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关键词： epilepsy   HLA   genetics   immunology  

摘要： Epilepsy is one of the most common neurological disorders. Disease etiology and pathogenesis are still not well understood. Genetic mutations are associated with 70% of epilepsies, while 30% are still enigmatic. Attempting to close the knowledge gap, we performed genetic analysis of a cohort of patients from the Middle East and North Africa, both understudied and highly consanguineous populations. Whole exome sequencing (WES) was carried out on 81 patients and their family members at a tertiary center in Qatar. We found damaging mutations in half of the patients: 15 in known epilepsy genes, and 19 in contested or unknown genes. The mutations include single nucleotide polymorphisms (SNVs), frameshifts, copy number variations (CNVs), and loss of homozygosity (LOH). Fifteen of the SNVs are novel, and seventeen are homozygous, reflective of the characteristics of the cohort. In addition, we used the WES data to type HLA alleles for 13 class I and II genes. We show that DRB3*01:01:02G is negatively associated with epilepsy, in contrast to DRB4*01:01:01G, which may be a risk allele. In addition to expanding the knowledge base of genes involved in epilepsy, our findings show that genetic predisposition, inclusive of immune genes, suggests a complex etiology.

关键词： glucose uptake   T cells   SGLT2   GLUT1   immunomodulation   IFN gamma   empagliflozin   phlorizin  

摘要： Glucose uptake in activated CD4+ T cells is essential for increased metabolic needs, synthesis of biomolecules and proliferation. Although, facilitated glucose transport is the predominant route for glucose entry at the time of activation, here we demonstrate role for the sodium-dependent glucose transporter SGLT2. By 72 h after activation, SGLT2 is expressed and functional in the human CD4+ T cells. SGLT2 inhibitors, phlorizin and empagliflozin decreased glucose uptake into the human CD4+ T cells compared to untreated cells. Phlorizin (25 mu mol/L) reduced glycolysis at 5.6 mmol/L glucose and IFN gamma levels at both 5.6 mmol/L and 16.7 mmol/L glucose. In contrast, empagliflozin (0.5 mu mol/L) only decreased IFN gamma levels in 16.7 mmol/L glucose. GABA enhanced phlorizin inhibition at both 5.6 mmol/L and 16.7 mmol/L glucose in the presence of insulin. Insulin strengthens GABAA receptors signaling in CD4+ T cells. The results are consistent with expression of SGLT2 after activation of human CD4+ T cells, that facilitates concentrating glucose uptake into the cells, enabling enhanced release of inflammatory molecules like IFN gamma. Importantly, inhibition of SGLT2 decreases IFN gamma release.

关键词： Anti-PF4 antibodies   HLA   SARS-CoV-2   thrombosis   thrombocytopenia   VITT  

摘要： Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare thrombotic disorder first identified in 2021 as a catastrophic syndrome associated with anti-SARS-CoV-2 adenoviral vector (AdV)-vaccine administration. It is characterized by the presence of oligo- or monoclonal anti-PF4 antibodies able to induce in vitro platelet activation in the presence of PF4. In addition to this immune-based pathomechanism, random splicing events of the Adv-vector DNA encoding for SARS-CoV-2 spike protein resulting in the secretion of soluble spike variants have been postulated as a possible pathophysiological mechanism. More recently, some novel clinical-pathological anti-PF4-associated entities also characterized by thrombosis, thrombocytopenia, and VITT-like antibodies but independent from heparin or AdV-vaccine administration have been identified. To date, these VITT-like disorders have been reported following the administration of vaccines different from anti-SARS-CoV-2 AdV-vaccines, like human papillomavirus (HPV) and mRNA-based COVID-19 vaccines, following a bacterial or viral respiratory infection, and in patients with a monoclonal gammopathy of undetermined significance. The purpose of this review is to provide an update on the knowledge on VITT pathogenesis, focusing on recent findings on anti-PF4 antibodies, on a possible genetic predisposition to VITT, on VITT-antibody intracellular activated pathways, on lipid metabolism alterations, and on new VITT-like disorders.

摘要： Macrophages, as key sentinel cells of the innate immune system, can retain memory of prior stimulus exposure. Interferon gamma (IFNγ) plays a central role in maintaining trained immunity and can induce potent memory in macrophages. Such memory is associated with the formation of enhancers that alter gene expression responses to subsequent stimuli. However, how such enhancers are maintained after cytokine exposure remains unclear. We report that durable IFNγ-induced enhancers can last for days after cytokine washout, yet the underlying persistence mechanism is not cell-intrinsic. IFNγ-treated macrophages continue to exhibit JAK/STAT signaling days after cytokine removal. Blocking IFNγ signaling with a JAK inhibitor or anti-IFNγ neutralizing antibodies after cytokine removal is sufficient to reverse IFNγ-induced enhancers and erase the potentiated state of the treated macrophages. Our findings suggest that epigenetic changes in macrophages do not inherently encode innate immune memory or a "potentiated" macrophage state, but in fact are themselves dependent on ongoing cytokine signaling. These findings suggest new possibilities for pharmacologic interventions to reverse aberrantly trained immune states associated with pathology.

