Medical genetics is the newest cutting-edge discipline that focuses on solving medical problems using genetics knowledge and methods. In China, medical genetics research activities initiated from a poor inner basis bu...Medical genetics is the newest cutting-edge discipline that focuses on solving medical problems using genetics knowledge and methods. In China, medical genetics research activities initiated from a poor inner basis but a prosperous outer environment. During the 40 years of reform and opening-up policy,Chinese scientists contributed significantly in the field of medical genetics, garnering considerable attention worldwide. In this review, we highlight the significant findings and/or results discovered by Chinese scientists in monogenic diseases, complex diseases, cancer, genetic diagnosis, as well as gene manipulation and gene therapy. Due to these achievements, China is widely recognized to be at the forefront of medical genetics research and development. However, the significant progress and development that has been achieved could not have been accomplished without sufficient funding and a wellconstructed logistics network. The successful implementation of translational and precise medicine sourced from medical genetics will depend on an open ethics policy and intellectual property protection,along with strong support at the national industry level.展开更多
AIM:To investigate macrophage migration inhibitory factor(MIF) expression and its clinical relevance in gastric cancer,and effects of MIF knockdown on proliferation of gastric cancer cells. METHODS:Tissue microarray c...AIM:To investigate macrophage migration inhibitory factor(MIF) expression and its clinical relevance in gastric cancer,and effects of MIF knockdown on proliferation of gastric cancer cells. METHODS:Tissue microarray containing 117 samples of gastric cancer and adjacent non-cancer normal tissues was studied for MIF expression by immunohistochemistry(IHC) semiquantitatively,and the association of MIF expression with clinical parameters was analyzed. MIF expression in gastric cancer cell lines was detected by reverse transcriptionpolymerase chain reaction(RT-PCR) and Western blot. Two pairs of si RNA targeting the MIF gene(MIF si-1 and MIF si-2) and one pair of scrambled si RNA as a negative control(NC) were designed and chemically synthesized. All si RNAs were transiently transfected in AGS cells with OligofectamineTM to knock down the MIF expression,with the NC group and mock group(OligofectamineTM alone) as controls. At 24,48,and 72 h after transfection,MIF m RNA was analyzed by RTPCR,and MIF and proliferating cell nuclear antigen(PCNA) proteins were detected by Western blot.The proliferative rate of AGS cells was assessed by methylthiazolyl tetrazolium(MTT) assay and colony forming assay.RESULTS:The tissue microarray was informative for IHC staining,in which the MIF expression in gastric cancer tissues was higher than that in adjacent noncancer normal tissues(P < 0.001),and high level of MIF was related to poor tumor differentiation,advanced T stage,advanced tumor stage,lymph node metastasis,and poor patient survival(P < 0.05 for all). After si RNA transfection,MIF m RNA was measured by real-time PCR,and MIF protein and PCNA were assessed by Western blot analysis. We found that compared to the NC group and mock group,MIF expression was knocked down successfully in gastric cancer cells,and PCNA expression was downregulated with MIF knockdown as well. The cell counts and the doubling times were assayed by MTT 4 d after transfection,and colonies formed were assayed by colony forming assay 10 d after transfection; all these showed significant changes in gastric cancer cells transfected with specific si RNA compared with the control si RNA and mock groups(P < 0.001 for all).CONCLUSION:MIF could be of prognostic value in gastric cancer and might be a potential target for small-molecule therapy.展开更多
AIM： To investigate the genotype and allelic frequencies of Cytochrome P450 2B6 polymorphisms in four southern Chinese populations.METHODS： DNA was obtained from blood samples from Han Chinese from Hong Kong and thr...AIM： To investigate the genotype and allelic frequencies of Cytochrome P450 2B6 polymorphisms in four southern Chinese populations.METHODS： DNA was obtained from blood samples from Han Chinese from Hong Kong and three minority groups,the Wa, Bulang and Lahu from Yunnan in southern China. Genotyping was performed using real-time PCR and confirmed by direct sequencing.RESULTS： A total of 507 subjects from southern China were studied. Results showed there is a high prevalence of 516G 〉 T （34.5%） in ethnic Chinese compared to literature reports on other Asian populations and Caucasians. The frequency of the 516TT genotype is higher in the Hah majority （23.1%） than in three other ethnic minority groups （i.e., 7.4%, 9.1% and 15.8%） in southern China.CONCLUSION： This was the first study to document the spectrum of CYP2B6 allelic variants and genotypes in a southern Chinese population. The 516G 〉 T allele is associated with a defective metabolism of efavirenz （EFV）, which therefore may predispose to drug toxicity.Treatment regimens for human immunodeficiency virus （HIV） and heroin addiction may need to be optimized in different populations because of the marked variability of the key metabolizing enzyme.展开更多
