Non-alcoholic fatty liver disease(NAFLD)is associated with mutations in lipopolysaccharide-binding protein(LBP),but the underlying epigenetic mechanisms remain understudied.Herein,LBP^(-/-)rats with NAFLD were establi...Non-alcoholic fatty liver disease(NAFLD)is associated with mutations in lipopolysaccharide-binding protein(LBP),but the underlying epigenetic mechanisms remain understudied.Herein,LBP^(-/-)rats with NAFLD were established and used to conduct integrative targetingactive enhancer histone H3 lysine 27 acetylation(H3K27ac)chromatin immunoprecipitation coupled with high-throughput and transcriptomic sequencing analysis to explore the potential epigenetic pathomechanisms of active enhancers of NAFLD exacerbation upon LBP deficiency.Notably,LBP^(-/-)reduced the inflammatory response but markedly aggravated high-fat diet(HFD)-induced NAFLD in rats,with pronounced alterations in the histone acetylome and regulatory transcriptome.In total,1128 differential enhancer-target genes significantly enriched in cholesterol and fatty acid metabolism were identified between wild-type(WT)and LBP^(-/-)NAFLD rats.Based on integrative analysis,CCAAT/enhancer-binding proteinβ(C/EBPβ)was identified as a pivotal transcription factor(TF)and contributor to dysregulated histone acetylome H3K27ac,and the lipid metabolism gene SCD was identified as a downstream effector exacerbating NAFLD.This study not only broadens our understanding of the essential role of LBP in the pathogenesis of NAFLD from an epigenetics perspective but also identifies key TF C/EBPβand functional gene SCD as potential regulators and therapeutic targets.展开更多
目的:旨在研究不同预后及严重程度的创伤性颅脑损伤(TBI)患者T淋巴细胞亚群和CRP水平分析。方法:回顾性分析宜春新建医院2022年5月—2023年6月收治的100例创伤性颅脑损伤患者临床数据。根据患者入院时格拉斯哥昏迷量表(Glasgow coma sca...目的:旨在研究不同预后及严重程度的创伤性颅脑损伤(TBI)患者T淋巴细胞亚群和CRP水平分析。方法:回顾性分析宜春新建医院2022年5月—2023年6月收治的100例创伤性颅脑损伤患者临床数据。根据患者入院时格拉斯哥昏迷量表(Glasgow coma scale,GCS)评分将其分为三组,轻型组(25例):GCS评分13~15分;中型组(33例):GCS评分9~12分;重型组(42例):GCS评分为3~8分,选取同期体检正常志愿者100例为对照组。根据TBI预后存活情况分为存活组90例、死亡组10例,观察并比较不同组别患者的T淋巴细胞亚群(CD4^(+)、CD8^(+)、CD4^(+)/CD8^(+))、C反应蛋白(CRP),并分析各指标之间的相关性。结果:不同颅脑损伤组血清CD8^(+)、CRP水平均高于对照组,CD4^(+)、CD3^(+)水平及CD4^(+)/CD8^(+)均低于对照组(P<0.05);重型组、中型组CD8^(+)水平均高于轻型组,CD4^(+)、CD3^(+)水平及CD4^(+)/CD8^(+)均低于轻型组(P<0.05);重型组CD8^(+)水平高于中型组,CD4^(+)、CD3^(+)水平及CD4^(+)/CD8^(+)均低于中型组(P<0.05);重型组CRP水平高于中型组和轻型组,中型组高于轻型组(P<0.05)。存活组CD4^(+)、CD4^(+)/CD8^(+)均较死亡组高,CD8^(+)、CPR均低(P<0.05)。根据Pearson统计分析显示,TBI患者的CRP与CD4^(+)、CD3^(+)、CD4^(+)/CD8^(+)均呈负相关,CRP与CD8^(+)呈正相关(P<0.05)。结论:不同预后及严重程度的创伤性颅脑损伤患者中,CRP水平与CD8^(+)呈正相关,与CD4^(+)、CD3^(+)及CD4^(+)/CD8^(+)均呈负相关,且严重程度越高CRP水平越高,CD4^(+)、CD3^(+)及CD4^(+)/CD8^(+)水平越低。展开更多
