天山北坡是中国农牧业发展基地,也是“一带一路”开发重点区域。气候变化和人类活动是影响天山北坡净初级生产力(Net Primary Productivity,NPP)的2个重要因素,定量评估气候变化和人类活动对天山北坡草场可持续性利用具有重要意义。该...天山北坡是中国农牧业发展基地,也是“一带一路”开发重点区域。气候变化和人类活动是影响天山北坡净初级生产力(Net Primary Productivity,NPP)的2个重要因素,定量评估气候变化和人类活动对天山北坡草场可持续性利用具有重要意义。该研究采用MODIS C6遥感数据、气象数据和野外实测数据,分析2004-2015年气候变化和人类活动对天山北坡NPP变化的影响。结果表明:2004-2015年天山北坡实际净初级生产力(Actual Net Primary Productivity,NPPA)介于128.67~170.49 g/(m^2·a)之间,总体呈现增加趋势;西部区域NPPA年均值最高,天山北坡NPPA的主要供给区是中西部区域。天山北坡不同区域年均温度及降水量呈现明显差异,降水对NPPA的影响大于温度。同时,人类活动对NPP的影响(Human Activities on Net Primary Productivity,NPPH),总体上由负作用逐渐向正作用转变,正作用增强区域主要分布在奇台县、木垒县和天山北坡东部部分地区,负作用逐渐增强区域主要分布在奎屯市及乌苏市部分地区。展开更多
目的·筛查青少年的成人起病型糖尿病(maturity-onset diabetes of the young,MODY)家系中NEUROD1基因突变,分析突变与中国人MODY6发病的相关性及其潜在的致病机制。方法·采用PCR-直接测序法对96例GCK/MODY2、HNF1A/MODY3、HNF...目的·筛查青少年的成人起病型糖尿病(maturity-onset diabetes of the young,MODY)家系中NEUROD1基因突变,分析突变与中国人MODY6发病的相关性及其潜在的致病机制。方法·采用PCR-直接测序法对96例GCK/MODY2、HNF1A/MODY3、HNF1B/MODY5突变阴性的中国MODY先证者进行NEUROD1突变筛查,同时比较96例MODY先证者与100例非糖尿病对照者NEUROD1基因变异的基因型频率。采用从头建模法构建NEUROD1蛋白野生型和突变体的3D结构,采用双荧光素酶报告基因系统检测野生型和突变体蛋白对胰岛素基因转录活性的影响。结果·在一个MODY家系中发现NEUROD1基因杂合错义突变Glu59Gln (NM_002500.5,c.175G>C)。3D结构分析发现,该突变将野生型中带负电荷的Glu59转化为突变中不带电荷的Gln59,导致两个盐桥键Glu59-Arg54和Glu59-Lys88缺失,并形成一个新的氢键Gln59-Arg54。与野生型相比,Glu59Gln突变体的胰岛素基因转录活性下降36.3%(P<0.05)。与非糖尿病对照相比,96例MODY先证者中Ala45Thr (G-A)变异的AA+GA基因型频率显著升高(P=0.002)。结论·Glu59Gln突变改变了NEUROD1蛋白N端的分子构象,导致其胰岛素基因转录活性显著下降,是该家系突变携带者胰岛素分泌缺陷的原因。Ala45Thr变异与MODY6先证者糖尿病发病年龄的提前有关。展开更多
Objective::In contrast to the most commonly reported forms of maturity-onset diabetes of the young(MODY),including MODY2,MODY3 and MODY5,MODY6 is a relatively rare subtype.To investigate whether NEUROD1 is responsible...Objective::In contrast to the most commonly reported forms of maturity-onset diabetes of the young(MODY),including MODY2,MODY3 and MODY5,MODY6 is a relatively rare subtype.To investigate whether NEUROD1 is responsible for MODY in Chinese individuals,we screened its mutations in MODY pedigrees and explored the potential pathogenic mechanisms.Methods::Polymerase chain reaction direct sequencing was performed to screen NEUROD1 mutations in 32 Chinese MODY probands who were negative for the GCK/MODY2,HNF1A/MODY3 and HNF1B/MODY5 genes in this observational study.In addition,we enrolled 201 unrelated,non-diabetic control subjects of Han Chinese descent.The functional significance of newly identified mutations was analyzed using clinical phenotype,pathophysiology and three-dimensional structure studies.This study was approved by the Institutional Review Board of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital,China(approval No.YS-2017-83)on March 3,2017.Results::E59Q(c.175 G>C,p.Glu59Gln),a heterozygous missense mutation in the NEUROD1 gene,was identified in one family with MODY.The Glu59 residue in NeuroD1 is highly conserved across mammalian species.Four diabetic patients carrying the mutation(a proband and her son,brother and sister)were lean,with a body mass index of 20.9(20.3-21.2)kg/m 2.Compared with their unaffected relatives(n=4),E59Q carriers(n=4)had significantly decreased ratios of fasting and 2-hour insulin to plasma glucose(both fasting plasma insulin/fasting plasma glucose and 2-hour postprandial plasma insulin/2-hour postprandial plasma glucose,P<0.005).The proband’s father had an E59Q mutation and normal glucose tolerance,which suggested non-penetrance.The E59Q mutation was not detected in other probands or in the 201 control subjects with normal glucose tolerance.Two salt-bridge bonds of Glu59 were disrupted at the Q59 mutation site.Conclusion::The NEUROD1-E59Q mutation changed the molecular conformation of the N-terminal in NeuroD1,which may decrease binding of the E59Q mutant to the insulin promoter and insulin gene transcription activity,therefore causing the MODY6 subtype with defective insulin secretion.展开更多
