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关键词： COVID 19   Genetic networks   Gene regulation   Gene regulatory networks   Gene expression   Network analysis   Permutation   Phenotypes  

摘要： COVID-19, severe acute respiratory syndrome coronavirus 2, rapidly spread worldwide. Severe and critical patients are expected to rapidly deteriorate. Although several studies have attempted to uncover the mechanisms underlying COVID-19 severity, most have focused on the perturbations of single genes. However, the complex mechanism of COVID-19 involves numerous perturbed genes in a molecular network rather than a single abnormal gene. Thus, we aimed to identify COVID-19 severity-specific markers in the Japanese population using gene network analysis. In order to reveal the severity-specific molecular interplays, we developed a novel computational network biology strategy that measures dissimilarity between networks based on the comprehensive information of gene network (i.e., expression levels of genes and network structure) by using Kullback-Leibler divergence. Monte Carlo simulations demonstrated the effectiveness of our strategy for differential gene network analysis. We applied this method to publicly available whole blood RNA-seq data from the Japan coronavirus disease 2019 Task Force and identified differentially regulated molecular interplays between 368 severe and 105 non-severe samples. Our analysis suggests the gene network between HLA class II, CIITA, and CD74 as a COVID-19 severity specific molecular marker. Although the association between HLA class II and COVID-19 has been demonstrated, our data analysis revealed that the molecular interplay of HLA class II with its target and/or regulator is a crucial marker for COVID-19 severity. Our findings from computational network biology analysis suggest that suppression and activation of the molecular interplay between HLA class II, CIITA, and CD74 provide crucial clues to uncover the mechanisms of COVID-19 severity.

关键词： multiepitope based vaccines   leishmaniosis   visceral leishmaniosis   HLA class I and class II promiscuous epitopes   Leishmania conserved antigens  

摘要： Introduction No vaccine is currently licensed against human visceral leishmaniasis (VL), a fatal CD4+ T cell immunosupressive disease against which chemotherapy is reduced to a few toxic drugs. The NH36 nucleoside hydrolase is a DNA metabolism vital enzyme present in all Leishmania species. A vaccine based on such a conserved antigen could protect against both VL and cutaneous leishmaniasis, whose epidemics geographically overlap. Increased frequencies of NH36-specific IL-2+TNF-alpha+IFN-gamma+-producing CD4+ T cells were associated with VL immune *** the sequences of HLA-Class I and Class II T cell epitopes were predicted in the NH36 peptide sequence using the Tepitope, Propred, IEDB and NetMHCpan EL 4.1 immune informatic tools. The epitopes were synthetized and used to study their reactivity with sera samples, and to stimulate the in vitro response of PBMC of human patients cured from VL, asymptomatic individuals and healthy blood donors of a non-endemic area. Cytokine production was studied intracellularly by flow cytometry (ICS) and cytokine secretion was measured in PBMC supernatants. The HLA typing of DNA patients and the analysis of epitope conservancy in the Leishmania genus were obtained. Two recombinant multiepitope proteins were designed, cloned in E. coli, expressed, purified and used for in vitro stimulation of PBMC of VL cured and asymptomatic *** We identified in silico fifteen NH36 conserved epitopes that correspond to promiscuous binders of HLA-DR, -DQ, -DP class II molecules, as well as HLA-A, B and C class I molecules. Collectively, these epitopes provide high worldwide population coverage of both class I and II alleles, and bound to alleles associated with VL susceptibility and resistance. VL asymptomatic individuals showed maximal frequencies of CD4+ and CD8+ multifunctional IL-2+TNF-alpha+IFN-gamma+-producing T lymphocytes in response to these epitopes, with secretion of TNF-alpha, IL-1 beta and IL-6. Two recombinant

关键词： colorectal cancer   EMT   extracellular vesicles   macrophage  

摘要： Emerging evidence shows that extracellular vesicles (EVs)-mediated cargo shuttling between different kinds of cells constantly occurs in the tumor microenvironment, leading to the progression of a variety of cancers, but the biological role of DNA enriched in EVs has not been fully elucidated. Here, nuclear chromatin-originated DNA fragments were identified in human serum-derived EVs and exhibited a mild increase in the colorectal cancer patient group, unveiling their potential as a biomarker for cancer diagnosis. Molecular experiments showed that chromatin and mitochondrial DNA fragments adhered to the outer membrane of EVs were released from colorectal cancer cells and transported into macrophages where they stimulated STING signaling cascades, resulting in enhanced STAT1 phosphorylation and IL6 production. Further experiments revealed that STAT1 functioned as a potential IL6 transcription regulator through directly locating at its promoter regions to facilitate IL6 expression in macrophages. In the tumor microenvironment, the accumulated IL6 released by macrophages, in turn, provoked colorectal cancer cell epithelial to mesenchymal transition (EMT) through activating IL6R/STAT3 signaling. Our findings highlighted the importance of DNA carried by EVs in shaping the tumor environment and revealed their potential as a clinical diagnostic biomarker for colorectal cancer.

