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phenotype prediction of nonsynonymous single nucleotide polymorphisms in human phase II drug/xenobiotic metabolizing enzymes: perspectives on molecular evolution

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Science China(Life Sciences) 2010年第10期53卷 1252-1262页

作者： HAO DaCheng XIAO PeiGen CHEN ShiLin Laboratory of Biotechnology College of EnvironmentDalian Jiaotong UniversityDalian 116028China Institute of Medicinal Plant Development Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100193China

Nonsynonymous single nucleotide polymorphisms (nsSNPs) in coding regions can lead to amino acid changes that might alter the protein’s function and account for susceptibility to disease and altered drug/xenobiotic response. Many nsSNPs have been found in genes encoding human phase II metabolizing enzymes; however, there is little known about the relationship between the genotype and phenotype of nsSNPs in these enzymes. We have identified 923 validated nsSNPs in 104 human phase II enzyme genes from the Ensembl genome database and the NCBI SNP database. Using PolyPhen, Panther, and SNAP algorithms, 44%?59% of nsSNPs in phase II enzyme genes were predicted to have functional impacts on protein function. Predictions largely agree with the available experimental annotations. 68% of deleterious nsSNPs were correctly predicted as damaging. This study also identified many amino acids that are likely to be functionally critical, but have not yet been studied experimentally. There was significant concordance between the predicted results of Panther and PolyPhen, and between SNAP non-neutral predictions and PolyPhen scores. Evolutionarily non-neutral (destabilizing) amino acid substitutions are thought to be the pathogenetic basis for the alteration of phase II enzyme activity and to be associated with disease susceptibility and drug/xenobiotic toxicity. Furthermore, the molecular evolutionary patterns of phase II enzymes were characterized with regards to the predicted deleterious nsSNPs.

关键词： phenotype PolyPhen Panther SNAP SNP phase II drug/xenobiotic metabolizing enzyme

Adaptive Multi-phenotype Based Gene Expression Programming Algorithm

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Chinese Journal of Electronics 2016年第5期25卷 807-816页

作者： LI Qu CHENG Hongbing YAO Min School of Computer Science and Technology Zhejiang University of Technology College of Computer Science Zhejiang University State Key Laboratory for Novel Software Technology Nanjing University

Expression theory is the mathematical foundation of evolutionary computation. In order to investigate the problems in Gene expression programming(GEP) expression theory, we clarified the difference between genotypic expression space and phenotypic expression space. We also presented phenotypic expression space definition and theory. Then we analyzed the reason of good and bad performance of different GEP algorithms based on expression space theory. We also proposed a new Adaptive multi-phenotype gene expression programming(AMGEP),in which the potential of genes is fully activated with gene combination. Experiments on benchmark problems showed that genotypic expression space and phenotypic expression space theory can explain the different performance of different algorithms and showed that AMGEP outperform other GEP algorithms in terms of search ability.

关键词： Gene expression programming(GEP) Genotype phenotype Population diversity

An integrative view of the signaling phenotype： Dynamic links between signals, physiology, behavior and social context

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Current Zoology 2014年第6期60卷 739-754页

作者： Maren N. VITOUSEK David M. ZONANA Rebecca J. SAFRAN Department of Neurobiology and Behavior Comell University Ithaca New York 14853 USA Department of Ecology and Evolutionary Biology University of Colorado Boulder Colorado 80309 USA

Signal traits are often linked with the physiological state and behavior of their bearer. Direct examination of the causal links among these variables has provided substantial insight into the information content of signals, and into the costs and benefits of signal expression. Yet recent empirical work suggests that the social context in which signals are developed and displayed can play a major role not only in how signals are received, but also in coordinating and mediating the signaling phenotype itself. Here we review both well-established and emerging evidence for direct feedbacks among an individual＇s physiological state, be- havior, and signal elaboration. We then describe an integrative view of signaling that takes into account the bidirectional rela- tionships among components of phenotype and the social context in which signals are developed and displayed. Integrating dy- namic feedback between context and phenotype within models of the evolution and maintenance of signals may yield insights into how signals evolve, how signaling phenotypes are coordinated and maintained on ecological and evolutionary time scales, and how static signals continue to convey relevant phenotypic information about their bearer through time.

关键词： Behavior phenotype Physiology Signal trait Social feedback Sexual selection

Effects of Taxotere on invasive potential and multidrug resistance phenotype in pancreatic carcinoma cell line SUIT-2

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World Journal of Gastroenterology 2001年第1期7卷 143-148页

作者： Edgar Staren Takeshi Iwamura Hubert Appert John Howard Department of Surgery Medical College of Ohio Toledo Ohio USA Department of Surgery Miyazaki Medical College Miyazaki Japan

INTRODUCTIONDevelopment of drug-resistance to chemotherapyand subsequent metastasis of tumor are primarilyresponsible for treatment failure and the death fromcancer. There have been many previous studies onthe relationship between expression of multidrugresistance (MDR) phenotype P-glycoprotein (P-gp)and the malignant properties of tumors, but theresults are often conflicting[1-8]. The difference intumor types or MDR phenotype induced by specificagents might account for this discrepancy. Taxotere(TXT), a member of the family of taxanes, hasantitumor activity through its effect of promotingthe polymerization of tubulin[9,10].

