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Molecular characteristics and evolutionary analysis of a very virulent infectious bursal disease virus

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Science China(Life Sciences) 2015年第8期58卷 731-738页

作者： LI Zan QI XiaoLe REN XianGang CUI Lei WANG XiaoMei ZHU Ping National Laboratory of Biomacromolecules Institute of Biophysics Chinese Academy of Sciences University of chinese Academy of Sciences division of Avian Infectious diseases State Key Laboratory of Veterinary Biotechnology Harbin Veterinary Research Institute Chinese Academy of Agricultural Sciences CAS Key Laboratory of RNA Biology Institute of Biophysics Chinese Academy of Sciences

Infectious bursal disease virus （IBDV） poses a significant threat to the poultry industry. Viral protein 2 （VP2）, the major struc- tural protein of IBDV, has been subjected to frequent mutations that have imparted tremendous genetic diversity to the virus. To determine how amino acid mutations may affect the virulence of IBDV, we built a structural model of VP2 of a very virulent strain of IBDV identified in China, vvIBDV Gx, and performed a molecular dynamics simulation of the interaction between virulence sites. The study showed that the amino acid substitutions that distinguish vvlBDV from attenuated IBDV （H253Q and T284A） favor a hydrophobic and flexible conformation of β-barrel loops in VP2, which could promote interac- tions between the virus and potential IBDV-specific receptors. Population sequence analysis revealed that the IBDV strains prevalent in East Asia show a significant signal of positive selection at virulence sites 253 and 284. In addition, a signal of co-evolution between sites 253 and 284 was identified. These results suggest that changes in the virulence of IBDV may result from both the interaction and the co-evolution of multiple amino acid substitutions at virulence sites.

关键词： infectious bursal disease virus very virulent strain virulence molecular characterization molecular evolution

NAT10 promotes cell proliferation by acetylating CEP170 mRNA to enhance translation efficiency in multiple myeloma

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Acta Pharmaceutica Sinica B 2022年第8期12卷 3313-3325页

作者： Rongfang Wei Xing Cui Jie Min Zigen Lin Yanyan Zhou Mengjie Guo Xiaojuan An Hao Liu Siegfried Janz Chunyan Gu Hongbo Wang Ye Yang Nanjing Hospital of chinese Medicine Affiliated to Nanjing University of chinese Medicine Nanjing 210022China School of Pharmacy Key Laboratory of Molecular Pharmacology and Drug Evaluation(Yantai University)Ministry of EducationCollaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of ShandongYantai UniversityYantai 264005China School of Medicine&Holistic Integrative Medicine Nanjing University of Chinese MedicineNanjing 210023China Department of Hematology Affiliated Hospital of Shandong University of Traditional Chinese MedicineJinan 250014China division of Hematology and Oncology Medical College of WisconsinMilwaukeeWI 53226USA Bohai Rim Advanced Research Institute for drug Discovery Yantai 264003China

Multiple myeloma(MM) is still an incurable hematologic malignancy, which is eagerly to the discovery of novel therapeutic targets and methods. N-acetyltransferase 10(NAT10) is the first reported regulator of mRNA acetylation that is activated in many cancers. However, the function of NAT10 in MM remains unclear. We found significant upregulation of NAT10 in MM patients compared to normal plasma cells, which was also highly correlated with MM poor outcome. Further enforced NAT10 expression promoted MM growth in vitro and in vivo, while knockdown of NAT10 reversed those effects. The correlation analysis of acetylated RNA immunoprecipitation sequencing(ac RIP-seq) and ribosome profiling sequencing(Ribo-seq) combined with RIP-PCR tests identified centrosomal protein 170(CEP170) as an important downstream target of NAT10. Interfering CEP170 expression in NAT10-OE cells attenuated the acceleration of cellular growth caused by elevated NAT10. Moreover,CEP170 overexpression promoted cellular proliferation and chromosomal instability(CIN) in ***, remodelin, a selective NAT10 inhibitor, suppressed MM cellular growth, induced cellular apoptosis in vitro and prolonged the survival of 5TMM3VT mice in vivo. Collectively, our data indicate that NAT10 acetylates CEP170 mRNA to enhance CEP170 translation efficiency, which suggests that NAT10 may serve as a promising therapeutic target in MM.

