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关键词： HLA   HLA-DRB4*01:03:38   novel allele   third-generation sequencing  

摘要： HLA-DRB4*01:03:38 differs from HLA-DRB4*01:03:01:01 by one nucleotide substitution at position 42 (G -> A) in exon 1.

关键词： 肾疾病   免疫球蛋白类   活组织检查   具有肾脏意义的单克隆免疫球蛋白病   诊断   分类  

摘要： 具有肾脏意义的单克隆免疫球蛋白病（monoclonal gammopathy of renal significance，MGRS）是一组由单克隆免疫球蛋白或其组分直接或间接导致肾脏损害的疾病。早期正确诊断MGRS，并针对致病B淋巴细胞或浆细胞克隆实施靶向疗法，对改善患者肾脏预后具有重要意义。肾活检作为确诊MGRS的金标准，不仅是明确诊断的关键手段，更是实现MGRS精准分型必不可少的环节。为帮助临床医师合理、规范地运用肾活检技术，在疾病早期准确诊断MGRS，MGRS肾活检诊断专家建议专家组组织编写了《MGRS肾活检诊断专家建议》。该建议深入阐述了MGRS的最新分类标准、肾活检适应证、检查方法和内容以及单克隆免疫球蛋白检测和克隆鉴定的方法，并凝练形成了6项具有临床指导价值的推荐意见，旨在为临床实践提供最新的循证依据，推动MGRS诊疗水平的提升。

关键词： TNF signaling pathway   WGCNA   bioinformatics   knee osteoarthritis   machine learning  

摘要： Knee osteoarthritis (KOA), a prevalent degenerative joint disease, involves complex inflammatory responses and signal pathway regulation in its pathogenesis. This study investigates the tumor necrosis factor signaling pathway's mechanistic role in KOA using diverse bioinformatics approaches. Initially, differential expression analysis identified 222 significant differentially expressed genes. Subsequent Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that these differentially expressed genes are mainly involved in inflammatory responses and cytokine signaling pathways. Weighted gene co-expression network analysis was then employed to identify the MEbrown module, which is closely associated with knee arthritis, and 20 key tumor necrosis factor signaling pathway-related genes were selected. Further analysis using LASSO regression and the Boruta algorithm screened out important genes, including MCL1, JUN, and GADD45B, whose superior performance in classification tasks was validated. Additionally, immune infiltration analysis revealed significant differences in immune cell distribution across knee arthritis samples, underscoring the critical role of inflammation regulation in disease progression. Overall, this study enhances the understanding of KOA pathogenesis and offers valuable insights for personalized treatment and, precision medicine.

关键词： 胆管肿瘤   胰十二指肠切除术   预后   远端胆管癌   淋巴细胞/单核细胞比值  

摘要： 目的探讨淋巴细胞/单核细胞比值(LMR)与远端胆管癌患者术后远期预后的相关性。方法通过回顾性病例对照研究方法分析2013年1月—2023年12月于首都医科大学附属北京朝阳医院因远端胆管癌接受根治性胰十二指肠切除术治疗的186例患者的临床资料，其中男性109例，女性77例，年龄(65.4±9.4)岁，年龄范围29~85岁。收集患者术前外周血常规检查资料，将患者分为高LMR组(LMR>2.98，n＝100)和低LMR组(LMR≤2.98，n＝86)，比较两组患者术前、术中、术后的临床特征。正态分布的计量资料以均数±标准差(±s)表示，组间比较采用成组t检验；非正态分布的计量资料以M(Q1，Q3)表示，组间比较采用Mann-Whitney U检验。计数资料组间比较采用χ2检验。单因素和多因素预后分析采用Cox比例风险回归模型，使用Kaplan-Meier估算法来创建生存曲线，分析评价远端胆管癌术后远期预后的影响因素。结果单因素分析结果表明，性别、年龄、体重指数、吸烟史、糖尿病史、心脑血管病史、癌胚抗原、手术时长、术中出血量、切缘状态、肿瘤细胞分化程度、是否有术后并发症对于远端胆管癌术后患者预后影响差异无统计学意义(P>0.05)，LMR、中性粒细胞/淋巴细胞比值、血小板/淋巴细胞比值、白蛋白、总胆红素、糖类抗原19-9、术中输血、肿瘤最大径、淋巴结转移对于远端胆管癌术后患者预后影响差异具有统计学意义(P<0.05)；多因素分析结果表明，LMR≤2.98(HR＝1.776，95%CI：1.153~2.736)、CA19-9>37 U/mL(HR＝1.521，95%CI：1.025~2.259)、淋巴结转移(HR＝1.601，95%CI：1.106~2.318)是影响患者预后的独立危险因素(P<0.05)。高LMR组术后1、3、5年累积生存率分别为91%、40%、20%，低LMR组患者的累积生存率为58.1%、15.1%、8.1%，差异具有统计学意义(P<0.05)。结论远端胆管癌患者术前LMR可提示远期预后，低LMR值提示患者预后不良。

