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关键词： HLA-DRB1   NGS   novel allele  

摘要： Five novel HLA-DRB1 alleles, HLA-DRB1*03:219, HLA-DRB1*04:171:02, HLA-DRB1*04:392, HLA-DRB1*11:01:52 and HLA-DRB1*11:342, were identified.

关键词： iPSC   Chimeric Antigen Receptor   Dendritic cell  

摘要： Background & AimImmunotherapy based on T cells expressing CARs has been shown to be a promising strategy for treating hematological tumors. However, similar results have not been reported for solid tumors. Therefore, other immune cells have been explored to express CARs for immunotherapy applications. Dendritic cells are a heterogeneous cell population specialized in antigen presentation, with great migratory capacity, representing good candidates for solid tumor therapies. Due to their scarcity in peripheral blood and low proliferative potential, an " off-the-shelf" source such as induced pluripotent stem cells is needed to enable their use in cell therapy. Thus, our aim is to develop iPSC-DCs expressing CAR as an alternative treatment for solid tumors. MethodologyElectroporation of the piggyBac transposon system was utilized to insert a CAR into an iPSC line. Differentiation of CAR-iPSCs was carried out following an established step-by-step protocol: (A) embryoid body formation, (B) generation of hematopoietic stem-like cells and (C) production of immune myeloid-like cells. Subsequently, differentiation into myeloid immune cells was induced using GM-CSF and IL-4 after 30 days. Flow cytometry was employed to analyze the phenotype of the differentiated cells. Co-culture of CAR-iPSC-DC cells with T cells was performed to observe induction of T cell proliferation. ResultsWe have achieved an initial transfection efficiency of 2%. Sequential cell sorting increased the purity of CAR-expressing cells to 95%, with stable expression maintained for over 40 days. We obtained differentiated cells with typical myeloid immune cell morphology, including a few macrophage-like cells, with large cytoplasmic vacuoles and numerous cells with dendrite projections, closely resembling DC morphology. Moreover, cells presented a HLA-DR+CD64lowXCR1high phenotype, similar to cDC1 found in PB. Preliminary data showed that these cDC1-like cells are able to induce CD3+ T cell proliferation in v

关键词： Intervertebral disc degeneration   Nucleus pulposus cells   KMT2D   miR-133a-5p   PFKFB2  

摘要： Background. Intervertebral disc (IVD) degeneration (IVDD) is characterized by structural destruction accompanied by accelerated signs of aging. This study aimed to investigate the mechanism of lysine methyltransferase 2D (KMT2D) in the proliferation, apoptosis, and inflammation of nucleus pulposus cells (NPCs) in IVDD. Methods. Mouse-derived NPCs were cultured and induced with interleukin-1 beta (IL-1(3) to establish cell models. KMT2D expression was detected by western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). KMT2D expression was interfered with, and the contents of IL-18, IL-6, and tumor necrosis factor (TNF) were detected by enzyme-linked immunosorbent assay. Cell proliferation, apoptosis, and the expression of miR-133a-5p and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2) were measured. The enrichment of KMT2D and Histone 3 Lysine 4 monomethylation/dimethylation (H3K4me1/2) on the miR-133a-5p promoter was analyzed by chromatin immunoprecipitation and qPCR. The binding of miR-133a-5p and PFKFB2 was analyzed by a dual-luciferase assay. Results. IL-1 (3 treatment promoted KMT2D expression in NPCs. KMT2D knockdown reduced inflammation and apoptosis and promoted the proliferation of IL-1(3-induced NPCs. Mechanistically, KMT2D upregulated miR-133a-5p expression by increasing the level of H3K4me2 at the miR-133a-5p promoter, thereby promoting the binding between miR-133a-5p and PFKFB2 and downregulating the transcription of PFKFB2. miR-133a-5p overexpression or PFKFB2 knockdown alleviated the protective effect of KMT2D knockdown on IL-1(3-induced NPCs. Conclusion. KMT2D promoted miR-133a-5p expression through H3K4me2 methylation, thereby promoting the binding of miR-133a-5p to PFKFB2, reducing the mRNA level of PFKFB2, promoting inflammation and apoptosis of IL-1(3-induced NPCs, and inhibiting NPC proliferation.

