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关键词： HLA-DQB1   NGS   novel allele  

摘要： Five novel HLA-DQB1 alleles, HLA-DQB1*02:01:51, -DQB1*03:390:02, -DQB1*03:573, -DQB1*04:105 and -DQB1*05:03:39 in Russian donors.

关键词： Human leukocyte antigen   Micropolymorphism   Crystallography   HIV   Psoriasis  

摘要： Micropolymorphisms drastically shape the antigen presentation characteristics of human leukocyte antigen class I (HLA-I) molecules, with profound implications for immune responses and disease susceptibility. HLA-C*12:02 and HLA-C*12:03 are closely related HLA-I allotypes that differ by a single amino acid substitution (R97W) but exhibit distinct associations with disease. HLA-C*12:02 has been shown to provide protective effects against HIV infection, playing a crucial role in controlling viral replication and slowing disease progression, whereas HLAC*12:03 is associated with increased susceptibility to psoriasis. We determined the X-ray crystal structures of the two allotypes presenting MARELHPEY (MY9) and RAFPGLRYV (RV9). Peptide residues that function as anchors, as well as those accessible for T-cell antigen receptor (TCR) contact, were identified. Our results, combined with those of biochemical studies, demonstrated that the R97W variation alters the peptide-binding groove (PBG) volume and charge, leading to conformational and stability changes in pHLA-C*12 complexes and ultimately affecting peptide-binding preferences for the two HLA-C*12 allotypes. This research not only advances our understanding of the impact of HLA-I micropolymorphisms but also offers clues for the use of structure-guided therapeutics to interfere with peptide binding.

关键词： colorectal cancer   AIM2 inflammasome  

关键词： Foot rot   F.necrophorum   Skin explant   TNF-alpha   TNFR1   NF-kappa B  

摘要： Foot rot is a contagious disease caused by ***. It is responsible for economic losses in dairy farming. Studies on foot rot in dairy cows are focused on the isolation and identification of pathogens and treatment methods. Few studies have reported inflammatory changes in tissues and regulatory mechanisms following infection. Here, the effects of *** infection on the skin explants and skin fibroblasts between the toes of cattle were analyzed using histopathology and other techniques. *** infection increased the epidermal thickness and number of hair follicles and sebaceous glands. Other skin appendages exhibited varying degrees of necrosis, and a significant infiltration of inflammatory cells was noted in the interdigital skin explants. The expressions of pro-inflammatory cytokines (IL-1 beta and TNF-alpha) and key genes in the inflammatory signalling pathway (TNFR1 and NF-kappa B p65) were elevated. Treatment with the TNFR1 inhibitor CAY10500 reduced inflammatory cell infiltration and alleviated TNFR1 and p65 expression. An inflammatory cell model was established using different proportions of *** to infect BDF cells. *** infection significantly inhibited the proliferation and viability of BDF cells and enhanced the expression of TRADD, TRAF2, TNF-alpha, and IL-18. CAY10500 reduced the *** infection-induced inflammatory response and induced inflammatory responses in interdigital skin explants and BDF cells by inhibiting the TNF-alpha/TNFR1/NF-kappa B signaling pathway. In summary, these findings provide new insights into the mechanism of inflammatory responses in dairy cows with foot rot.

关键词： CD8+T cells   gastric cancer   IL36RN   prognosis   tumor microenvironment  

摘要： BackgroundGastric cancer (GC) remains a prevalent and lethal malignancy worldwide, underscoring the urgent need to identify novel therapeutic targets and elucidate the tumor microenvironment (TME) to enhance clinical ***36RN mRNA expression in GC tissues was analyzed using The Cancer Genome Atlas (TCGA) dataset. Bioinformatics approaches, cellular models, and clinical tissue microarrays were employed to investigate the functional role of IL36RN, its interactions within the TME, and its prognostic ***36RN expression was markedly upregulated in GC tissues and associated with unfavorable survival outcomes. Functional assays demonstrated that IL36RN silencing suppressed GC cell proliferation and invasion. Elevated IL36RN expression correlated with enhanced CD8+ T cell infiltration in the TME and served as an independent prognostic indicator in ***36RN represents a potential prognostic biomarker and therapeutic target in GC, offering novel avenues for precision oncology and immunotherapeutic intervention.

关键词： HLA   HLA-A*32:01:64   novel allele   sequencing-based typing  

摘要： HLA-A*32:01:64 differs from HLA-A*32:01:01:01 by one nucleotide substitution in codon 56 in exon 2.

关键词： antigen presentation   autoimmunity   diabetes   MHC  

摘要： Chimeric antigen receptor macrophage (CAR-M) therapy has shown great promise in solid malignancies;however, the phenotypic re-domestication of CAR-Ms in the immunosuppressive tumor niche restricts their antitumor immunity. We here report an in situ engineered chimeric interleukin (IL)-2 signaling receptor (CSR) for controllably manipulating the proinflammatory phenotype of CAR-Ms, augmenting their sustained tumoricidal immunity. Specifically, our in-house-customized lipid nanoparticles efficiently introduce dual circular RNAs into macrophages to generate CSR-functionalized CAR-Ms. The intracellular inflammatory signaling pathway of CAR-Ms can be stimulated with the IL-2 therapeutic via the synthetic IL-2 receptor, which induces the antitumor phenotype shifting of CAR-Ms. Moreover, hydrogel-mediated combinatory treatment with lipid nanoparticles and IL-2 remodels the immunosuppressive tumor microenvironment and promotes tumor regression in renal carcinoma animal models. In summary, our findings establish that the proinflammatory phenotype of CAR-Ms can be modulated by a synthetic IL-2 receptor, benefiting the antitumor immunotherapy of CAR-Ms with broad application in other solid malignancies.