Objective The leptin receptor,encoded by the LEPR gene,is involved in tumorigenesis.A potential functional variant of LEPR,rs1137101(Gln223Arg),has been extensively investigated for its contribution to the risk of dig...Objective The leptin receptor,encoded by the LEPR gene,is involved in tumorigenesis.A potential functional variant of LEPR,rs1137101(Gln223Arg),has been extensively investigated for its contribution to the risk of digestive system(DS)cancers,but results remain conflicting rather than conclusive.Here,we performed a case–control study and subsequent meta-analysis to examine the association between rs1137101 and DS cancer risk.Methods A total of 1,727 patients with cancer(gastric/liver/colorectal:460/480/787)and 800 healthy controls were recruited.Genotyping of rs1137101 was conducted using a polymerase chain reactionrestriction fragment length polymorphism(PCR-RFLP)assay and confirmed using Sanger sequencing.Twenty-four eligible studies were included in the meta-analysis.Results After Bonferroni correction,the case–control study revealed that rs1137101 was significantly associated with the risk of liver cancer in the Hubei Chinese population.The meta-analysis suggested that rs1137101 is significantly associated with the risk of overall DS,gastric,and liver cancer in the Chinese population.Conclusion The LEPR rs1137101 variant may be a genetic biomarker for susceptibility to DS cancers(especially liver and gastric cancer)in the Chinese population.展开更多
Duchenne muscular dystrophy(DMD)and Becker muscular dystrophy(BMD)are caused by mutations in the DMD gene.The aim of this study is to identify pathogenic DMD variants in probands and reduce the risk of recurrence of t...Duchenne muscular dystrophy(DMD)and Becker muscular dystrophy(BMD)are caused by mutations in the DMD gene.The aim of this study is to identify pathogenic DMD variants in probands and reduce the risk of recurrence of the disease in affected families.Variations in 100 unrelated DMD/BMD patients were detected by multiplex ligation-dependent probe amplification(MLPA)and next-generation sequencing(NGS).Pathogenic variants in DMD were successfully identified in all cases,and 11 of them were novel.The most common mutations were intragenic deletions(69%),with two hotspots located in the 5'end(exons 2–19)and the central of the DMD gene(exons 45–55),while point mutations were observed in 22%patients.Further,c.1149+1G>A and c.1150?2A>G were confirmed by hybrid minigene splicing assay(HMSA).This two splice site mutations would lead to two aberrant DMD isoforms which give rise to severely truncated protein.Therefore,the clinical use of MLPA,NGS,and HMSA is an effective strategy to identify variants.Importantly,eight embryos were terminated pregnancies according to prenatal diagnosis and a healthy boy was successfully delivered by preimplantation genetic diagnosis(PGD).Early and accurate genetic diagnosis is essential for prenatal diagnosis/PGD to reduce the risk of recurrence of DMD in affected families.展开更多
The Naxi of Northwest Yunnan,China use medicinal plants to treat skin conditions related to traditional lifestyles in extreme environments.However,modernization endangers both the medicinal plants used to treat skin c...The Naxi of Northwest Yunnan,China use medicinal plants to treat skin conditions related to traditional lifestyles in extreme environments.However,modernization endangers both the medicinal plants used to treat skin conditions and traditional knowledge.Therefore,investigation and documentation of the medicinal plants used and associated traditional knowledge is necessary.In this study,we conducted an ethnobotanical survey in 12 Naxi communities in Northwest Yunnan.For this purpose,we used semistructured surveys to interview 840 informants from Naxi communities.We used informant consensus factor and use frequency as quantitative indices to evaluate the importance of medicinal plant species.A total of 161 medicinal plant species belonging to 69 families were documented.The highest informant consensus factor(ICF)values were recorded for skin nourishing(ICF?0.849),frostbite and chapped skin(ICF?0.833).These skin treatments are highly related to the environment and lifestyle of Naxi communities.The main active compounds of plants used to treat skin conditions in Naxi communities are known to have skin-treating properties.This study reveals that the skin conditions treated by the Naxi are associated with traditional medicine culture and social economic development.In addition,this study uses ethnobotanical indices to explain how skin condition treatments are linked to the natural environment of Naxi communities.展开更多