AIM:To characterise the viral kinetics of enterovirus 71 (EV71).METHODS:In this study,human rhabdomyosarcoma (RD) cells were infected with EV71 at different multiplicity of infection (MOI).After infection,the cytopath...AIM:To characterise the viral kinetics of enterovirus 71 (EV71).METHODS:In this study,human rhabdomyosarcoma (RD) cells were infected with EV71 at different multiplicity of infection (MOI).After infection,the cytopathic effect (CPE) was monitored and recorded using a phase contrast microscope associated with a CCD camera at different time points post viral infection (0,6,12,24 h post infection).Cell growth and viability were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in both EV71 infected and mock infected cells at each time point.EV71 replication kinet-ics in RD cells was determined by measuring the total intracellular viral RNA with real-time reverse-transcription polymerase chain reaction (qRT-PCR).Also,the intracellular and extracellular virion RNA was isolated and quantified at different time points to analyze the viral package and secretion.The expression of viral protein was determined by analyze the levels of viral structure protein VP1 with Western blotting.RESULTS:EV71 infection induced a significant CPE as early as 6 h post infection (p.i.) in both RD cells infected with high ratio of virus (MOI 10) and low ratio of virus (MOI 1).In EV71 infected cells,the cell growth was inhibited and the number of viable cells was rapidly decreased in the later phase of infection.EV71 virions were uncoated immediately after entry.The intracellular viral RNA began to increase at as early as 3 h p.i.and the exponential increase was found between 3 h to 6 h p.i.in both infected groups.For viral structure protein synthesis,results from western-blot showed that intracellular viral protein VP1 could not be detected until 6 h p.i.in the cells infected at either MOI 1 or MOI 10;and reached the peak at 9 h p.i.in the cells infected with EV71 at both MOI 1 and MOI 10.Simultaneously,the viral package and secretion were also actively processed as the virus underwent rapid replication.The viral package kinetics was comparable for both MOI 1 and MOI 10 infected groups.It was observed that at 3 h p.i,the intracellular virions obviously decreased,thereafter,the intracellular virions began to increase and enter into the exponential phase until 12 h p.i.The total amounts of intracellular virons were decreased from 12 to 24 h p.i.Consistent with this result,the increase of virus secretion occurred during 6 to 12 h p.i.CONCLUSION:The viral kinetics of EV71 were established by analyzing viral replication,package and secretion in RD cells.展开更多
Pathway analysis,also known as gene-set enrichment analysis,is a multilocus analytic strategy that integrates a priori,biological knowledge into the statistical analysis of high-throughput genetics data.Originally dev...Pathway analysis,also known as gene-set enrichment analysis,is a multilocus analytic strategy that integrates a priori,biological knowledge into the statistical analysis of high-throughput genetics data.Originally developed for the studies of gene expression data,it has become a powerful analytic procedure for indepth mining of genome-wide genetic variation data.Astonishing discoveries were made in the past years,uncovering genes and biological mechanisms underlying common and complex disorders.However,as massive amounts of diverse functional genomics data accrue,there is a pressing need for newer generations of pathway analysis methods that can utilize multiple layers of high-throughput genomics data.In this review,we provide an intellectual foundation of this powerful analytic strategy,as well as an update of the state-of-the-art in recent method developments.The goal of this review is threefold:(1)introduce the motivation and basic steps of pathway analysis for genome-wide genetic variation data;(2)review the merits and the shortcomings of classic and newly emerging integrative pathway analysis tools;and(3)discuss remaining challenges and future directions for further method developments.展开更多
AIM: To test whether oral L-81 treatment could im-prove the condition of mice with diabetes and to investigate how L-81 regulates microsomal triglyceride transfer protein (MTP) activity in the liver. METHODS: Genetica...AIM: To test whether oral L-81 treatment could im-prove the condition of mice with diabetes and to investigate how L-81 regulates microsomal triglyceride transfer protein (MTP) activity in the liver. METHODS: Genetically diabetic (db/db) mice were fed on chow supplemented with or without L-81 for 4 wk. The body weight, plasma glucose level, plasma lipid profile, and adipocyte volume of the db/db mice were assessed after treatment. Toxicity of L-81 was also evaluated. To understand the molecular mecha-nism, HepG2 cells were treated with L-81 and the effects on apolipoprotein B (apoB) secretion and mRNA level of the MTP gene were assessed.RESULTS: Treatment of db/db mice with L-81 sig-nificantly reduced and nearly normalized their body weight, hyperphagia and polydipsia. L-81 also markedly decreased the fasting plasma glucose level, improved glucose tolerance, and attenuated the elevated levels of plasma cholesterol and triglyceride. At the effective dosage, little toxicity was observed. Treatment of HepG2 cells with L-81 not only inhibited apoB secretion, but also signif icantly decreased the mRNA level of the MTP gene. Similar to the action of insulin, L-81 exerted its effect on the MTP promoter. CONCLUSION: L-81 represents a promising candidate in the development of a selective insulin-mimetic mol-ecule and an anti-diabetic agent.展开更多