关键词： 3 beta-hydroxy-5-cholestenoic acid   fibrosis   hepatic steatosis   IL22RA1   oxysterol  

摘要： Background and Aims: An imbalance in lipid metabolism is the main cause of NAFLD. While the pathogenesis of lipid accumulation mediated by extrahepatic regulators has been extensively studied, the intrahepatic regulators modulating lipid homeostasis remain unclear. Previous studies have shown that systemic administration of IL-22 protects against NAFLD;however, the role of IL-22/IL22RA1 signaling in modulating hepatic lipid metabolism remains uncertain. Approach and Results: This study shows that hepatic IL22RA1 is vital in hepatic lipid regulation. IL22RA1 is downregulated in palmitic acid-treated mouse primary hepatocytes, as well as in the livers of NAFLD model mice and patients. Hepatocyte-specific Il22ra1 knockout mice display diet-induced hepatic steatosis, insulin resistance, impaired glucose tolerance, increased inflammation, and fibrosis compared with flox/flox mice. This is attributed to increased lipogenesis mediated by the accumulation of hepatic oxysterols, particularly 3 beta-hydroxy-5-cholestenoic acid (3 beta HCA). Mechanistically, hepatic IL22RA1 deficiency facilitates 3 beta HCA deposition through the activating transcription factor 3/oxysterol 7 alpha-hydroxylase axis. Notably, 3 beta HCA facilitates lipogenesis in mouse primary hepatocytes and human liver organoids by activating liver X receptor-alpha signaling, but IL-22 treatment attenuates this effect. Additionally, restoring oxysterol 7 alpha-hydroxylase or silencing hepatic activating transcription factor 3 reduces both hepatic 3 beta HCA and lipid contents in hepatocyte-specific Il22ra1 knockout mice. Conclusions: These findings indicate that IL22RA1 plays a crucial role in maintaining hepatic lipid homeostasis in an activating transcription factor 3/oxysterol 7 alpha-hydroxylase-dependent manner and establish a link between 3 beta HCA and hepatic lipid homeostasis.

关键词： aspergillus   IL-6 signaling   inflammation   influenza   influenza associated pulmonary aspergillosis  

摘要： Viral infections increase host susceptibility to opportunistic pathogens like Aspergillus fumigatus (AF), exacerbating disease severity and prolonging its clinical course. Interleukin-6 (IL-6) drives pathological inflammation in viral infections such as COVID-19, but its role in influenza, particularly with secondary AF infection, remains unclear. Using a mouse model of post-influenza AF infection, including IL-6 knockout mice, we found that IL-6 signaling promotes neutrophilic lung inflammation but is not required for pathogen clearance of either influenza or AF. However, IL-6 deficiency increases epithelial cell damage, as indicated by elevated RAGE levels in bronchoalveolar lavage fluid. In contrast, lung capillary permeability (measured by IgM levels in BAL) and tissue injury (assessed histologically) remain unaffected in the absence of IL-6 signaling. These findings reveal a nuanced role for IL-6 in post-influenza AF infection, underscoring its contribution to lung inflammation and epithelial integrity.

关键词： Bayes theorem   ethnicity   haematopoietic stem cells   haplotypes   HLA   registries  

