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摘要： ObjectivesPulmonary arterial hypertension (PAH) is characterized by the remodeling of the pulmonary vascular bed leading to elevation of the pulmonary arterial pressure. Oxidized fatty acids, such as hydroxyeicosatetraenoic acids (HETEs), play a critical role in PAH. We have previously established that dietary supplementation of 15-HETE is sufficient to cause PH in mice, suggesting a role for the gut-lung axis. However, the mechanisms are not *** of RNA-seq data obtained from the lungs and intestines of mice on 15-HETE diet together with transcriptomic data from PAH patient lungs identified IFN inducible protein 44 (IFI44) as the only gene significantly upregulated in mice and humans. We demonstrate that IFI44 is also significantly increased in PBMCs from PAH patients. In mice, 15-HETE diet enhances IFI44 and its inducer IFN alpha 4 expression sequentially in the intestine first and then in the lungs. IFI44 expression in PAH is highly correlated with expression of Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL), which is upregulated in CD8 cells in PH lungs of both mice and humans. We show that IFN alpha 4 produced by intestinal epithelial cells facilitates IFI44 expression in CD8 cells. Finally, we demonstrate that IFN receptor 1-KO in mice do not develop PH on 15-HETE diet. In addition, silencing IFI44 expression in the lungs of mice on 15-HETE diet prevents the development of PH and is associated with significantly lower expression of IFI44 and TRAIL in CD8 cells in the *** data reveal a novel gut-lung axis driven by 15-HETE in PH.

关键词： 香青藤   缺血性脑卒中   脑缺血再灌注损伤   网络药理学   肿瘤坏死因子-α   缺氧诱导因子-1α  

摘要： 目的：基于网络药理学、分子对接及实验验证探讨香青藤拮抗脑缺血再灌注损伤的作用机制。方法：通过文献搜索获取香青藤的主要活性成分；借助SwissTargetPrediction预测成分作用靶点；通过GeneCards、DrugBank等数据库获取缺血性脑卒中的相关靶点；导入STRING平台及Cytoscape 3.8.0软件构建蛋白互作网络与“成分-交集靶点”网络，通过DAVID6.8数据库进行GO功能富集分析与KEGG通路富集分析，AGFR软件进行分子对接验证。构建大鼠MCAO脑缺血再灌注模型，通过TTC染色、神经学行为评分、HE染色及尼氏染色评估香青藤提取物对脑缺血的改善作用，Western blot法检测缺血脑皮层中核心靶点蛋白表达。结果：经筛选获得香青藤活性成分23个，拮抗脑缺血的潜在靶标186个。GO分析结果显示香青藤拮抗脑缺血的关键靶点主要集中在血管内皮细胞迁移的积极调节等生物过程、血红素结合等分子功能。KEGG富集分析显示香青藤可能通过调控VEGF、HIF-1、TNF、PI3K-Akt等信号通路调节血管生成、炎症、凋亡等过程，其发挥拮抗脑缺血作用的潜在主要活性成分是：无根藤辛、甘草素、illigerate C、illigerate A、illigerate F、illigerate G。分子对接结果证明illigerate F、甘草素等成分与核心靶点ERK1、TNF等有较强的结合能力。动物实验结果显示，与正常对照组相比，模型对照组神经行为学评分和梗死面积显著增加，缺血皮层神经细胞坏死、胞核固缩，神经元数量减少(P<0.01)，缺血区TNF-α表达及其下游ERK1/2的磷酸化水平和Cleaved Caspase3表达上调，HIF-1α、EPO蛋白表达下调(P<0.01)；与模型对照组相比，香青藤提取物能显著改善脑缺血再灌注(CIR)大鼠行为学评分、降低脑梗死面积并有效改善缺血脑皮层组织损伤，明显降低TNF-α、Cleaved Caspase3表达及ERK1/2的磷酸化表达 (P<0.05或P<0.01)，促进缺血区HIF-1α、EPO蛋白表达(P<0.05或P<0.01)。结论：基于网络药理学筛选与体内实验探究发现香青藤能通过靶向TNF-α及HIF-1α通路而抑制凋亡和炎症，进而减轻脑缺血再灌注损伤。

摘要： Class I MHC molecules present peptides derived from intracellular antigens on the cell surface for immune surveillance, and specific targeting of these peptide-MHC (pMHC) complexes could have considerable utility for treating diseases. Such targeting is challenging as it requires readout of the few outward facing peptide antigen residues and the avoidance of extensive contacts with the MHC carrier which is present on almost all cells. Here we describe the use of deep learning-based protein design tools to design small proteins that arc above the peptide binding groove of pMHC complexes and make extensive contacts with the peptide. We identify specific binders for ten target pMHCs which when displayed on yeast bind the on-target pMHC tetramer but not closely related peptides. For five targets, incorporation of designs into chimeric antigen receptors leads to T-cell activation by the cognate pMHC complexes well above the background from complexes with peptides derived from proteome. Our approach can generate high specificity binders starting from either experimental or predicted structures of the target pMHC complexes, and should be widely useful for both protein and cell based pMHC targeting.

