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The Traf2 and NcK interacting kinase inhibitor NCB-0846 suppresses seizure activity involving the decrease of GRIA1

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Genes & Diseases 2024年第3期11卷 452-467页

作者： Min Wang Yixue Gu Qiubo Li Bangzhe Feng Xinke Lv Hao Zhang Qingxia Kong Zhifang Dong Xin Tian Yanke Zhang Department of Neurology Affiliated Hospital of Jining Medical UniversityJiningShandong 272000China Department of Neurology The First Affiliated Hospital of Chongqing Medical UniversityChongqing Key Laboratory of NeurologyChongqing 400016China Department of Pediatrics Affiliated Hospital of Jining Medical UniversityJiningShandong 272000China Department of Neurosurgery Affliated Hospital of Jining Medical UniversityJiningShandong 272000China Pediatric Research Institute Ministry of Education Key Laboratory of Child Development and DisordersNational Clinical Research Center for Child Health and DisordersChongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory DisordersChildren's Hospital of Chongqing Medical UniversityChongqing 400014China Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of SciencesShanghai 200031China

Epilepsy,one of the most common neurological disorders,is characterized by spon-taneous recurrent *** lobe epilepsy(TLE)is one of the most common medically intractable seizure ***2-and NcK-interacting kinase(TNIK)has recently attracted attention as a critical modulation target of many neurological and psychiatric disorders,but its role in epilepsy remains *** this study,we hypothesized the involvement of TNIK in epilepsy and investigated TNIK expression in patients with intractable TLE and in a pilocarpineinduced rat model of epilepsy by western blotting,immunofluorescence,and immunohistochemistry.A pentylenetetrazole(PTZ)-induced epilepsy rat model was used to determine the effect of the TNIK inhibitor NCB-0846 on behavioral manifestations of ***(Co-IP)/mass spectrometry(MS)was used to identify the potential *** Co-IP,we detected and confirmed the main potential TNIK *** fractionation was used to establish the effect of NCB-0846 on the expression of the main interactors in postsynaptic density(PSD)*** found that TNIK was primarily located in neurons and decreased significantly in epilepsy model rats and TLE patients compared with ***-0846 delayed kindling progression and decreased seizure ***-IP/MS identified 63 candidate TNIK interactors in rat hippocampi,notably ***-IP showed that TNIK might correlate with endogenous GRIA1,SYN2,PSD-95,CaMKIV,GABRG1,and *** addition,the significant decrease in GRIA1 in hippocampal total lysate and PSDs after NCB-0846 treatment might help modify the progression of PTZ *** results suggest that TNIK contributes to epileptic pathology and is a potential antiepileptic drug target.

关键词： Epilepsy NCB-0846 Rat TLE TNIK Traf2-and NcK-interacting kinase

Ocular surface heat flux density as a biomarker related to diabetic retinopathy(pilot study)

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Advances in Ophthalmology Practice and Research 2024年第3期4卷 107-111页

作者： Lukyan Anatychuk Roman Kobylianskyi Oleg Zadorozhnyy Taras Kustryn Illia Nasinnyk Andrii Korol Institute of Thermoelectricity of the national academy of Sciences of Ukraine and the Ministry of education and Science of Ukraine ChernivtsiUkraine Yuriy Fedkovych Chernivtsi National UniversityChernivtsiUkraine Nataliya Pasyechnikova State Institution“The Filatov Institute of Eye Diseases and Tissue Therapy of the national academy of medical Sciences of Ukraine” OdesaUkraine

Dear Editor,Thermoregulation ensures a constant body temperature and is critical for maintaining homeostasis in the human body.^(1)In healthy individuals,body temperature is well-balanced and fluctuates within a narrow range.^(2)The normal continuous course of metabolic reactions in the human body and its vital activity in various conditions depends on the temperature equilibrium.^(3)

关键词： homeostasis narrow body

Charting epimutation dynamics in human hematopoietic differentiation Xiaohuan Qina

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Blood Science 2024年第3期6卷 1-10页

