Genetic diversity is an essential indicator that echoes the natural selection and environmental adaptation of a species. Isolated small populations are vulnerable to genetic drift, inbreeding, and limited gene flow; thus, assessing their genetic diversity is critical in conservation. In this study, we studied the genetic diversity of black-and-white snub-nosed monkeys (Rhinopithecus bieti) using neutral microsatellites and five adaptive major histocompatibility complex (MHC) genes. Two DQA1 alleles, two DQB1 alleles, two DRB1 alleles, two DRB5 alleles, and three DPB1 alleles were isolated from a population. The results indicate that neutral microsatellites demonstrate a high degree of heterozygosity and polymorphism, while adaptive MHC genes display a high degree of heterozygosity and moderate polymorphism. The results also show that balancing selection has prominently influenced the MHC diversity of the species during evolution: (1) significant positive selection is identified at several amino acid sites (primarily at and near antigen-binding sites) of the DRB1, DRB5, and DQB1 genes; (2) phylogenetic analyses display the patterns of trans-species evolution for all MHC loci. This study provides valuable genetic diversity insights into black-and-white snub-nosed monkeys, which dwell at the highest altitude and have experienced the harshest environmental selection of all primates globally since the Pleistocene. Such results provide valuable scientific evidence and a reference for making or amending conservation strategies for this endangered primate species.

BACKGROUND: Gastrointestinal malignancies encompass a diverse group of cancers that pose significant challenges to global health. The major histocompatibility complex (MHC) plays a pivotal role in immune surveillance, orchestrating the recognition and elimination of tumor cells by the immune system. However, the intricate regulation of MHC gene expression is susceptible to dynamic epigenetic modification, which can influence functionality and pathological outcomes.
METHODS: By understanding the epigenetic alterations that drive MHC downregulation, insights are gained into the molecular mechanisms underlying immune escape, tumor progression, and immunotherapy resistance. This systematic review examines the current literature on epigenetic mechanisms that contribute to MHC deregulation in esophageal, gastric, pancreatic, hepatic and colorectal malignancies. Potential clinical implications are discussed of targeting aberrant epigenetic modifications to restore MHC expression and 0 the effectiveness of immunotherapeutic interventions.
CONCLUSIONS: The integration of epigenetic-targeted therapies with immunotherapies holds great potential for improving clinical outcomes in patients with gastrointestinal malignancies and represents a compelling avenue for future research and therapeutic development.

Human leukocyte antigen (HLA) typing is of great importance in clinical applications such as organ transplantation, blood transfusion, disease diagnosis and treatment, and forensic analysis. In recent years, nanopore sequencing technology has emerged as a rapid and cost-effective option for HLA typing. However, due to the principles and data characteristics of nanopore sequencing, there was a scarcity of robust and generalizable bioinformatics tools for its downstream analysis, posing a significant challenge in deciphering the thousands of HLA alleles present in the human population. To address this challenge, we developed NanoHLA as a tool for high-resolution typing of HLA class I genes without error correction based on nanopore sequencing. The method integrated the concepts of HLA type coverage analysis and the data conversion techniques employed in Nano2NGS, which was characterized by applying nanopore sequencing data to NGS-liked data analysis pipelines. In validation with public nanopore sequencing datasets, NanoHLA showed an overall concordance rate of 84.34% for HLA-A, HLA-B, and HLA-C, and demonstrated superior performance in comparison to existing tools such as HLA-LA. NanoHLA provides tools and solutions for use in HLA typing related fields, and look forward to further expanding the application of nanopore sequencing technology in both research and clinical settings. The code is available at https://github.com/langjidong/NanoHLA .