Identical-by-descent(IBD)is a fundamental genomic characteristic in population genetics and has been widely used for population history reconstruction.However,limited by the nature of IBD,which could only capture the ...Identical-by-descent(IBD)is a fundamental genomic characteristic in population genetics and has been widely used for population history reconstruction.However,limited by the nature of IBD,which could only capture the relationship between two individuals/haplotypes,existing IBD-based history inference is constrained to two populations.In this study,we propose a framework by leveraging IBD sharing in multipopulation and develop a method,MatrixiBD,to reconstruct recent multi-population migration history.Specifically,we employ the structured coalescent theory to precisely model the genealogical process and then estimate the IBD sharing across multiple populations.Within our model,we establish a theoretical connection between migration history and IBD sharing.Our method is rigorously evaluated through simulations,revealing its remarkable accuracy and robustness.Furthermore,we apply MatrixiBD to Central and South Asia in the Human Genome Diversity Project and successfully reconstruct the recent migration history of three closely related populations in South Asia.By taking into account the IBD sharing across multiple populations simultaneously,MatrixlBD enables us to attain clearer and more comprehensive insights into the history of regions characterized by complex migration dynamics,providing a holistic perspective on intricate patterns embedded within the recent population migration history.展开更多
Background:Choosing the appropriate antipsychotic drug(APD)treatment for patients with schizophrenia(SCZ)can be challenging,as the treatment response to APD is highly variable and difficult to predict due to the lack ...Background:Choosing the appropriate antipsychotic drug(APD)treatment for patients with schizophrenia(SCZ)can be challenging,as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers.Previous studies have indicated the association between treatment response and genetic and epigenetic factors,but no effective biomarkers have been identified.Hence,further research is imperative to enhance precision medicine in SCZ treatment.Methods:Participants with SCZ were recruited from two randomized trials.The discovery cohort was recruited from the CAPOC trial(n=2307)involved 6 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,Quetiapine,Aripiprazole,Ziprasidone,and Haloperidol/Perphenazine(subsequently equally assigned to one or the other)groups.The external validation cohort was recruited from the CAPEC trial(n=1379),which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,and Aripiprazole groups.Additionally,healthy controls(n=275)from the local community were utilized as a genetic/epigenetic reference.The genetic and epigenetic(DNA methylation)risks of SCZ were assessed using the polygenic risk score(PRS)and polymethylation score,respectively.The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis,methylation quantitative trait loci,colocalization,and promoteranchored chromatin interaction.Machine learning was used to develop a prediction model for treatment response,which was evaluated for accuracy and clinical benefit using the area under curve(AUC)for classification,R^(2) for regression,and decision curve analysis.Results:Six risk genes for SCZ(LINC01795,DDHD2,SBNO1,KCNG2,SEMA7A,and RUFY1)involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response.The developed and externally validated prediction model,which incorporated clinical information,PRS,genetic risk score(GRS),and proxy methylation level(proxyDNAm),demonstrated positive benefits for a wide range of patients receiving different APDs,regardless of sex[discovery cohort:AUC=0.874(95%CI 0.867-0.881),R^(2)=0.478;external validation cohort:AUC=0.851(95%CI 0.841-0.861),R^(2)=0.507].Conclusions:This study presents a promising precision medicine approach to evaluate treatment response,which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ.Trial registration Chinese Clinical Trial Registry(https://www.chictr.org.cn/),18 Aug 2009 retrospectively registered:CAPOC-ChiCTR-RNC-09000521(https://www.chictr.org.cn/showproj.aspx?proj=9014),CAPEC-ChiCTRRNC-09000522(https://www.chictr.org.cn/showproj.aspx?proj=9013).展开更多
Familial dysautonomia(FD), a hereditary sensory and autonomic neuropathy, is caused by a mutation in the Elongator complex protein 1(ELP1) gene that leads to a tissue-specific reduction of ELP1 protein. Our work to ge...Familial dysautonomia(FD), a hereditary sensory and autonomic neuropathy, is caused by a mutation in the Elongator complex protein 1(ELP1) gene that leads to a tissue-specific reduction of ELP1 protein. Our work to generate a phenotypic mouse model for FD headed to the discovery that homozygous deletion of the mouse Elp1 gene leads to embryonic lethality prior to mid-gestation. Given that FD is caused by a reduction, not loss, of ELP1, we generated two new mouse models by introducing different copy numbers of the human FD ELP1 transgene into the Elp1 knockout mouse(Elp1) and observed that human ELP1 expression rescues embryonic development in a dose-dependent manner. We then conducted a comprehensive transcriptome analysis in mouse embryos to identify genes and pathways whose expression correlates with the amount of ELP1. We found that ELP1 is essential for the expression of genes responsible for nervous system development. Further, gene length analysis of the differentially expressed genes showed that the loss of Elp1 mainly impacts the expression of long genes and that by gradually restoring Elongator, their expression is progressively rescued. Finally, through evaluation of co-expression modules, we identified gene sets with unique expression patterns that depended on ELP1 expression.展开更多
Autism spectrum disorders （ASD） are a group of neurodevelopmental disorders that affect up to 1.5% of population in the world. Recent large scale genomic studies show that genetic causes of ASD are very heterogeneou...Autism spectrum disorders （ASD） are a group of neurodevelopmental disorders that affect up to 1.5% of population in the world. Recent large scale genomic studies show that genetic causes of ASD are very heterogeneous. Gene ontology, pathway analysis and animal model studies have revealed several potential converging mechanisms including postsynaptic dysfunction of excitatory synapses. In this review, we focus on the structural and functional specializations of dendritic spines, and describe their defects in ASD. We use Fragile X syndrome, Rett syndrome and Phe- lan-McDermid syndrome, three of the most studied neurodevelopmental disorders with autism features, as examples to demonstrate the significant contribution made by mouse models towards the understanding of monogenic ASD. We envision that the development and application of new technologies to study the function ofdendritic spines in valid animal models wi l l eventually lead to innovative treatments for ASD.展开更多
