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关键词： epitope presentation   pretrained language model   deep learning  

摘要： Background Precise prediction of epitope presentation on human leukocyte antigen (HLA) molecules is crucial for advancing vaccine development and immunotherapy. Conventional HLA-peptide binding affinity prediction tools often focus on specific alleles and lack a universal approach for comprehensive HLA site analysis. This limitation hinders efficient filtering of invalid peptide *** We introduce TransHLA, a pioneering tool designed for epitope prediction across all HLA alleles, integrating Transformer and Residue CNN architectures. TransHLA utilizes the ESM2 large language model for sequence and structure embeddings, achieving high predictive accuracy. For HLA class I, it reaches an accuracy of 84.72% and an area under the curve (AUC) of 91.95% on IEDB test data. For HLA class II, it achieves 79.94% accuracy and an AUC of 88.14%. Our case studies using datasets like CEDAR and VDJdb demonstrate that TransHLA surpasses existing models in specificity and sensitivity for identifying immunogenic epitopes and *** TransHLA significantly enhances vaccine design and immunotherapy by efficiently identifying broadly reactive peptides. Our resources, including data and code, are publicly accessible at https://***/SkywalkerLuke/TransHLA

关键词： Ilex rotunda   antioxidant   IL-2   MAPK   NF-kappa B   phenolics  

摘要： Ilex rotunda, an evergreen tree in the holly family, is a traditional medicine with a high phenolic content and various pharmacological effects. This study aimed to investigate phenolic constituents from enriched fractions guided by a total phenolic assay along with a feature-based molecular network. Nine compounds were isolated and identified using multiple chromatography and spectroscopic techniques. These isolates exhibited significantly high antioxidative effects in both free radical scavenging and ROS assays. They also remarkedly alternated interleukin (IL)-2 production in CD3/CD28-stimulated Jurkat T cells. The Western blotting assay suggested that these active compounds might decrease IL-2 production by blocking the activation of NF-kappa B and MAPK signaling pathways by downregulating the phosphorylation of p38 and p65 proteins as well as ERK and JNK kinases. Molecular docking data confirmed the above-mentioned biological properties of those active compounds by evaluating their binding affinities for target proteins. Our findings offer guidance for assessing the potential of phenolic chemicals from I. rotunda as pharmacological products to improve oxidative stress and enhance immune response in more in-depth studies.

关键词： pelvic pain   endometriosis   infertility   sNCAM   sIL-2R alpha   VAS score  

摘要： Introduction Pelvic pain, often associated with endometriosis, significantly affects women's quality of life. This study explored the soluble neural cell adhesion molecules (sNCAM), soluble interleukin 2 receptor alpha (sIL-2R alpha), and IL-2 levels in the serum and peritoneal fluid of infertile women with pelvic *** We enrolled 86 infertile women aged 24 to 41 years undergoing diagnostic laparoscopy: 44 women with endometriosis and 42 women who acted as controls. Pain intensity was assessed using the visual analog scale. The soluble molecules were measured using enzyme-linked immunosorbent *** Serum and peritoneal sNCAM, sIL-2R alpha, and IL-2 levels were statistically significantly higher in women with pelvic pain. Both serum and peritoneal sNCAM levels correlated with visual analog scale scores, indicating a relationship between these markers and pain severity. Elevated peritoneal sIL-2R alpha levels were also associated with pelvic pain. Receiver operating characteristic curve analysis showed the potential of serum sNCAM in distinguishing between mild and moderate to severe *** Elevated levels of sNCAM, sIL-2R alpha, and IL-2 in serum and peritoneal fluid correlate with pelvic pain severity in infertile women, suggesting their involvement in disease pathogenesis and potential as objective biomarkers for pain assessment in endometriosis. Further research is needed to validate these findings for clinical use.