作者： Jiayi Lu Peng Wu Chunyong Zhang Lei Shi Ping Zhu State Key Laboratory of Experimental Hematology National Clinical Research Center for Blood DiseasesHaihe Laboratory of Cell EcosystemDepartment of Stem Cell and Regenerative MedicineInstitute of Hematology and Blood Diseases HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjinChina The Province and Ministry Co-sponsored Collaborative Innovation Center for medical Epigenetics Key Laboratory of Immune Microenvironment and Disease(Ministry of Education)Department of Biochemistry and Molecular BiologySchool of Basic Medical SciencesTianjin Medical UniversityTianjinChina

DNA methylation plays a critical role in hematopoietic *** is a stochastic variation in DNA methylation that induces epigenetic ***,the effects of epimutations on normal hematopoiesis and hematopoietic diseases remain *** this study,we developed a Julia package called EpiMut that enabled rapid and accurate quantification of *** was used to evaluate and provide an epimutation landscape in steady-state hematopoietic differentiation involving 13 types of blood cells ranging from hematopoietic stem/progenitor cells to mature *** showed that substantial genomic regions exhibited epigenetic variations rather than significant differences in DNA methylation levels between the myeloid and lymphoid *** dynamics of epimutations were observed during the differentiation of each ***,we found that epimutation significantly enriched signals associated with lineage ***,epimutations in hematopoietic stem cells(HSCs)derived from various sources and acute myeloid leukemia were related to the function of HSCs and malignant cell *** together,our study comprehensively documented an epimutation map and uncovered its important roles in human hematopoiesis,thereby offering insights into hematopoietic regulation.

关键词： DNA methylation Epimutation Hematopoietic differentiation Hematopoietic stem cell

Tim4 deficiency reduces CD301b+macrophage and aggravates periodontitis bone loss

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International Journal of Oral Science 2024年第2期16卷 280-292页

作者： Ziming Wang Hao Zeng Can Wang Jiaolong Wang Jing Zhang Shuyuan Qu Yue Han Liu Yang Yueqi Ni Wenan Peng Huan Liu Hua Tang Qin Zhao Yufeng Zhang State Key Laboratory of Oral&Maxillofacial Reconstruction and Regeneration Key Laboratory of Oral Biomedicine Ministry of EducationHubei Key Laboratory of StomatologySchool&Hospital of StomatologyTaikang Center for Life and Medical SciencesWuhan UniversityWuhanChina School of Stomatology Nanchang UniversityNanchangChina Institute of Infection and Immunity Science and Technology Innovation CenterShandong First Medical University&Shandong Academy of Medical SciencesJinanChina medical Research Institute School of MedicineWuhan UniversityWuhanChina

Periodontitis is a common chronic inflammatory disease that causes the periodontal bone destruction and may ultimately result in tooth *** the progression of periodontitis,the osteoimmunology microenvironment in periodontitis is damaged and leads to the formation of pathological alveolar bone ***301b^(+)macrophages are specific to the osteoimmunology microenvironment,and are emerging as vital booster for conducting bone ***,the key upstream targets of CD301b^(+)macrophages and their potential mechanism in periodontitis remain *** this study,we concentrated on the role of Tim4,a latent upstream regulator of CD301b^(+)*** first demonstrated that the transcription level of Timd4(gene name of Tim4)in CD301b^(+)macrophages was significantly upregulated compared to CD301b^(-) macrophages via high-throughput RNA ***,several Tim4-related functions such as apoptotic cell clearance,phagocytosis and engulfment were positively regulated by CD301b^(+)*** single-cell RNA sequencing analysis subsequently discovered that Cd301b and Timd4 were specifically co-expressed in *** following flow cytometric analysis indicated that Tim4 positive expression rates in total macrophages shared highly synchronized dynamic changes with the proportions of CD301b^(+)macrophages as periodontitis ***,the deficiency of Tim4 in mice decreased CD301b^(+)macrophages and eventually magnified alveolar bone resorption in ***,Tim4 controlled the p38 MAPK signaling pathway to ultimately mediate CD301b^(+)macrophages *** a word,Tim4 might regulate CD301b^(+)macrophages through p38 MAPK signaling pathway in periodontitis,which provided new insights into periodontitis immunoregulation as well as help to develop innovative therapeutic targets and treatment strategies for periodontitis.