Objective: To study the correlation of body mass index with Th1/Th2 balance, adhesion molecules and insulin signal transduction in infertile patients. Methods: A total of 132 patients who received diagnostic curettage...Objective: To study the correlation of body mass index with Th1/Th2 balance, adhesion molecules and insulin signal transduction in infertile patients. Methods: A total of 132 patients who received diagnostic curettage due to infertility in Tangshan Maternal and Child Health Hospital between June 2015 and March 2016 were selected as the research subjects and divided into the normal group with BMI<25 kg/m2, the overweight group with BMI 25-30 kg/m2 and the obesity group with BMI > 30 kg/m2 according to BMI, and the levels of Th1/Th2 cytokines in serum as well as the expression of Th1/Th2 transcription factors, adhesion molecules and insulin signal pathway molecules in endometrial tissue were detected. Results:IFN-γ and TNF-α levels in serum of obesity group and overweight group were significantly higher than those of control group while IL-4, IL-5 and IL-13 levels in serum as well as CD44V6, N-cadherin, FAK, ICAM-1, GLUT-4, IRS-1, PI3K and AKT mRNA expression in endometrial tissue were significantly lower than those of control group;IFN-γ and TNF-α levels in serum of obesity group were significantly higher than those of overweight group while IL-4, IL-5 and IL-13 levels in serum as well as CD44V6, N-cadherin, FAK, ICAM-1, GLUT-4, IRS-1, PI3K and AKT mRNA expression in endometrial tissue were significantly lower than those of overweight group. Conclusion: Weight gain can aggravate the Th1/Th2 disorder, reduce the adhesion molecule expression and hinder the insulin signal transduction in infertile patients.展开更多
Background:Spinocerebellar ataxia type 2(SCA2)is a neurodegenerative disease marked by significant clinical and genetic heterogeneity,primarily caused by expanded CAG mutations in the ATXN2 gene.The unstable expansion...Background:Spinocerebellar ataxia type 2(SCA2)is a neurodegenerative disease marked by significant clinical and genetic heterogeneity,primarily caused by expanded CAG mutations in the ATXN2 gene.The unstable expansion of CAG repeats disrupts the genetic stability of animal models,which is detrimental to disease research.Methods:In this study,we established a mouse model in which CAG repeats do not undergo microsatellite instability(MSI)across generations.A humanized ATXN2 cDNA with four CAA interruptions within 73 CAG expansions was inserted into the Rosa26 locus of C57BL/6J mice.A 23 CAG control mouse model was also generated to verify ATXN2 integration and expression.Results:In our model,the number of CAG repeats remained stable during transmission,with no CAG repeat expansion observed in 64 parent-to-offspring transmissions.Compared with SCA2-Q23 mice,SCA2-Q73 mice exhibited progressive motor impairment,reduced Purkinje cell count and volume(indicative of cell atrophy),and muscle atrophy.These observations in the mice suggest that the behavioral and neuropathological phenotypes may reflect the features of SCA2 patients.RNA-seq analysis of the gastrocnemius muscle in SCA2-Q73 mice showed significant changes in muscle differentiation and development gene expression at 56 weeks,with no significant differences at 16 weeks compared to SCA2-Q23 mice.The expression level of the Myf6 gene significantly changed in the muscles of aged mice.Conclusion:In summary,the establishment of this model not only provides a stable animal model for studying CAG transmission in SCA2 but also indicates that the lack of long-term neural stimulation leads to muscle atrophy.展开更多
To the Editor:Varicocele(VC)is a vascular disease and considered as the main cause of male infertility.^([1])The incidence of VC in the common male population was 4.4–22.6%,of which the incidence of primary infertili...To the Editor:Varicocele(VC)is a vascular disease and considered as the main cause of male infertility.^([1])The incidence of VC in the common male population was 4.4–22.6%,of which the incidence of primary infertility was 35–40%,while the incidence of secondary infertility was as high as 80%.^([2])The exact pathophysiological mechanism of male infertility caused by VC and regulative molecules are still unclear.Clear and definite molecular markers of VC disease are helpful for early prevention and timely treatment.This study aimed to screen candidate regulative molecules playing a role in male infertility caused by VC.展开更多
Genetically modified pigs are valuable models of human disease and donors of xenotransplanted organs.Conventional gene targeting in pig somatic cells is extremely inefficient.Zinc-finger nuclease(ZFN)technology has be...Genetically modified pigs are valuable models of human disease and donors of xenotransplanted organs.Conventional gene targeting in pig somatic cells is extremely inefficient.Zinc-finger nuclease(ZFN)technology has been shown to be a powerful tool for efficiently inducing mutations in the genome.However,ZFN-mediated targeting in pigs has rarely been achieved.Here,we used ZFNs to knock out the porcineα-1,3-galactosyl-transferase(GGTA1)gene,which generates Gal epitopes that trigger hyperacute immune rejection in pig-to-human transplantation.Primary pig fibroblasts were transfected with ZFNs targeting the coding region