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关键词： SDC4   NF-kappa B   Target gene   Cancer cells  

摘要： Syndecan-4 (SDC4), a key member of the sulfated heparan sulfate proteoglycan (SDC) family, plays an important role in cell signaling. However, its function and regulatory mechanisms in tumors remain poorly understood. In this study, bioinformatic analysis revealed that SDC4 is significantly overexpressed in 16 types of tumors and positively correlated with poor prognosis in four types of these diseases. Knockdown of SDC4 inhibited tumor cell migration. Further analysis showed six transcription factors, including NF-kappa B, which potentially regulate SDC4 transcription. The UCSC Genome Browser database showed NF-kappa B binding peaks covered the SDC4 promoter in TNF alpha-stimulated tumor cells. ChIP-qPCR assay confirmed that TNF alpha treatment led to NF-kappa B binding at the SDC4 promoter, a genomic region also enriched for the active transcription mark H3K27Ac. qRT-PCR results demonstrated that TNF alpha treatment upregulated SDC4 in tumor cells. Immunofluorescence assay or qRT-PCR showed that the NF-kappa B inhibitor Bay11-7082 blocked TNF alpha-induced nuclear translocation of NF-kappa B, while both qRT-PCR and Western blot analyses showed Bay11-7082 could inhibit TNF alpha-induced upregulation of SDC4 at both mRNA and protein levels. Furthermore, SDC4 expression was positively correlated with NF-kappa B subunit RelA expression across 22 tumor types. In conclusion, this study identifies SDC4 as an oncogenic target gene of NF-kappa B, providing new insights for the development of anti-tumor therapies targeting the NF-kappa B pathway.

摘要： Chronic graft-versus-host disease (cGVHD) remains the leading cause of nonrelapse morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Effective therapeutic agents targeting dysregulated cytokines including interleukin-17 (IL-17) and colony-stimulating factor 1 (CSF-1) have been defined in preclinical models of cGVHD, and efficacy in subsequent clinical trials has led to their recent US Food and Drug Administration approval. Despite this, these agents are effective in only a subset of patients, expensive, difficult to access outside the United States, and used in a trial-and-error fashion. The ability to readily discern druggable, dysregulated immunity in these patients is desperately needed to facilitate the selection of appropriate treatment and to potentially identify high-risk individuals for preemptive therapy. We used single-cell sequencing-based approaches in our informative preclinical cGVHD models to "reverse engineer" temporal IL-17 and CSF-1 signatures in mouse blood that could be used to interrogate patients. We defined distinct, nonintuitive IL-17 and CSF-1 signatures in mouse blood monocytes that could be identified in relevant monocyte populations within 70% of patients at diagnosis of cGVHD and in half of patients at day +100 after HCT who subsequently developed cGVHD. These signatures can now be evaluated prospectively in clinical studies to help delineate potential responder and nonresponders to relevant therapeutics targeting these pathways.

关键词： Allograft rejection   Liver transplantation   Single-cell sequencing   Intermediate monocytes   Resistin-CAP1 pathway   PBMCs   peripheral blood single nucleated cells   LT   liver transplantation   AR   allograft rejection   CNIs   calcineurin inhibitors   mTOR   mammalian target of rapamycin   APCs   antigen-presenting cells   MHC   major histocompatibility complex   TCMR   T cell-mediated rejection   MPAs   monocyte-platelet aggregates   scRNA-seq   single-cell RNA sequencing   IRI   ischemia-reperfusion injury   ALT   alanine transaminase   AST   aspartate transaminase   INR   international normalized ratio   HSCs   hepatic stellate cells   NK   natural killer   pDCs   plasmacytoid dendritic cells   PP   periportal   PC   pericentral   KC   kupffer cells   LSECs   liver sinusoidal endothelial cells   cMo   classical monocytes   intMo   intermediate monocyte   ncMo   non-classical monocytes   pMo   patrolling monocytes   GO   gene ontology   UMAP   uniform manifold approximation and projection   BN   brown norway   PCA   principal component analysis   PMA   phorbol-12-myristate-13-acetate   IONO   ionomycin (calcium salt)   OD   optical density   RAI   rejection activity index   H&E   hematoxylin and eosin   ELISA   enzyme-linked immunosorbent assay   IHC   immunohistochemistry  

