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摘要： Human birth weight is under stabilizing selection, seeking balance between extremes of high and low, thereby reducing fetal and maternal perinatal mortality risk. Certain combinations of maternal killer immunoglobulin-like receptor () and paternally derived fetal human leuokocyte antigen-C () alleles were previously associated with higher risk of high and low birth weight in a study with limited sample size (n=1,316). Using recently developed methods to impute and haplotypes using single nucleotide polymorphism (SNP) genotype data, we tested associations of fetal and maternal genotypes with offspring birth weight in a large sample. We imputed haplotypes using the KIR*IMP imputation software in 10,602 mother-offspring pairs of European descent from singleton pregnancies from five studies. Using mixed linear regression models to account for mothers with multiple children, we tested associations between maternal vs haplotypes (, genotypes) as well as copy number of activating receptor gene (0, 1, 2 copies of the gene) in the presence of fetal alleles, and offspring birth weight. Associations were analyzed in each cohort before performing a meta-analysis to estimate the interaction effects between maternal and fetal on birth weight across the entire sample. The haplotypes achieved imputation accuracy estimated at >95% in most of the cohorts. No interaction effects were observed between either the maternal vs. haplotype or the maternal locus and fetal . When specifically trying to replicate the previously associated combination of maternal and paternally inherited fetal , there was a negligible change in offspring birth weight for each additional allele and of paternal origin (7g lower birth weight per allele [95% CI: -54, 40], = 0.78). We found little evidence of association between birth weight and maternal haplotypes or fetal and were unable to replicate previously reported findings. Our observations reinforce the importance of replication and th

关键词： AAV2   HAdV   HLA   adeno-associated virus 2   adenovirus   autoantibodies   paediatric hepatitis  

摘要： An outbreak of severe acute hepatitis of unknown aetiology in children (HUAC) was reported by the United Kingdom (UK) in spring 2022. Within days, a corresponding increase was identified in Ireland. A multi-agency incident management team (IMT), led by the Health Protection Surveillance Centre (HPSC), established a national case definition, trawling questionnaire, testing protocol and communications plan. Between 1 October 2021 and 12 May 2023, 44 probable and three possible cases of HUAC were identified in Ireland with a median age of 3 years. Adeno-associated virus 2 (AAV2), detected in 18 of 31 probable cases, and SARS-CoV-2 antibodies in 22 of 37 of probable cases were the most common infectious agents, followed by human herpes virus 7 (18/33) and adenovirus (20/44). Immunological findings included the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele in 17 of 32 cases. Autoantibodies were found in 15 of 40 patients. Our findings corroborate those of the UK, which suggested a link between HUAC and AAV2 and another virus, in children predisposed due to presence of a particular HLA class II type. Close collaboration with the UK, the European Centre for Disease Prevention and Control (ECDC) and World Health Organization (WHO) was invaluable in the investigation.

关键词： TNF-alpha   TNF-alpha receptors   TNF-alpha-binding peptide   TNFR1-binding peptide   TNFR2-binding peptide   TNF-alpha inhibition   TNF-alpha blocker  

摘要： Tumor necrosis factor alpha (TNF-alpha) is a pro-inflammatory cytokine associated with TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2), which play important roles in several inflammatory diseases. There is a growing interest in developing alternative molecules that can be used as TNF blockers. In this study, we focused on TNF-alpha-, TNFR1-, and TNFR2-mimicking peptides to inhibit TNF-alpha receptor binding in various ways. Six peptides (OB1, OB2, OB5, OB6, OB7, and OB8) were developed to bind TNFR1, TNFR2, and TNF-alpha. OB1 and OB2 bound to TNF-alpha with lower Kd values of 300 and 46.7 nM, respectively, compared to previously published sequences. These synthetic peptides directly and indirectly inhibited TNF-alpha in vitro without cytotoxicity to L929 cells, and OB1 significantly inhibited apoptosis in the presence of hTNF-alpha. Peptides developed in this study may prove to be useful for therapeutic inhibition of TNF-alpha.

关键词： ADSCs   Myoblast   5-aza-C   IL-6   STAT1  

摘要： BackgroundEctopic fat is also formed in muscles as well as the liver, where adipose-derived mesenchymal stem cells (ADSCs) promote adipogenesis. On the other hand, after muscle injury, muscle satellite cells (SCs) contribute to muscle repair through myodifferentiation. Human ADSCs are multipotent stem cells, but it remains unclear whether they are involved in myoblast differentiation. The aim is to find a novel myogenic cytokine and its signaling pathway that promotes the differentiation of human ADSCs-a potential source of new muscle precursor cells-into *** array kit was used to detect cytokines produced by ADSCs. After treating ADSCs with the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-aza-C) and different JAK inhibitors, MyHC1, a myodifferentiation marker, was detected by immunofluorescence staining and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression status of signaling molecules was determined by Western blotting and the recruitment of transcription factors to the MYOG promoter by chromatin immunoprecipitation (ChIP).ResultsIL-6 was detected at high concentrations in the culture supernatant of ADSCs. ADSCs stimulated with 5-aza-C became strongly positive for MyHC1 on day 21 post-stimulation. When co-stimulated with 5-aza-C and IL-6/sIL-6R, ADSCs became positive for MyHC1 protein and upregulated MYOG mRNA as early as day 14 post-stimulation. Co-stimulation with 5-aza-C and IL-6/sIL-6R resulted in phosphorylation of STAT1 and STAT3. The addition of a JAK2 inhibitor, but not JAK1/3 inhibitors, abolished the MyHC1 positivity and phosphorylation of STAT1 and STAT3. Co-stimulation with 5-aza-C and IL-6/sIL-6R during the myogenesis process resulted in the recruitment of STAT1, but not STAT3, to the MYOG promoter. Myoblast differentiation induced by stimulation with 5-aza-C was enhanced by activation of the IL-6/JAK2/STAT1/MYOG ***, sustained IL-6/JAK2/STAT1 activation may ser