Background:Schizophrenia(SCZ)is a complex psychiatric disorder associated with widespread alterations in the subcortical brain structure.Hemispheric asymmetries are a fundamental organizational principle of the human ...Background:Schizophrenia(SCZ)is a complex psychiatric disorder associated with widespread alterations in the subcortical brain structure.Hemispheric asymmetries are a fundamental organizational principle of the human brain and relate to human psychological and behavioral characteristics.We aimed to explore the state of thalamic lateralization of SCZ.Methods:We used voxel-based morphometry(VBM)analysis,whole-brain analysis of low-frequency fluctuations(ALFF),fractional amplitude of low-frequency fluctuations(fALFF),and resting-state seed-based functional connectivity(FC)analysis to investigate brain structural and functional deficits in SCZ.Also,we applied Pearson’’s correlation analysis to validate the correlation between Positive and Negative Symptom Scale(PANSS)scores and them.Results:Compared with healthy controls,SCZ showed increased gray matter volume(GMV)of the left thalamus(t=2.214,p=0.029),which positively correlated with general psychosis(r=0.423,p=0.010).SCZ also showed increased ALFF in the putamen,the caudate nucleus,the thalamus,fALFF in the nucleus accumbens(NAc),and the caudate nucleus,and decreased fALFF in the precuneus.The left thalamus showed significantly weaker resting-state FC with the amygdala and insula in SCZ.PANSS negative symptom scores were negatively correlated with the resting-state FC between the thalamus and the insula(r=-0.414,p=0.025).Conclusions:Collectively,these results suggest the possibility of aberrant laterality in the left thalamus and its FC with other related brain regions involved in the limbic system.展开更多
Schizophrenia(SCH)is a complex and severe mental disorder with high prevalence,disability,mortality and carries a heavy disease burden,the lifetime prevalence of SCH is around 0.7%–1.0%,which has a profound impact on...Schizophrenia(SCH)is a complex and severe mental disorder with high prevalence,disability,mortality and carries a heavy disease burden,the lifetime prevalence of SCH is around 0.7%–1.0%,which has a profound impact on the individual and society.In the clinical practice of SCH,key problems such as subjective diagnosis,experiential treatment,and poor overall prognosis are still challenging.In recent years,some exciting discoveries have been made in the research on objective biomarkers of SCH,mainly focusing on genetic susceptibility genes,metabolic indicators,immune indices,brain imaging,electrophysiological characteristics.This review aims to summarize the biomarkers that may be used for the prediction and diagnosis of SCH.展开更多
Schizophrenia is a life-long,complex mental illness that still lacks satisfactory treatments.In recent years,increasing numbers of candidate biomarkers of schizophrenia occurrences and drug responses to schizophrenia ...Schizophrenia is a life-long,complex mental illness that still lacks satisfactory treatments.In recent years,increasing numbers of candidate biomarkers of schizophrenia occurrences and drug responses to schizophrenia therapies have been successfully identified by many omics studies.This review discusses the latest discoveries regarding effective drug targets and relevant drug classifications in schizophrenia.It also assesses our understanding of biomarkers for drug efficacy and adverse drug reactions in current schizophrenia treatments using omics technologies.Future applications in clinical practice have been proposed based on these new findings,and are now considered highly promising strategies to better treat schizophrenia.Finally,we explore several novel approaches that aim to reveal additional genetic signatures of schizophrenia using multi-omics data,which are hoped to improve the diagnosis and treatment of this illness in the future.展开更多
基金supported by Ministry of Science and Technology Project (2017YFC1001302 and 2016YFC0906400)the Grant of Shanghai Brain-Intelligence Project from the Shanghai Science and Technology Committee (STCSM) (16JC1420500)Shanghai Jiao Tong University Medical Engineering Cross Research Foundation (YG2014MS07)
文摘Medical genetics is the newest cutting-edge discipline that focuses on solving medical problems using genetics knowledge and methods. In China, medical genetics research activities initiated from a poor inner basis but a prosperous outer environment. During the 40 years of reform and opening-up policy,Chinese scientists contributed significantly in the field of medical genetics, garnering considerable attention worldwide. In this review, we highlight the significant findings and/or results discovered by Chinese scientists in monogenic diseases, complex diseases, cancer, genetic diagnosis, as well as gene manipulation and gene therapy. Due to these achievements, China is widely recognized to be at the forefront of medical genetics research and development. However, the significant progress and development that has been achieved could not have been accomplished without sufficient funding and a wellconstructed logistics network. The successful implementation of translational and precise medicine sourced from medical genetics will depend on an open ethics policy and intellectual property protection,along with strong support at the national industry level.