关键词： Carcinoma Pancreatic Neoplasms Taxoids Antineoplastic Agents, Phytogenic Biocompatible Materials Collagen Drug Combinations Drug Resistance, Multiple Drug Resistance, Neoplasm Fluorescent Dyes Humans In Vitro Laminin Neoplasm Invasiveness P-Glycoprotein Paclitaxel derivatives phenotype Proteoglycans RNA, Neoplasm Research Support, Non-U.S. Gov't Rhodamine 123 Tumor Cells, Cultured

Kinetics of the phenotype and Function of Murine Peritoneal Macrophages Following Acute Inflammation

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Cellular & Molecular Immunology 2004年第1期1卷 57-62页

作者： QingliWu YonghongFeng YifuYang Jingliu WenliangZhou PeilanHe RuZhou XiaoyuLi JianpingZou LaboratoryofImmunopharmacology＆StateKeyLaboratoryofDrugResearch ShanghaiInstituteofMateriaMedica.ShanghaiInstitutesforBiologicalSciencesChineseAcademyofSciencesShanghai201203.China StateKeyLaboratoryofDrugResearch ShanghaiInstituteofMateriaMedica ShanghaiInstitutesforBilogicalSciences ChineseAcademyofSciences555ZuchongzhiRoadZhangjiangHi-TechParkShanghai201203China

This study was undertaken to have a better understand for the process and the underlying mechanisms to limit macrophage activation and population of activated macrophages.A comprehensive kinetics of cytokine production was performed in murine peritoneal macrophages recovered from Balb/c mice at various time during the course of an intraperitoneal injection with thioglycollate (TG).The expression of cell surface molecules such as MHC-Ⅰ,MHC-Ⅱ,B7-1 and B7-2 of these macrophages were also determined by flow *** present findings of our research suggested that the population of activated macrophages and the activation of macrophages (including cytokines production and expression of cell surface functional molecules) were strictly controlled during inflammation *** is one of the important mechanisms to retain the host *** & Molecular Immunology.2004;1(1):57-62.

关键词： macrophage cytokine phenotype self-regulation

Association of extraintestinal manifestations of inflammatory bowel disease in a province of western Hungary with disease phenotype:Results of a 25-year follow-up study

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World Journal of Gastroenterology 2003年第10期9卷 2300-2307页

作者： Laszlo Lakatos Tunde Pandur Gyula David Zsuzsanna Balogh Pal Kuronya Arpad Tollas Peter Laszlo Lakatos 1~(st) Department of Medicine Csolnoky F.Province HospitalVeszprem Department of Medicine Grof Eszterhazy HospitalPapa Department of Infectious Diseases Magyar Imre HospitalAjka Department of Medicine Mumcipal HospitalVarpalota 1~(st) Department of Medicine Semmelweis UniversityBudapestHungary

AIM:IBD is a systemic disease associated with a large number of extraintestinal manifestations (EIMs).Our aim was to determine the prevalence of EIMs in a large IBD cohort in Veszprem Province in a 25-year follow-up study. METHODS:Eight hundred and seventy-three IBD patients were enrolled (ulcerative colitis/UC/:619,m/f:317/302, mean age at presentation:38.3 years,average disease duration:11.2 years;Crohn's disease/CD/:254,m/f:125/129, mean age at presentation:32.5 years,average disease duration:9.2 years).Intestinal,extraintestinal signs and laboratory tests were monitored *** alteration suggesting an EIMs was investigated by a specialist. RESULTS:A total of 21.3% of patients with IBD had EIM (UC:15.0%,CD:36.6%).Age at presentation did not affect the likelihood of *** of EIMs was higher in women and in CD,ocular complications and primary sclerosing cholangitis (PSC) were more frequent in *** UC there was an increased tendency of EIM in patients with a more extensive *** complications were more frequent in CD (22.4% vsUC 10.2%,P<0.01).In UC positive family history increased the risk of joint complications (OR:3.63).In CD the frequency of type-1 peripheral arthritis was increased in patients with penetrating disease (P=0.028).PSC was present in 1.6% in UC and 0.8% in *** complications were present in 3.8% in UC and 10.2% in CD,the rate of ocular complications was around 3% in both *** complications were glomerulonephritis,autoimmune hemolytic anaemia and celiac disease. CONCLUSION:Prevalence of EIM in Hungarian IBD patients is in concordance with data from Western *** high number of EIM supports a role for complex follow-up in these patients.

