Congenital heart disease(CHD)is the mnost comman birth defect,with 34%of cases attrib utedto genetic variants.NOTCH1,a multi-domain transmembrane protein,regulates heart developmert bycontrolling the differantiation a...Congenital heart disease(CHD)is the mnost comman birth defect,with 34%of cases attrib utedto genetic variants.NOTCH1,a multi-domain transmembrane protein,regulates heart developmert bycontrolling the differantiation and migration of myocardial mesoderm cells,and different variants are presentin differnt types of CHD.In this review,we aim to provide a detailed description of NOTCH1 structuraldomains and their functions,highlighting NOTCH1 variants in CHD and the molecular mechanisms throughwhich they contribute to CHD occurrence,NOTCH1 has two main domains,the NOTCH extracellulardomain(NBCD)and the NOTCH intracellular domain(NICD).NECD facilitates ligand binding and NICDformation,while the NICD functions as a transcrip tion factor,forming complexes with co-factors in thenucleus to initiate gene transcription.Amnong the NOTCH1 variants associated with CHD occurrence,most are loss-of-function variants.Moreover,most of the variants are located in theEGF-like domain.Themolecular mechanism behind the NOTCH1 variant-associated CHD occurrence appears to be either due to aloss-of-function or missense variant.In the loss-of-function mutations,NOTCH1 haploinsufficiency is notedand directly reduces theNICD production,causing CHD ocaurrence.In the less common case of missensevariant,only a mild NOTCH1 malfuncticn is observed,but insufficient to directly lead to CHD occurrence.However,when a missense variant is combined with a risk factor,such as exposure to an environmentaltoxin,the cumulative effect can lead to CHD.Understanding the genetic and molecular mechanisms linkingNOTCH1 variants to CHD is crucial for improving clinical management and patient quality of life.展开更多
A class of singularly perturbed semi-linear boundary value problems with discontinuous functions is examined in this article. Using the boundary layer function method, the asymptotic solution of such a problem is give...A class of singularly perturbed semi-linear boundary value problems with discontinuous functions is examined in this article. Using the boundary layer function method, the asymptotic solution of such a problem is given and shown to be uniformly effective. The existence and uniqueness of the solution for the system is also proved. Numerical result is presented as an illustration to the theoretical result.展开更多
Understanding genetic variant functionality is essential for advancing animal genomics and precision breeding.However,the lack of comprehensive functional genomic annotations in animals limits the effectiveness of mos...Understanding genetic variant functionality is essential for advancing animal genomics and precision breeding.However,the lack of comprehensive functional genomic annotations in animals limits the effectiveness of most variant function assessment methods.In this study,we gather 1030 raw epigenomic datasets from 10 animal species and systematically annotate 7 types of key regulatory regions,creating a comprehensive functional annotation map of animal genomic variants.Our findings demonstrate that integrating variants with regulatory annotations can identify tissues and cell types underlying economic traits,underscoring the utility of these annotations in functional variant discovery.Using our functional annotations,we rank the functional potential of genetic variants and classify over 127 million candidate variants into 5 functional confidence categories,with high-confidence variants significantly enriched in eQTLs and trait-associated SNPs.Incorporating these variants into genomic prediction models can improve estimated breeding value accuracy,demonstrating their practical utility in breeding programs.To facilitate the use of our results,we develop the Integrated Functional Mutation(IFmut:http://www.ifmutants.com:8212)platform,enabling researchers to explore regulatory annotations and assess the functional potential of animal variants efficiently.Our study provides a robust framework for functional genomic annotations in farm animals,enhancing variant function assessment and breeding precision.展开更多