关键词： period upstream eventually

Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma

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Cancer Communications 2024年第2期44卷 226-250页

作者： Weiren Liu Huqiang Wang Qianfu Zhao Chenyang Tao Weifeng Qu Yushan Hou Run Huang Zimei Sun Guiqi Zhu Xifei Jiang Yuan Fang Jun Gao Xiaoling Wu Zhixiang Yang Rongyu Ping Jiafeng Chen Rui Yang Tianhao Chu Jian Zhou Jia Fan Zheng Tang Dong Yang Yinghong Shi Department of Liver Surgery and Transplantation Liver Cancer InstituteZhongshan HospitalFudan UniversityKey Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationShanghaiP.R.China Research Unit of Liver cancer Recurrence and Metastasis Chinese Academy of Medical SciencesBeijingP.R.China State Key Laboratory of medical Proteomics Beijing Proteome Research CenterNational Center for Protein Sciences(Beijing)Beijing Institute of LifeomicsBeijingP.R.China

Background:Intrahepatic cholangiocarcinoma(iCCA)is a highly heteroge-neous and lethal hepatobiliary tumor with few therapeutic *** metabolic reprogramming of tumor cells plays an essential role in the develop-ment of tumors,while the metabolic molecular classification of iCCA is largely ***,we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients,hoping to provide a novel perspective to understand and treat ***:We performed integrated multiomics analysis in 116 iCCA samples,including whole-exome sequencing,bulk RNA-sequencing and proteome *** on the non-negative matrix factorization method and the protein abundance of metabolic genes in human genome-scale metabolic models,the metabolic subtype of iCCA was *** and prognostic gene analy-ses were used to compare overall survival(OS)differences between metabolic *** proliferation analysis,5-ethynyl-2’-deoxyuridine(EdU)assay,colony formation assay,RNA-sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinaseα(DGKA)in iCCA ***:Three metabolic subtypes(S1-S3)with subtype-specific biomarkers of iCCA were *** metabolic subtypes presented with distinct prog-noses,metabolic features,immune microenvironments,and genetic *** S2 subtype with the worst survival showed the activation of some special metabolic processes,immune-suppressed microenvironment and Kirsten ratsar-coma viral oncogene homolog(KRAS)/AT-rich interactive domain 1A(ARID1A)*** the S2 subtype-specific upregulated proteins,DGKA was further identified as a potential drug target for iCCA,which promoted cell proliferation by enhancing phosphatidic acid(PA)metabolism and activating mitogen-activated protein kinase(MAPK)***:Viamultiomics analyses,we identified three metabolic subtypes of iCCA,revealing

关键词： diacylglycerol kinaseα intrahepatic cholangiocarcinoma MAPK signaling metabolic classifi-cation multiomics analysis phosphatidic acid metabolism

Variations in the Prevalence of Anemia of Varying Severity Among Urban Non-Pregnant Women—China,2021

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China CDC weekly 2024年第10期6卷 175-180页

作者： Xiaoxi Liu Bo Wang Sailimai Man Heling Bao Yuanyuan Huang Canqing Yu Jun Lyu Linhong Wang Liming Li Hui Liu Institute of medical Information Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijingChina Peking University Health Science Center Meinian Public Health Institute BeijingChina Meinian Institute of Health BeijingChina Peking University Center for Public Health and Epidemic Preparedness&Response BeijingChina Department of Epidemiology and Biostatistics School of Public HealthPeking UniversityBeijingChina Key Laboratory of Epidemiology of Major Diseases(Peking University) Ministry of EducationBeijingChina national Center for Chronic and Non-communicable Disease Control and Prevention Chinese Center for Disease Control and PreventionBeijingChina

Summary What is already known about this topic?Anemia is a significant public health issue affecting women *** studies in China predominantly concentrated on anemia in pregnant or reproductiveage women,leaving a gap i... 详细信息

关键词： Anemia anemia China.

