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摘要： Genetic variation in the human leukocyte antigen (HLA) region is thought to influence susceptibility to and severity of a variety of infectious diseases. Several studies have explored a possible relationship between HLA genetics and SARS-CoV-2 infection, although mixed results, small sample sizes, and difficulty controlling for exposure risk have made it difficult to draw firm conclusions. Here, a dataset of 419,234 subjects with HLA genotype data and COVID-19 PCR test results was studied. A baseline analysis was performed to examine the association of non-HLA factors on COVID-19 positivity. Then, multivariate logistic regressions, incorporating single and paired HLA alleles, were performed and then corrected for significant factors from the baseline analysis. Proxies for socioeconomic status and exposure risk were significantly associated with COVID-19 positivity across all ancestry groups studied. Forty-one single HLA alleles displayed significant association with COVID-19 positivity;after controlling for socioeconomic status and exposure risk, only eight significant associations remained. Additionally, two HLA allele pairs were associated with test positivity after correction. Of all variables, socioeconomic status showed the greatest effect size. The results from this study suggest that many, if not all, of the reported associations between HLA alleles and SARS-CoV-2 infection may be spurious, owing to confounding factors.

关键词： depression   Il1r1   oxidative stress   lipid metabolism   diagnostic potential   mendelian randomization   drug target  

摘要： Background Depression is a complex mental disorder where oxidative stress and lipid metabolism disorders play crucial roles, yet their connection requires further exploration. This study aims to investigate the roles of oxidative stress and lipid metabolism disorders in depression using bioinformatics methods and Mendelian randomization *** A differential gene expression analysis was performed on the GSE76826 dataset, followed by identification of the intersection with genes related to OS. Subsequently, support vector machine (SVM) and random forest algorithms were employed to determine the optimal division of feature variables. The diagnostic performance was evaluated using a ROC diagnostic model and Diagnostic Nomogram. Furthermore, Mendelian randomization (MR) analysis was conducted to explore the causal relationship between the gene and depression. The expression patterns of key genes in brain tissue were analyzed using the Human eFP Browser database, while their associations with metabolism-related genes were investigated using the STRING database. Finally, DrugnomeAI was utilized to assess the drug development potential of these genes, and small molecule compounds targeting them were identified through dgidb and ChEMBL databases;molecular docking studies were then conducted to evaluate their binding *** By conducting a comprehensive analysis of oxidative stress-related genes and depression-related target genes, we have successfully identified 12 overlapping genes. These 12 genes were selected using support vector machine and random forest algorithms. Upon analyzing the diagnostic model, it was revealed that EPAS1 and IL1R1 serve as key biomarkers for OS in depression, with IL1R1 exhibiting the highest diagnostic potential among them. Additionally, MRfen analysis suggests that IL1R1 may play a protective role against depression. Notably, this gene exhibits high expression levels in crucial brain regions such as the olfactory bulb, corp

关键词： Lung cancer   Abscopal effect   Microwave ablation   alpha-PD-L1  

摘要： Background and purpose: Microwave ablation (MWA) has demonstrated promising potential in instigating an antitumor immune response, potentially resulting in the regression of distant tumors. Nevertheless, the observed abscopal effect remains modest, and its underlying mechanism remains poorly elucidated. This study aims to systematically examine the utilization of alpha-PD-L1 to enhance the abscopal effect induced by MWA and to comprehensively investigate the associated mechanisms. Methods: The Lewis lung cancer model was employed to investigate the abscopal effect of MWA and alpha-PD-L1 co- treatment. The maturation status of bone marrow-derived dendritic cells (BMDCs) was observed after stimulating with the fragments of tumor cells harvested by microwave treatment. Flow cytometry analysis was employed to scrutinize the ratio of T cells and dendritic cells, along with the quantification of IFN-gamma and GzmB expression levels. The expression of CXCL9 or PD-L1 was detected by immunofluorescence. Results: Local MWA treatment on one site of tumor did not yield a significant reduction in the volume of distant tumors. However, when combined with intraperitoneal alpha-PD-L1 injection, a notable abscopal effect was induced, resulting in decreased distant tumor volume and prolonged survival in mice. Flow cytometry analysis revealed an increase in infiltrating and activated CD8+ T cells in distant tumors, with up-regulation of IFN-gamma and GzmB expression. Notably, the expression of CXCR3 was increased in CD8+ T cells. The mRNA and protein levels of CXCL9 were elevated within distant tumors, concomitant with increased infiltration of macrophages. Moreover, dendritic cells (DCs) in tumor-draining lymph nodes (TDLNs) exhibited enhanced maturation. Additionally, in vitro experiments showed enhanced maturation of BMDCs following stimulation with fragments of Lewis cells harvested via microwave treatment. Conclusions: MWA exhibited the potential to stimulate systemic immune resp