关键词： T-2 toxin   Immunotoxicity   Gut microbiota-spleen axis   Nano-selenium   Mitigation  

摘要： T-2 toxin is one of the most toxic A trichothecene mycotoxins prevalent in the environment and food chain, which brings severe health hazards to both animals and humans and it can significantly damage immune function. In this study, we comprehensively explained the impact of T-2 toxin on the spleen through gut microbiota-spleen axis by integrating the transcriptome and microbiome. Our results revealed that dietary T-2 toxin >= 1.0 mg/kg exposure significantly inhibited the growth performance and caused spleen injury in broilers chicks, accompanied by oxidative stress and histopathological damage. Cecal microbiome analysis suggested that T-2 toxin exposure caused gut microbial dysbiosis, especially leading to the decrease of some beneficial bacteria genera that enhanced gut barrier and reduced inflammation, including Blautia, Coprococcus, Lachnospira and Anaerostipes belonging to Lachnospiraceae family. Transcriptome analysis suggested that T-2 toxin exposure directly caused splenic inflammation and immune-related signaling, such as cytokine-cytokine receptor interaction, Toll-like receptor signaling pathway, NOD-like receptor signaling pathway and JAK-STAT signaling pathway. Furthermore, by integrating the transcriptome and microbiome analysis, we found that spleen damage induced by T-2 toxin was associated with the abnormal activation of IL-6/JAK/STAT1 signaling pathway-mediated inflammation and apoptosis, which was further verified by western bolt analysis. Notably, dietary selenium supplementation could protect chicks from T-2 toxin-induced adverse effects on growth performance and spleen injury by inhibiting the expression of the IL-6/JAK/STAT1 signaling-related genes. In summary, our findings provided new insights into the immunotoxicity mechanisms of T-2 toxin in the chickens' spleen and highlighted the potential of selenium to alleviate T-2 toxin-induced immunotoxicity.

关键词： histocompatibility and immunogenetics   transplantation   highly sensitized patients   HLA   transplant immunology  

关键词： donor   otra   allows   compatible   mhc-specific   thymus   transplantation   vaccination  

摘要： Organ transplantation is the last-resort option to treat organ ***,less than 10％of patients benefit from this only option due to lack of major histocompatibility complex(MHC)-matched donor organs and 25％-80％of donated organs could not find MHC-matched recipients.T cell allorecognition is the principal mechanism for allogeneic graft *** herein present a"donor MHC-specific thymus vaccination"(DMTV)strategy to induce T cell tolerance to both autologous and allogeneic donor *** MHC molecules were expressed in the recipient thymus through adeno-associated virus-mediated delivery,which led to stable expression of allogeneic MHC together with the autologous MHC in the engineered *** local T cell education,those T cells recognizing either autologous MHC or allogeneic MHC were equally *** constructed C57BU6-MHC and BALB/c-MHC dual immunocompatible mice via thymus vaccination of C57BU6-MHC into the BALB/c thymus and observed long-term graft tolerance after transplantation of C57BU6 skin and C57BU6 mouse embryonic stem cells into the vaccinated BALB/c *** also validated our DMTV strategy in a bone marrow,liver,thymus(BLT)-humanized mouse model for immunocompatible allotransplantation of human embryonic stem *** study suggests that the DMTV strategy is a potent avenue to introduce a donor compatible immune system in recipients,which overcomes the clinical dilemma of the extreme shortage of MHC-matched donor organs for treating patients with end-stage organ failure.