关键词： HZD   PI3K/AKT   Psoriasis   TNF-α/IL-6   network pharmacology  

摘要： INTRODUCTION:Hua-Zhuo-Ning-Fu decoction (HZD) is a traditional Chinese medicine prescription that has been clinically used by Chinese medical master Wang Xinlu for treating psoriasis. However, the specific molecular mechanisms remain unclear. METHODS:To identify the effective compounds of HZD and psoriasis-related genes, we conducted comprehensive searches in public databases, including TCMSP, SwissTargetPrediction, Gene Cards, and OMIM. Based on the degree values, core genes of HZD against psoriasis were determined. Furthermore, the affinity energy between the active compounds of HZD and their core targets was validated via molecular docking. Finally, the anti-psoriasis effects and potential mechanisms of HZD were examined in M5-stimulated HaCaT cells in vitro and IMQ-induced psoriasis mice in vivo. RESULTS:Network pharmacological analysis of HZD for psoriasis treatment identified 43 active components and 243 targets. Topological and molecular docking analyses identified interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) as core targets for its anti-psoriasis effects. Specifically, the docking energy of isovitexin with IL-6 was lower (-7.30 kcal/mol), and that of baicalin with TNF-α was lower (-6.70 kcal/mol). KEGG analysis revealed that the main pathway was the PI3K/AKT pathway. HZD inhibited cell viability, inflammation, and oxidative stress in M5- induced HaCaT cells. Animal experiments demonstrated that HZD alleviated psoriatic dermatitis, histopathological features, and inflammation in IMQ-induced mice with psoriatic plaques. Notably, HZD inhibited the expression of TNF-α and IL-6 and the activation of the PI3K/AKT pathway both in vivo and in vitro. DISCUSSION:Specific upstream/downstream regulators of the PI3K/AKT axis regulated by HZD still need to be explored. Further investigation is essential to clarify the functional relationship between the predicted targets and active components. CONCLUSION:In summary, HZD potentially mitigated inflammatory respons

关键词： Anti-IL-6 receptor antibody   Microglia   Aquaporin-4   IL-6   NMOSD  

摘要： Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease characterized by periods of remission and relapse;severe relapses often lead to permanent neurological disability. Satralizumab, an anti--interleukin-6 receptor (anti-IL-6R) antibody, has been proven in previous studies to reduce the frequency and severity of relapses in patients with NMOSD. There are several reports on the mechanisms through which anti-IL-6R antibodies are thought to suppress relapse. However, the mechanisms underlying how anti-IL-6R antibodies reduce the severity of myelitis have not been elucidated. We investigated the effect of an anti-IL-6R antibody (MR16-1) on the severity of myelitis in an AQP4 peptide-immunized mice model. This mouse model exhibits NMOSD-like pathological characteristics and the production of anti-AQP4 autoantibodies. Unlike the previously reported experimental protocol where antibody and peptide are administered simultaneously, we tested delayed administration of MR16-1 (9 days after peptide immunization). We found that delayed MR16-1 administration suppressed the clinical score of AQP4 peptide-immunized mice experiencing myelitis. Mice treated with MR16-1 showed a greater percentage of CD11c+ microglia in the spinal cord, along with upregulated expression of phagocytosis-related genes. Blockade of IL-6R by anti-IL-6R antibodies may suppress the severity of myelitis by increasing CD11c+ microglia and enhancing phagocytic function in AQP4 peptide-immunized mice.