Understanding the topography in active tectonic areas and assessing the rates and models of active deformation in the upper crust are primary objectives in tectonic geomorphology studies. The drainage pattern of river...Understanding the topography in active tectonic areas and assessing the rates and models of active deformation in the upper crust are primary objectives in tectonic geomorphology studies. The drainage pattern of river systems is highly sensitive to tectonically induced changes, and it often preserves the records of the formation and progression of most tectono-geomorphic processes within its boundaries. Therefore, the evolution of landforms is a consequence of the evolution of individual drainage basins in which they are formed. Assessing the rates of tectonic deformation using geomorphic data is a traditionally adopted method to characterize the nature of active faults. Globally, the Digital Elevation Model(DEM) is widely used as a crucial tool to analyze the morphotectonic features of drainage basins. In this study, some geomorphic indices were applied to investigate the impact of tectonism on landscape along the Karahay?t Fault and its associated drainage areas. These geomorphic indices are mountain front sinuosity(Smf values between 1.17-1.52), valley floor width-to-height ratio(Vf values between 0.25-1.46), basin asymmetry factor(AF values between 15-72), drainage basin shape(Bs values between 3.18-6.01), hypsometric integral and curve(HI values between 0.32-047), channel sinuosity(S values between 1-1.6), normalized steepness index(Ksn values between 1-390) and Chi integral(χ values between 200-4400). The development of drainage areas on the hanging wall and footwall block of the Karahayit Fault differs depending on the uplift. The drainage areas developed on the hanging wall present different patterns depending on the regional uplift caused by the fault. This reveals that the fault contributed significantly to the development of drainage areas and regional uplift in the region. In addition, the maximum earthquake magnitude that may occur in the future on the Karahayit Fault, whose activity is supported by geomorphic indices, is calculated as 6.23. Since an earthquake of this magnitude may cause loss of life and property in the region, precautions should be taken.展开更多
目的系统评价ABCB1基因C3435T多态性对他汀类药物降脂疗效的影响。方法计算机检索PubMed、Web of Science、the Cochrane Library、中国知网和维普网,收集患者使用他汀类药物的队列研究,检索时限为建库至2023年11月1日。筛选文献、提取...目的系统评价ABCB1基因C3435T多态性对他汀类药物降脂疗效的影响。方法计算机检索PubMed、Web of Science、the Cochrane Library、中国知网和维普网,收集患者使用他汀类药物的队列研究,检索时限为建库至2023年11月1日。筛选文献、提取数据、评价质量后,采用RevMan 5.4软件进行Meta分析。结果共纳入11项文献,共计1575例患者。Meta分析结果显示,显性遗传模型下,CT+TT型患者的低密度脂蛋白胆固醇(LDL-C)降低程度[MD=-1.87,95%CI(-3.62,-0.13),P=0.04]、总胆固醇(TC)降低程度[MD=-1.42,95%CI(-2.80,-0.04),P=0.04]均显著高于CC型;CT+TT型患者的高密度脂蛋白胆固醇(HDL-C)升高程度[MD=-0.65,95%CI(-2.48,1.18),P=0.49]、甘油三酯(TG)降低程度[MD=-0.05,95%CI(-2.94,2.84),P=0.97]与CC型比较,差异均无统计学意义。隐性遗传模型下,TT型患者的TC降低程度[MD=2.26,95%CI(0.97,3.56),P=0.0006]、HDL-C升高程度[MD=2.38,95%CI(0.42,4.35),P=0.02]均显著高于CC+CT型;CC+CT型患者的LDL-C降低程度[MD=1.53,95%CI(-0.10,3.15),P=0.07]、TG降低程度[MD=0.06,95%CI(-2.98,3.10),P=0.97]与TT型比较,差异均无统计学意义。加性遗传模型下,TT型患者的TC降低程度[MD=2.98,95%CI(1.27,4.69),P=0.0006]、LDL-C降低程度[MD=2.84,95%CI(0.67,5.01),P=0.01]均显著高于CC型;TT型患者的HDL-C升高程度[MD=2.40,95%CI(-0.17,4.97),P=0.07]、TG降低程度[MD=0.97,95%CI(-2.93,4.87),P=0.63]与CC型比较,差异均无统计学意义。结论血脂异常患者接受他汀类药物治疗时,LDL-C、TC降低效果可能与ABCB1基因C3435T杂合和纯合突变有关,即与CC型患者比较,CT或TT型患者的LDL-C、TC降低效果可能更明显;HDL-C升高效果可能与纯合突变有关,即与CC+CT型患者比较,TT型患者的HDL-C升高效果可能更明显;而TG变化可能与ABCB1基因C3435T多态性无关。展开更多