摘要： The circadian rhythm of the immune system helps to protect against pathogens1-3;however, the role of circadian rhythms in immune homeostasis is less well understood. Innate T cells are tissue-resident lymphocytes with key roles in tissue homeostasis4-7. Here we use single-cell RNA sequencing, a molecular-clock reporter and genetic manipulations to show that innate IL-17-producing T cells-including gamma delta T cells, invariant natural killer T cells and mucosal-associated invariant T cells-are enriched for molecular-clock genes compared with their IFN gamma-producing counterparts. We reveal that IL-17-producing gamma delta (gamma delta 17) T cells, in particular, rely on the molecular clock to maintain adipose tissue homeostasis, and exhibit a robust circadian rhythm for ROR gamma t and IL-17A across adipose depots, which peaks at night. In mice, loss of the molecular clock in the CD45 compartment (Bmal1 triangle Vav1) affects the production of IL-17 by adipose gamma delta 17 T cells, but not cytokine production by alpha beta or IFN gamma-producing gamma delta (gamma delta IFN gamma) T cells. Circadian IL-17 is essential for de novo lipogenesis in adipose tissue, and mice with an adipocyte-specific deficiency in IL-17 receptor C (IL-17RC) have defects in de novo lipogenesis. Whole-body metabolic analysis in vivo shows that Il17a-/-Il17f-/- mice (which lack expression of IL-17A and IL-17F) have defects in their circadian rhythm for de novo lipogenesis, which results in disruptions to their whole-body metabolic rhythm and core-body-temperature rhythm. This study identifies a crucial role for IL-17 in whole-body metabolic homeostasis and shows that de novo lipogenesis is a major target of IL-17. Innate IL-17-producing T cells-in particular, adipose gamma delta 17 T cells-are enriched in molecular-clock genes, and the circadian expression of IL-17A and ROR gamma t by these cells has a role in maintaining local homeostasis and regulating lipogenesis.

关键词： IL1-beta   inflammation   leukocyte trafficking   monocyte  

摘要： IL1-beta plays a central role in inflammation but its biological action needs to be tightly controlled. Such negative regulation can be exerted by the decoy receptor IL1R2. However, IL1R2 biology in immune cells remains poorly characterized, in particular in monocytes. Using conditional deficient mice, we show that Il1r2 deficiency in monocytes does not affect their steady-state life cycle but dysregulates their trafficking to inflamed tissues in models of peritonitis and neuro-inflammation. Mechanistically, we found that Il1r2 deficiency in monocytes increases CCL2 secretion in the inflamed peritoneum, thereby amplifying monocyte recruitment from blood. In autoimmune neuro-inflammation, Il1r2 deficiency in monocytes exacerbates disease severity. Our findings suggest that the specific action of IL1R2 in monocytes contributes to a feedback mechanism for fine-tuning the numbers of recruited monocytes during inflammation.

关键词： biomedical engineering   neoantigen prediction   deep learning   multi allelic HLA   MHC   antigen processing  

摘要： Introduction The identification of peptides eluted from HLA complexes by mass spectrometry (MS) can provide critical data for deep learning models of antigen presentation prediction and promote neoantigen vaccine design. A major challenge remains in determining which HLA allele eluted peptides correspond *** To address this, we present a tool for prediction of multiple allele (MA) presentation called LRMAHpan, which integrates LSTM network and ResNet_CA network for antigen processing and presentation prediction. We trained and tested the LRMAHpan BA (binding affinity) and the LRMAHpan AP (antigen processing) models using mass spectrometry data, subsequently combined them into the LRMAHpan PS (presentation score) model. Our approach is based on a novel pHLA encoding method that enables the integration of neoantigen prediction tasks into computer vision methods. This method aggregates MA data into a multichannel matrix and incorporates peptide sequences to efficiently capture binding *** LRMAHpan outperforms standard predictors such as NetMHCpan 4.1, MHCflurry 2.0, and TransPHLA in terms of positive predictive value (PPV) when applied to MA data. Additionally, it can accommodate peptides of variable lengths and predict HLA class I and II presentation. We also predicted neoantigens in a cohort of metastatic melanoma patients, identifying several shared *** Our results demonstrate that LRMAHpan significantly improves the accuracy of antigen presentation predictions.