关键词： Resveratrol glycoside   Peritoneal fibrosis   NLRP3   Inflammation   Epithelial-mesenchymal transition  

摘要： ObjectiveResveratrol glycoside (also known as polydatin, PLD), known for its anti-inflammatory and anti-fibrotic properties, has shown potential in mitigating fibrosis in various organs. This study aimed to investigate the effects of PLD on high glucose-induced peritoneal fibrosis and its underlying mechanisms, focusing on the NOD-like receptor protein 3 (NLRP3)/interleukin-1 beta (IL-1 beta)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) *** Sprague-Dawley rats were divided into three groups: control, peritoneal fibrosis, and resveratrol glycoside treatment. Histological and immunohistochemical analyses were performed to assess peritoneal fibrosis. Human peritoneal mesothelial cells (HMrSV5) were treated with high glucose and PLD to evaluate cell morphology, viability, and the expression of fibrosis and inflammatory markers via Western Blot and *** significantly reduced peritoneal fibrosis in rats, as evidenced by histological analyses showing decreased tissue thickness and collagen deposition. It also downregulated the expression of transforming growth factor beta 1 (TGF-beta 1), collagen type I (Col I), alpha-smooth muscle actin (alpha-SMA), vascular endothelial growth factor (VEGF), NLRP3, phosphorylated p65 subunit of NF-kappa B (p-p65), IL-1 beta, interleukin-18 (IL-18), cleaved caspase-1 p20 subunit (caspase-1p20) and ROS level, while upregulating E-cadherin. In HMrSV5 cells, PLD mitigated high glucose-induced epithelial-mesenchymal transition, angiogenesis, reactive oxygen species (ROS) production and inflammation, which was reversed by overexpression of NLRP3, suggesting the involvement of the NLRP3/IL-1 beta/NF-kappa B *** alleviates high glucose-induced peritoneal fibrosis, angiogenesis, ROS production and inflammation by inhibiting the NLRP3/IL-1 beta/NF-kappa B signaling pathway, highlighting its potential as a therapeutic agent for peritoneal fibrosis.

关键词： 腹膜透析相关性腹膜炎   扶肾颗粒   驻留巨噬细胞   细胞因子   中药复方   随机对照试验  

摘要： 目的观察扶肾颗粒干预Vsig4驻留巨噬细胞治疗腹膜透析相关性腹膜炎（PDAP）的临床疗效和作用机制。方法本研究通过随机对照试验评估扶肾颗粒联合抗生素治疗PDAP的有效性。纳入天津中医药大学第一附属医院2023年7月—2024年2月就诊的40例PDAP患者，随机分为扶肾颗粒组20例，对照组20例。对照组控制患者血压、血糖，予患者腹腔注射敏感抗生素治疗14天。扶肾颗粒组在对照组的基础上，加用口服扶肾颗粒治疗，每次2袋，每天2次，共治疗14天。记录患者PDAP转阴时间及腹膜透析总超滤量变化；收集PDAP治疗前后的腹膜透析液样本，检测腹腔Vsig4驻留巨噬细胞、T细胞和细胞因子IL-6、IL-10、TNF-α的变化。结果扶肾颗粒组患者平均转阴时间[（2.50±0.26）天]短于对照组[（3.30±0.25）天，t=-2.223,P=0.032]。与对照组比较，第3天时扶肾颗粒组超滤量更多（P<0.05）。与本组治疗前比较，两组IL-6、IL-10、TNF-α浓度降低（P<0.01）；扶肾颗粒组CD3+T细胞、CD14+巨噬细胞、Vsig4+巨噬细胞、Vsig4+巨噬细胞/CD14+巨噬细胞水平升高（P<0.05,P<0.01），对照组CD3+T细胞、Vsig4+巨噬细胞、Vsig4+巨噬细胞/CD14+巨噬细胞水平亦升高（P<0.05,P<0.01）。与对照组比较，扶肾颗粒组Vsig4+巨噬细胞的比例及IL-10浓度更高（P<0.05）,IL-6浓度更低（P<0.01）。结论PDAP患者早期应用扶肾颗粒能够缩短腹透液常规转阴时间，其作用机制可能与其调节Vsig4驻留巨噬细胞比例和细胞因子浓度减轻腹腔炎症反应有关。

关键词： opioid use disorder   OUD   medications for opioid use disorder   MOUD   HIV reservoir   cytotoxic T lymphocytes   single-cell multiomics   DOGMA-seq   single-cell RNA-seq   single-cell ATAC-seq   TNF   AP-1  

