptibility to AAV is multifactorial and most likely caused by an amalgamation of genetic and environmental factors. The aim of the present study was to explore the distribution of human leukocyte antigen (HLA)-DRB1/DQB1, protein tyrosine phosphatase non-receptor type 22 (PTPN22) and cytotoxic T-Lymphocyte-associated protein 4 (CTLA-4) polymorphisms in North Indian AAV patients and their associations with clinical and pathological characteristics associated with the disease. METHODS A total of 150 AAV patients and 150 healthy controls were recruited. The clinical classification showed 128 as granulomatosis with polyangiitis (GPA) and 21 as microscopic polyangiitis. Only 1 case of eosinophilic granulomatosis with polyangiitis was encountered, which was excluded from analysis. HLA-DRB1/DQB1 alleles were determined by polymerase chain reaction-sequence-specific primer (PCR-SSP) method and single nucleotide variant genotyping for CTLA-4 and PTPN22 was done by simple probe-based SNP arrays. RESULTS A significant predispositional association of DRB1*03 and DQB1*02 alleles, were confirmed in proteinase 3 (PR3)-AAV patients, whereas DRB1*10, DRB1*14 and DQB1*05 were protective alleles in AAV, PR3-AAV and GPA patients. GG genotype of CTLA-4 + 49A/G was increased in patients as compared to controls and showed an association with AAV, PR3-AAV and GPA patients. CONCLUSION The study indicated strong genetic associations were linked with PR3 antineutrophil cytoplasmic antibody specificity and it appears that PR3-AAV and MPO-AAV have distinct genetic backgrounds. © 2020 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.Realistic assessments of the impacts of global warming on population extinction risk are likely to require an integrated analysis of the roles of standing genetic variation, microhabitat thermal complexity, and the inter-individual variation of heat tolerance due to both genetic differences and seasonal acclimatization effects. selleck chemicals Here, we examine whether balancing selection and microhabitat temperature heterogeneity can interact to enhance the population persistance to thermal stress for the black mussel Septifer virgatus. We deployed biomimetic data loggers on the shore to measure the microhabitat-specific thermal variation from June 2014 to April 2016. Thermal tolerance of specimens was indexed by measuring effects of temperature on heart rate. Genotyping of specimens was performed using double digestion restriction association RADSeq (ddRADseq). Our results show that inter-individual variations in thermal tolerance correlate significantly with genetic differences at some specific gene loci, and that heterozygotes have higher thermal tolerances than homozygotes.