关键词： immunotherapy   immune checkpoint inhibitor   cancer   atezolizumab   gilvetmab   corticosteroid   IL-12   prednisolon  

摘要： Background Immunotherapy using immune checkpoint inhibitors (ICIs) represents a promising therapeutic approach for canine cancer patients. Similar to human cancer patients, the concurrent use of corticosteroids may attenuate the efficacy of immune checkpoint inhibitors in dogs. In this study, we evaluated the impact of corticosteroid therapy on canine peripheral blood mononuclear cell (cPBMC) composition and the in vitro response to Programmed Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) axis blockade and recombinant human Interleukin-12 (rhIL-12) *** cPBMC samples were collected from 24 healthy, 44 cancer-bearing untreated, and 33 cancer-bearing corticosteroid pre-treated dogs. Lymphocytes were polyclonally stimulated with Staphylococcal Enterotoxin B (SEB) and either atezolizumab, a cross-functional anti-PD-L1 ICI, or rhIL-12. We analyzed the absolute and relative changes in canine interferon-gamma (cIFN gamma) production. Stimulation with gilvetmab, a recently developed canine anti-PD-1 ICI, revealed comparable results to atezolizumab. Moreover, we assessed the influence of corticosteroid pre-treatment on cPBMC composition by flow *** Corticosteroid treatment significantly affected the immune profile, primarily the monocytic compartment, and functional cIFN gamma response of cPBMCs. Nevertheless, responses to immunotherapy appeared to be highly *** Overall, we observed trends suggesting that prior corticosteroid therapy may compromise the efficacy of PD-1/PD-L1 axis blockade and IL-12 in dogs with cancer. While the dose and timing of corticosteroid administration in this study reflected clinical reality and would not justify withholding this emerging therapeutic option, corticosteroid pretreatment may be a confounder for PD-1/PD-L1 axis blockade or IL-12 therapy in canine oncology.

关键词： 副溶血弧菌   Ⅲ型分泌系统   vopD基因   生物学特性   多克隆抗体制备  

摘要： 【背景】副溶血弧菌（Vibrio parahaemolyticus， Vp）是一种重要的人兽共患病病原菌，能够引发食源性肠胃炎。Ⅲ型分泌系统（type Ⅲ secretion systems， T3SS）是一种复杂的纳米机器，能够将效应蛋白递送至真核细胞。副溶血弧菌有两套Ⅲ型分泌系统（T3SS1和T3SS2），其中VopD作为T3SS1的易位子，参与效应蛋白的递送，然而VopD的具体生物学功能尚未阐明。【目的】进一步探讨VopD在副溶血弧菌致病机制中的作用，并系统评估对副溶血弧菌生物学特性的影响。【方法】以POR-3为基础菌株，通过同源重组法构建vopD基因缺失与回补株，明确vopD缺失对副溶血弧菌生长能力、生物被膜形成能力、溶血活性以及细胞黏附能力的影响；同时，检测vopD缺失及回补株对HeLa细胞的毒性作用，并通过制备多克隆抗体检测VopD蛋白的分泌情况。【结果】vopD基因的缺失对副溶血弧菌的生长能力无显著影响，但显著降低了其生物被膜形成能力、溶血活性以及细胞黏附能力。与POR-3相比，vopD基因缺失株对HeLa细胞的毒性作用在感染后60、90、120min均显著下降，而回补株的毒性恢复至野生株水平；通过构建原核表达载体，诱导表达并纯化VopD蛋白，免疫小鼠制备多克隆抗体，Western blot分析显示在vopD缺失株和T3SS1缺失株POR-2中未检测到分泌的VopD蛋白，且POR-3、RIMD2210633以及vopD回补株中成功检测到VopD蛋白分泌，表明VopD蛋白由T3SS1分泌。【结论】vopD基因参与调控副溶血弧菌生物被膜形成、溶血活性和细胞黏附功能，同时影响副溶血弧菌对HeLa细胞的毒性作用；制备的多克隆抗体可有效检测细菌中VopD的分泌与表达。