关键词： Multiple myeloma Target NAT10 Acetylation CEP170 Chromosomal instability Translation Remodelin

Covalent inhibitor targets KRas^(G12C):A new paradigm for drugging the undruggable and challenges ahead

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Genes & diseases 2023年第2期10卷 403-414页

作者： Hui-yu Li Wei-liang Qi Yu-xiang Wang Ling-hua Meng division of Anti-tumor pharmacology Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of chinese Academy of Sciences Beijing 100049China College of Pharmacy Nanchang UniversityNanchangJiangxi 330006China

KRAS is one of the most commonly mutated oncogenes in cancers and therapeutics directly targeting the KRas have been *** the different known mutants,KRas^(G12C) has been proved to be successfully targeted *** covalent inhibitors selectively targeting KRas^(G12C) have shown promising efficacy against cancers harboring KRAS G12C mutation in clinical trials and AMG510(sotorasib)has been approved for the treatment of KRAS G12C-mutated locally advanced or metastatic non-small cell lung ***,the overall responsive rate of KRas^(G12C) inhibitors was around 50%in patients with non-small cell lung cancer and the efficacy in patients with colorectal cancer or appendiceal cancer appears to be less *** is of great importance to discover biomarkers to distinguish patients who are likely ***,adaptive resistance would occur inevitably with the persistent administration like other molecularly targeted *** combinatorial regimens have been studied in an effort to potentiate the efficacy of KRas^(G12C) inhibitors in preclinical *** review summarized the recent progress of covalent KRas^(G12C) inhibitors with a focus on identifying biomarkers to predict or monitor the efficacy and proposing rational drug combinations based on elucidation of the mechanisms of drug resistance.

关键词： Biomarkers Covalent KRas^(G12C)inhibitors drug resistance Human cancers KRAS^(G12C)mutation

MicroRNA-99a mimics inhibit M1 macrophage phenotype and adipose tissue inflammation by targeting TNFα

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Cellular & Molecular Immunology 2019年第5期16卷 495-507页

作者： Anant Jaiswal Sukka Santosh Reddy Mohita Maurya Preeti Maurya Manoj Kumar Barthwal division of pharmacology Council of Scientific and Industrial Research-Central Drug Research Institute(CSIR-CDRI)Lucknow 226031 U.P.India Academy of Scientific and Innovative Research New Delhi 110025India

In human adipose tissue and obesity,miR-99a expression is negatively correlated with ***,the present study investigated the role of miR-99a in macrophage phenotype activation and adipose tissue inflammation.M2 BMDMs showed a significant increase in miR-99a expression when compared to the M0 and M1 ***-switching experiments established an association between upregulated miR-99a expression and the M2 *** of miR-99a prevented M1 phenotype activation and attenuated bactericidal ***,knockdown of miR-99a abolished M2 phenotype *** means of in silico target prediction tools and a luciferase reporter assay,TNFαwas identified as a direct target of *** of TNFαrecapitulated the effect of miR-99a overexpression in M1 *** a db/db mice model,miR-99a expression was reduced in eWAT and F4/80+*** overexpression of miR-99a in db/db mice attenuated adipocyte hypertrophy with increased CD301 and reduced CD86 *** cytometry analysis also showed an increased M2 and a reduced M1 macrophage *** of miR-99a also improved the diabetic dyslipidemia and insulin signaling in eWAT and liver,with an attenuated expression of gluconeogenesis and cholesterol metabolism genes in the ***,adoptive transfer of miR-99a-overexpressing macrophages in the db/db mice recapitulated in vivo miR-99a mimic effects with increased M2 and reduced M1 macrophage populations and improved systemic glucose,insulin sensitivity,and insulin signaling in the eWAT and *** present study demonstrates that miR-99a mimics can regulate macrophage M1 phenotype activation by targeting TNFα.miR-99a therapeutics in diabetic mice reduces the adipose tissue inflammation and improves insulin sensitivity.