关键词： 肿瘤坏死因子α拮抗剂   自身免疫性肝炎   英夫利昔单抗   阿达木单抗   依那西普  

摘要： 目的 探讨肿瘤坏死因子α（TNF-α）拮抗剂相关自身免疫性肝炎（AIH）的临床特点。方法 检索中文和英文数据库，收集各数据库建库至2023年5月30日有关TNF-α拮抗剂引起AIH的相关文献，对患者的一般资料、用药信息、AIH症状、干预措施和转归等进行统计分析。结果 共纳入患者44例，其中男性11例，女性33例，年龄9～69岁；44例患者开始应用TNF-α拮抗剂治疗至诊断AIH的中位时间为5个月，19例患者描述了临床表现，包括腹痛（42.1%）、厌食（31.6%）、关节痛（26.3%）等。发生AIH后患者肝功能指标有不同程度的升高，免疫指标亦有升高或呈阳性，肝组织病理学检查主要表现为界面性肝炎（52.3%）、炎性浸润（50.0%）、肝细胞坏死（11.4%）等；停用TNF-α拮抗剂后转氨酶恢复正常中位时间为2个月。结论 TNF-α拮抗剂引起的AIH以英夫利昔单抗居多，好发于女性患者，多数患者转氨酶和免疫指标异常，临床使用TNF-α拮抗剂应注意监测。发生AIH后应予以停药，视病情给予糖皮质激素和/或硫唑嘌呤。

关键词： Talaromyces marneffei infection   Anti-IFN-gamma autoantibodies   HIV   Computed tomography   Clinical laboratory tests  

摘要： Background To explore the clinical and chest CT features of Talaromycosis marneffei (TSM), and to compare the differences between anti-IFN-gamma autoantibodies-positive and HIV-positive cases. Methods Clinical data and chest CT images of 54 HIV-negative patients with Talaromyces marneffei (TM) infection and positive anti-interferon-gamma (anti-IFN-gamma) autoantibody were retrospectively analyzed. Ninety-three HIV-positive patients with TM infection during the same period were included as controls. Differences between groups were compared by the two-sample t-test and the Mann-Whitney U test, respectively. Results The time from symptom onset to diagnosis of TSM with positive anti-IFN-gamma autoantibodies was significantly longer than that of controls (P < 0.001). BALF/sputum and lymph nodes were the better specimens for detecting TM in the anti-IFN-gamma autoantibody-positive group, while TM were more often isolated or detected in blood samples in the other group. Patients with TM infection tended to present with cough, expectoration, and fever. Compared with controls, anti-IFN-gamma antibody-positive patients with TM infection had a higher incidence of shortness of breath, skin lesions, joint pain, and high CD4/CD8 ratio (P < 0.05). There were only 1 and 6 cases with negative lung involvements in CT scans in anti-IFN-gamma autoantibody-positive patients and HIV-positive patients with TM infection, respectively. In the remaining patients, chest CT manifestations were diverse, mainly presenting as fibrous cord-like lesions, lymph node enlargement, and sporadic nodules. The incidences of patchy consolidation, air bronchogram, pleural effusion and pleural thickening were higher in anti-IFN-gamma autoantibody-positive patients with TM infection than those of controls (P < 0.05). Conclusions Anti-IFN-gamma antibody positive patients with TM infection showed a longer diagnostic interval. clinical specimens from which TM was isolated or detected were different between the t

摘要： HLA class I alleles of archaic origin may have been retained in modern humans because they provide immunity against diseases to which archaic humans had evolved resistance. According to this model, archaic introgressed alleles were somehow distinct from those that evolved in African populations. Here we show that HLA-B*73:01, a rare allotype with putative archaic origins, has a relatively rare peptide binding motif with an unusually long-tailed peptide length distribution. We also find that HLA-B*73:01 combines a restricted and unique peptidome with high-cell surface expression, characteristics that make it well-suited to combat one or a number of closely-related pathogens. Furthermore, a crystal structure of HLA-B*73:01 in complex with KIR2DL2 highlights differences from previously solved structures with HLA-C molecules. These molecular characteristics distinguish HLA-B*73:01 from other HLA class I alleles previously investigated and may have provided early modern human migrants that inherited this allele with a selective advantage as they colonized Europe and Asia.