To better understand the effect of a new split variant of human asialoglycoprotein receptor (ASGPR H1b) on ASGPR ligands’ binding ability, we established a functional cell line which expresses ASGPR.The full lengths ...To better understand the effect of a new split variant of human asialoglycoprotein receptor (ASGPR H1b) on ASGPR ligands’ binding ability, we established a functional cell line which expresses ASGPR.The full lengths of ASGPRH1a and H2c fragments from human liver were amplified by reverse transcript PCR (RT-PCR) and inserted into eukaryotic expression vector pIRES2EFP, pCDNA3.1 (Zeo+) respectively.The recombinants were cotransfected into HeLa cells.After selection by using Neocin and Zeocin, a stably transfected cell line was established, which was designated 4-1-6.The transcription and expression of ASGPRH1a and H2c in 4-1-6 were confirmed by RT-PCR, Western blotting and immunofluorescence.The endocytosis function of the artificial "ASGPR" on the surface of 4-1-6 was tested by FACS.It was found that the cell line 4-1-6 could bind ASGPR natural ligand molecular asialo-orosomucoid (ASOR).After the eukaryotic plasmid H1b/pCDNA3.1 (neo) was transfected into cell line 4-1-6, H1b did not down-regulate the ligand binding ability of ASGPR.The eukaryotic expression plasmid H1b/pcDNA3.1 (neo) and H2c/pcDNA3.1 (neo) were co-transfected transiently into Hela cell.Neither single H1b nor H1b and H2c could bind ASOR.In conclusion, a functional cell line of human asialoglycoprotein receptor (ASGPR) which expresses both H1a and H2c stably was established.The new split variant H1b has no effect on ASGPR binding to ASOR.ASGPRH1b alone can’t bind to ASOR, it yet can’t form functional complex with ASGPRH2c.展开更多
In this paper a new method to realize rational generalized transfer functions of linearshift-variant digital filters through state feedback is presented In some practical applications therequired characteristics of th...In this paper a new method to realize rational generalized transfer functions of linearshift-variant digital filters through state feedback is presented In some practical applications therequired characteristics of the filter change slowly.Under these circumstances,the proposedmethod is very effective and the resulting filter structure is simple.A numerical example isprovided to show the performance of the method.展开更多
目的观察咳喘镇定汤在小儿咳嗽变异性哮喘治疗中的作用及对患儿嗜酸性粒细胞计数(eosinophil count,EOS)、白介素-23(interleukin-23,IL-23)/辅助性T细胞17(helper T cells17,Th17)轴的影响。方法选取2020年8月—2023年2月收治的小儿咳...目的观察咳喘镇定汤在小儿咳嗽变异性哮喘治疗中的作用及对患儿嗜酸性粒细胞计数(eosinophil count,EOS)、白介素-23(interleukin-23,IL-23)/辅助性T细胞17(helper T cells17,Th17)轴的影响。方法选取2020年8月—2023年2月收治的小儿咳嗽变异性哮喘患儿104例,将患儿采用简单随机法分为两组。常规组给予止咳化痰、抗炎、平喘等常规治疗,咳喘镇定汤组在常规组基础上采用咳喘镇定汤辅助治疗。检测组间及组内T淋巴亚群、EOS、巨噬细胞炎症蛋白-1α(macrophage inflammatory protein-1α,MIP-1α)、Clara细胞分泌蛋白16(clara cell secreted protein 16,CC-16)、嗜酸细胞活化趋化因子(Eotaxin)、IL-23/Th17轴、小气道功能水平。评估组间及组内咳嗽症状评分、中医证候评分差异。统计组间疗效和不良反应。结果治疗前T淋巴亚群、CC-16、Eotaxin等差异无统计学意义(P>0.05)。两组治疗后CD_(8)^(+)、EOS、MIP-1α、Eotaxin降低,CC-16、CD_(4)^(+)、CD_(4)^(+)/CD_(8)^(+)升高,咳喘镇定汤组治疗后CD_(8)^(+)、EOS、MIP-1α、Eotaxin低于常规组,CC-16、CD_(4)^(+)、CD_(4)^(+)/CD_(8)^(+)高于常规组(P<0.05)。治疗前比较IL-23/Th17轴差异无统计学意义(P>0.05)。两组治疗后IL-23、Th17、白介素-17(interleukin-17,IL-17)降低,咳喘镇定汤组治疗后IL-23/Th17轴低于常规组(P<0.05)。治疗前相关评分无差异(P>0.05)。两组治疗后咳嗽症状评分、中医证候评分降低,咳喘镇定汤组治疗后咳嗽症状评分、中医症候评分低于常规组(P<0.05)。治疗前小气道功能无差异(P>0.05)。两组治疗后小气道功能升高,咳喘镇定汤组治疗后小气道功能高于常规组(P<0.05)。咳喘镇定汤组治愈13例,显效和有效共35例,总有效率92.31%高于常规组,差异有统计学意义(P<0.05)。结论咳喘镇定汤可通过调控小儿咳嗽变异性哮喘患儿IL-23/Th17轴,改善T淋巴亚群和小气道功能,减轻咳嗽症状,提高疗效。展开更多
