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关键词： Intestinal microbiota   Antiviral innate immunity   Zebrafish  

摘要： BackgroundEvidence has accumulated to demonstrate that intestinal microbiome can inhibit viral infection. However, our knowledge of the signaling pathways and identity of specific commensal microbes that mediate the antiviral response is limited. Zebrafish have emerged as a powerful animal model for study of vertebrate-microbiota interactions. Here, a rhabdoviral infection model in zebrafish allows us to investigate the modes of action of microbiome-mediated antiviral *** observed that oral antibiotics-treated and germ-free zebrafish exhibited greater spring viremia of carp virus (SVCV) infection. Mechanistically, depletion of the intestinal microbiome alters TLR2-Myd88 signaling and blunts neutrophil response and type I interferon (IFN) antiviral innate immunity. Through 16S rRNA sequencing of the intestinal contents from control and antibiotic(s)-treated fish, we identified a single commensal bacterial species, Cetobacterium somerae, that can restore the TLR2- and neutrophil-dependent type I IFN response to restrict SVCV infection in gnotobiotic zebrafish. Furthermore, we found that C. somerae exopolysaccharides (CsEPS) was the effector molecule that engaged TLR2 to mediate the type I IFN-dependent antiviral ***, our results suggest a conserved role of intestinal microbiome in regulating type I IFN antiviral response among vertebrates and reveal that the intestinal microbiome inhibits viral infection through a CsEPS-TLR2-type I IFN signaling axis in zebrafish.7E-apxbKV4cu6qTqgWcuKAVideo AbstractConclusionsTogether, our results suggest a conserved role of intestinal microbiome in regulating type I IFN antiviral response among vertebrates and reveal that the intestinal microbiome inhibits viral infection through a CsEPS-TLR2-type I IFN signaling axis in zebrafish.7E-apxbKV4cu6qTqgWcuKAVideo Abstract

关键词： Adoptive cell therapy - ACT   T cell Receptor - TCR   Solid tumor   Cytokine   Tumor infiltrating lymphocyte - TIL  

摘要： Background Adoptive T-cell therapy has demonstrated clinical activity in B-cell malignancies, offering hope for its application to a broad spectrum of cancers. However, a significant portion of patients with solid tumors experience primary or secondary resistance to this treatment modality. Target antigen loss resulting either from non-uniform antigen expression or defects in antigen processing and presentation machinery is one well-characterized resistance mechanism. Constitutively expressed membrane-anchored interleukin-12 (caIL-12) has demonstrated enhanced antitumor activity and low systemic exposure in multiple preclinical adoptive T-cell treatment models with homogeneous tumor antigen expression. In this study, we assess the therapeutic impact of caIL-12 on target antigen-negative variants in syngeneic mouse *** Target antigen-positive tumors were generated by transducing B16F10 melanoma cells (B16) or Lewis Lung Carcinoma cells (LLC) with a construct expressing the OVA antigen, SIINFEKL, tagged to ubiquitin (B16-U-OVA, LLC-U-OVA), while B16 or LLC tumors served as antigen-negative variants. C57BL/6J mice were subcutaneously injected with heterogeneous tumors composed of 80% B16-U-OVA and 20% B16. Bilateral tumors were established by injecting the left flank with B16-U-OVA or LLC-U-OVA tumors and the right flank injected with B16 or LLC tumors. The tumor-bearing mice then underwent 5.5 Gy total body irradiation, followed by adoptive transfer of OT-I TCR-T cells engineered with or without *** TCR-T cells (OT-I) delivered caIL-12 to the B16-U-OVA tumor sites and induced robust tumor control and survival benefits in mice bearing a heterogeneous tumor with OVA-negative variants. caIL-12 exerted its effect on OVA-negative B16 variants primarily by priming and activating endogenous antitumor CD8 T cells via antigen spreading. In addition, antigen spreading induced by OT-I-caIL-12 resulted in controlling OVA-negative tumors implanted at distant

关键词： 牛结节性皮肤病病毒   A27L蛋白   重组表达   单克隆抗体   IFA  

摘要： 本研究旨在获得牛结节性皮肤病病毒（LSDV）抗原A27L的重组蛋白并制备其单克隆抗体。对LSDV的A27L进行生物信息学分析，人工合成基因全长并构建至原核表达质粒pET15b上，在大肠杆菌BL21中重组表达并纯化。用该抗原免疫BALB/c小鼠，制备单克隆抗体，利用ELISA方法检测单抗与羊痘病毒的特异反应性，利用IFA的方法检测单抗与LSDV的反应特异性。结果显示，本研究成功获得了可溶的重组A27L重组蛋白，大小约为17 kDa，该抗原能够很好的识别牛结节性皮肤病阳性血清，与阴性血清无交叉反应；获得的1B7和3H10单抗能与A27L抗原及羊痘AV41疫苗毒发生特异性反应；IFA结果进一步显示，2株单克隆抗体能特异性识别LSDV，但是无法对LSDV和AV41进行区分。本研究的研究结果为建立羊痘病毒及牛结节性皮肤病病毒的检测方法、中和抗体的研发以及亚单位疫苗的开发奠定了基础。