关键词： keloid   keratinocyte   inflammation   IL-33   epidermis  

摘要： Introduction Keloids are benign fibroproliferative disorders characterized by excessive collagen deposition and inflammation that extend beyond the original wound boundaries. IL-33 is an alarmin cytokine released upon cellular damage or stress. Dysregulation of IL-33 in epidermal keratinocytes compromises the skin barrier and triggers chronic *** In this study, we first noticed an increased expression of IL-33 in the keratinocytes of keloid epidermis through histological staining. Then, an increased expression of IL-33 receptor (ST2) in the lymphocytes infiltrating the superficial dermis of keloid scars were identified through histological staining and flow cytometry analysis. The IFN-gamma-IL-33 loop between lymphocytes and keratinocytes were further revealed by flow cytometry and Western blotting analysis. The abnormal keratinocyte differentiation in epiderm is mediated by IFN-gamma-IL-33 loop were confirmed by in vitro studies in HaCaT cells via Western blotting analysis and immunofluorescence staining. Finally, the IFN-gamma-IL-33 loop were also verified in cocultured peripheral blood mononuclear cells and HaCaT through ELISA *** Our results demonstrate that IL-33 levels are significantly elevated in the epidermis of keloid tissues, where it functions as an alarmin, promoting a chronic inflammatory response. We further reveal a feedback loop between IL-33 and interferon-gamma (IFN-gamma), whereby IL-33 induces IFN-g production in lymphocytes, which in turn stimulates keratinocytes to produce more IL-33. This loop contributes to impaired keratinocyte differentiation and skin barrier dysfunction, exacerbating the inflammatory *** By elucidating the role of the IL-33/ST2 axis in keloid formation, this research provides valuable insights into potential therapeutic targets for managing this challenging condition.

关键词： 母胎界面   IL-33   蜕膜免疫细胞   Maternal-Fetal Interface   IL-33   Decidual Immune Cells  

摘要： 白细胞介素-33 (IL-33)是一种与多种免疫调节过程相关的细胞因子，它在免疫调节、炎症反应以及多种疾病的发生发展过程中发挥着重要作用，亦在维持妊娠状态下的免疫稳态中扮演重要角色。母胎界面由滋养细胞、蜕膜基质细胞及蜕膜免疫细胞构成，其中蜕膜免疫细胞包括自然杀伤(NK)细胞、T细胞、B细胞、巨噬细胞、树突状细胞等。妊娠过程中，胎儿对于母体而言为同种半异体移植物，因此保持母胎界面的免疫平衡尤为重要，而本文通过研究IL-33对于蜕膜免疫细胞的影响及相关机制的研究进展，从而进一步探索了妊娠过程中母胎局部免疫平衡的维持。

关键词： 肺炎链球菌   补体系统   免疫逃避   表面蛋白   Streptococcus Pneumoniae   Complement System   Immune Evasion   Pneumococcal Surface Proteins  

摘要： 尽管抗生素及疫苗的使用降低了肺炎链球菌肺炎的发病率及病死率，肺炎链球菌性疾病仍然是全球5岁以下儿童感染和死亡的常见原因。补体系统对肺炎链球菌的免疫防御相关研究众多，研究表明肺炎球菌表面蛋白在限制补体介导的免疫系统的溶菌过程和吞噬过程中发挥了重要的作用。本文综述了肺炎链球菌表面蛋白为逃避机体补体系统介导的免疫反应的机制，为后续相关研究开展提供借鉴。

关键词： Caspase-1   IL-1   高血压   冠状动脉病变   Caspase-1   IL-1   Hypertension   Coronary Artery Disease  

摘要： 目的：探讨高血压患者血清含半胱氨酸的天冬氨酸蛋白水解酶-1 (Caspase-1)、白细胞介素-1β (IL-1β)水平与冠状动脉病变的关系。方法：选取2022年11月至2024年11月期间在包头医学院第一附属医院进行冠状动脉造影检查的高血压患者121例(高血压组)和同时段体检健康人群40例(对照组)。比较两组患者一般资料，通过酶联免疫吸附测定法检测两组血清Caspase-1、IL-1β水平，通过多元无序Logistic回归分析模型分析其对高血压患者冠状动脉病变的诊断价值。结果：与对照组相比，高血压组患者血清Caspase-1、IL-1β水平升高(P < 0.05)。冠心病组血清Caspase-1、IL-1β水平高于冠状动脉粥样硬化组和造影正常组，冠状动脉粥样硬化组血清Caspase-1、IL-1β水平高于造影正常组(P < 0.05)。多元无序Logistic回归分析模型分析后显示，高血压组患者中年龄增加是冠心病及冠状动脉粥样硬化的独立危险因素(P < 0.05)；Caspase-1降低、IL-1β降低为冠心病及冠状动脉粥样硬化的独立保护因素(P < 0.05)。结论：高血压病人血清Caspase-1、IL-1β水平，与冠状动脉病变具有一定诊断价值，高血压病人血清Caspase-1、IL-1β水平升高与患者冠脉病变发生密切相关。