关键词： Adolescent Adult Age Distribution Aged Aged, 80 and over Anemia, Iron-Deficiency Bile Duct Diseases Child Colitis, Ulcerative Crohn Disease Eye Diseases Female Follow-Up Studies Humans Hungary Joint Diseases Liver Diseases Male Middle Aged phenotype Prevalence

Adipocyte-derived microvesicles from obese mice induce M1 macrophage phenotype through secreted miR-155

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Journal of Molecular Cell Biology 2016年第6期8卷 505-517页

作者： Yaqin Zhang Hongliang Mei Xiaoai Chang Fang Chen Yunxia Zhu Xiao Han Key Laboratory of Human Functional Genomics of Jiangsu Province Department of Biochemistry and Molecular BiologyNanjing Medical University140 Hanzhong RoadNanjing 210029China

The pro-inflammatory profile of M1 macrophage accumulation in adipose tissue is a central event leading to the metabolic complications of ***,the mechanisms by which M1 macrophages are enriched in adipose tissue during weight gain remain incompletely ***,we investigated the effects of adipocyte-derived microvesicles(ADM)on modulating macrophage phenotype in mice and explored the involved molecular signalling *** found that,compared with ADM from lean mice(SD ADM),ADM from obese mice(HFD ADM)significantly enhanced M1 marker *** quantitative RTPCR assay demonstrated that miR-155 was upregulated in both HFD ADM and HFD ADM-treated *** depleting miR-155 expression in HFD ADM and increasing miR-155 level in SD ADM,we further illustrated that miR-155 in ADM-induced M1 macrophage ***,in contrast to SD ADM,HFD ADM significantly decreased the protein level of SOCS1,a proven miR-155 target,leading to activation of STAT1,and suppression of STAT6 signalling;these effects were reversed by silencing miR-155 in HFD ***,the supernatant of bone marrow-derived macrophages pre-stimulated with miR-155-bearing ADM interfered with insulin signalling and insulin-induced glucose uptake in ***,these results provide the first evidence that M1 macrophage polarization can be mediated by miR-155-bearing ADM,which reciprocally regulates insulin signalling and glucose uptake in *** study reveals a novel mechanism through which obesity induces an imbalance in the M1-to-M2 macrophage ratio in adipose tissue,thus causing chronic inflammation and local insulin resistance.

关键词： adipocyte macrophage phenotype microvesicle miR-155

Heterogeneity of chronic obstructive pulmonary disease:from phenotype to genotype

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Frontiers of Medicine 2013年第4期7卷 425-432页

作者： Xu Chen Xiaomao Xu Fei Xiao Key Laboratory of Geriatrics Beijing Institute of Geriatrics Department of Respiratory Medicine Beijing HospitalMinistry of HealthBeijing 100730China

Chronic obstructive pulmonary disease(COPD)is one of the leading causes of morbidity and mortality throughout the world and is mainly characterized by persistent airflow *** that multiple systems other than the lung can be impaired in COPD patients,the traditional FEV1/FVC ratio shows many limitations in COPD diagnosis and *** heterogeneities are found in terms of clinical manifestations,physiology,imaging findings,and inflammatory reactions in COPD patients;thus,phenotyping can provide effective information for the prognosis and ***,phenotypes are often based on symptoms or pathophysiological impairments in late-stage COPD,and the role of phenotypes in COPD prevention and early diagnosis remains *** shortcoming may be overcome by the potential genotypes defined by the heterogeneities in certain *** review briefly describes the heterogeneity of COPD,with focus on recent advances in the correlations between genotypes and *** potential roles of these genotypes and phenotypes in the molecular mechanisms and management of COPD are also elucidated.

关键词： chronic obstructive pulmonary disease heterogeneity phenotype genotype prediction

Genotype-phenotype correlations in Chinese patients with TGFBI gene-linked corneal dystrophy

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2011年第4期12卷 287-292页

作者： Yan LONG Yang-shun GU Wei HAN Xiu-yi LI Ping YU Ming QI Department of Ophthalmology the First Affiliated Hospital School of Medicine Zhejiang University Hangzhou 310003 China Department of Medical Genetics School of Medicine Zhejiang University Hangzhou 310029 China

In this paper,we report the clinical and molecular features of the distinct TGFBI (human transforming growth factor β-induced,OMIM No.601692) gene-linked corneal ***,five pedigrees and ten unrelated individuals diagnosed as corneal dystrophy were *** venous DNA was extracted,and then amplified by polymerase chain reaction (PCR) and scanned for mutation by single-stranded conformation polymorphism (SSCP).Direct DNA sequencing was used to analyze the mutations of the TGFBI *** our study,thirty patients from five pedigrees and ten sporadic patients were diagnosed as four TGFBI gene-linked corneal dystrophies of granular corneal dystrophy type I (GGCD I),Avellino corneal dystrophy (ACD),lattice corneal dystrophy type I (LCD I),and lattice corneal dystrophy type ⅢA (LCD IIIA),and in total,seven disease-causing mutations,namely R555W,A546D,A546T,and T538P mutations in exon 12,R124H and R124C mutations in exon 4,and P501T mutation in exon 11,were identified,while four polymorphisms of V327V,L472L,F540F,and 1665-1666insC were screened in exons 8,11,and *** study ascertained the tight genotype-phenotype relationship and confirmed the clinical and genetic features of four TGFBI gene-linked corneal dystrophies.

关键词： TGFBI gene Corneal dystrophy Genotype phenotype Mutation