摘要： The accumulation of CD103+ CD8 tumor-resident memory T (TRM) cells is predictive of response to cancer immunotherapy. Here, we show that a therapeutic peptide vaccine controls tumor growth in wild-type mice, but not in CD103-knockout mice. CD8 tumor-infiltrating T lymphocytes include two major TRM subpopulations expressing either CD49a or CD103 integrin, with a subset co-expressing CD103 and Tcf-1. Vaccination induces a decrease in the percentage of Tcf-1+CD103+ TRM-like cells and expansion of CD49a+ TRM displaying an effector/exhausted profile. Tcf-1+CD103+ TRM-cell density increases in tumors from transgenic mice constitutively expressing active TGF-D-type-2-receptor and wild-type mice challenged with neutralizing anti-IL-12 antibodies. The stimulation of CD8 T cells with recombinant (r)TGF-D combined with anti-CD3 antibodies results in an increase in the proportion of Tcf-1+CD103+ cells, whereas rIL-12 decreases CD103 expression. These results highlight the opposite effects of TGF-D and IL-12 in the regulation of TRM-cell development and suggest that targeting Tcf-1+CD103+ CD8 TRM may improve immunotherapy efficacy.

关键词： tRNA   queuosine   RNA modifications   queuine   MHC-II  

摘要： Queuosine (Q) is a conserved tRNA modification in the wobble anticodon position of tRNAs that read codons of Tyr/His/Asn/Asp. Eukaryotic tRNA Q-modification requires the metabolite queuine - derived from diet or catabolism of the gut microbiome - and a host-genome encoded enzyme complex, QTRT1/QTRT2. tRNA Q-modification has been shown to regulate translational efficiency, but the response of the mammalian transcriptome and tRNAome to tRNA Q-modification in the context of cell proliferation has not been thoroughly investigated. Using cells that differ only in their tRNA Q-modification levels, we found that both human HEK293T cultures and the primary, murine bone marrow-derived dendritic cells (BMDCs) proliferate faster when tRNA Q-modification level is high. We carried out tRNA-seq and mRNA-seq to elucidate the molecular mechanisms underlying this phenotype, revealing distinct tRNA modification and transcriptome changes associated with altered proliferation. In both cell types, the m2 tRNA modification is positively correlated to Q-modification, consistent with its reported role in enhancing translational efficiency. We also find that elevated Q-modification levels result in transcriptome changes, but in a context-dependent manner. In HEK293T cells, upregulated genes are in catabolic processes and signaling pathway activation;whereas in BMDCs, upregulated genes are in immune response mediation, proliferation, and immunoglobulin diversification. Codon usage analysis of differentially expressed transcripts is consistent with Q-modification enhancing the translation of ribosomal proteins, which increases cell proliferation. We also find that tRNA Q-modification increases surface presentation of MHC-II in BMDCs. Our results provide insights into the broader implications of tRNA Q-modifications in regulating diverse biological functions. (c) 2025 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： Biomass fuel   IL-17A   Neuroinflammation   Neurodegeneration   Lung-brain axis  

摘要： Biomass fuel (BMF) exposure is known to cause respiratory inflammation, but its impact on the central nervous system (CNS) and the mechanisms underlying this effect remain unclear. BMF combustion releases particulate matter (PM2.5), triggering systemic inflammation, which is linked to an increased risk of neurodegenerative diseases such as Parkinson's disease (PD). This study revealed that prolonged BMF exposure leads to dopaminergic neuron loss, increased alpha-synuclein (alpha-syn) phosphorylation, and neuroinflammation, resulting in motor and cognitive impairments in mice. Mechanistically, BMF activates the interleukin-17A (IL-17A) signalling pathway in the periphery, promoting Th cell infiltration across the blood-brain barrier, which stimulates astrocytes to release IL-17A and activates IL-17 receptor A (IL-17RA) on microglia. Transcriptomic and metabolomic analyses revealed that BMF exposure significantly disrupts immune and neurotransmitter pathways. Importantly, IL-17A knockout (IL-17A-/-) mice exhibit marked improvements in motor and cognitive functions and reduced neuroinflammation following BMF exposure. These findings identify IL-17A as a critical mediator of the lung-brain axis, orchestrating PD-related immune responses within both the CNS and peripheral nervous system. The IL-17A pathway represents a promising therapeutic target for PD and the related neuroinflammatory changes associated with environmental pollutant exposure.