关键词： CDO1   AKT   Cysteine metabolism   Tumorigenesis  

摘要： Inflammatory pathways are often hijacked by cancer cells to favor their own proliferation and survival. Cysteine dioxygenase type 1 (CDO1), an iron-dependent thiol dioxygenase enzyme, catalyzes the rate-limiting step for cysteine oxidation, and so that functions as an important regulator of cellular cysteine availability. However, whether inflammatory environment affects CDO1 activity and cysteine oxidation and its potential impact on tumor growth remains substantially elusive. In the present study, we demonstrate that CDO1 activity and cysteine oxidation is inhibited upon IL-6 treatment, without noticeable alterations in CDO1 expression. Mechanistically, AKT1 phosphorylates CDO1 T89 under IL-6 treatment, which represses CDO1 enzymatic activity by disrupting iron incorporation. Further, AKT1-mediated CDO1 T89 phosphorylation is required for IL-6-elicited oral squamous cell carcinoma (OSCC) growth, and is associated with the progression of OSCC development. The present data discover a new mechanism by which AKT1-mediated CDO1 T89 phosphorylation governs cysteine oxidation to support OSCC growth, thereby highlighting its value as a potential anti-tumor target.

关键词： Dectin-1   AT   TNF-alpha   NF-kappa B   HbA1c   Diabetes  

摘要： Background Dectin-1, a key innate immune receptor, plays a critical role in cellular responses and is implicated in chronic inflammation and metabolic syndromes. This study addresses a pivotal gap in elucidating the regulatory mechanism governing Dectin-1 expressionin obesity and diabetes, hypothesizing that hyperglycemia and TNF-alpha synergistically upregulate Dectin-1 in adipose tissue (AT), thereby exacerbating inflammatory responses and contributing to metabolic dysfunction. Methods The study included 95 overweight and obese Kuwaiti individuals, categorized into prediabetic (HbA1c < 6.5%) and diabetic (HbA1c >= 6.5%) groups. Anthropometric and clinical measurements were recorded. AT biopsies were obtained for RNA extraction and immunohistochemistry. Pre-adipocytes from lean and obese individuals were cultured, differentiated into adipocytes, and treated with TNF-alpha under normal or high-glucose conditions to assess Dectin-1 expression. Chromatin immunoprecipitation (ChIP) assays analyzed NF-kappa B binding to the Dectin-1 promoter. Wildtype and TNF-alpha-/- mice were used to evaluate TNF-alpha's effect on Dectin-1 expression in AT. Results Our data demonstrate that hyperglycemic obesity significantly induces Dectin-1 expression in AT through the TNF-alpha/NF-kappa B signaling pathway. In a cohort of 95 obese individuals, subdivided into prediabetics (HbA1c < 6.5%, n = 49) and diabetics (HbA1c >= 6.5%, n = 46), a strong positive correlation was observed between AT Dectin-1 transcripts and plasma HbA1c levels exclusively in diabetic participants, underscoring the specificity of Dectin-1 upregulation in hyperglycemic conditions. Elevated Dectin-1 expression was consistently associated to increased inflammation markers. Immunohistochemical analysis revealed co-localization and concurrent upregulation of Dectin-1 and TNF-alpha proteins in hyperglycemic AT. Functional assays in TNF-alpha deficient mice and human adipocytes further validated that TNF-alpha and hyper