Birinapant, an antagonist of the inhibitor of apoptosis proteins, upregulates MHCs in tumor cells and displays a better tumoricidal effect when used in combination with immune checkpoint inhibitors, indicating that Birinapant may affect the antigen presentation pathway; however, the mechanism remains elusive. Based on high-resolution mass spectrometry and in vitro and in vivo models, we adopted integrated genomics, proteomics, and immunopeptidomics strategies to study the mechanism underlying the regulation of tumor immunity by Birinapant from the perspective of antigen presentation. Firstly, in HT29 and MCF7 cells, Birinapant increased the number and abundance of immunopeptides and source proteins. Secondly, a greater number of cancer/testis antigen peptides with increased abundance and more neoantigens were identified following Birinapant treatment. Moreover, we demonstrate the existence and immunogenicity of a neoantigen derived from insertion/deletion mutation. Thirdly, in HT29 cell-derived xenograft models, Birinapant administration also reshaped the immunopeptidome, and the tumor exhibited better immunogenicity. These data suggest that Birinapant can reshape the tumor immunopeptidome with respect to quality and quantity, which improves the presentation of CTA peptides and neoantigens, thus enhancing the immunogenicity of tumor cells. Such changes may be vital to the effectiveness of combination therapy, which can be further transferred to the clinic or aid in the development of new immunotherapeutic strategies to improve the anti-tumor immune response.

Peptide binding to major histocompatibility complex (MHC) proteins plays a critical role in T-cell recognition and the specificity of the immune response. Experimental validation such peptides is extremely resource-intensive. As a result, accurate computational prediction of binding peptides is highly important, particularly in the context of cancer immunotherapy applications, such as the identification of neoantigens. In recent years, there is a significant need to continually improve the existing prediction methods to meet the demands of this field. We developed ConvNeXt-MHC, a method for predicting MHC-I-peptide binding affinity. It introduces a degenerate encoding approach to enhance well-established panspecific methods and integrates transfer learning and semi-supervised learning methods into the cutting-edge deep learning framework ConvNeXt. Comprehensive benchmark results demonstrate that ConvNeXt-MHC outperforms state-of-the-art methods in terms of accuracy. We expect that ConvNeXt-MHC will help us foster new discoveries in the field of immunoinformatics in the distant future. We constructed a user-friendly website at http://www.combio-lezhang.online/predict/, where users can access our data and application.

The major histocompatibility complex (MHC) can recognize and bind to external peptides to generate effective immune responses by presenting the peptides to T cells. Therefore, understanding the binding modes of peptide-MHC complexes (pMHC) and predicting the binding affinity of pMHCs play a crucial role in the rational design of peptide vaccines. In this study, we employed molecular dynamics (MD) simulations and free energy calculations with an Alanine Scanning with Generalized Born and Interaction Entropy (ASGBIE) method to investigate the protein-peptide interaction between HLA-A*02:01 and the G9209 peptide derived from the melanoma antigen gp100. The energy contribution of individual residue was calculated using alanine scanning, and hotspots on both the MHC and the peptides were identified. Our study shows that the pMHC binding is dominated by the van der Waals interactions. Furthermore, we optimized the ASGBIE method, achieving a Pearson correlation coefficient of 0.91 between predicted and experimental binding affinity for mutated antigens. This represents a significant improvement over the conventional MM/GBSA method, which yields a Pearson correlation coefficient of 0.22. The computational protocol developed in this study can be applied to the computational screening of antigens for the MHC1 as well as other protein-peptide binding systems.

UNASSIGNED: Zhilong Huoxue Tongyu (ZL) capsule is a classical traditional Chinese medicine (TCM) with satisfactory curative effects. Endothelial cell (EC) dysfunction plays an important role during myocardial fibrosis (MF). But the therapeutic effect of ZL capsule on EC dysfunction remains unknown in the development of MF. This study aims to investigate the effect of ZL capsule on EC dysfunction during MF in vivo.
UNASSIGNED: The model of MF is established in vivo by injecting isoproterenol for 14 days, simultaneously, we examined the therapeutic effect of ZL capsule on MF in vivo. An integrative approach combining biomarker examination, echocardiography and myocardial fibrosis condition using Hematoxylin-eosin staining, Masson staining, and Sirius red staining were performed to assess the efficacy of ZL capsule against MF. Subsequently, comprehensive immunofluorescence staining was performed to evaluate the therapeutic effect of ZL capsule on EC dysfunction.
UNASSIGNED: Prior to experiments, analysis of the published single-cell sequencing data was performed and it was discovered that EC dysfunction plays an important role. Further pharmacological results showed that ZL capsule could alleviate fibrosis injury and collagen fiber deposition. The mechanism investigation results showed that the endothelial-to-mesenchymal transition (EndMT) and MHC class-II (MHC-II) expression in EC were improved. In addition, ZL capsule can attenuate the inflammatory response during MF by intervening the activation of CD4+T cell mediated by EC. For the first time, we provided evidence that ZL capsule could improve MF by alleviating EC dysfunction via the regulation of EndMT and expression of MHC-II.
UNASSIGNED: Myocardial fibrosis, Chinese Herbal Medicine, Traditional Medicine, Endothelium, dysfunction, Endothelial-to-mesenchymal transition.