摘要： Human umbilical cord mesenchymal stem cells (hUC-MSCs) have shown potential as a therapeutic option for lupus nephritis (LN), particularly in patients refractory to conventional treatments. Despite extensive translational research on MSCs, the precise mechanisms by which MSCs migrate to the kidney and restore renal function remain incompletely understood. Here, we aim to clarify the spatiotemporal characteristics of hUC-MSC migration into LN kidneys and their interactions with host cells in microenvironment. This study elucidates that the migration of hUC-MSCs to the LN kidney is driven by elevated levels of CXCL10, predominantly produced by glomerular vascular endothelial cells through the IFN-gamma/IRF1-KPNA4 pathway. Interestingly, the blockade of CXCL10-CXCR3 axis impedes the migration of hUC-MSCs to LN kidney and negatively impacts therapeutic outcomes. Single cell-RNA sequencing analysis underscores the importance of this axis in mediating the regulatory effects of hUC-MSCs on the renal immune environment. Furthermore, hUC-MSCs have been observed to induce and secrete interleukin 4 inducible gene 1 (IL4I1) in response to the microenvironment of LN kidney, thereby suppressing Th1 cells. Genetically ablating IL4I1 in hUC-MSCs abolishes their therapeutic effects and prevents the inhibition of CXCR3+ Th1 cell infiltration into LN kidneys. This study provides valuable insights into the significant involvement of CXCL10-CXCR3 axis in hUC-MSC migration to the LN kidneys and the subsequent remodeling of renal immune microenvironment. Regulating the CXCL10-CXCR3 axis and IL4I1 secretion may be developed as a novel therapeutic strategy to improve treatment outcomes of LN.

关键词： Antigens  

摘要： The binding of peptides to class-I Major Histocompability Complex (MHC) receptors and their subsequent recognition downstream by T-cell receptors are crucial processes for most multicellular organisms to be able to fight various diseases. Thus, the identification of peptide antigens that can elicit an immune response is of immense importance for developing successful therapies for bacterial and viral infections, even cancer. Recently, studies have demonstrated the importance of peptide-MHC (pMHC) structural analysis, with pMHC structural modeling methods gradually becoming more popular in peptide antigen identification workflows. Most of the pMHC structural modeling tools provide an ensemble of candidate peptide poses in the MHC-I cleft, each associated with a score stemming from a scoring function, with the top scoring pose assumed to be the most representative of the ensemble. However, identifying the binding mode, that is, the peptide pose from the ensemble that is closer to an unavailable native structure, is not trivial. Oftentimes, the peptide poses characterized as best by a protein-ligand scoring function are not the ones that are the most representative of the actual structure. In this work, we frame the peptide binding pose identification problem as a Learning-to-Rank (LTR) problem. We present RankMHC, an LTR-based pMHC binding mode identification predictor, which is specifically trained to predict the most accurate ranking of an ensemble of pMHC conformations. RankMHC outperforms classical peptide-ligand scoring functions, as well as previous Machine Learning (ML)-based binding pose predictors. We further demonstrate that RankMHC can be used with many pMHC structural modeling tools that use different structural modeling protocols.

关键词： 孤独症谱系障碍   胰岛素样生长因子-1   白介素-17A   诊断价值  

摘要： 目的 探讨胰岛素样生长因子-1（insulin-likegrowthfactor-1，IGF-1）和白介素-17A（interleukin-17A，IL-17A）在儿童孤独症谱系障碍（autismspectrumdisorder，ASD）中的诊断价值。方法 于2023年1月至2023年12月在武汉儿童医院儿童保健科招募1～6岁86例高度疑似ASD的患儿，采用精神障碍诊断和统计手册-5（DSM-5）筛选出ASD组和对照组，检测2组患儿的血清IGF-1及IL-17A水平。结果 确诊ASD组56例，占比65%（56/86）；ASD组血清IGF-1和IL-17A水平高于对照组，差异有统计学意义（P＜0.05）；分别对不同临床特征的血清IGF-1和IL-17A水平进行比较发现，ASD组血清IGF-1和IL-17A水平与年龄、性别比较差异均无统计学意义（P＞0.05）；重度ASD组的血清IL-17A水平高于轻中度组（P＜0.05），而重度与轻中度ASD2组间血清IGF-1水平差异无统计学意义（P＞0.05）；进行Logistic回归分析结果显示，血清IGF-1和IL-17A高表达是ASD发生的影响因素（OR＞1，P＜0.05）；ROC曲线分析表明，血清IGF-1和IL-17A水平单独及联合检测诊断ASD的曲线下面积（AUC）分别为0.644、0.630、0.720，联合检测诊断价值较高。结论 血清IGF-1和IL-17A具有早期诊断ASD的潜能，两者联合检测有利于提高ASD诊断价值。