Gut Microbiota and Cytokine Profile in Cirrhosis

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Journal of Clinical and Translational Hepatology 2024年第8期12卷 689-700页

作者： Irina Efremova Roman Maslennikov Anna Kudryavtseva Anastasia Avdeeva George Krasnov Mikhail Diatroptov Vyacheslav Bakhitov Salekh Aliev Natalia Sedova Maria Fedorova Elena Poluektova Oxana Zolnikova Nariman Aliev Anna Levshina Vladimir Ivashkin Department of Internal Medicine Gastroenterology and HepatologySechenov UniversityMoscowRussia Post-Genomic Research Laboratory Engelhardt Institute of Molecular BiologyRussian Academy of SciencesMoscowRussia V.A.Nasonova Research Institute of Rheumatology MoscowRussia Consultative and Diagnostic Center 2 of the Moscow Health Department MoscowRussia First Hospital Surgery Department Pirogov Russian National Research Medical UniversityMoscowRussia Department of Clinical Laboratory Diagnostics FGBOU DPO“Russian Medical Academy of Continuing Professional Education of the Ministry of Health of the Russian Federation”MoscowRussia The Interregional Public Organization“Scientific Community for the Promotion of the Clinical Study” MoscowRussia

Background and Aims:Gut dysbiosis and abnormal cytokine profiles are common in *** study aimed to evaluate the correlations between ***:In the blood plasma of cirrhosis patients and controls,27 cytokines were examined using a multiplex *** plasma levels of nitrites(stable metabolites of the endothelial dysfunction biomarker nitric oxide)and lipopolysaccharide(LPS)were *** fecal microbiota was assessed by 16S rRNA gene ***:Levels of IL-1b,IL-2,IL-6,IL-13,IP-10,IFN-g,TNF-a,LPS,and nitrites were higher in cirrhosis patients than in controls,while levels of IL-4,IL-7,and PDGF-BB were *** LPS level was directly correlated with the levels of IL-1b,IL1-Ra,IL-9,IL-17,PDGF-BB,IL-6,TNF-a,and *** nitrite level was significantly directly correlated with the levels of TNF-a,GM-CSF,IL-17,and IL-12,and inversely correlated with the IL-7 ***-a levels were directly correlated with ascites severity and the abundance of Negativicutes,Enterobacteriaceae,Veillonellaceae,and Klebsiella,while inversely correlated with the abundance of Firmicutes,Clostridia,and ***-g levels were directly correlated with the abundance of Bacteroidaceae,Lactobacillaceae,Bacteroides,and Megasphaera,and inversely correlated with the abundance of Verrucomicrobiota,Akkermansiaceae,Coriobacteriaceae,Akkermansia,Collinsella,and ***-1b levels were directly correlated with the abundance of Comamonadaceae and Enterobacteriaceae and inversely correlated with the abundance of Marinifilaceae and ***-6 levels were directly correlated with the abundance of Enterobacteriaceae,hepatic encephalopathy,and ascites severity,and inversely correlated with the abundance of Peptostreptococcaceae,Streptococcaceae,and ***:The abundance of harmful gut microbiota taxa and endotoxinemia directly correlates with the levels of proinflammatory cytokines.

关键词： Endotoxin Leaky gut Gut microbiome Systemic inflammation Gut-liver axis Endotoxemia

Targeting a disintegrin and metalloprotease(ADAM)17-CD122 axis enhances CD8^(+)T cell effector differentiation and anti-tumor immunity

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Signal Transduction and Targeted Therapy 2024年第7期9卷 3097-3111页

作者： Lina Sun Anjun Jiao Haiyan Liu Renyi Ding Ning Yuan Biao Yang Cangang Zhang Xiaoxuan Jia Gang Wang Yanhong Su Dan Zhang Lin Shi Chenming Sun Aijun Zhang Lianjun Zhang Baojun Zhang Department of Pathogenic Microbiology and Immunology School of Basic Medical SciencesXi’an Jiaotong UniversityXi’anShaanxi 710061China Institute of Infection and Immunity Translational Medicine InstituteXi’an Jiaotong University Health Science CenterXi’anShaanxi 710061China Key Laboratory of Environment and Genes Related to Diseases Ministry of EducationXi’anShaanxi 710061China Xi’an Key Laboratory of Immune Related Diseases Xi’anShannxi 710061China Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy Cancer InstituteXuzhou Medical UniversityXuzhouJiangsuChina Department of Pediatrics Qilu Hospital of Shandong UniversityJinanChina national Key Laboratory of Immunity and Inflammation Suzhou Institute of Systems MedicineChinese Academy of Medical Sciences&Peking Union Medical CollegeSuzhou 215123 JiangsuChina Key Laboratory of Synthetic Biology Regulatory Elements Suzhou Institute of Systems MedicineChinese Academy of Medical Sciences&Peking Union Medical CollegeSuzhou 215123 JiangsuChina