摘要： Background & Aims Lymphocytes are widely recognized as the primary mediators of cellular rejection post-liver transplantation. However, conventional immunosuppressive regimens that target lymphocytes, such as calcineurin phosphatase inhibitors, corticosteroids, or lymphocyte-depleting antibodies, can only partially mitigate rejection while inducing severe adverse effects. This necessitates the search for novel immunotherapeutic targets. Methods We harnessed the power of single-cell RNA sequencing and spatial transcriptome in 24 rat transplanted liver and peripheral blood single nucleated cells (PBMCs) samples to derive gene expression signatures recapitulating 13 cell phenotypes. We used flow cytometry, multifactor assays and multiple recombinant assays to validate in vitro and in vivo the role of the target protein Resistin on human T-cell function, as well as the Resistin-CAP1 interaction. Gold nanoparticles were used to package Retn siRNA sequences to validate the role of Retn knockdown on acute rejection after liver transplantation. Results By distinguishing between donor and recipient cells, we delineate the dynamic landscape of immune cells during allograft rejection and their spatial distributions across donors and recipients. Our findings underscore the pivotal role of recipient derived intermediate monocytes in cellular rejection. Using CellChat ligand-receptor analysis, we identify the Resistin-CAP1 pathway as a key mechanism by which intermediate monocytes participate in T cell-mediated rejection reactions. We confirm that Resistin knockdown significantly alleviates acute rejection after rat liver transplantation, markedly extending the survival of recipients using innovative nanogold technology. Conclusion These findings offer insights into the dynamic changes in the alloimmune microenvironment, pinpointing intermediate monocytes as potential diagnostic and immunotherapeutic targets during allograft rejection. This study holds significant importance in a

摘要： Evidence for disassortative mating based on the human-specific MHC, i.e. HLA, is equivocal . Initial evidence for disassortative HLA-pairing in the European-descent Hutterites has tended not to replicate in other populations. Recent studies, rather, reflect assortative mating associated with cosmopolitan population structure . Although their configuration is more relevant to the majority of human evolutionary history, few small-scale, endogamous populations have been examined. Here, we test whether the extent of HLA dissimilarity between individuals influences mate choice by contrasting chosen partnerships (both "love" marriages and informal partnerships) with arranged partnerships among the Himba, an endogamous and formerly natural fertility group living in northern Namibia. With targeted sequencing we typed eight classical HLA genes for n=366 individuals and recorded self-reported partnership types and informal partnerships discovered through shared biological offspring. Across 249 known partnerships, we find no difference in HLA dissimilarity between chosen and arranged partnerships and no effect of the two partnership types that differs from a random, background distribution of partnerships. We also looked directly for fitness benefits of the potential offspring genotypes by testing HLA-based pathogen binding affinities, but also found no difference between arranged and chosen partners and no effects that differed from random partners. It is possible that due to high background HLA diversity in the Himba, most unrelated individuals in the population are sufficiently dissimilar at the HLA that there are few fitness benefits to offspring by maximizing mate dissimilarity. We do find, however, extensive haplotype sharing at the HLA region, suggestive of recent positive selection . Episodes of fluctuating positive selection may be a more important driver in maintenance of HLA polymorphism than disassortative mating.

关键词： MHC-I   adaptive immune responses   immune evasion   MHC-I assembly   MHC-I transport   MHC-I expression  

摘要： Among various pathogens, viruses pose significant threats to the livestock and poultry industry, resulting in substantial annual costs due to production losses and vaccination. The MHC-I presentation pathway is a crucial surveillance mechanism for preventing viral infections. Consequently, many viruses have evolved sophisticated strategies to inhibit the presentation of viral peptides by MHC-I to CD8+ T-cells, thereby evading the immune system. Understanding the mechanisms that suppress the MHC-I pathway and identifying specific binding peptides are essential for comprehending viral immune evasion and developing effective animal vaccines. This review summarizes the viral strategies for evading immune recognition, including the inhibition of MHC-I molecules synthesis, degradation, transport, and assembly, which affect MHC-I surface expression during viral infections. We also present evidence that MHC-I surface expression is frequently lost during numerous viral infections in livestock and poultry and offer new insights into the underlying mechanisms through which viruses inactivate the MHC-I antigen presentation pathway. Collectively, these advanced findings on viral evasion from the MHC-I pathway could inform the development of more effectives strategies to restore immunological control over viral infections and improve vaccines for the livestock and poultry industry.