关键词： inflammation macrophage CD86

Experimental study on pore pressure in rock-soil slope during reservoir water level fluctuation

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Science China(Technological Sciences) 2005年第z1期48卷 196-208页

作者： LIU Yuewu CHEN Huixin LIU Qingquan GONG Xin ZHANG Dawei LI Lianxiang division of Engineering Science Institute of Mechanics Chinese Academy of Sciences Beijing 100080 Division of Engineering Science Institute of Mechanics Chinese Academy of Sciences Beijing 100080 Division of Engineering Science Institute of Mechanics Chinese Academy of Sciences Beijing 100080 Division of Engineering Science Institute of Mechanics Chinese Academy of Sciences Beijing 100080 Division of Engineering Science Institute of Mechanics Chinese Academy of Sciences Beijing 100080 Division of Engineering Science Institute of Mechanics Chinese Academy of Sciences Beijing 100080

A test system was developed for measuring the pore pressure in porous media, and a new model was devised for the pore pressure testing in both saturated and unsaturated rock-soil. Laboratory experiments were carried out to determine the pore pressure during water level fluctuation. The variations of transient pore pressure vs. time at different locations of the simulated rock-soil system were acquired and processed, and meanwhile the deformation and failure of the model are observed. The experiment results show that whether the porous media are saturated or not, the transient pore pressure is mainly dependent on the water level fluctuation, and coupled with the variation of the stress field.

关键词： landslide, pore pressure, reservoir water level, rock-soil.

Quantification of flupirtine maleate polymorphs using X-ray powder diffraction

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chinese Chemical Letters 2016年第11期27卷 1666-1672页

作者： Yu-Mei Zhao Zhi-Bing Zheng Song Li Laboratory of Computer-Aided drug Design & Discovery Beijing Institute of Pharmacology and Toxicology Laboratory of Structure Identification Beijing Institute of Pharmacology and Toxicology State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and Toxicology

Flupirtine maleate, a pharmaceutical compound for treating psychotic disease in clinics, has seven polymorphs. Form A, with better crystal stability and bioavailability, has been widely used as the pharmaceutical crystal form. Unfortunately, it is usually found in a polymorphic mixture with form B. In this study, pure crystal forms of A and B were prepared and characterized by X-ray powder diffraction （XRPD）, Fourier transform infrared spectroscopy （FT-IR） and thermal analysis. An XRPD-based method for the quantitative determination of the amount of the flupirtine maleate polymorphs form A and form B was also established through a systematic optimization of instrumental parameters. The results of the analytical methodology validation showed that the XPRD method had a broad quantitative range of 0- 100% （w/w）, good linear relationship, with R2= 0.999, excellent repeatability and precision and low limits of detection （LoD） of 0.15% （w/w） and quantification （LoQ） of 0.5% （w/w）. The results also showed that the single-peak method was not as good as the whole pattern in reducing the influence of the preferred orientation, but this can be compensated for by a systematic optimization of instrumental parameters and validating the analytical methodology to reduce errors and obtain a good, repeatable, sensitive, and accurate method. This XRPD method can be used to analyze mixtures of flupirtine maleate polymorphs （forms A and B） quantitatively and control the quality of the bulk drug.

关键词： Flupirtine maleate X-ray powder diffraction Quantitative analysis of polymorphs Preferred orientation Transmission

High-throughput screening against thioredoxin glutathione reductase identifies novel inhibitors with potential therapeutic value for schistosomiasis

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Infectious diseases of Poverty 2015年第1期4卷 300-315页

作者： Ting Li Peter D.Ziniel Pan-qing He Valerie P.Kommer Gregory J.Crowther Min He Qing Liu Wesley C.Van Voorhis David L.Williams Ming-Wei Wang The National Center for drug Screening Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Department of Immunology and Microbiology Rush University Medical CenterChicagoIL 60612USA division of Allergy and Infectious diseases University of WashingtonSeattleWA 98195USA

Background:Schistosomiasis,a parasitic disease also known as bilharzia and snail fever,is caused by different species of flatworms,such as Schistosoma mansoni(***).Thioredoxin glutathione reductase(TGR)from ***(SmTGR)is a well-characterized drug target for schistosomiasis,yet no anti-SmTGR compounds have reached clinical trials,suggesting that therapeutic development against schistosomiasis might benefit from additional scaffolds targeting this ***:A high-throughput screening(HTS)assay in vitro against SmTGR was developed and applied to a diverse compound *** activity was quantified with ThioGlo®,a reagent that fluoresces upon binding to the free sulfhydryl groups of the reaction product GSH(reduced glutathione).Results:We implemented an HTS effort against 59,360 synthetic *** the primary screening,initial hits(928 or 1.56%)showing greater than 90%inhibition on SmTGR activity at a final concentration of 10μM for each compound were *** tests were carried out to confirm the effects of these hits and to explore the concentration-dependent response *** a result,74 of them(0.12%)representing 17 chemical scaffolds were confirmed and showed a great concentration-dependent inhibitory trend against SmTGR,including structures previously shown to be lethal to schistosomal *** these,two scaffolds displayed a limited structure-activity *** tested in cultured larvae,39 compounds had cidal activity in 48 h,and five of them killed larvae completely at 3.125μ*** these,three compounds also killed adult worms ex vivo at concentrations between 5μM and 10μ***:These confirmed hits may serve as starting points for the development of novel therapeutics to combat schistosomiasis.