关键词： HLA-G 3'UTR   Polymorphisms   Diplotypes   Unexplained pregnancy loss   Chromosome abnormality  

摘要： Objectives Human leukocyte antigen G (HLA-G) plays a crucial role in pregnancy. Pregnancy loss (PL) is caused by a variety of causes, such as fetal chromosomal abnormalities, maternal hypertension and diabetes, immune causes, spontaneous immune diseases, infections, unknown causes, etc. This study reports on the association of fetal HLA-G 3'UTR polymorphisms and diplotypes with chromosomally abnormal fetuses (CAF) or unexplained pregnancy loss (UPL). Methods A total of 552 specimens were collected and grouped by next-generation sequencing technology (NGS) and fetal survival: UPL (112 cases), CAF (170 cases) and control (258 cases). The polymorphisms of HLA-G 3'UTR in all samples were detected by Sanger sequencing. The genotypes, haplotypes and diplotypes of HLA-G 3'UTR were analyzed. The classification and regression tree (CART) analysis was used to evaluate the role of HLA-G diplotypes in predicting fetal outcomes. The correlations between CAF or UPL and maternal age, paternal age, times of miscarrage, times of delivery were analyzed by logistic regression. Results The frequencies of HLA-G + 2960del/del and + 3035CC genotypes were remarkablly increased in CAF than those in control group. The frequencies of HLA-G + 2960ins/del, + 3010CC, + 3035TC, + 3142GG, + 3187AA in CAF were significantly lower than those in normal fetuses. Through genetic models and logistic regression analysis, the dominant model of HLA-G 3'UTR genotypes [such as + 2960 (OR = 1.27, 95% CI = 1.05-1.54, p = 0.016), + 3010 (OR = 0.78, 95% CI = 0.63-0.97, p = 0.026), + 3035 (OR = 1.22, 95% CI = 1.00-1.49, p = 0.047), + 3142 (OR = 0.76, 95% CI = 0.62-0.95, p = 0.014) and + 3187 (OR = 0.80, 95% CI = 0.65-0.99, p = 0.041)] were dramatically associated with CAF. However, the frequencies of HLA-G + 3010GC, + 3142GC and + 3187AG in fetuses with UPL were memorably decreased than those in normal fetuses. No significant difference was found in the frequencies of HLA-G haplotypes in all groups. However, the

关键词： HLA-G antigens   Stomach neoplasm   Prognosis   Haplotypes   Clinical relevance   Tumor escape  

摘要： Gastric cancer ranks fifth in both world prevalence and lethality, with a 5-year survival of less than 30%. HLA-G, a non-classical class I HLA gene, has emerged as a potential marker for cancer susceptibility and prognosis due to its immunomodulatory properties. Its level of expression is regulated by polymorphisms in the 3' untranslated region (3'UTR) polymorphisms, which form various combined haplotypes (UTR-1 to -9). In this study, we examined HLA-G 3'UTR polymorphisms in paired tissue samples from 111 patients with gastric adenocarcinoma and 119 healthy controls. Polymorphism analysis was performed using PCR and Sanger sequencing, followed by statistical analysis using SNPStats software. Survival analysis was conducted using Kaplan-Meier curves and multivariate Cox regression models. High-expressor HLA-G 3'UTR haplotypes (UTR-1 and UTR-6) were significantly associated with gastric cancer susceptibility, indicating a potential role in tumor immune evasion. Additionally, the 14 base pair insertion/deletion polymorphism (14 bp I/D) emerged as a prognostic marker, with D/D genotype carriers showing lower survival rates compared to I/D and I/I genotype carriers. Our study highlights the clinical relevance of HLA-G polymorphisms in gastric cancer, suggesting their potential as prognostic markers and therapeutic targets. Further elucidation of HLA-G-related pathways could lead to personalized treatment strategies and improved patient outcomes in gastric cancer.