关键词： Neuroinflammation   Interleukin-17A   Amyloid-beta   Alzheimer's disease  

摘要： Proinflammatory cytokines, especially interleukin-17 A (IL-17 A) have been found to be significantly associated with AD patients. IL-17 A amplifies neuroinflammation during AD pathology. This study highlighted the ability of IL-17 A to exacerbate amyloid-beta-induced pathology in animals. The AD pathology was induced with repeated intranasal administration of A beta along with recombinant mouse IL-17 A (rmIL-17) at 1, 2 and 4 mu g/kg for seven alternate days. Although, the combination of rmIL-17 and A beta did not have severe effects on memory of the animals, but it drastically increased the IL-17 A mediated signaling, level of proinflammatory cytokines, oxidative stress and reduced antioxidants in the hippocampus and cortex regions of the animal brains. Interestingly, combining rmIL-17 with A beta also triggered the expression of AD structural markers like pTau, amyloid-beta and BACE1 in the brain regions. Furthermore, rmIL-17 with A beta exposure stimulated astrocytes and microglia leading to activation of proinflammatory signaling in the brain of the animals. These results showed the propensity of IL-17 A to promote severity of AD pathology and suggest IL-17 A as potent therapeutic target to control AD progression.

关键词： interferon-gamma   Crohn's disease   intestinal epithelial cell   intestinal organoid   enteroid   programmed cell death   PANoptosis   selective JAK1 inhibitor  

摘要： Background Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) and is considered a Th1-mediated disease, supported by the over-expression of interferon-gamma (IFN-gamma) in the intestinal lamina propria. IFN-gamma has a pleiotropic effect on the intestinal epithelial cells (IECs), suggesting that IFN-gamma-induced responses may differ between epithelial cell *** We established human small intestinal organoids (enteroids) derived from non-IBD controls and CD patients. Using human enteroids, the major response of IECs induced by IFN-gamma was evaluated, focusing on the IFN-gamma-induced programmed cell death (PCD) pathway. Identified IFN-gamma-induced responses were validated in surgically resected intestinal samples and publicly available single-cell RNA-sequencing *** IFN-gamma stimulated programmed cell death (PCD) of IECs in both control and CD enteroids in a dose-dependent manner. Pyroptosis, apoptosis. and necroptosis were activated in enteroids, suggesting that PANoptosis was the main process of IFN-gamma-induced PCD in IECs. The response to IFN-gamma depends on the cell type of the IECs. IFN-gamma induced depletion of enterocytes with upregulation of PANoptosis-associated genes, while leading to expansion of goblet cells without significant change in PANoptosis-associated gene expression. Individual PCD inhibitors were insufficient to block IFN-gamma-induced cytotoxicity, whereas the selective JAK1 inhibitor (upadacitinib) effectively blocked IFN-gamma-induced cytotoxicity and PANoptosis. Furthermore, PANoptosis was significantly activated in surgically resected tissues and in publicly available single-cell RNA-sequencing datasets of intestinal tissues from patients with *** IFN-gamma induces PANoptosis in enterocytes, which can be treated with a selective JAK1 inhibitor in patients with CD.

关键词： GDM   IDO   HLA-G   联合表达   GDM   IDO   HLA-G   Joint Expression  

摘要： 妊娠期糖尿病(GDM)是妊娠期间常见的糖代谢异常疾病。本文探讨了吲哚胺2,3-双加氧酶(IDO)与人类白细胞抗原-G (HLA-G)两种免疫调节分子在GDM中的表达及临床意义。本文指明IDO在妊娠期间的活性增加有助于保护胎儿免受母体免疫系统的攻击，但在GDM条件下会造成IDO活性降低。HLA-G通过抑制免疫细胞功能维持母胎间免疫平衡，但GDM会导致血清中可溶性HLA-G水平下降甚至变异。IDO活性降低和HLA-G表达变化提示免疫耐受受损，联合检测这两种分子可为GDM的早期诊断、病情监控及治疗评估提供重要信息。