基金Supported by Grants from the National Natural Science Foundation of China,No.81072044the Guangdong Natural Science Foundation,No.S2011010004653
文摘AIM:To investigate macrophage migration inhibitory factor(MIF) expression and its clinical relevance in gastric cancer,and effects of MIF knockdown on proliferation of gastric cancer cells. METHODS:Tissue microarray containing 117 samples of gastric cancer and adjacent non-cancer normal tissues was studied for MIF expression by immunohistochemistry(IHC) semiquantitatively,and the association of MIF expression with clinical parameters was analyzed. MIF expression in gastric cancer cell lines was detected by reverse transcriptionpolymerase chain reaction(RT-PCR) and Western blot. Two pairs of si RNA targeting the MIF gene(MIF si-1 and MIF si-2) and one pair of scrambled si RNA as a negative control(NC) were designed and chemically synthesized. All si RNAs were transiently transfected in AGS cells with OligofectamineTM to knock down the MIF expression,with the NC group and mock group(OligofectamineTM alone) as controls. At 24,48,and 72 h after transfection,MIF m RNA was analyzed by RTPCR,and MIF and proliferating cell nuclear antigen(PCNA) proteins were detected by Western blot.The proliferative rate of AGS cells was assessed by methylthiazolyl tetrazolium(MTT) assay and colony forming assay.RESULTS:The tissue microarray was informative for IHC staining,in which the MIF expression in gastric cancer tissues was higher than that in adjacent noncancer normal tissues(P < 0.001),and high level of MIF was related to poor tumor differentiation,advanced T stage,advanced tumor stage,lymph node metastasis,and poor patient survival(P < 0.05 for all). After si RNA transfection,MIF m RNA was measured by real-time PCR,and MIF protein and PCNA were assessed by Western blot analysis. We found that compared to the NC group and mock group,MIF expression was knocked down successfully in gastric cancer cells,and PCNA expression was downregulated with MIF knockdown as well. The cell counts and the doubling times were assayed by MTT 4 d after transfection,and colonies formed were assayed by colony forming assay 10 d after transfection; all these showed significant changes in gastric cancer cells transfected with specific si RNA compared with the control si RNA and mock groups(P < 0.001 for all).CONCLUSION:MIF could be of prognostic value in gastric cancer and might be a potential target for small-molecule therapy.
基金Supported by The South China National Research Centre for Integrated Biosciences, and has been conducted collaboratively between Zhongshan University (ZU)The Chinese University of Hong Kong
文摘AIM： To investigate the genotype and allelic frequencies of Cytochrome P450 2B6 polymorphisms in four southern Chinese populations.METHODS： DNA was obtained from blood samples from Han Chinese from Hong Kong and three minority groups,the Wa, Bulang and Lahu from Yunnan in southern China. Genotyping was performed using real-time PCR and confirmed by direct sequencing.RESULTS： A total of 507 subjects from southern China were studied. Results showed there is a high prevalence of 516G 〉 T （34.5%） in ethnic Chinese compared to literature reports on other Asian populations and Caucasians. The frequency of the 516TT genotype is higher in the Hah majority （23.1%） than in three other ethnic minority groups （i.e., 7.4%, 9.1% and 15.8%） in southern China.CONCLUSION： This was the first study to document the spectrum of CYP2B6 allelic variants and genotypes in a southern Chinese population. The 516G 〉 T allele is associated with a defective metabolism of efavirenz （EFV）, which therefore may predispose to drug toxicity.Treatment regimens for human immunodeficiency virus （HIV） and heroin addiction may need to be optimized in different populations because of the marked variability of the key metabolizing enzyme.