关键词： interleukin-2   SLE   immunotherapy   engineered T cells   IL-2  

摘要： Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, which is mainly caused by the imbalance of immune cells. Current treatment regimens predominately rely on corticosteroids and immunosuppressive agents, accompanied by various side effects. Interleukin-2 (IL-2) is deemed an important cytokine for innate immune cells and adaptive immune cells, especially for the promotion of Treg cells. By combining IL-2/IL-2R system with engineered T cell-based immunotherapies to enhance the therapeutic efficacy of engineered T cells shows its potential in autoimmune diseases. But the pleiotropy of IL-2 may cause simultaneous stimulation and systemic toxicity, limiting its therapeutic use. There is a growing focus on using IL-2 in combination strategies for synergistic immune enhancement. In this article, we review the IL-2/IL-2R signaling, including IL-2 dependent signaling and IL-2 independent signaling, and discuss its functions in regulation of different immune cells. In addition, we summarize major clinical application of low-dose IL-2 treatment in SLE with or without other agents, such as rapamycin, tocilizumab and rituximab, present the IL-2 variants and fusion proteins designed for SLE, and highlight the future trends for research on these cytokine-based immunotherapies. It will help to design further optimized IL-2-based therapy for SLE.

摘要： Calciphylaxis is an orphan disease characterized by dermal microvessel thrombosis, inflicting painful cutaneous necrosis. It occurs predominantly in patients with end-stage kidney disease and has high mortality, elusive pathogenesis, and no approved therapies. We demonstrate that sera from patients with calciphylaxis induced de novo synthesis of interleukin-6 (IL-6) and soluble IL-6 receptor (IL-6R) and stimulated Janus kinase-2 (JAK) and signal transducer and activator of transcription (STAT)-3 phosphorylation in primary human dermal microvascular endothelial cells (ECs). Calciphylaxis skin demonstrated an altered microenvironment characterized by a gain of proximal and distal IL-6 ligand-receptor interactions. Microvessels are the predominant senders and recipients of IL-6 signaling, which, along with up-regulated A disintegrin and metalloproteinase 17 in dermal vasculature and interstitial IL-6R, supported trans-IL-6 signaling in calciphylaxis lesions. Calciphylaxis serum up-regulated thymidine phosphorylase (TYMP) in ECs. TYMP up-regulated IL-6, which activated tissue factor (TF), a primary trigger of the extrinsic coagulation cascade. IL-6-TF signaling in ECs was partially triggered by elevated IL-6 and kynurenine amounts in calciphylaxis serum and was inhibited by anti-IL-6 treatment. The TF-inducing ability of calciphylaxis serum is correlated with disease activity and response to IL-6 inhibitors in ECs. Calciphylaxis is therefore a combination of serum-inducing TYMP-IL-6-TF signaling in ECs and a heterogeneous permissive local dermal microenvironment. The latter is characterized by microvessels initiating IL-6 signaling and multiway cross-talk with adipocytes and eccrine glands, perpetuating the sinister thrombotic milieu. Our results support exploring the IL-6-TF-inducing ability of calciphylaxis serum as an activity marker and IL-6 as a therapeutic target for uremic calciphylaxis.

关键词： 棉铃虫   细胞色素P450   基因克隆   原核表达纯化   多克隆抗体  

摘要： 【目的】通过克隆及表达棉铃虫CYP6AE17和CYP6AE19基因，制备鼠抗棉铃虫细胞色素P450(CYP6AE17、CYP6AE19)多克隆抗体，为进一步研究细胞色素P450酶在棉铃虫中的功能奠定基础，为棉铃虫的绿色防控提供理论依据。【方法】构建重组质粒p ET32a-CYP6AE，诱导表达并纯化重组蛋白，将其作为抗原免疫小鼠，制备多克隆抗体，利用ELISA检测多克隆抗体的效价，通过Western blot检测多克隆抗体的特异性。【结果】CYP6AE17、CYP6AE19基因CDS序列全长分别为1572和1587 bp，分别编码523和528个氨基酸。SDS-PAGE分析结果表明，CYP6AE17和CYP6AE19基因均可在大肠杆菌原核表达系统中高效诱导表达，重组蛋白主要以包涵体形式存在。ELISA结果表明，制备的鼠抗棉铃虫CYP6AE17和CYP6AE19多克隆抗体效价分别达1∶1024000和1∶512000，且均可特异性识别棉铃虫体内的天然P450蛋白。【结论】该研究结果为进一步深入研究棉铃虫细胞色素P450酶的功能奠定了材料基础，为棉铃虫防治新靶标的开发提供了理论依据。