of GGTA1.Eighteen mono-allelic and four biallelic knockout cell clones were obtained after drug selection with efficiencies of 23.4%and 5.2%,respectively.The biallelic cells were used to produce cloned pigs via somatic cell nuclear transfer(SCNT).Three GGTA1 null piglets were born,and one knockout primary fibroblast cell line was established from a cloned fetus.Gal epitopes on GGTA1 null pig cells were completely eliminated from the cell membrane.Functionally,GGTA1 knockout cells were protected from complement-mediated immune attacks when incubated with human serum.This study demonstrated that ZFN is an efficient tool in creating gene-modified pigs.GGTA1 null pigs and GGTA1 null fetal fibroblasts would benefit research and pig-to-human transplantation.展开更多
Background Lysosomes digest extracellular material from the endocytic pathway and intracellular material from the autophagic pathway.This process is performed by the resident hydrolytic enzymes activated by the highly...Background Lysosomes digest extracellular material from the endocytic pathway and intracellular material from the autophagic pathway.This process is performed by the resident hydrolytic enzymes activated by the highly acidic pH within the lysosomal lumen.Lysosome pH gradients are mainly maintained by the vacuolar(H+)ATPase(or V-ATPase),which pumps protons into lysosomal lumen by consuming ATP.Dysfunction of V-ATPase affects lysosomal acidification,which disrupts the clearance of substrates and leads to many disorders,including neurodegenerative diseases.Main body As a large multi-subunit complex,the V-ATPase is composed of an integral membrane V0 domain involved in proton translocation and a peripheral V1 domain catalyzing ATP hydrolysis.The canonical functions of V-ATPase rely on its H+-pumping ability in multiple vesicle organelles to regulate endocytic traffic,protein processing and degradation,synaptic vesicle loading,and coupled transport.The other non-canonical effects of the V-ATPase that are not readily attributable to its proton-pumping activity include membrane fusion,pH sensing,amino-acid-induced activation of mTORC1,and scaffolding for protein-protein interaction.In response to various stimuli,V-ATPase complex can reversibly dissociate into V1 and V0 domains and thus close ATP-dependent proton transport.Dysregulation of pH and lysosomal dysfunction have been linked to many human diseases,including neurodegenerative disorders such as Alzheimer disease,Parkinson’s disease,amyotrophic lateral sclerosis as well as neurodegenerative lysosomal storage disorders.Conclusion V-ATPase complex is a universal proton pump and plays an important role in lysosome acidification in all types of cells.Since V-ATPase dysfunction contributes to the pathogenesis of multiple neurodegenerative diseases,further understanding the mechanisms that regulate the canonical and non-canonical functions of V-ATPase will reveal molecular details of disease process and help assess V-ATPase or molecules related to its regulation as therapeutic targets.展开更多
The major mechanism for ring chromosome formation is thought to result from breakage and reunion at the breakpoints on the long and short arms of a chromosome.This fusion event can produce terminal arm inversions,dele...The major mechanism for ring chromosome formation is thought to result from breakage and reunion at the breakpoints on the long and short arms of a chromosome.This fusion event can produce terminal arm inversions,deletions,and duplications that determine the resulting phenotype.[1] Ring chromosome 13 is relatively uncommon,with an estimated incidence of 1/58,000 live births.展开更多
基金supported by the Fundamental Research Funds for the Central Universities(WUT:2020IB029)。
文摘Objective The leptin receptor,encoded by the LEPR gene,is involved in tumorigenesis.A potential functional variant of LEPR,rs1137101(Gln223Arg),has been extensively investigated for its contribution to the risk of digestive system(DS)cancers,but results remain conflicting rather than conclusive.Here,we performed a case–control study and subsequent meta-analysis to examine the association between rs1137101 and DS cancer risk.Methods A total of 1,727 patients with cancer(gastric/liver/colorectal:460/480/787)and 800 healthy controls were recruited.Genotyping of rs1137101 was conducted using a polymerase chain reactionrestriction fragment length polymorphism(PCR-RFLP)assay and confirmed using Sanger sequencing.Twenty-four eligible studies were included in the meta-analysis.Results After Bonferroni correction,the case–control study revealed that rs1137101 was significantly associated with the risk of liver cancer in the Hubei Chinese population.The meta-analysis suggested that rs1137101 is significantly associated with the risk of overall DS,gastric,and liver cancer in the Chinese population.Conclusion The LEPR rs1137101 variant may be a genetic biomarker for susceptibility to DS cancers(especially liver and gastric cancer)in the Chinese population.
