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关键词： HLA-B*55:141   next-generation sequencing   novel allele  

摘要： HLA-B*55:141 differs from HLA-B*55:08 by a single nucleotide substitution at position 363 G>C in exon 3.

关键词： Antibody   Coinfection   Epitope   Eplet   Immunogenic   Polyreactive   Superinfection  

摘要： Chronic rejection remains an obstacle to long-term allograft survival. Donor-specific anti-HLA antibodies (DSA) play a significant role in causing chronic antibody-mediated allograft rejection. Exposure to mismatched HLA antigens via transfusion, pregnancy, or transplanted tissue has been described in the literature as an immunogenic stimulus of anti-HLA antibodies. Yet anti-HLA antibodies also develop in the absence of traditional sensitization events and molecular mimicry has been postulated as a stimulus for these naturally occurring alloantibodies. While heterologous reactivity has been documented between virus components and allogeneic T cells, there is insufficient evidence to support the development of anti-HLA antibodies from viral components. We hypothesized that anti-HLA antibodies may develop following viral coinfection or superinfection. The objectives of this investigation included: 1) developing an in-silico algorithm to identify viral peptide components that exhibit HLA-specific homology, and 2) identifying cellular changes that take place during ischemia/reperfusion injury which could facilitate the generation of novel anti-HLA antibodies from viral sources. We developed the neoepitope transplant rejection and autoimmune disease (NETRAD) algorithm to identify amino acid sequence homology between viral envelope proteins and HLA. The algorithm integrates post-translational protein modifications that are consistent with ischemia/reperfusion injury. Seventy-two HLA-specific epitopes were demarcated as examples using this approach. In conclusion, we present in-silico evidence which supports the identification of anti-HLA antibodies as a subset of polyreactive antibodies generated from stress-modified viral envelope proteins. Remarkably, each targeted HLA epitope associated with a distinct anti-HLA antibody could be consistently attributed to a major envelope glycoprotein component of Epstein Barr virus. Transplant Immunology manuscript # TRIM-D-24-00351.

关键词： TNF-alpha   Aptamers   Aptasensors   Aptamer therapeutics   Biosensors  

摘要： Tumor necrosis factor-alpha (TNF-alpha) is a pivotal cytokine in the pathogenesis of numerous inflammatory and autoimmune diseases. Precise and sensitive detection of TNF-alpha is essential for both clinical applications and research endeavors. In the realm of cytokine detection, particularly TNF-alpha, the development of highly sensitive and specific biosensors has become a focal point. The biosensing landscape encompasses a variety of biorecognition elements, each with its unique set of characteristics. TNF inhibitors come with a significant price tag and, notably, do not yield positive responses in all patients. Despite the availability of numerous FDA-approved biologic agents (e.g., infliximab, adalimumab, certolizumab pegol, etc.) and monoclonal antibodies (e.g., adalimumab) targeting TNF-alpha, aptamers tailored for blocking TNF-alpha activities have yet to receive approval. Aptamers have rapidly gained recognition as readily available, versatile, and highly effective molecular tools for both therapeutic and diagnostic purposes in the context of TNF-alpha. In this manuscript, we explore the potential of short single-stranded DNA or RNA sequences known as aptamers as biorecognition elements in biosensors designed for the detection of TNF-alpha. We delve into the progress made in the development of aptamerbased TNF-alpha inhibitors and shed light on successful studies in this burgeoning field.

关键词： HLA   HLA-A*68:322   novel allele   sequencing-based typing  

摘要： HLA-A*68:322 differs from HLA-A*68:45 by three nucleotide changes in exon 2.