基金Supported by Research Grant Council (RGC,CUHK4428/06M)a commissioned grant of the Research Fund for Control of Infectious Diseases (CU-09-02-02)Food and Health Bureau,the Government of Hong Kong Special Administration Region (HKSAR)
文摘AIM:To characterise the viral kinetics of enterovirus 71 (EV71).METHODS:In this study,human rhabdomyosarcoma (RD) cells were infected with EV71 at different multiplicity of infection (MOI).After infection,the cytopathic effect (CPE) was monitored and recorded using a phase contrast microscope associated with a CCD camera at different time points post viral infection (0,6,12,24 h post infection).Cell growth and viability were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in both EV71 infected and mock infected cells at each time point.EV71 replication kinet-ics in RD cells was determined by measuring the total intracellular viral RNA with real-time reverse-transcription polymerase chain reaction (qRT-PCR).Also,the intracellular and extracellular virion RNA was isolated and quantified at different time points to analyze the viral package and secretion.The expression of viral protein was determined by analyze the levels of viral structure protein VP1 with Western blotting.RESULTS:EV71 infection induced a significant CPE as early as 6 h post infection (p.i.) in both RD cells infected with high ratio of virus (MOI 10) and low ratio of virus (MOI 1).In EV71 infected cells,the cell growth was inhibited and the number of viable cells was rapidly decreased in the later phase of infection.EV71 virions were uncoated immediately after entry.The intracellular viral RNA began to increase at as early as 3 h p.i.and the exponential increase was found between 3 h to 6 h p.i.in both infected groups.For viral structure protein synthesis,results from western-blot showed that intracellular viral protein VP1 could not be detected until 6 h p.i.in the cells infected at either MOI 1 or MOI 10;and reached the peak at 9 h p.i.in the cells infected with EV71 at both MOI 1 and MOI 10.Simultaneously,the viral package and secretion were also actively processed as the virus underwent rapid replication.The viral package kinetics was comparable for both MOI 1 and MOI 10 infected groups.It was observed that at 3 h p.i,the intracellular virions obviously decreased,thereafter,the intracellular virions began to increase and enter into the exponential phase until 12 h p.i.The total amounts of intracellular virons were decreased from 12 to 24 h p.i.Consistent with this result,the increase of virus secretion occurred during 6 to 12 h p.i.CONCLUSION:The viral kinetics of EV71 were established by analyzing viral replication,package and secretion in RD cells.
基金supported by National Institutes of Health R00 MH101367 and R01 MH119243(to P.H.Lee)。
文摘Pathway analysis,also known as gene-set enrichment analysis,is a multilocus analytic strategy that integrates a priori,biological knowledge into the statistical analysis of high-throughput genetics data.Originally developed for the studies of gene expression data,it has become a powerful analytic procedure for indepth mining of genome-wide genetic variation data.Astonishing discoveries were made in the past years,uncovering genes and biological mechanisms underlying common and complex disorders.However,as massive amounts of diverse functional genomics data accrue,there is a pressing need for newer generations of pathway analysis methods that can utilize multiple layers of high-throughput genomics data.In this review,we provide an intellectual foundation of this powerful analytic strategy,as well as an update of the state-of-the-art in recent method developments.The goal of this review is threefold:(1)introduce the motivation and basic steps of pathway analysis for genome-wide genetic variation data;(2)review the merits and the shortcomings of classic and newly emerging integrative pathway analysis tools;and(3)discuss remaining challenges and future directions for further method developments.
基金Supported by The Area of Excellence scheme of University Grants Committeethe Research Grant Council Grant, HKU 7642/05M to MCL, from Hong Kong
文摘AIM: To test whether oral L-81 treatment could im-prove the condition of mice with diabetes and to investigate how L-81 regulates microsomal triglyceride transfer protein (MTP) activity in the liver. METHODS: Genetically diabetic (db/db) mice were fed on chow supplemented with or without L-81 for 4 wk. The body weight, plasma glucose level, plasma lipid profile, and adipocyte volume of the db/db mice were assessed after treatment. Toxicity of L-81 was also evaluated. To understand the molecular mecha-nism, HepG2 cells were treated with L-81 and the effects on apolipoprotein B (apoB) secretion and mRNA level of the MTP gene were assessed.RESULTS: Treatment of db/db mice with L-81 sig-nificantly reduced and nearly normalized their body weight, hyperphagia and polydipsia. L-81 also markedly decreased the fasting plasma glucose level, improved glucose tolerance, and attenuated the elevated levels of plasma cholesterol and triglyceride. At the effective dosage, little toxicity was observed. Treatment of HepG2 cells with L-81 not only inhibited apoB secretion, but also signif icantly decreased the mRNA level of the MTP gene. Similar to the action of insulin, L-81 exerted its effect on the MTP promoter. CONCLUSION: L-81 represents a promising candidate in the development of a selective insulin-mimetic mol-ecule and an anti-diabetic agent.
基金supported by the Fundamental Research Funds for the Central Universities(2023JBMC011)the National Natural Science Foundation of China(NSFC)Grant(12271026)the Beijing Natural Science Foundation Grant(L222051).