基金supported by the National Natural Science Foundation of China(81971875,82300661)Natural Science Foundation of Anhui province(2308085QH246)+3 种基金Natural Science Foundation of the Anhui Higher Education Institutions(KJ2021A0205)Basic and Clinical Cooperative Research Program of Anhui Medical University(2019xkjT002,2019xkjT022,2022xkjT013)Talent Training Program,School of Basic Medical Sciences,Anhui Medical University(2022YPJH102)National College Students Innovation and Entrepreneurship Training Program of China(202210366024)。
文摘Non-alcoholic fatty liver disease(NAFLD)is associated with mutations in lipopolysaccharide-binding protein(LBP),but the underlying epigenetic mechanisms remain understudied.Herein,LBP^(-/-)rats with NAFLD were established and used to conduct integrative targetingactive enhancer histone H3 lysine 27 acetylation(H3K27ac)chromatin immunoprecipitation coupled with high-throughput and transcriptomic sequencing analysis to explore the potential epigenetic pathomechanisms of active enhancers of NAFLD exacerbation upon LBP deficiency.Notably,LBP^(-/-)reduced the inflammatory response but markedly aggravated high-fat diet(HFD)-induced NAFLD in rats,with pronounced alterations in the histone acetylome and regulatory transcriptome.In total,1128 differential enhancer-target genes significantly enriched in cholesterol and fatty acid metabolism were identified between wild-type(WT)and LBP^(-/-)NAFLD rats.Based on integrative analysis,CCAAT/enhancer-binding proteinβ(C/EBPβ)was identified as a pivotal transcription factor(TF)and contributor to dysregulated histone acetylome H3K27ac,and the lipid metabolism gene SCD was identified as a downstream effector exacerbating NAFLD.This study not only broadens our understanding of the essential role of LBP in the pathogenesis of NAFLD from an epigenetics perspective but also identifies key TF C/EBPβand functional gene SCD as potential regulators and therapeutic targets.
文摘目的:分析趋化因子受体8(C⁃C motif chemokine receptor 8,CCR8)在卵巢癌肿瘤浸润性调节性T细胞(regulatory T cell,Treg)中的表达,探讨CCR8对Treg分化的作用。方法:构建C57BL/6小鼠卵巢癌细胞ID8荷瘤模型;流式细胞术检测小鼠肿瘤组织、脾脏和外周血中Treg上CCR8的表达比例,CCR8^(+)Treg上免疫检查点相关蛋白程序性细胞死亡蛋白1(programmed cell death protein 1,PD⁃1)、细胞素性T淋巴细胞抗原4(cytotoxic T⁃lymphocyte antigen 4,CTLA⁃4)、可诱导的T细胞共刺激分子(inducible T cell costimulators,ICOS)、淋巴细胞激活基因3(lymphocyte activation gene 3,LAG⁃3)的表达;流式细胞术检测CCR8变构抑制剂AZ084加入前后对C57BL/6小鼠脾脏中初始CD4^(+)T细胞向Treg分化的影响。结果:卵巢癌荷瘤小鼠肿瘤中Treg上的CCR8表达相比脾脏、外周血的Treg显著增高;相比CCR8^(-)Treg,CCR8^(+)Treg上免疫检查点相关蛋白表达更高;AZ084有效抑制小鼠脾脏中初始CD4^(+)T细胞向Treg的分化。结论:CCR8^(+)Treg在肿瘤浸润性Treg中占主要比例,CCR8作为卵巢癌浸润性Treg的主要标志物,变构CCR8蛋白可以抑制Treg的分化。靶向消除CCR8^(+)Treg可为改善卵巢癌肿瘤微环境的免疫抑制状态提供新思路。