文摘天山北坡是中国农牧业发展基地,也是“一带一路”开发重点区域。气候变化和人类活动是影响天山北坡净初级生产力(Net Primary Productivity,NPP)的2个重要因素,定量评估气候变化和人类活动对天山北坡草场可持续性利用具有重要意义。该研究采用MODIS C6遥感数据、气象数据和野外实测数据,分析2004-2015年气候变化和人类活动对天山北坡NPP变化的影响。结果表明:2004-2015年天山北坡实际净初级生产力(Actual Net Primary Productivity,NPPA)介于128.67~170.49 g/(m^2·a)之间,总体呈现增加趋势;西部区域NPPA年均值最高,天山北坡NPPA的主要供给区是中西部区域。天山北坡不同区域年均温度及降水量呈现明显差异,降水对NPPA的影响大于温度。同时,人类活动对NPP的影响(Human Activities on Net Primary Productivity,NPPH),总体上由负作用逐渐向正作用转变,正作用增强区域主要分布在奇台县、木垒县和天山北坡东部部分地区,负作用逐渐增强区域主要分布在奎屯市及乌苏市部分地区。
文摘目的·筛查青少年的成人起病型糖尿病(maturity-onset diabetes of the young,MODY)家系中NEUROD1基因突变,分析突变与中国人MODY6发病的相关性及其潜在的致病机制。方法·采用PCR-直接测序法对96例GCK/MODY2、HNF1A/MODY3、HNF1B/MODY5突变阴性的中国MODY先证者进行NEUROD1突变筛查,同时比较96例MODY先证者与100例非糖尿病对照者NEUROD1基因变异的基因型频率。采用从头建模法构建NEUROD1蛋白野生型和突变体的3D结构,采用双荧光素酶报告基因系统检测野生型和突变体蛋白对胰岛素基因转录活性的影响。结果·在一个MODY家系中发现NEUROD1基因杂合错义突变Glu59Gln (NM_002500.5,c.175G>C)。3D结构分析发现,该突变将野生型中带负电荷的Glu59转化为突变中不带电荷的Gln59,导致两个盐桥键Glu59-Arg54和Glu59-Lys88缺失,并形成一个新的氢键Gln59-Arg54。与野生型相比,Glu59Gln突变体的胰岛素基因转录活性下降36.3%(P<0.05)。与非糖尿病对照相比,96例MODY先证者中Ala45Thr (G-A)变异的AA+GA基因型频率显著升高(P=0.002)。结论·Glu59Gln突变改变了NEUROD1蛋白N端的分子构象,导致其胰岛素基因转录活性显著下降,是该家系突变携带者胰岛素分泌缺陷的原因。Ala45Thr变异与MODY6先证者糖尿病发病年龄的提前有关。
基金supported by the National Natural Science Foundation of China(Nos.81970686,81770791,81471012,81270876,to LL)the Interdisciplinary Program of Shanghai Jiao Tong University,China(No.YG2019ZDA08,to LL)+1 种基金the Shanghai Leading Talent,China(No.SLJ15055,to LL)the National Institute of Diabetes and Digestive and Kidney Diseases(No.SC1DK104821,to YL)
文摘Objective::In contrast to the most commonly reported forms of maturity-onset diabetes of the young(MODY),including MODY2,MODY3 and MODY5,MODY6 is a relatively rare subtype.To investigate whether NEUROD1 is responsible for MODY in Chinese individuals,we screened its mutations in MODY pedigrees and explored the potential pathogenic mechanisms.Methods::Polymerase chain reaction direct sequencing was performed to screen NEUROD1 mutations in 32 Chinese MODY probands who were negative for the GCK/MODY2,HNF1A/MODY3 and HNF1B/MODY5 genes in this observational study.In addition,we enrolled 201 unrelated,non-diabetic control subjects of Han Chinese descent.The functional significance of newly identified mutations was analyzed using clinical phenotype,pathophysiology and three-dimensional structure studies.This study was approved by the Institutional Review Board of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital,China(approval No.YS-2017-83)on March 3,2017.Results::E59Q(c.175 G>C,p.Glu59Gln),a heterozygous missense mutation in the NEUROD1 gene,was identified in one family with MODY.The Glu59 residue in NeuroD1 is highly conserved across mammalian species.Four diabetic patients carrying the mutation(a proband and her son,brother and sister)were lean,with a body mass index of 20.9(20.3-21.2)kg/m 2.Compared with their unaffected relatives(n=4),E59Q carriers(n=4)had significantly decreased ratios of fasting and 2-hour insulin to plasma glucose(both fasting plasma insulin/fasting plasma glucose and 2-hour postprandial plasma insulin/2-hour postprandial plasma glucose,P<0.005).The proband’s father had an E59Q mutation and normal glucose tolerance,which suggested non-penetrance.The E59Q mutation was not detected in other probands or in the 201 control subjects with normal glucose tolerance.Two salt-bridge bonds of Glu59 were disrupted at the Q59 mutation site.Conclusion::The NEUROD1-E59Q mutation changed the molecular conformation of the N-terminal in NeuroD1,which may decrease binding of the E59Q mutant to the insulin promoter and insulin gene transcription activity,therefore causing the MODY6 subtype with defective insulin secretion.
