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Phosphorylated protein chip combined with artificial intelligence tools for precise drug screening

Journal of Biomedical Research 2024年第3期38卷 195-205页

作者： Katsuhisa Horimoto Yuki Suyama Tadamasa Sasaki Kazuhiko Fukui Lili Feng Meiling Sun Yamin Tang Yixuan Zhang Dongyin Chen Feng Han SOCIUM inc. Tokyo 1350064Japan International Medical Center Saitama Medical UniversitySaitama 350-1298Japan Artificial Intelligence Research Center National Institute of Advanced Industrial Science and TechnologyTokyo 1350064Japan Department of Informatics and Data Science Sanyo-Onoda City UniversityYamaguchi 7560884Japan International Joint Laboratory for Drug Target of Critical illnesses School of PharmacyNanjing Medical UniversityNanjingJiangsu 211166China Department of Physiology School of Basic Medical SciencesNanjing Medical UniversityNanjingJiangsu 211166China Gusu School Nanjing Medical UniversitySuzhouJiangsu 215001China National Vaccine Innovation Platform Nanjing Medical UniversityNanjingJiangsu 211166China

We have developed a protein array system,named"Phospho-Totum",which reproduces the phosphorylation state of a sample on the *** protein array contains 1471 proteins from 273 known signaling *** to the activation degrees of tyrosine kinases in the sample,the corresponding groups of substrate proteins on the array are phosphorylated under the same *** addition to measuring the phosphorylation levels of the 1471 substrates,we have developed and performed the artificial intelligence-assisted tools to further characterize the phosphorylation state and estimate pathway activation,tyrosine kinase activation,and a list of kinase inhibitors that produce phosphorylation states similar to that of the *** Phospho-Totum system,which seamlessly links and interrogates the measurements and analyses,has the potential to not only elucidate pathophysiological mechanisms in diseases by reproducing the phosphorylation state of samples,but also be useful for drug discovery,particularly for screening targeted kinases for potential drug kinase inhibitors.

关键词： Phospho-Totum protein array signal transduction pathways artificial intelligence tools drug screening

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A two-phase study evaluating the relationship between Thimerosal-containing vaccine administration and the risk for an autism spectrum disorder diagnosis in the United States

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Translational Neurodegeneration 2013年第1期2卷 183-194页

作者： David A Geier Brian S Hooker Janet K Kern Paul G King Lisa K Sykes Mark R Geier the institute of chronic illnesses inc 14 Redgate CtSilver SpringMDUSA Simpson University ReddingCAUSA University of Texas Southwestern Medical Center at Dallas DallasTXUSA CoMeD inc Silver SpringMDUSA

Background:Autism spectrum disorder(ASD)is defined by standardized criteria of qualitative impairments in social interaction,qualitative impairments in communication,and restricted and stereotyped patterns of behavior,interests,and activities.A significant number of children diagnosed with ASD suffer a loss of previously-acquired skills,which is suggestive of neurodegeneration or a type of progressive encephalopathy with an etiological pathogenic basis occurring after *** date,the etiology of ASD remains under debate,however,many studies suggest toxicity,especially from mercury(Hg),in individuals diagnosed with an *** present study evaluated concerns about the toxic effects of organic-Hg exposure from Thimerosal(49.55%Hg by weight)in childhood vaccines by conducting a two-phased(hypothesis generating/hypothesis testing)study with documented exposure to varying levels of Thimerosal from ***:A hypothesis generating cohort study was undertaken to evaluate the relationship between exposure to organic-Hg from a Thimerosal-containing Diphtheria-Tetanus-acellular-Pertussis(DTaP)vaccine in comparison to a Thimerosal-free DTaP vaccine administered,from 1998 through 2000,for the risk of ASD as reported in the Vaccine Adverse Event Reporting System(VAERS)database(phase I).A hypothesis testing case–control study was undertaken to evaluate the relationship between organic-Hg exposure from Thimerosal-containing hepatitis B vaccines administered at specific intervals in the first six months of life among cases diagnosed with an ASD and controls born between 1991 through 1999 in the Vaccine Safety Datalink(VSD)database(phase II).Results:In phase I,it was observed that there was a significantly increased risk ratio for the incidence of ASD reported following the Thimerosal-containing DTaP vaccine in comparison to the Thimerosal-free DTaP *** phase II,it was observed that cases diagnosed with an ASD were significantly more likely than controls to rece

关键词： Autism Ethylmercury Merthiolate Thimerosal Thiomersal Vaccine

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Evidence of neurodegeneration in autism spectrum disorder