关键词： HIV latency   LRA   Piezo1   Yoda1   omics  

摘要： There is currently no cure for HIV because of the presence of latent viral reservoirs in people with HIV (PWH) on antiretroviral therapy (ART). Latency-reversing agents (LRAs) that can effectively reactivate and destroy latent HIV are being developed as a possible cure for HIV. Here, we identify Yoda1, a Piezo1 agonist, as a novel LRA. Yoda1 reactivated latent HIV in vitro ACH2 cells and ex vivo PBMCs from an HIV patient on ART. Yoda1 induced infectious virus production and HIV gene expression via Piezo1 activation and calcium signaling. Transcriptomic and proteomic analyses revealed a unique latent HIV reactivation pathway involving T cell activation, upregulation of TCR/CD3 and HLA genes, as well as modulation of host and viral transcription and translation that favors viral gene expression. These findings suggest further testing and development of Yoda1 as an effective LRA to reactivate latent HIV and destroy latent reservoirs for the cure of HIV.

摘要： T cell priming is characterized by an initial activation phase that involves stable interactions with dendritic cells (DCs). How activated T cells receive the paracrine signals required for their differentiation once they have disengaged from DCs and resumed their migration has been unclear. We identified a distinct priming phase that favors CD8 T cells expressing receptors with high affinity for antigen. CXCR3 expression by CD8 T cells was required for their hours-long reengagement with DCs in specific subfollicular niches in lymph nodes. CD4 T cells paused briefly at the sites of CD8 T cell and DC interactions and provided Interleukin-2 (IL-2) before moving to another DC. Our results highlight a previously unappreciated phase of cell-cell interactions during T cell priming and have direct implications for vaccinations and cellular immunotherapies.

关键词： IL-6   STAT3   colitis   Akkermansia muciniphila   Crohn's disease  

摘要： Background Inflammatory bowel disease is a long-standing inflammatory disorder that influences the intestinal tract. The intent of this research is to explore whether the relative abundance of Akkermansia muciniphila is related to the IL6/STAT3 pathway and the fundamental molecular mechanisms of A. muciniphila on a trinitrobenzene sulfonic acid (TNBS)-induced enteritis mouse model, including the expression of inflammatory cytokines and proteins in the IL6/STAT3 signaling *** The association between the A. muciniphila and IL6/STAT3 was investigated by using mucosal biopsies and fecal samples. TNBS-induced colitis mouse models were performed to elucidate the underlying mechanisms. The alteration of intestinal microbiota was organized by 16s rRNA *** In Crohn's disease patients, the level of STAT3 and IL-6 presented a negative relationship with A. muciniphila. The expression of IL-6, p-STAT3, and STAT3 was downregulated in A.m+TNBS group, indicating A. muciniphila may inhibit the IL6/STAT3 pathway in TNBS-induced enteritis in vivo. To investigate the potential defensive role of A. muciniphila supplementation in vivo with TNBS-induced enteritis, 16S rRNA sequencing was performed to analyze changes in the intestinal microbiota composition. The results revealed a marked increase in microbial diversity and abundance within the A. muciniphila-treated group, suggesting a beneficial modulation of the gut microbiome associated with the *** Our findings declared that A. muciniphila supplementation alleviates gastrointestinal inflammation through IL-6/STAT3 signaling pathway. This protective effect was mediated by the downregulation of the IL-6 and STAT3, highlighting a potential mechanism by which A. muciniphila modulates inflammatory responses. This work disclosed that A. muciniphila demonstrates a defensive influence against TNBS-induced enteritis in vivo, proposing it qualified as a unique therapeutic focusing on modulating

摘要： The function of islet macrophages is poorly understood. They promote glucose-stimulated insulin secretion (GSIS) in lean mice, however, the underlying mechanism has remained unclear. We show that activation of the free fatty acid receptor FFAR4 on islet macrophages leads to interleukin-6 (IL-6) release and that IL-6 promotes beta-cell function. This mechanism is required for GSIS in lean male mice, but does not function anymore in islets from people with obesity and obese type 2 diabetic male mice. In islets from obese mice, FFAR4 downstream signaling in macrophages is strongly reduced, resulting in impaired FFAR4-mediated IL-6 release. However, IL-6 treatment can still improve GSIS in islets from people with obesity and obese type 2 diabetic mice. These data show that a defect in FFAR4-mediated macrophage activation contributes to reduced GSIS in type 2 diabetes and suggest that reactivating islet macrophage FFAR4 and promoting or mimicking IL-6 release from islet macrophages improves GSIS in type 2 diabetes.