文摘Identical-by-descent(IBD)is a fundamental genomic characteristic in population genetics and has been widely used for population history reconstruction.However,limited by the nature of IBD,which could only capture the relationship between two individuals/haplotypes,existing IBD-based history inference is constrained to two populations.In this study,we propose a framework by leveraging IBD sharing in multipopulation and develop a method,MatrixiBD,to reconstruct recent multi-population migration history.Specifically,we employ the structured coalescent theory to precisely model the genealogical process and then estimate the IBD sharing across multiple populations.Within our model,we establish a theoretical connection between migration history and IBD sharing.Our method is rigorously evaluated through simulations,revealing its remarkable accuracy and robustness.Furthermore,we apply MatrixiBD to Central and South Asia in the Human Genome Diversity Project and successfully reconstruct the recent migration history of three closely related populations in South Asia.By taking into account the IBD sharing across multiple populations simultaneously,MatrixlBD enables us to attain clearer and more comprehensive insights into the history of regions characterized by complex migration dynamics,providing a holistic perspective on intricate patterns embedded within the recent population migration history.
基金supported by the National Natural Science Foundation of China(81825009,82071505,81901358)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-I2MC&T-B-099,2019-I2M-5–006)+2 种基金the Program of Chinese Institute for Brain Research Beijing(2020-NKX-XM-12)the King’s College London-Peking University Health Science Center Joint Institute for Medical Research(BMU2020KCL001,BMU2019LCKXJ012)the National Key R&D Program of China(2021YFF1201103,2016YFC1307000).
文摘Background:Choosing the appropriate antipsychotic drug(APD)treatment for patients with schizophrenia(SCZ)can be challenging,as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers.Previous studies have indicated the association between treatment response and genetic and epigenetic factors,but no effective biomarkers have been identified.Hence,further research is imperative to enhance precision medicine in SCZ treatment.Methods:Participants with SCZ were recruited from two randomized trials.The discovery cohort was recruited from the CAPOC trial(n=2307)involved 6 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,Quetiapine,Aripiprazole,Ziprasidone,and Haloperidol/Perphenazine(subsequently equally assigned to one or the other)groups.The external validation cohort was recruited from the CAPEC trial(n=1379),which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,and Aripiprazole groups.Additionally,healthy controls(n=275)from the local community were utilized as a genetic/epigenetic reference.The genetic and epigenetic(DNA methylation)risks of SCZ were assessed using the polygenic risk score(PRS)and polymethylation score,respectively.The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis,methylation quantitative trait loci,colocalization,and promoteranchored chromatin interaction.Machine learning was used to develop a prediction model for treatment response,which was evaluated for accuracy and clinical benefit using the area under curve(AUC)for classification,R^(2) for regression,and decision curve analysis.Results:Six risk genes for SCZ(LINC01795,DDHD2,SBNO1,KCNG2,SEMA7A,and RUFY1)involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response.The developed and externally validated prediction model,which incorporated clinical information,PRS,genetic risk score(GRS),and proxy methylation level(proxyDNAm),demonstrated positive benefits for a wide range of patients receiving different APDs,regardless of sex[discovery cohort:AUC=0.874(95%CI 0.867-0.881),R^(2)=0.478;external validation cohort:AUC=0.851(95%CI 0.841-0.861),R^(2)=0.507].Conclusions:This study presents a promising precision medicine approach to evaluate treatment response,which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ.Trial registration Chinese Clinical Trial Registry(https://www.chictr.org.cn/),18 Aug 2009 retrospectively registered:CAPOC-ChiCTR-RNC-09000521(https://www.chictr.org.cn/showproj.aspx?proj=9014),CAPEC-ChiCTRRNC-09000522(https://www.chictr.org.cn/showproj.aspx?proj=9013).
基金supported by National Institutes of Health grants (R37NS095640 to S.A.S.)the Francis Crick Institute (to PC and JQS)
文摘Familial dysautonomia(FD), a hereditary sensory and autonomic neuropathy, is caused by a mutation in the Elongator complex protein 1(ELP1) gene that leads to a tissue-specific reduction of ELP1 protein. Our work to generate a phenotypic mouse model for FD headed to the discovery that homozygous deletion of the mouse Elp1 gene leads to embryonic lethality prior to mid-gestation. Given that FD is caused by a reduction, not loss, of ELP1, we generated two new mouse models by introducing different copy numbers of the human FD ELP1 transgene into the Elp1 knockout mouse(Elp1) and observed that human ELP1 expression rescues embryonic development in a dose-dependent manner. We then conducted a comprehensive transcriptome analysis in mouse embryos to identify genes and pathways whose expression correlates with the amount of ELP1. We found that ELP1 is essential for the expression of genes responsible for nervous system development. Further, gene length analysis of the differentially expressed genes showed that the loss of Elp1 mainly impacts the expression of long genes and that by gradually restoring Elongator, their expression is progressively rescued. Finally, through evaluation of co-expression modules, we identified gene sets with unique expression patterns that depended on ELP1 expression.