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Translational Neurodegeneration 2013年第1期2卷 113-118页

作者： Janet K Kern David A Geier Lisa K Sykes Mark R Geier institute of chronic illnesses IncorporationSilver SpringMDUSA University of Texas Southwestern Medical Center at Dallas DallasTXUSA CoMeD IncorporationSilver SpringMDUSA

Autism spectrum disorder(ASD)is a neurological disorder in which a significant number of children experience a developmental regression characterized by a loss of previously-acquired skills and *** of neurological function in ASD,as observed in affected children who have regressed,can be explained as *** there is research evidence of neurodegeneration or progressive encephalopathy in ASD,the issue of neurodegeneration in ASD is still under *** of neurodegeneration in the brain in ASD includes:(1)neuronal cell loss,(2)activated microglia and astrocytes,(3)proinflammatory cytokines,(4)oxidative stress,and(5)elevated 8-oxo-guanosine *** evidence from this review suggests that neurodegeneration underlies the loss of neurological function in children with ASD who have experienced regression and loss of previously acquired skills and abilities,and that research into treatments to address the issue of neurodegeneration in ASD are warranted.

关键词： Autism spectrum disorder(ASD) Autism Neurodegeneration Regression Neuronal cell loss Microglia Oxidative stress Cytokines

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A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes

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Protein & Cell 2024年第2期15卷 98-120页

作者： Shanshan Yang Chengyu Liu Mengmeng Jiang Xiaoqian Liu Lingling Geng Yiyuan Zhang Shuhui Sun Kang Wang jian Yin Shuai Ma Si Wang Juan Carlos Izpisua Belmonte Weiqi Zhang Jing Qu Guang-Hui Liu Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders Xuanwu Hospital Capital Medical UniversityBeijing 100053China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Translational Medicine Center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing 100101China Xuanwu Hospital Capital Medical University Beijing 100053China University of Chinese Academy of Sciences Beijing 100049China institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China Beijing institute for Stem Cell and Regenerative Medicine Beijing 100101China Aging Biomarker Consortium Beijing 100101China Altos Labs Inc.San DiegoCA 94022USA

Aging increases the risk ofliver diseases and systemic susceptibility to aging-related ***,cell type-specific changes and the underlying mechanism of liver aging in higher vertebrates remain incompletely ***,we constructed the first single-nucleus transcriptomic landscape of primate liver aging,in which we resolved cell type-specific gene expression fluctuation in hepatocytes across three liver zonations and detected aberrant cell-cell interactions between hepatocytes and niche *** in-depth dissection of this rich dataset,we identifed impaired lipid metabolism and upregulation of chronic inflammation-related genes prominently associated with declined liver functions during *** particular,hyperactivated sterol regulatory element-binding protein(SREBP)signaling was a hallmark of the aged liver,and consequently,forced activation of SREBP2 in human primary hepatocytes recapitulated in vivo aging phenotypes,manifesting as impaired detoxification and accelerated cellular *** study expands our knowledge of primate liver aging and informs the development of diagnostics and therapeutic interventions for liver aging and associated diseases.

关键词： single-nucleus RNA sequencing liver hepatocytes aging senescence SREBP2

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Neg-Entropy Mechanism as a Target for Natural Medicines

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Engineering 2024年第7期38卷 11-12页

作者： Tian-Le Gao Hui-Hui Guo Jian-Dong Jiang institute of Materia Medica Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China institute of Medicinal Biotechnology Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China

Current strategies for drug discovery research mainly focus on molecular targets,in which structure biology plays a central role,such as the detailed mechanism of a drug-target *** principle of this approach is the presumed molecular mechanism or genetic background of the disease being *** this approach has brought progress in understanding the mode of action for some drugs,most prevalent illnesses-especially chronic diseases-are multifactorial and present with a group of symptoms,as is often the case in cardiovascular diseases,metabolic disorders,cancers,and so *** newly emerging term“multi-morbidity”(i.e.,multiple co-occurring diseases)describes a grand challenge for this strategy,and successful drug intervention for multimorbidity should be multifaceted[1].So,our research team has shifted its attention to a new direction that views the disease as a whole instead of a single-molecule abnormality,and focusing on drugs with multiple targets.