关键词： CD8(+) T cells   CMV vectors   HIV vaccine   MHC-E  

摘要： Strain 68-1 rhesus CMV (RhCMV) vectors induce immune responses that mediate early, complete replication arrest of SIV infection in similar to 60% of vaccinated rhesus macaques (RMs). This unique efficacy depends on the ability of these vectors to elicit effector memory (EM)-biased CD8(+) T cells recognizing SIV peptides presented by MHC-E, rather than MHC-Ia. These efficacious responses still occurred when spread of the 68-1 vector was impaired by deletion of the viral anti-host intrinsic immunity factor phosphoprotein 71 (pp71), but efficacy was lost with a more stringent attenuation strategy based on destabilization of Rh108, the ortholog of the essential human CMV (HCMV) transcription factor UL79 that is required for late viral gene expression. Although unable to produce infectious progeny (ie single-cycle infection), Rh108-deficient vectors elicited durable, high frequency, EM-biased, SIV-specific CD8(+) T-cell responses in RMs, but these responses were MHC-Ia-restricted and therefore non-efficacious. Here, we tested a different single-cycle attenuation strategy based on deletion (Delta) of the glycoprotein L (gL) that is essential for viral entry but allows for late gene expression and viral assembly. Delta gL 68-1 RhCMV/SIV vectors, grown on gL-complementing fibroblasts, were robustly immunogenic at doses above 10(5) PFU, generating high frequency, EM-biased, SIV-specific CD8(+) T-cell responses that were also unconventionally restricted, including the MHC-E restriction associated with efficacy. Indeed, these single-cycle vectors manifested replication arrest efficacy in 70% of vaccinated RMs, further linking MHC-E restriction with efficacy, and demonstrating that 68-1 RhCMV/SIV efficacy does not require vector dissemination within the host.

关键词： cartilage degradation   condylar chondrocytes   DDX5   temporomandibular joint osteoarthritis   tumor necrosis factor signaling  

摘要： Background: Temporomandibular joint osteoarthritis (TMJOA) is a prevalent musculoskeletal condition characterized by pain, cartilage degeneration, and subchondral bone loss. Objective: This study sought to identify specific targets for the treatment of TMJOA. Method: Through high-throughput RNA-seq analysis in condylar chondrocytes (NC vs. MS), we discovered that DDX5 was downregulated and closely negatively related to the progression of TMJOA. Similarly, we found that DDX5 was downregulated in injured condylar cartilage of patients as well as the condyles of UAC-induced TMJOA mice. The chondrocyte-specific deletion of Ddx5 aggravated tissue destruction in TMJOA modeling by inducing degradation of extracellular matrix (ECM). Results: The loss of DDX5 facilitated chondrocyte degradation and the occurrence of joint inflammation in condylar chondrocytes. In addition, the local injection of AAV overexpressing DDX5 significantly alleviated inflammation, cartilage degradation, and subchondral bone loss in TMJOA mice. RNA-seq analysis revealed that the DDX5 deficiency mostly activated the TNF-induced nuclear factor-kappa B (NF-kappa B) signaling pathway causing the occurrence of TMJOA. Conclusion: Mechanistically, the inhibition of DDX5 accelerated cartilage degeneration by activating TNF-induced NF-kappa B signaling. Thus, DDX5 emerges as a potential effective drug target for future therapeutic approaches in TMJOA.

关键词： 埃博拉病毒   原核表达   GP1蛋白   多克隆抗体   间接ELISA  

摘要： 建立一种检测扎伊尔型埃博拉病毒(Zaire Ebola virus，ZEBOV) 特异抗体的间接酶联免疫吸附剂测定 (enzyme linked immunosorbent assay，ELISA)方法。以ZEBOV GP基因全长为模板，利用PCR扩增GP1基因，克隆至pET-30a（+）载体，利用大肠杆菌表达系统表达并纯化GP1蛋白。纯化后的蛋白作为包被抗原，通过棋盘法确定抗原包被质量浓度及血清稀释度等条件，建立ZEBOV抗体间接ELISA检测方法，并对建立的ELISA检测方法进行特异性、敏感性、重复性评价。结果显示，原核表达成功制备GP1蛋白，将其作为间接ELISA包被抗原，通过优化反应条件，确定抗原最佳包被质量浓度为0.5 g/L，血清最佳稀释度为1:3 200，酶标二抗最佳稀释度为1:20 000，且该方法具有优异的特异性、敏感性以及重复性。结果表明，本研究利用大肠杆菌表达系统成功表达并纯化出高纯度的GP1蛋白，建立基于ZEBOV糖蛋白GP1抗体间接ELISA检测方法，该检测方法特异性强、灵敏度高、重复性好，为进一步研究GP1生物学功能以及检测血清中ZEBOV抗体检测提供了技术支持。

关键词： Chimeric antigen receptor