摘要： While the World Marrow Donor Association global database currently offers approximately 42.7 million potential donors and cord blood units to patients in need of haematopoietic cell transplant, lack of eight HLA-matched donors remains a significant barrier. The Registry of Unmet Need (RUN) Project seeks to address disparities in transplant access for patients with rare HLA genotypes, particularly those from populations that have been historically underrepresented and underserved by global donor registries. Patients eligible for this study searched for an unrelated donor for transplant between 2015 and 2017 and, at that time, lacked a potential eight-of-eight HLA-matched unrelated donor (MUD). Sixteen donor registries contributed data from 3654 patients using standardised data-collection project templates. To address this unmet need, pooled data were analysed to identify trends and inform global recruitment strategies. Patient genotypes were queried against the global inventory at later timepoints in 2018 and 2023 to determine whether potential matches had been recruited within the years since the initial search. Patient haplotypes were imputed using an open-source method referencing US population frequencies. The imputation process used five continental reference populations and 21 detailed populations derived from the NMDP database. The method provided a Bayesian inference of population membership. A control group consisting of US patients that yielded 1000 or more potential matches was used for comparison. RUN patient haplotype and genotype frequencies were substantially lower compared with controls;both the more frequent and less frequent haplotypes in RUN patients were found to be approximately 100 times less common than those in the control group. We identified 782 potential cases in which a potential MUD was recruited after the initial RUN patient search was performed;while this result is being further investigated, clear patterns of where these new matches ca

关键词： Rheumatoid arthritis   WGCNA   Immune cell  

摘要： Purpose: Rheumatoid arthritis (RA) is an immune system disorder disease accompanied with severe joint damage. However, the molecular mechanism of RA with insensitive to medicine remains insufficient. Thus, this study aims to identify the biomarkers of RA patients with inadequate responses (IR) toward disease-modifying antirheumatic drug (DMARD) and antitumor necrosis factor (TNF) therapies, using multidimensional analyses. Methods: Gene expression data GSE45291 originating from clinics were downloaded from the Gene Expression Omnibus public database (GEO). Differentially expressed genes (DEGs) closely associated with DMARD&TNF-IR RA were identified using the Limma R package. Weighted gene co-expression network analysis (WGCNA) was carried out to identify critical genes. The CIBERSORT algorithm and single sample Gene Set Enrichment Analysis (ssGSEA) were employed for immune infiltration analysis and functional enrichment analysis, respectively. Lastly, mRNA expression levels of the identified hub genes in inflammatory conditions of collagen-induced arthritis (CIA) rats and lipopolysaccharide (LPS)-induced RAW264.7 cells were further observed using RT-qPCR. Results: In this work, a total of 17 genes were identified as hub genes. Of these, the expression levels of UHMK1, ELK4, APOC2, and SFT2D1 were significantly lowered in inflammatory conditions. GSEA indicated B cells with the immune-related genes play an essential role in the course of DMARD&TNF-IR RA. Notable differences in immune cell proportions (activated. Dendritic. cell, CD56 bright. Natural. killer. Cell, gamma. Delta. T. cell, MDSC, macrophage) were observed between normal and disease groups, suggesting immune involvement. Conclusion: The findings of this study provide additional understanding of the detection of DMARD&TNF-IR RA.

关键词： BPS   3-Indoleglyoxylic Acid   Mitochondrial   Organoids  

摘要： Bisphenol S (BPS) has become extensively used in the manufacturing of consumer products. BPS mainly enters the body through food and water, with oral exposure targeting the gastrointestinal tract. However, its safety profile remains contentious and warrants further investigation. In this study, we aimed to assess whether BPS exerts harmful effects on the body in the absence of overt pathological damage. Our results revealed that although BPS did not lead to significant histopathological damage, it induced intestinal barrier dysfunction. Additionally, in vitro investigations utilizing NCM460 cells and human-derived colorectal organoids demonstrated that BPS exposure induced mitochondrial reactive oxygen species (ROS) levels in intestinal endocrine cells (EECs), upregulating the expression of inflammatory mediators TNF-alpha and CXCL10. Using a DSS-induced colitis mouse model, it was found that BPS exposure exacerbates the progression of intestinal inflammatory diseases. Analysis of single-cell databases demonstrated a significant reduction in the expression of CHGA, a functional protein of enteroendocrine cells (EECs), in patients with inflammatory bowel disease (IBD). The expression of CHGA showed a significant negative correlation with the expression of IL17. Notably, supplementation with 3-Indoleglyoxylic acid effectively mitigates the intestinal damage induced by BPS. These findings highlight the role of mitochondrial oxidative stress and IL-17/CXCL10/TNF-alpha signaling in BPS-induced intestinal damage and demonstrate the therapeutic potential of 3-Indoleglyoxylic acid in mitigating these effects.