文摘目的:旨在研究不同预后及严重程度的创伤性颅脑损伤(TBI)患者T淋巴细胞亚群和CRP水平分析。方法:回顾性分析宜春新建医院2022年5月—2023年6月收治的100例创伤性颅脑损伤患者临床数据。根据患者入院时格拉斯哥昏迷量表(Glasgow coma scale,GCS)评分将其分为三组,轻型组(25例):GCS评分13~15分;中型组(33例):GCS评分9~12分;重型组(42例):GCS评分为3~8分,选取同期体检正常志愿者100例为对照组。根据TBI预后存活情况分为存活组90例、死亡组10例,观察并比较不同组别患者的T淋巴细胞亚群(CD4^(+)、CD8^(+)、CD4^(+)/CD8^(+))、C反应蛋白(CRP),并分析各指标之间的相关性。结果:不同颅脑损伤组血清CD8^(+)、CRP水平均高于对照组,CD4^(+)、CD3^(+)水平及CD4^(+)/CD8^(+)均低于对照组(P<0.05);重型组、中型组CD8^(+)水平均高于轻型组,CD4^(+)、CD3^(+)水平及CD4^(+)/CD8^(+)均低于轻型组(P<0.05);重型组CD8^(+)水平高于中型组,CD4^(+)、CD3^(+)水平及CD4^(+)/CD8^(+)均低于中型组(P<0.05);重型组CRP水平高于中型组和轻型组,中型组高于轻型组(P<0.05)。存活组CD4^(+)、CD4^(+)/CD8^(+)均较死亡组高,CD8^(+)、CPR均低(P<0.05)。根据Pearson统计分析显示,TBI患者的CRP与CD4^(+)、CD3^(+)、CD4^(+)/CD8^(+)均呈负相关,CRP与CD8^(+)呈正相关(P<0.05)。结论:不同预后及严重程度的创伤性颅脑损伤患者中,CRP水平与CD8^(+)呈正相关,与CD4^(+)、CD3^(+)及CD4^(+)/CD8^(+)均呈负相关,且严重程度越高CRP水平越高,CD4^(+)、CD3^(+)及CD4^(+)/CD8^(+)水平越低。
文摘Understanding the topography in active tectonic areas and assessing the rates and models of active deformation in the upper crust are primary objectives in tectonic geomorphology studies. The drainage pattern of river systems is highly sensitive to tectonically induced changes, and it often preserves the records of the formation and progression of most tectono-geomorphic processes within its boundaries. Therefore, the evolution of landforms is a consequence of the evolution of individual drainage basins in which they are formed. Assessing the rates of tectonic deformation using geomorphic data is a traditionally adopted method to characterize the nature of active faults. Globally, the Digital Elevation Model(DEM) is widely used as a crucial tool to analyze the morphotectonic features of drainage basins. In this study, some geomorphic indices were applied to investigate the impact of tectonism on landscape along the Karahay?t Fault and its associated drainage areas. These geomorphic indices are mountain front sinuosity(Smf values between 1.17-1.52), valley floor width-to-height ratio(Vf values between 0.25-1.46), basin asymmetry factor(AF values between 15-72), drainage basin shape(Bs values between 3.18-6.01), hypsometric integral and curve(HI values between 0.32-047), channel sinuosity(S values between 1-1.6), normalized steepness index(Ksn values between 1-390) and Chi integral(χ values between 200-4400). The development of drainage areas on the hanging wall and footwall block of the Karahayit Fault differs depending on the uplift. The drainage areas developed on the hanging wall present different patterns depending on the regional uplift caused by the fault. This reveals that the fault contributed significantly to the development of drainage areas and regional uplift in the region. In addition, the maximum earthquake magnitude that may occur in the future on the Karahayit Fault, whose activity is supported by geomorphic indices, is calculated as 6.23. Since an earthquake of this magnitude may cause loss of life and property in the region, precautions should be taken.