Anti-PD-1/PD-L1 immune checkpoint blockade(ICB)therapy has revolutionized clinical cancer treatment,while abnormal PD-L1 or HLA-l expression in patients can significantly impact the therapeutic efficacy.Somatic mutati...Anti-PD-1/PD-L1 immune checkpoint blockade(ICB)therapy has revolutionized clinical cancer treatment,while abnormal PD-L1 or HLA-l expression in patients can significantly impact the therapeutic efficacy.Somatic mutations in cancer cells that modulate these critical regulators are closely associated with tumor progression and ICB response.However,a systematic interpretation of cancer immune-related mutations is stll lacking.Here,we harnessed the ABEmax system to establish a large-scale sgRNA library encompassing approximately 820,000 sgRNAs that target all feasible serine/threonine/tyrosine residues across the human genome,which systematically unveiled thousands of novel mutations that decrease or augment PD-L1 or HLA-I expression.Beyond residues associated with phosphorylation events,our screens also identified functional mutations that affect mRNA or protein stability,DNA binding capacity,protein-protein interactions,and enzymatic catalytic activity,leading to either gene inactivation or activation.Notably,we uncovered certain mutations that concurrently modulate PD-L1 and HLA-I expression,represented by the clinically relevant mutation SETD2_Y1666.We demonstrated that this mutation induces consistent phenotypic effects across multiple cancer cell lines and enhances the efficacy of immunotherapy in different tumor models.Our findings provide an unprecedented resource of functional residues that regulate cancer immunosurveillance,offering valuable guidance for clinical diagnosis,ICB therapy,and the development of innovative drugs for cancer treatment.展开更多
基金the National Natural Science Foundation of China,GrantNos.82100321 and 82370353.
文摘Congenital heart disease(CHD)is the mnost comman birth defect,with 34%of cases attrib utedto genetic variants.NOTCH1,a multi-domain transmembrane protein,regulates heart developmert bycontrolling the differantiation and migration of myocardial mesoderm cells,and different variants are presentin differnt types of CHD.In this review,we aim to provide a detailed description of NOTCH1 structuraldomains and their functions,highlighting NOTCH1 variants in CHD and the molecular mechanisms throughwhich they contribute to CHD occurrence,NOTCH1 has two main domains,the NOTCH extracellulardomain(NBCD)and the NOTCH intracellular domain(NICD).NECD facilitates ligand binding and NICDformation,while the NICD functions as a transcrip tion factor,forming complexes with co-factors in thenucleus to initiate gene transcription.Amnong the NOTCH1 variants associated with CHD occurrence,most are loss-of-function variants.Moreover,most of the variants are located in theEGF-like domain.Themolecular mechanism behind the NOTCH1 variant-associated CHD occurrence appears to be either due to aloss-of-function or missense variant.In the loss-of-function mutations,NOTCH1 haploinsufficiency is notedand directly reduces theNICD production,causing CHD ocaurrence.In the less common case of missensevariant,only a mild NOTCH1 malfuncticn is observed,but insufficient to directly lead to CHD occurrence.However,when a missense variant is combined with a risk factor,such as exposure to an environmentaltoxin,the cumulative effect can lead to CHD.Understanding the genetic and molecular mechanisms linkingNOTCH1 variants to CHD is crucial for improving clinical management and patient quality of life.
基金Supported by National Natural Science Foundation of China(11071075, 11171113)National Natural Science Foundation of China-subsidized by CAS Knowledge Innovation Project (30921064,90820307)+1 种基金Shang Natural Science Foundation(10ZR1409200)Division of Computational Science,E-institute of Shanghai Jiaotong University(E03004)
文摘A class of singularly perturbed semi-linear boundary value problems with discontinuous functions is examined in this article. Using the boundary layer function method, the asymptotic solution of such a problem is given and shown to be uniformly effective. The existence and uniqueness of the solution for the system is also proved. Numerical result is presented as an illustration to the theoretical result.