关键词： Acute respiratory distress syndrome   Endoplasmic reticulum stress   Pyroptosis   Thapsigargin   Interleukin 33  

摘要： Background: Inflammatory activation of pulmonary microvascular endothelial cells (PMVECs) initiated by endoplasmic reticulum stress (ERS) contributes to acute respiratory distress syndrome (ARDS). Interleukin 33 (IL-33) has pro-inflammatory and transcriptional regulatory effects. Therefore, this study intends to investigate the effect of IL-33 on ERS and pyroptosis in the hPMVEC. Methods: The hPMVEC-associated ARDS cell model was induced with lipopolysaccharide (LPS) and treated with 4-PBA (ERS inhibitor), thapsigargin (ERS activator), or IL-33 neutralizing antibody. Western blot and IF staining were performed to analyze the expression of cell-cell junction-associated (Cx37, Cx40, Cx43, Occludin, and Zo1), ERS-associated (ATF6, IRE1a, and p-Erk), and pyroptosis-associated (NLRP3, IL-1 beta, and IL-18) proteins. Bioinformatics identified differential expression of IL-33 in ARDS-related datasets and targets of thapsigargin. Results: IL-33 was highly expressed in serum of ARDS patients and in ARDS cohorts from multiple GEO datasets (GSE237260, GSE216635, GSE89953, GSE263867, and GSE5883), and was significantly correlated with clinical features. 4-PBA decreased permeability and IL-33 levels, and increased Cx37, Cx40 and Cx43 levels in the ARDS cell model. IL-33 neutralizing antibody effectively augmented the levels of Cx43 and Zo-1, and diminished the levels of ATF6, IRE1a, p-Erk, NLRP3, IL-1 beta, IL-18, ROS, and Ca2 +. The therapeutic effect of IL-33 neutralizing antibodies was reverted by thapsigargin. Moreover, the Swiss Target Prediction and Super-PRED databases obtained 140 and 122 thapsigargin targets, which had 14 intersections. These intersections were associated with immunity, inflammation, apoptosis, pyroptosis, and Ca2+ homeostasis. Notably, CASP8 and PTGS2 interacted with IL-33 in these intersections. Conclusion: IL-33 promotes ERS and pyroptosis, thereby contributing to barrier damage in ARDS cell models. IL- 33 is a promising therapeutic target for ARDS.

关键词： caspase-8   cathepsins   chronic diseases   cognition   inflammation   microglia signalling  

摘要： Background. Organ transplantation reverses cognitive impairment in chronic kidney disease (CKD), indicating that cognitive impairment driven by CKD is therapeutically amendable. We recently demonstrated that impaired cognition in CKD is linked to interleukin1S (IL-1 S) release from microglia and IL-1 receptor type 1 signalling in neuronal cells, thereby identifying a signalling pathway that can be exploited therapeutically. However, the mechanism of IL-1 S maturation in microglia in CKD remains unknown. We hypothesized that microglia cells require caspase-1 for CKD-driven cognitive impairment. Methods. We used a combination of single-cell analyses, in situ analyses, genetically modified mouse models (including newly generated Cre-LoxP mouse models) and in vitro models. The current study builds on a recently identified intercellular cross-talk between microglia and neurons that impairs cognition in CKD. Results. Here we show that despite NLRP3 inflammasome activation in the brain and protection of mice with constitutive NLRP3 deficiency from CKD-induced cognitive impairment, caspase-1 is not required for IL-1 S maturation in microglia and targeted caspase-1 deficiency in microglia does not improve cognition in CKD mice. These data indicate that IL-1 S maturation in microglia is independent of the NLRP3-caspase-1 interaction in CKD. Indeed, microglia activation in CKD induces noncanonical, cathepsin C-caspase-8- mediated IL-1 S maturation. Depletion of cathepsin C or caspase-8 blocks IL-1 S maturation in microglia. Preliminary analyses suggest that noncanonical microglia IL-1 S maturation occurs also in diabetes mellitus. Conclusion. These results identify a noncanonical IL-1 S-maturation pathway as a potential therapeutic target to combat microgliainduced neuronal dysfunction in CKD and possibly other peripheral diseases.