基金the National Key Research and Development Program of China(No.2016YFC1000703)the Medicine and Health Science and Technology Plan Projects in Zhejiang Province(No.2014KYA246)the National Natural Science Foundation of China(Nos.81801441 and 81300532)
文摘Duchenne muscular dystrophy(DMD)and Becker muscular dystrophy(BMD)are caused by mutations in the DMD gene.The aim of this study is to identify pathogenic DMD variants in probands and reduce the risk of recurrence of the disease in affected families.Variations in 100 unrelated DMD/BMD patients were detected by multiplex ligation-dependent probe amplification(MLPA)and next-generation sequencing(NGS).Pathogenic variants in DMD were successfully identified in all cases,and 11 of them were novel.The most common mutations were intragenic deletions(69%),with two hotspots located in the 5'end(exons 2–19)and the central of the DMD gene(exons 45–55),while point mutations were observed in 22%patients.Further,c.1149+1G>A and c.1150?2A>G were confirmed by hybrid minigene splicing assay(HMSA).This two splice site mutations would lead to two aberrant DMD isoforms which give rise to severely truncated protein.Therefore,the clinical use of MLPA,NGS,and HMSA is an effective strategy to identify variants.Importantly,eight embryos were terminated pregnancies according to prenatal diagnosis and a healthy boy was successfully delivered by preimplantation genetic diagnosis(PGD).Early and accurate genetic diagnosis is essential for prenatal diagnosis/PGD to reduce the risk of recurrence of DMD in affected families.
基金This study was funded by Natural Science Foundation of China(No.31670340 and No.31970357)Bio-Innovation Center of DR PLANT,Kunming Institute of Botany,Chinese Academy of Sciences.
文摘The Naxi of Northwest Yunnan,China use medicinal plants to treat skin conditions related to traditional lifestyles in extreme environments.However,modernization endangers both the medicinal plants used to treat skin conditions and traditional knowledge.Therefore,investigation and documentation of the medicinal plants used and associated traditional knowledge is necessary.In this study,we conducted an ethnobotanical survey in 12 Naxi communities in Northwest Yunnan.For this purpose,we used semistructured surveys to interview 840 informants from Naxi communities.We used informant consensus factor and use frequency as quantitative indices to evaluate the importance of medicinal plant species.A total of 161 medicinal plant species belonging to 69 families were documented.The highest informant consensus factor(ICF)values were recorded for skin nourishing(ICF?0.849),frostbite and chapped skin(ICF?0.833).These skin treatments are highly related to the environment and lifestyle of Naxi communities.The main active compounds of plants used to treat skin conditions in Naxi communities are known to have skin-treating properties.This study reveals that the skin conditions treated by the Naxi are associated with traditional medicine culture and social economic development.In addition,this study uses ethnobotanical indices to explain how skin condition treatments are linked to the natural environment of Naxi communities.