关键词： drugs diseases cardiovascular

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Association of cardiometabolic multimorbidity with all-cause and cardiovascular disease mortality among Chinese hypertensive patients

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Journal of Geriatric Cardiology 2024年第2期21卷 211-218页

作者： Luo-Xi XIAO Zi-Yu WANG Jiang-Tao LI Hai-Mei WANG Yi-Ming HAO Pan ZHOU Yu-Lin HUANG Qiu-Ju DENG Yong-Chen HAO Na YANG Li-Zhen HAN Zhao YANG Ping-Ping JIA Yue QI Jing LIU Center for Clinical and Epidemiologic Research Beijing Anzhen HospitalCapital Medical UniversityBeijing Institute of HeartLung and Blood Vessel DiseasesBeijing Municipal Key Laboratory of Clinical EpidemiologyBeijingChina

BACKGROUND Hypertension usually clusters with multiple ***,the association between cardiometabolic multimorbidity(CMM)and mortality in hypertensive patients is *** study aimed to investigate the association between CMM and all-cause and cardiovascular disease(CVD)mortality in Chinese patients with *** The data used in this study were from the China National Survey for Determinants of Detection and Treatment Status of Hypertensive Patients with Multiple Risk Factors(CONSIDER),which comprised 5006 participants aged 19–91 *** was defined as the presence of one or more of the following morbidities:diabetes mellitus,dyslipidemia,chronic kidney disease,coronary heart disease,and *** proportional hazard models were used to calculate the hazard ratios(HR)with 95%CI to determine the association between the number of CMMs and both all-cause and CVD *** Among 5006 participants[mean age:58.6±10.4 years,50%women(2509 participants)],76.4%of participants had at least one *** mortality rate was 4.57,4.76,8.48,and 16.04 deaths per 1000 person-years in hypertensive patients without any comorbidity and with one,two,and three or more morbidities,*** the fully adjusted model,hypertensive participants with two cardiometabolic diseases(HR=1.52,95%CI:1.09–2.13)and those with three or more cardiometabolic diseases(HR=2.44,95%CI:1.71–3.48)had a significantly elevated risk of all-cause *** findings were similar for CVD mortality but with a greater increase in risk *** In this study,three-fourths of hypertensive patients had *** with two or more comorbidities was associated with a significant increase in the risk of all-cause and cardiovascular mortality among hypertensive patients,suggesting more intensive treatment and control in this high-risk patient group.

关键词： hypertensive patients morbidity

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以负熵机制为靶点的天然药物研究（英文）

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Engineering 2024年第7期 11-12页

作者：高天乐郭慧慧蒋建东 institute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical College institute of Medicinal Biotechnology Chinese Academy of Medical Sciences & Peking Union Medical College

Current strategies for drug discovery research mainly focus on molecular targets,in which structure biology plays a central role,such as the detailed mechanism of a drug–target *** principle of this approach is the presumed molecular mechanism or genetic background of the disease being *** this approach has brought progress in understanding the mode of action for some drugs,most prevalent illnesses-especially chronic diseases-are multifactorial and present with a group of symptoms,as is often the case in cardiovascular diseases,metabolic disorders,cancers,and so forth.

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Microglial glutaminase 1 mediates chronic restraint stress-induced depression-like behaviors and synaptic damages

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Signal Transduction and Targeted Therapy 2024年第1期9卷 40-43页

作者： Huili Chen Shengyang Fu Xiangyu Li Meng Shi Jiazhen Qian Shu Zhao Ping Yuan Lu Ding Xiaohuan Xia Jialin C.Zheng Center for Translational Neurodegeneration and Regenerative Therapy Tongji Hospital affiliated to Tongji University School of Medicine200065 ShanghaiChina Department of Cardio-Pulmonary Circulation Shanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghaiChina Translational Research institute of Brain and Brain-Like Intelligence Shanghai Fourth People’s Hospital affiliated to Tongji University School of Medicine200434 ShanghaiChina

Dear Editor,Major depressive disorder(MDD)is one of the most common psychiatric illnesses that significantly increase the risk of suicide.1 Stress-triggered dysfunctions of microglia have been identified as a commonly occurred pathological feature of MDD.1–3 Microglial dysfunction contributes to the pathogenesis of MDD via immunoresponses/neuroinflammation-mediated neural damage and pathological synapse loss-mediated neural circuit disruption.1 Although the involvement of microglia in MDD has been widely investigated,the molecular mechanisms underlying microglial dysfunction remain largely ***,we identified glutaminase 1(Gls1)as one key protein that participates in microglial dysfunction.4–6 Gls1 catalyzes the hydrolysis of glutamine to produce glutamate in the brain.4 Besides its well-known role in excitatory neurotoxicity,we found Gls1 up-regulation in microglia in animal models of Alzheimer’s disease and ischemic stroke.4,7 Gls1 activates microglia to overproduce cytokines and release inflammatory extracellular vesicles,therefore leading to neuroinflammation in animal models of Alzheimer’s disease and ischemic stroke.4–6 More importantly,Gls1 has been found to be up-regulated in the brains of MDD patients,and microglial Gls1 deficiency mitigated LPS-induced depression-like behaviors.8 However,LPS exposure is not an appropriate model to mimic MDD phenotypes,leaving the involvement of Gls1 in MDD an undetermined question.