The major histocompatibility complexes of vertebrates play a key role in the immune response. Antigen-presenting cells are loaded on MHC I molecules, which mainly present endogenous antigens; when MHC I presents exogenous antigens, this is called cross-presentation. The discovery of cross-presentation provides an important theoretical basis for the study of exogenous antigens. Cross-presentation is a complex process in which MHC I molecules present antigens to the cell surface to activate CD8+ T lymphocytes. The process of cross-representation includes many components, and this article briefly outlines the origins and development of MHC molecules, gene structures, functions, and their classical presentation pathways. The cross-presentation pathways of MHC I molecules, the cell lines that support cross-presentation, and the mechanisms of MHC I molecular transporting are all reviewed. After more than 40 years of research, the specific mechanism of cross-presentation is still unclear. In this paper, we summarize cross-presentation and anticipate the research and development prospects for cross-presentation.

Adoptive cell therapy (ACT) with tumor-specific T cells has been shown to mediate durable cancer regression. Tumor-specific T cells are also the basis of other therapies, notably cancer vaccines. The main target of tumor-specific T cells are neoantigens resulting from mutations in self-antigens over the course of malignant transformation. The detection of neoantigens presents a major challenge to T cells because of their high structural similarity to self-antigens, and the need to avoid autoimmunity. How different a neoantigen must be from its wild-type parent for it to induce a T cell response is poorly understood. Here we review recent structural and biophysical studies of T cell receptor (TCR) recognition of shared cancer neoantigens derived from oncogenes, including p53R175H, KRASG12D, KRASG12V, HHATp8F, and PIK3CAH1047L. These studies have revealed that, in some cases, the oncogenic mutation improves antigen presentation by strengthening peptide-MHC binding. In other cases, the mutation is detected by direct interactions with TCR, or by energetically driven or other indirect strategies not requiring direct TCR contacts with the mutation. We also review antibodies designed to recognize peptide-MHC on cell surfaces (TCR-mimic antibodies) as an alternative to TCRs for targeting cancer neoantigens. Finally, we review recent computational advances in this area, including efforts to predict neoepitope immunogenicity and how these efforts may be advanced by structural information on peptide-MHC binding and peptide-MHC recognition by TCRs.

Streptococcus suis (S. suis) is widely acknowledged as a significant zoonotic pathogen in Southeast Asia and China, which has led to a substantial number of fatalities in both swine and humans. Despite the prevalent use of mice as the primary animal model to study S. suis pathogenesis, the substantial differences in the major histocompatibility complex (MHC) between humans and mice underscore the ongoing exploration for a more suitable and effective animal model. In this study, humanized transgenic HLA-A11/DR1 genotypes mice were used to evaluate the differences between humanized HLA and murine H2 in S. suis infection. Following intravenous administration of S. suis suspensions, we investigated bacterial load, cytokine profiles, pathological alterations, and immune cell recruitment in both Wild-type (WT) and humanized mice across different post-infection time points. Relative to WT mice, humanized mice exhibited heightened pro-inflammatory cytokines, exacerbated tissue damage, increased granulocyte recruitment with impaired resolution, notably more pronounced during the late infection stage. Additionally, our examination of bacterial clearance rates suggests that HLA-A11/DR1 primarily influences cell recruitment and mitochondrial reactive oxygen species (ROS) production, which affects the bacterial killing capacity of macrophages in the late stage of infection. The reduced IL-10 production and lower levels of regulatory T cells in humanized mice could underlie their compromised resolution ability. Intervention with IL-10 promotes bacterial clearance and inflammatory regression in the late stages of infection in transgenic mice. Our findings underscore the heightened sensitivity of HLA-A11/DR1 mice with impaired resolution to S. suis infection, effectively mirroring the immune response seen in humans during infection. The humanized HLA-A11/DR1 mice could serve as an optimal animal model for investigating the pathogenic and therapeutic mechanisms associated with sepsis and other infectious diseases.