CD8^(+)T cell immune responses are regulated by multi-layer networks,while the post-translational regulation remains largely *** ectodomain shedding is an important post-translational process orchestrating receptor expression and signal transduction through proteolytic cleavage of membrane ***,by targeting the sheddase A Disintegrin and Metalloprotease(ADAM)17,we defined a post-translational regulatory mechanism mediated by the ectodomain shedding in CD8^(+)T *** and proteomic analysis revealed the involvement of post-translational regulation in CD8^(+)T cells.T cellspecific deletion of ADAM17 led to a dramatic increase in effector CD8^(+)T cell differentiation and enhanced cytolytic effects to eliminate pathogens and ***,ADAM17 regulated CD8^(+)T cells through cleavage of membrane ***17 inhibition led to elevated CD122 expression and enhanced response to IL-2 and IL-15 stimulation in both mouse and human CD8^(+)T ***,inhibition of ADAM17 in CD8^(+)T cells improved the efficacy of chimeric antigen receptor(CAR)T cells in solid *** findings reveal a critical post-translational regulation in CD8^(+)T cells,providing a potential therapeutic strategy of targeting ADAM17 for effective anti-tumor immunity.

关键词： immunity stimulation involvement

Association and its population heterogeneities between low-density lipoprotein cholesterol and all-cause and cardiovascular mortality: A population-based cohort study

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中华医学杂志(英文版) 2024年第17期137卷 2024 Jul 30页

作者： Lu Jiapeng Zhang Haibo Chen Bowang Yang Yang Cui Jianlan Xu Wei Song Lijuan Yang Hao He Wenyan Zhang Yan Peng Wenyao Li Xi national Clinical Research Center for Cardiovascular Diseases State Key Laboratory of Cardiovascular Disease Fuwai Hospital National Center for Cardiovascular Diseases Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China Shenzhen Clinical Research Center for Cardiovascular Diseases Fuwai Hospital Chinese Academy of Medical Sciences Shenzhen Guangdong China Central China Sub-center of the national Center for Cardiovascular Diseases Zhengzhou Henan China

Background: The association and its population heterogeneities between low-density lipoprotein cholesterol (LDL-C) and all-cause and cardiovascular mortality remain unknown. We aimed to examine the dose-dependent associations of LDL-C levels with specific types of cardiovascular disease (CVD) mortality and heterogeneities in the associations among different population ***: A total of 2,968,462 participants aged 35-75 years from China Health Evaluation And risk Reduction through nationwide Teamwork (ChinaHEART) (2014-2019) were included. Cox proportional hazard models and Fine-Gray subdistribution hazard models were used to estimate associations between LDL-C categories (99.9, 100.0-129.9 [reference group], 130.0-159.9, 160.0-189.9, and ≥190.0 mg/dL) and all-cause and cause-specific ***: During a median follow-up of 3.7 years, 57,391 and 23,241 deaths from all-cause and overall CVD were documented. We observed J-shaped associations between LDL-C and death from all-cause, overall CVD, coronary heart disease (CHD), and ischemic stroke, and an L-shaped association between LDL-C and hemorrhagic stroke (HS) mortality (P for non-linearity 9.9 mg/dL), very low LDL-C levels (95% confidence interval [CI]: 1.06-1.14) and HS mortality (HR: 1.37, 95% CI: 1.29-1.45). Very high LDL-C levels (≥190.0 mg/dL) were associated with increased risk of overall CVD (HR: 1.51, 95% CI: 1.40-1.62) and CHD mortality (HR: 2.08, 95% CI: 1.92-2.24). The stronger associations of very low LDL-C with risk of CVD mortality were observed in individuals with older age, low or normal body mass index, low or moderate 10-year atherosclerotic CVD risk, and those without diagnosed CVD or taking statins. Stronger associations between very high LDL-C levels and all-cause and CVD mortality were observed in younger peop

关键词： Low-density lipoprotein cholesterol Mortality Association study Population heterogeneity Prospective cohort study