基金supported by the National Natural Science Foundation of China(32341051)the grant from Department of Agriculture and Rural Affairs of Hubei Province(HBZY2023B006-02)+2 种基金the National Funding(2023ZD04050)the National Natural Science Foundation of China Outstanding Youth(32125035)the National Key R&D Young Scientists Project(2022YFD1302000).
文摘Understanding genetic variant functionality is essential for advancing animal genomics and precision breeding.However,the lack of comprehensive functional genomic annotations in animals limits the effectiveness of most variant function assessment methods.In this study,we gather 1030 raw epigenomic datasets from 10 animal species and systematically annotate 7 types of key regulatory regions,creating a comprehensive functional annotation map of animal genomic variants.Our findings demonstrate that integrating variants with regulatory annotations can identify tissues and cell types underlying economic traits,underscoring the utility of these annotations in functional variant discovery.Using our functional annotations,we rank the functional potential of genetic variants and classify over 127 million candidate variants into 5 functional confidence categories,with high-confidence variants significantly enriched in eQTLs and trait-associated SNPs.Incorporating these variants into genomic prediction models can improve estimated breeding value accuracy,demonstrating their practical utility in breeding programs.To facilitate the use of our results,we develop the Integrated Functional Mutation(IFmut:http://www.ifmutants.com:8212)platform,enabling researchers to explore regulatory annotations and assess the functional potential of animal variants efficiently.Our study provides a robust framework for functional genomic annotations in farm animals,enhancing variant function assessment and breeding precision.
基金supported by grants from the National Major Science and Technology Special Project for Infectious Diseases of China (No.2008ZX10002-011)National High Technology Research and Development of China (Program 863) (No.2006AA02Z128)the National Natural Science Foundation of China (Nos.30700701,30571646)
文摘To better understand the effect of a new split variant of human asialoglycoprotein receptor (ASGPR H1b) on ASGPR ligands’ binding ability, we established a functional cell line which expresses ASGPR.The full lengths of ASGPRH1a and H2c fragments from human liver were amplified by reverse transcript PCR (RT-PCR) and inserted into eukaryotic expression vector pIRES2EFP, pCDNA3.1 (Zeo+) respectively.The recombinants were cotransfected into HeLa cells.After selection by using Neocin and Zeocin, a stably transfected cell line was established, which was designated 4-1-6.The transcription and expression of ASGPRH1a and H2c in 4-1-6 were confirmed by RT-PCR, Western blotting and immunofluorescence.The endocytosis function of the artificial "ASGPR" on the surface of 4-1-6 was tested by FACS.It was found that the cell line 4-1-6 could bind ASGPR natural ligand molecular asialo-orosomucoid (ASOR).After the eukaryotic plasmid H1b/pCDNA3.1 (neo) was transfected into cell line 4-1-6, H1b did not down-regulate the ligand binding ability of ASGPR.The eukaryotic expression plasmid H1b/pcDNA3.1 (neo) and H2c/pcDNA3.1 (neo) were co-transfected transiently into Hela cell.Neither single H1b nor H1b and H2c could bind ASOR.In conclusion, a functional cell line of human asialoglycoprotein receptor (ASGPR) which expresses both H1a and H2c stably was established.The new split variant H1b has no effect on ASGPR binding to ASOR.ASGPRH1b alone can’t bind to ASOR, it yet can’t form functional complex with ASGPRH2c.
文摘In this paper a new method to realize rational generalized transfer functions of linearshift-variant digital filters through state feedback is presented In some practical applications therequired characteristics of the filter change slowly.Under these circumstances,the proposedmethod is very effective and the resulting filter structure is simple.A numerical example isprovided to show the performance of the method.