关键词： Cardiac stem cells   apoptosis   autophagy   interleukin-6   hypoxia   miR-98  

摘要： Background: The heavy burden of cardiovascular diseases demands innovative therapeutic strategies dealing with cardiomyocyte loss. Cardiac Stem Cells (CSCs) are renewable cells in the myocardium with differentiation and endocrine functions. However, their functions are significantly inhibited in conditions of severe hypoxia or inflammation. The mechanism of hypoxia affecting CSCs is not clear. Interleukin-6 (IL-6) appears active in both hypoxic and inflammatory microenvironments. The aim of this study was to explore whether IL-6 is related to CSC apoptosis and autophagy under severe hypoxia. Methods: In this study, rat CSCs were extracted by alternate digestion. The interaction of miR-98 and IL-6 mRNA was detected by the dual luciferase method, and qPCR was applied to confirm the effect of miR-98 on IL-6 expression. The effect of IL-6 on CSC apoptosis was measured by flow cytometry and the effect of IL-6 on CSC autophagy by transmission electron microscopy. The western blot method was applied to detect the effect of IL-6 on the expressions of proteins related to apoptosis and autophagy. ANOVA and Dunnett T3's test were employed in the statistical analysis. When p < 0.05, the difference was significant. Results: Under severe hypoxia conditions, IL-6 increased CSC apoptosis and decreased p-STAT3 expression significantly. CSC apoptosis increased significantly after inhibition of the STAT3 signaling pathway under severe hypoxia. IL-6 could also significantly inhibit CSCs' autophagy and block their autophagy flow under severe hypoxic conditions. Meanwhile, it was confirmed that miR-98 had a binding site on IL-6 mRNA and miR-98 significantly inhibited IL-6 mRNA expression in CSCs under severe hypoxic conditions. Conclusion: miR-98/IL-6/STAT3 has been found to be involved in the regulation of CSCs' apoptosis and autophagy under severe hypoxic conditions and there might be a mutual linkage between CSCs' apoptosis and their autophagy.

关键词： COVID-19   HLA-A antigens   HLA-B antigens   HLA-C antigens   HLA-DR antigens  

摘要： The HLA system is a crucial immune response component against infectious agents, including SARS-CoV-2. Certain polymorphisms may impart varying levels of protection or vulnerability to COVID-19. This research aims to understand the possible relationship between HLA polymorphisms and the susceptibility to COVID-19 and its severity. We recruited 290 hospitalised Iranian COVID-19 patients (130 severe and 160 moderate). Using PCR-SSP methods, we conducted a detailed analysis of polymorphisms in HLA class I (HLA-A, HLA-B, and HLA-C) and II (HLA-DRB1 and HLA-DQB1) molecules at low resolution. The study found that certain HLA alleles, including HLA-B*49, HLA-B*52, HLA-C*12, HLA-DRB1*04, and HLA-DQB1*05, were associated with disease susceptibility. Additionally, HLA-A*23, DRB1*10, and DRB1*13 were indicators of disease severity. The study also noted that individuals carrying the HLA-A*23 allele showed a significant decrease in lymphocyte levels and an elevated likelihood of developing thrombosis. We hypothesise that a maladaptive immune response may occur based on these findings. This might be due to the strong affinity of the HLA-A*23 allele group for presenting a wide range of SARS-CoV-2 peptides. Such a presentation possibly leads to a cytokine storm, followed by lymphocyte apoptosis and an increase in platelet count.

关键词： ADME/T characteristics   drug-like properties   Matricaria chamomilla L   molecular dynamics simulation   rheumatoid arthritis  

摘要： Chamomile, emphasized as an herbal remedy with healing potential for human health, is used in traditional medicine. In this study, the potential of compounds derived from Matricaria chamomilla L. against IL-6, JAK-1 and TNF-alpha target proteins associated with rheumatoid arthritis (RA) was compared with known inhibitors. The drug-likeness and ADME/T properties of these compounds were investigated using online tools, and molecular docking and molecular dynamics simulations of the selected structures were examined. IL-6, JAK-1 and TNF-alpha formed stable complexes with apigenin, quercetin and galaxolide, respectively, demonstrating that these compounds exhibit potential inhibitory activity against RA.