关键词： High-throughput screening Schistosomiasis Inhibitor Thioredoxin glutathione reductase

Overlap of functional heartburn and gastroesophageal reflux disease with irritable bowel syndrome

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World Journal of Gastroenterology 2013年第35期19卷 5787-5797页

作者： Nicola de Bortoli Irene Martinucci Massimo Bellini Edoardo Savarino Vincenzo Savarino Corrado Blandizzi Santino Marchi division of Gastroenterology University of Pisa division of Gastroenterology University of Padua division of Gastroenterology University of Genoa division of pharmacology and Chemotherapy University of Pisa

Several studies indicate a significant degree of overlap between irritable bowel syndrome(IBS)and gastroesophageal reflux disease(GERD).Likewise,both functional heartburn(FH)and IBS are functional digestive disorders that may occur in the same ***,data establishing a solid link between FH and IBS are lacking,mainly because the clinical definition of FH has undergone substantial changes over the *** available literature on the overlap between GERD or FH and IBS highlights considerable heterogeneity in terms of the criteria and diagnostic procedures used to assess heartburn and *** particular,several epidemiological studies included patients with concomitant IBS and GERD without any attempt to distinguish FH(as defined by the RomeⅢcriteria)from GERD via pathophysiological *** of these critical issues,there is preliminary evidence supporting a significantdegree of FH-IBS *** underscores the need for studies based on updated diagnostic criteria and accurate pathophysiological classifications,particularly to distinguish FH from *** distinction would represent an essential starting point to achieving a better understanding of pathophysiology in the subclasses of patients with GERD and FH and properly assessing the different degrees of overlap between IBS and the subcategories of *** present review article intends to appraise and critically discuss current evidence supporting a possible concomitance of GERD or FH with IBS in the same patients and to highlight the pathophysiological relationships between these disorders.

关键词： Functional gastrointestinal disorders Gastroesophageal reflux disease/Gastro-oesophageal reflux disease Irritable bowel syndrome Acidity(esophageal) Hypersensitivity

Association of invasive treatment and lower mortality of patients ≥ 80 years with acute myocardial infarction: a propensity-matched analysis

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Journal of Geriatric Cardiology 2018年第11期15卷 666-674页

作者： Shuo-Lin LIU Na-Qiong WU Meng ZHANG Jing-Lu JIN Bing-Yang ZHOU Qian DONG Jian-Jun LI division of Dyslipidemia 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

Objective To investigate whether invasive strategy was associated with lower mortality in chinese patients ≥ 80 years with acute myocardial infarction (AMI). Methods We used retrospective data from our center between 2013 and 2017. During a median of 17.4 (interquartile range: 7.3–32.3) months follow-up, 120 deaths were recorded among 514 consecutive patients ≥ 80 years with AMI. The patients were divided into two groups: invasive treatment group (IT group, n = 269) and conservative treatment group (CT group, n = 245), which were also then compared with propensity score matching. Results High mortality was found in CT group compared with that in the IT one. Cox proportional hazard regression analysis showed that invasive treatment was associated with lower mortality of patients ≥ 80 years. Moreover, the results revealed that the patients in IT group had lower in-hospital mortality (3.35% vs. 9.39%, P = 0.005). Besides, the Kaplan-Meier analysis revealed that the mortality was significantly lower in IT group compared with that in CT group using entire and propensity-matched cohort analysis (P chinese patients ≥ 80 years with AMI, which consists with previous studies in spite of either ST elevated myocardial infarction (STEMI) or non-STEMI (NSTEMI) patients.

关键词： Mortality Myocardial infarction Percutaneous coronary intervention The elderly