文摘Objective: To study the correlation of body mass index with Th1/Th2 balance, adhesion molecules and insulin signal transduction in infertile patients. Methods: A total of 132 patients who received diagnostic curettage due to infertility in Tangshan Maternal and Child Health Hospital between June 2015 and March 2016 were selected as the research subjects and divided into the normal group with BMI<25 kg/m2, the overweight group with BMI 25-30 kg/m2 and the obesity group with BMI > 30 kg/m2 according to BMI, and the levels of Th1/Th2 cytokines in serum as well as the expression of Th1/Th2 transcription factors, adhesion molecules and insulin signal pathway molecules in endometrial tissue were detected. Results:IFN-γ and TNF-α levels in serum of obesity group and overweight group were significantly higher than those of control group while IL-4, IL-5 and IL-13 levels in serum as well as CD44V6, N-cadherin, FAK, ICAM-1, GLUT-4, IRS-1, PI3K and AKT mRNA expression in endometrial tissue were significantly lower than those of control group;IFN-γ and TNF-α levels in serum of obesity group were significantly higher than those of overweight group while IL-4, IL-5 and IL-13 levels in serum as well as CD44V6, N-cadherin, FAK, ICAM-1, GLUT-4, IRS-1, PI3K and AKT mRNA expression in endometrial tissue were significantly lower than those of overweight group. Conclusion: Weight gain can aggravate the Th1/Th2 disorder, reduce the adhesion molecule expression and hinder the insulin signal transduction in infertile patients.
基金CAMS Innovation Fund for Medical Sciences,Grant/Award Number:CIFMS,2021-I2M-1-024The Joint Fund for the Department of Science and Technology of Yunnan Province-Kunming Medical University,Grant/Award Number:202201AY070001-007+1 种基金Open Research Fund Project of Yunnan Provincial Key Laboratory of Pharmacology of Natural Medicines,Grant/Award Number:YKLPNP-G2403The Science and Technology Leading Talent Program of Yunnan Province,Grant/Award Number:202405AB350002。
文摘Background:Spinocerebellar ataxia type 2(SCA2)is a neurodegenerative disease marked by significant clinical and genetic heterogeneity,primarily caused by expanded CAG mutations in the ATXN2 gene.The unstable expansion of CAG repeats disrupts the genetic stability of animal models,which is detrimental to disease research.Methods:In this study,we established a mouse model in which CAG repeats do not undergo microsatellite instability(MSI)across generations.A humanized ATXN2 cDNA with four CAA interruptions within 73 CAG expansions was inserted into the Rosa26 locus of C57BL/6J mice.A 23 CAG control mouse model was also generated to verify ATXN2 integration and expression.Results:In our model,the number of CAG repeats remained stable during transmission,with no CAG repeat expansion observed in 64 parent-to-offspring transmissions.Compared with SCA2-Q23 mice,SCA2-Q73 mice exhibited progressive motor impairment,reduced Purkinje cell count and volume(indicative of cell atrophy),and muscle atrophy.These observations in the mice suggest that the behavioral and neuropathological phenotypes may reflect the features of SCA2 patients.RNA-seq analysis of the gastrocnemius muscle in SCA2-Q73 mice showed significant changes in muscle differentiation and development gene expression at 56 weeks,with no significant differences at 16 weeks compared to SCA2-Q23 mice.The expression level of the Myf6 gene significantly changed in the muscles of aged mice.Conclusion:In summary,the establishment of this model not only provides a stable animal model for studying CAG transmission in SCA2 but also indicates that the lack of long-term neural stimulation leads to muscle atrophy.
基金supported by grants from the National Natural Science Foundation of China(Nos.81401192 and 81973864)Fundamental Research Program of Shanxi Province(No.20210302123348)Four"Batches"Innovation Project of Invigorating Medical through Science and Technology of Shanxi Province(No.2022XM25)
文摘To the Editor:Varicocele(VC)is a vascular disease and considered as the main cause of male infertility.^([1])The incidence of VC in the common male population was 4.4–22.6%,of which the incidence of primary infertility was 35–40%,while the incidence of secondary infertility was as high as 80%.^([2])The exact pathophysiological mechanism of male infertility caused by VC and regulative molecules are still unclear.Clear and definite molecular markers of VC disease are helpful for early prevention and timely treatment.This study aimed to screen candidate regulative molecules playing a role in male infertility caused by VC.