关键词： involvement inflammation media

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ADT-OH improves intestinal barrier function and remodels the gut microbiota in DSS-induced colitis

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Frontiers of Medicine 2023年第5期17卷 972-992页

作者： Zhiqian Bi Jia Chen Xiaoyao Chang Dangran Li Yingying Yao Fangfang Cai Huangru Xu Jian Cheng Zichun Hua Hongqin Zhuang The State Key Laboratory of Pharmaceutical Biotechnology College of Life SciencesNanjing UniversityNanjing210023China Changzhou High-Tech Research institute of Nanjing University and Jiangsu TargetPharma Laboratories inc. Changzhou213164China School of Biopharmacy China Pharmaceutical UniversityNanjing211198China institute of Neuroscience Soochow UniversitySuzhou215123China

Owing to the increasing incidence and prevalence of inflammatory bowel disease(IBD)worldwide,effective and safe treatments for IBD are urgently *** sulfide(H2S)is an endogenous gasotransmitter and plays an important role in *** date,H2S-releasing agents are viewed as potential anti-inflammatory *** slow-releasing H_(2)S donor 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione(ADT-OH),known as a potent therapeutic with chemopreventive and cytoprotective properties,has received attention ***,we reported its anti-inflammatory effects on dextran sodium sulfate(DSS)-induced acute(7 days)and chronic(30 days)*** found that ADT-OH effectively reduced the DSS-colitis clinical score and reversed the inflammation-induced shortening of colon ***,ADT-OH reduced intestinal inflammation by suppressing the nuclear factor kappa-B *** vivo and in vitro results showed that ADT-OH decreased intestinal permeability by increasing the expression of zonula occludens-1 and occludin and blocking increases in myosin II regulatory light chain phosphorylation and epithelial myosin light chain kinase protein expression *** addition,ADT-OH restored intestinal microbiota dysbiosis characterized by the significantly increased abundance of Muribaculaceae and Alistipes and markedly decreased abundance of Helicobacter,Mucispirillum,Parasutterella,and *** ADT-OH-modulated microbiota can alleviate DSS-induced colitis and negatively regulate the expression of local and systemic proinflammatory ***,ADT-OH is safe without any short-term(5 days)or long-term(30 days)toxicological adverse effects and can be used as an alternative therapeutic agent for IBD treatment.

关键词： inflammatory bowel disease ADT-OH intestinal permeability gut microbiota

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SELDI-TOF-MS in chronic obstructive pulmonary disease

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Chinese Science Bulletin 2013年第6期58卷 634-640页

作者： ZHANG Xia ZHANG Jie LI Qi WU XiaoYi WANG Ting WANG YuLing Beijing Chest Hospital Capital Medical University Beijing Tuberculosis and Thoracic Tumor Research institute Department of Respiratory Diseases Beijing Tiantan HospitalCapital Medical University Beijing De Yi Biosystems inc

chronic obstructive pulmonary disease(COPD) has a profound impact on daily life,yet remains underdiagnosed and *** study aims to discover potential protein biomarkers for diagnosis and classification of ***-seven COPD patients and 40 controls were divided into a training set(30 COPD patients,20 healthy controls) and a test set(27 COPD patients,20 healthy controls).Serum proteomic profiles were measured using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry(SELDI-TOF-MS).A classification tree was established using Biomarker Pattern Software(BPS).Next we screened distinct proteins present in patients with acute exacerbations of COPD(AECOPD),stable COPD and healthy controls,in order to establish diagnostic models for classification of *** peaks showed statistically significant differences between COPD patients and healthy controls(P inchip technology is a quick,easy and practical,high throughput analytic *** shows the diagnostic models established by distinguished proteomic peaks can discriminate COPD patients from healthy control and can identify different stages of *** will provide a highly accurate approach for diagnosis and clinical staging of COPD.

关键词：慢性阻塞性肺疾病慢性阻塞性肺病蛋白质组学电离飞行时间质谱诊断模型 COPD 生物标志物分类树

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