摘要： People living with HIV (PLWHs) have higher risk of opioid use disorder (OUD). Whether medications for opioid use disorder (MOUDs) change immune responses in HIV infection is unknown. We examined the immune profiles in PLWHs before and 3 months after initiation of the mu opioid receptor agonist methadone, partial agonist buprenorphine, and antagonist naltrexone. Using single-cell DOGMA-seq, we profiled 29,462 peripheral blood immune cells in 12 PLWHs. We found that naltrexone treatment increased type I interferon (IFN) responses while buprenorphine increased tumor necrosis factor (TNF) responses in cytotoxic T cell population. We found that HIV+ cells in PLWHs with OUD upregulated PTPN13 and TAF5L, both of which are associated with HIV replication. We found trends suggesting increased HIV RNA expression after methadone and decreased HIV RNA expression after buprenorphine and naltrexone initiation. Overall, PLWHs treated with MOUD had improved immune responses and decreased HIV expression.

关键词： Asthma   Immunology   Inflammation   Pulmonology  

摘要： The mechanism of neutrophilic and mixed neutrophilic-eosinophilic asthma is poorly understood. We found that extracellular DNA and nucleosomes (Nuc) were elevated in the airways from neutrophilic-eosinophilic asthma patients and correlated with bronchoalveolar lavage neutrophils. Bronchial tissue from neutrophilic-eosinophilic asthma expressed increased DNA sensor-positive cells. Intranasally administered DNA did not induce airway hyperreactivity (AHR) or any pathology but induced AHR and neutrophilic-eosinophilic inflammation when co- administered with the allergen Alternaria (Alt). Nuc alone induced anti-inflammatory/defensive genes whereas the Nuc-Alt combo increased TNF and innate cytokines. The Alt-Nuc phenotype was abolished in Cgas-/-, ALR-/-, Sting-/-, LysMCre:Stingf/f, IL7RCre:Rorαf/f and Tnfr2-/- mice. Alt, unexpectedly, played an essential role in the Nuc-induced phenotype. It abrogated Nuc-induction of anti-inflammatory genes, facilitated Nuc uptake, induced ILC2s, which, in presence of Nuc, produced high levels of TNFα and promoted neutrophilic infiltration. We established a paradigm where allergens inhibit the anti-inflammatory effects of DNA/Nuc and facilitate STING-TNFα-driven neutrophilic-eosinophilic inflammation in asthma.

关键词： 非洲猪瘟病毒   单克隆抗体   M1249L蛋白  

摘要： 本研究旨在制备非洲猪瘟病毒（ASFV）M1249L蛋白的单克隆抗体并分析其亚型、灵敏性及反应性。首先对M1249L（673 aa～1249 aa）序列进行密码子优化，并将该片段插入pET-28a载体中，构建原核表达质粒；经过转化、挑取单克隆、诱导表达及蛋白纯化，用纯化后的M1249L截短蛋白免疫小鼠；经细胞融合、有限稀释法筛选分泌抗体的杂交瘤细胞株，进行亚型鉴定和腹水制备。采用蛋白质免疫印迹（Western-blot）和间接免疫荧光试验（IFA）检测该单抗的反应性。结果显示，该单抗1D6重链属于IgG1型，轻链为Kappa型，腹水抗体效价可达1∶1 024 000。Western-blot结果显示，该单克隆抗体能够特异性识别ASFV感染后不同时间点猪肺泡巨噬细胞（PAMs）表达的M1249L蛋白以及HEK 293T细胞转染不同质粒量后表达的M1249L蛋白。IFA结果显示，在ASFV感染的PAMs细胞中出现绿色荧光，表明有良好的反应性。综上所述，本研究成功制备出M1249L单克隆抗体，为后续研究M1249L蛋白的生物学功能和ASFV诊断检测奠定了基础。

关键词： Positive ions  

摘要： As the CO2 concentration in the atmosphere is relatively low, directly capturing CO2 from the air remains a challenge. Herein, a dual-functionalized strategy is developed to construct a series of IL@ZIF-8 composite materials by regulating the spatial distribution of nitrogen sites of the anion and the amine content of the cation in the ionic liquid (IL). The introduction of functional sites significantly enhances the capture capability of composite materials toward low-concentration CO2. The IL composed of pyrazole (Py) with adjacent nitrogen sites exhibits stronger interaction with CO2 due to its lower viscosity and higher electron cloud density. The IL@ZIF-8 constructed with tetraethylenepentamine (TEPA) as the cation and Py demonstrates optimal CO2 capture capability, which is attributed to TEPA's balance of abundant amine groups and moderate viscosity. [TEPA][Py]@ZIF-8 exhibits a remarkable dynamic CO2 capture capacity under simulated air conditions, and in situ FT-IR analysis reveals its reversible adsorption mechanism. This study provides a new strategy for the development of novel adsorbents for low-concentration CO2 capture.