文摘目的观察咳喘镇定汤在小儿咳嗽变异性哮喘治疗中的作用及对患儿嗜酸性粒细胞计数(eosinophil count,EOS)、白介素-23(interleukin-23,IL-23)/辅助性T细胞17(helper T cells17,Th17)轴的影响。方法选取2020年8月—2023年2月收治的小儿咳嗽变异性哮喘患儿104例,将患儿采用简单随机法分为两组。常规组给予止咳化痰、抗炎、平喘等常规治疗,咳喘镇定汤组在常规组基础上采用咳喘镇定汤辅助治疗。检测组间及组内T淋巴亚群、EOS、巨噬细胞炎症蛋白-1α(macrophage inflammatory protein-1α,MIP-1α)、Clara细胞分泌蛋白16(clara cell secreted protein 16,CC-16)、嗜酸细胞活化趋化因子(Eotaxin)、IL-23/Th17轴、小气道功能水平。评估组间及组内咳嗽症状评分、中医证候评分差异。统计组间疗效和不良反应。结果治疗前T淋巴亚群、CC-16、Eotaxin等差异无统计学意义(P>0.05)。两组治疗后CD_(8)^(+)、EOS、MIP-1α、Eotaxin降低,CC-16、CD_(4)^(+)、CD_(4)^(+)/CD_(8)^(+)升高,咳喘镇定汤组治疗后CD_(8)^(+)、EOS、MIP-1α、Eotaxin低于常规组,CC-16、CD_(4)^(+)、CD_(4)^(+)/CD_(8)^(+)高于常规组(P<0.05)。治疗前比较IL-23/Th17轴差异无统计学意义(P>0.05)。两组治疗后IL-23、Th17、白介素-17(interleukin-17,IL-17)降低,咳喘镇定汤组治疗后IL-23/Th17轴低于常规组(P<0.05)。治疗前相关评分无差异(P>0.05)。两组治疗后咳嗽症状评分、中医证候评分降低,咳喘镇定汤组治疗后咳嗽症状评分、中医症候评分低于常规组(P<0.05)。治疗前小气道功能无差异(P>0.05)。两组治疗后小气道功能升高,咳喘镇定汤组治疗后小气道功能高于常规组(P<0.05)。咳喘镇定汤组治愈13例,显效和有效共35例,总有效率92.31%高于常规组,差异有统计学意义(P<0.05)。结论咳喘镇定汤可通过调控小儿咳嗽变异性哮喘患儿IL-23/Th17轴,改善T淋巴亚群和小气道功能,减轻咳嗽症状,提高疗效。
基金supported by funds from Changping Laboratory,the National Natural Science Foundation of China(NSFC 31930016)Beijing Advanced Innovation Center for Genomics at Peking University,and the Peking-Tsinghua Center for Life Sciences(to W.W.)+2 种基金Additional support was provided by the China Postdoctoral Science Foundation(2020M670031,to Y.L2020M670053,to Y-S.L.)the Taishan Scholarship(tsqn202312362,to Y-S.L.).
文摘Anti-PD-1/PD-L1 immune checkpoint blockade(ICB)therapy has revolutionized clinical cancer treatment,while abnormal PD-L1 or HLA-l expression in patients can significantly impact the therapeutic efficacy.Somatic mutations in cancer cells that modulate these critical regulators are closely associated with tumor progression and ICB response.However,a systematic interpretation of cancer immune-related mutations is stll lacking.Here,we harnessed the ABEmax system to establish a large-scale sgRNA library encompassing approximately 820,000 sgRNAs that target all feasible serine/threonine/tyrosine residues across the human genome,which systematically unveiled thousands of novel mutations that decrease or augment PD-L1 or HLA-I expression.Beyond residues associated with phosphorylation events,our screens also identified functional mutations that affect mRNA or protein stability,DNA binding capacity,protein-protein interactions,and enzymatic catalytic activity,leading to either gene inactivation or activation.Notably,we uncovered certain mutations that concurrently modulate PD-L1 and HLA-I expression,represented by the clinically relevant mutation SETD2_Y1666.We demonstrated that this mutation induces consistent phenotypic effects across multiple cancer cell lines and enhances the efficacy of immunotherapy in different tumor models.Our findings provide an unprecedented resource of functional residues that regulate cancer immunosurveillance,offering valuable guidance for clinical diagnosis,ICB therapy,and the development of innovative drugs for cancer treatment.