文摘Autism spectrum disorders （ASD） are a group of neurodevelopmental disorders that affect up to 1.5% of population in the world. Recent large scale genomic studies show that genetic causes of ASD are very heterogeneous. Gene ontology, pathway analysis and animal model studies have revealed several potential converging mechanisms including postsynaptic dysfunction of excitatory synapses. In this review, we focus on the structural and functional specializations of dendritic spines, and describe their defects in ASD. We use Fragile X syndrome, Rett syndrome and Phe- lan-McDermid syndrome, three of the most studied neurodevelopmental disorders with autism features, as examples to demonstrate the significant contribution made by mouse models towards the understanding of monogenic ASD. We envision that the development and application of new technologies to study the function ofdendritic spines in valid animal models wi l l eventually lead to innovative treatments for ASD.
基金National Natural Science Foundation of China(Grant/Award Number:81701326)National Key Research and Development Program of China(Grant/Award Number:2016YFC1307004)+3 种基金Multidisciplinary Team for Cognitive Impairment of Shanxi Science and Technology Innovation Training Team(Grant/Award Number:201705D131027)Special Project of Scientific Research Plan Talents of Shanxi Provincial Health Commission(Grant/Award Number:2020081)Shanxi Provincial Science and Technology Achievements Transformation and Guidance Project(Grant/Award Numbers:201904D131020,81971601)Shanxi Province Overseas Students Science and Technology Activity Funding Project(Grant/Award Number:20200038)。
文摘Background:Schizophrenia(SCZ)is a complex psychiatric disorder associated with widespread alterations in the subcortical brain structure.Hemispheric asymmetries are a fundamental organizational principle of the human brain and relate to human psychological and behavioral characteristics.We aimed to explore the state of thalamic lateralization of SCZ.Methods:We used voxel-based morphometry(VBM)analysis,whole-brain analysis of low-frequency fluctuations(ALFF),fractional amplitude of low-frequency fluctuations(fALFF),and resting-state seed-based functional connectivity(FC)analysis to investigate brain structural and functional deficits in SCZ.Also,we applied Pearson’’s correlation analysis to validate the correlation between Positive and Negative Symptom Scale(PANSS)scores and them.Results:Compared with healthy controls,SCZ showed increased gray matter volume(GMV)of the left thalamus(t=2.214,p=0.029),which positively correlated with general psychosis(r=0.423,p=0.010).SCZ also showed increased ALFF in the putamen,the caudate nucleus,the thalamus,fALFF in the nucleus accumbens(NAc),and the caudate nucleus,and decreased fALFF in the precuneus.The left thalamus showed significantly weaker resting-state FC with the amygdala and insula in SCZ.PANSS negative symptom scores were negatively correlated with the resting-state FC between the thalamus and the insula(r=-0.414,p=0.025).Conclusions:Collectively,these results suggest the possibility of aberrant laterality in the left thalamus and its FC with other related brain regions involved in the limbic system.
基金supported by Academy of Medical Sciences Research Unit(2019-I2M-5-006)Chinese Institute for Brain Research at Beijing(2020-NKX-XM-12)+2 种基金Guizhou Province science and technology plan project([2020]4Y064)National Natural Science Foundation of China(81825009,http://dx.doi.org/10.13039/501100001809)PKUHSC-KCL Joint Medical Research(BMU2020KCL001).
文摘Schizophrenia(SCH)is a complex and severe mental disorder with high prevalence,disability,mortality and carries a heavy disease burden,the lifetime prevalence of SCH is around 0.7%–1.0%,which has a profound impact on the individual and society.In the clinical practice of SCH,key problems such as subjective diagnosis,experiential treatment,and poor overall prognosis are still challenging.In recent years,some exciting discoveries have been made in the research on objective biomarkers of SCH,mainly focusing on genetic susceptibility genes,metabolic indicators,immune indices,brain imaging,electrophysiological characteristics.This review aims to summarize the biomarkers that may be used for the prediction and diagnosis of SCH.
基金This work was supported by grants from the 863 Program(No.2012AA02A515,2012AA021802)the National Natural Science Foundation of China(No.81773818,81273596,30900799,81671326)+3 种基金the National Key Research and Development Program of China(No.2017YFC0909303,2016YFC0905000,2016YFC0905002,2016YFC1200200,2016YFC0906400)the 4th Three-year Action Plan for Public Health of Shanghai,China(No.15GWZK0101)Shanghai Pujiang Program,China(No.17PJD020)Shanghai Key Laboratory of Psychotic Disorders,China(No.13dz2260500).
文摘Schizophrenia is a life-long,complex mental illness that still lacks satisfactory treatments.In recent years,increasing numbers of candidate biomarkers of schizophrenia occurrences and drug responses to schizophrenia therapies have been successfully identified by many omics studies.This review discusses the latest discoveries regarding effective drug targets and relevant drug classifications in schizophrenia.It also assesses our understanding of biomarkers for drug efficacy and adverse drug reactions in current schizophrenia treatments using omics technologies.Future applications in clinical practice have been proposed based on these new findings,and are now considered highly promising strategies to better treat schizophrenia.Finally,we explore several novel approaches that aim to reveal additional genetic signatures of schizophrenia using multi-omics data,which are hoped to improve the diagnosis and treatment of this illness in the future.