关键词： Cytokines   Immunology   Infectious disease   Malaria   NK cells  

摘要： *** infection can trigger high levels of inflammation that lead to fever and sometimes severe disease. People living in malaria-endemic areas gradually develop resistance to symptomatic malaria and control both parasite numbers and the inflammatory response. We previously found that adaptive NK cells correlated with reduced parasite load and protection from symptoms. We also found that murine NK cell production of IL-10 protected mice from experimental cerebral malaria. Human NK cells can also secrete IL-10, but it is unknown what NK cell subsets produce IL-10 or if this is affected by malaria experience. We hypothesized that NK cell immunoregulation may lower inflammation and reduce fever induction. Here, we showed that NK cells from participants with malaria experience make significantly more IL-10 than participants with no malaria experience. We then determined the proportions of NK cells that are cytotoxic and produce IFN-gamma and/or IL-10 and identified a signature of adaptive and checkpoint molecules on IL-10-producing NK cells. Lastly, we found that coculture with primary monocytes, Plasmodium-infected RBCs, and antibody induced IL-10 production by NK cells. These data suggest that NK cells may contribute to protection from malaria symptoms via IL-10 production.

关键词： Cell biology   Collagens   Extracellular matrix   Fibrosis   Therapeutics  

摘要： Dupuytren's disease is a common fibroproliferative disease of the palmar fascia of the hand, with advanced cases treated surgically. Anti-TNF injection has undergone phase 2 trials and may be effective in slowing early-stage disease progression. Here we sought to determine how new synthesis of type I collagen in Dupuytren's differs from normal palmar fascia samples and to analyze the role of TNF in aberrant collagen synthesis. Model nonfibrotic but fibrous connective tissues were used to analyze active type I collagen protein synthesis in development, aging, and degenerative disease, where it was restricted to early development and ruptured tissue. Dupuytren's tissue was shown to actively synthesize type I collagen, including abnormal type I collagen homotrimer. TNF-alpha reduced COL1A2 gene expression only in the presence of serum in 2D cell culture and had opposing effects on collagen protein production in the presence or absence of serum. TNF-alpha had only limited effects in 3D tendon-like constructs. Anti-TNF did not reduce type I collagen synthesis in 3D tendon-like constructs or prevent type I collagen homotrimer synthesis in Dupuytren's tissue. Hence, modulation of the TNF-alpha pathway in Dupuytren's disease is unlikely to prevent the pathological collagen accumulation that is characteristic of fibrosis.

关键词： 肾移植   IgA肾病   移植后排斥反应  

摘要： 目的：总结1例肾移植术后排斥反应合并免疫球蛋白A(IgA)肾病复发患者的临床资料，为肾移植术后相关并发症的诊治提供参考。方法：回顾性分析1例肾移植术后排斥反应合并IgA肾病复发患者的临床资料。结合文献复习，对该类患者的临床诊疗进行总结。结果：一位43岁男性终末期肾病患者，移植前患有IgA肾病且供体特异性抗体检测呈阴性，既往无致敏事件，移植后7个月出现混合性排斥反应且IgA肾病复发。给予强化免疫抑制和静脉注射免疫球蛋白治疗后症状好转，继续随访观察。结论：该病例主要特点包括诊断具有复杂病理变化，但临床表现不明显病人的挑战，这增加了误诊或延误诊断的风险，长期随访对于有效管理和监测这类病人至关重要。

摘要： Alopecia areata (AA) is an autoimmune disease that is clinically characterized by hair loss and histologically by a peribulbar infiltrate of CD8 and CD4 T cells. Prior studies have focused on the role of CD8 T cells in the development of AA; however, the role of CD4 T cells remains unclear. Here, we demonstrate that CD4 T cells from the skin draining lymph nodes (SDLN) of AA mice transferred disease into recipient mice. Further, these cells exhibited a T-helper type 1 (Th1) effector transcriptional and phenotypic profile. The pathogenic activity of these CD4 T cells was dependent upon the presence of endogenous CD8 T cells and host IFN-γ responsiveness. Targeted deletion of CD4 T cell-mediated production of IFN-γ abrogated the ability of this cell population to transfer disease. Together, these data provide mechanistic insights into pathways that lead to AA development, strengthening our understanding of the disease and inviting studies into exploring novel therapeutic strategies for human patients.