基金supported by grants from Ministry of Science and Technology of China(2011CBA01001,2012AA020503)the National Science Fund for Distinguished Young Scholars(31025016)+4 种基金the National Natural Science Foundation of China(31271577)Novel Agricultural Variety Breeding Project of Zhejiang Province(2012C12906-8)the Fundamental Research Funds for the Central Universitiesthe Key Construction Pro-gram of the National"985"Project(118000+193411801/006)the Research Fund for the Doctoral Program of Higher Education of China(20120101110089)
文摘Genetically modified pigs are valuable models of human disease and donors of xenotransplanted organs.Conventional gene targeting in pig somatic cells is extremely inefficient.Zinc-finger nuclease(ZFN)technology has been shown to be a powerful tool for efficiently inducing mutations in the genome.However,ZFN-mediated targeting in pigs has rarely been achieved.Here,we used ZFNs to knock out the porcineα-1,3-galactosyl-transferase(GGTA1)gene,which generates Gal epitopes that trigger hyperacute immune rejection in pig-to-human transplantation.Primary pig fibroblasts were transfected with ZFNs targeting the coding region of GGTA1.Eighteen mono-allelic and four biallelic knockout cell clones were obtained after drug selection with efficiencies of 23.4%and 5.2%,respectively.The biallelic cells were used to produce cloned pigs via somatic cell nuclear transfer(SCNT).Three GGTA1 null piglets were born,and one knockout primary fibroblast cell line was established from a cloned fetus.Gal epitopes on GGTA1 null pig cells were completely eliminated from the cell membrane.Functionally,GGTA1 knockout cells were protected from complement-mediated immune attacks when incubated with human serum.This study demonstrated that ZFN is an efficient tool in creating gene-modified pigs.GGTA1 null pigs and GGTA1 null fetal fibroblasts would benefit research and pig-to-human transplantation.
基金This work was supported in part by grants R01NS107505 and R01NS095269 to Z.M.
文摘Background Lysosomes digest extracellular material from the endocytic pathway and intracellular material from the autophagic pathway.This process is performed by the resident hydrolytic enzymes activated by the highly acidic pH within the lysosomal lumen.Lysosome pH gradients are mainly maintained by the vacuolar(H+)ATPase(or V-ATPase),which pumps protons into lysosomal lumen by consuming ATP.Dysfunction of V-ATPase affects lysosomal acidification,which disrupts the clearance of substrates and leads to many disorders,including neurodegenerative diseases.Main body As a large multi-subunit complex,the V-ATPase is composed of an integral membrane V0 domain involved in proton translocation and a peripheral V1 domain catalyzing ATP hydrolysis.The canonical functions of V-ATPase rely on its H+-pumping ability in multiple vesicle organelles to regulate endocytic traffic,protein processing and degradation,synaptic vesicle loading,and coupled transport.The other non-canonical effects of the V-ATPase that are not readily attributable to its proton-pumping activity include membrane fusion,pH sensing,amino-acid-induced activation of mTORC1,and scaffolding for protein-protein interaction.In response to various stimuli,V-ATPase complex can reversibly dissociate into V1 and V0 domains and thus close ATP-dependent proton transport.Dysregulation of pH and lysosomal dysfunction have been linked to many human diseases,including neurodegenerative disorders such as Alzheimer disease,Parkinson’s disease,amyotrophic lateral sclerosis as well as neurodegenerative lysosomal storage disorders.Conclusion V-ATPase complex is a universal proton pump and plays an important role in lysosome acidification in all types of cells.Since V-ATPase dysfunction contributes to the pathogenesis of multiple neurodegenerative diseases,further understanding the mechanisms that regulate the canonical and non-canonical functions of V-ATPase will reveal molecular details of disease process and help assess V-ATPase or molecules related to its regulation as therapeutic targets.
文摘The major mechanism for ring chromosome formation is thought to result from breakage and reunion at the breakpoints on the long and short arms of a chromosome.This fusion event can produce terminal arm inversions,deletions,and duplications that determine the resulting phenotype.[1] Ring chromosome 13 is relatively uncommon,with an estimated incidence of 1/58,000 live births.
