线粒体是真核细胞中最重要的能量产生细胞器,在物质代谢、细胞信号转导、氧化应激,以及多种形式的细胞死亡途径中发挥关键的调控作用。线粒体拥有独立于细胞核基因组的DNA——线粒体DNA(mtDNA),但是只编码13条多肽链、22个转运RNA(tRNA)...线粒体是真核细胞中最重要的能量产生细胞器,在物质代谢、细胞信号转导、氧化应激,以及多种形式的细胞死亡途径中发挥关键的调控作用。线粒体拥有独立于细胞核基因组的DNA——线粒体DNA(mtDNA),但是只编码13条多肽链、22个转运RNA(tRNA)和2个核糖体RNA(r RNA)。线粒体内的其他蛋白质都是由核基因(n DNA)编码的,这两个基因组协同工作,维持细胞的正常功能和稳态。已鉴定的人类细胞线粒体蛋白质组含有超过1158种蛋白质,它们分别定位于线粒体外膜、膜间隙、内膜和基质中,参与氧化磷酸化、三羧酸循环、分裂-融合动力学,以及维持线粒体稳态等重要功能。线粒体稳态和线粒体功能的正常发挥与线粒体蛋白酶密切相关,这些线粒体蛋白酶通过调节线粒体蛋白的活性,去除受损的或不必要的蛋白质,从而维持线粒体稳态并确保细胞存活。其中一组功能依赖于ATP结合和水解的线粒体AAA+蛋白酶(ATPases associated with diverse cellular activities,AAA+proteases),不仅执行降解错误折叠蛋白质的功能,还在线粒体融合蛋白的加工成熟、呼吸链复合物组装、mtDNA复制/转录等过程中发挥关键作用。研究发现,这些线粒体AAA+蛋白酶的基因突变或者表达异常导致其酶活性改变,严重损害线粒体结构和功能的完整性,并导致多种神经系统疾病的发生。本文主要以Lon蛋白酶1(Lon peptidase 1,LONP1)、酵母线粒体逃逸基因1样蛋白1(yeast mitochondrial escape 1 like 1,YME1L1)和ATP酶家族基因3样蛋白2(ATPase family gene 3-like 2,AFG3L2)等3种线粒体AAA+蛋白酶为例,详细阐述了它们的序列相似性和结构特点,以及在线粒体中的不同定位与功能。通过总结这3种蛋白酶基因突变与神经系统疾病的关系,发现已报道的疾病相关突变主要位于ATPase结构域和水解酶或肽酶结构域。因此,解析这些蛋白酶关键结构域的结构和突变导致的功能变化及其对线粒体乃至细胞稳态的影响,将为理解疾病机制和研发靶向干预策略提供参考。展开更多
目的 分析AFG2A基因新发复合杂合变异导致伴有听力损失、癫痫发作和大脑异常的神经发育障碍(NEDHSB)一家系的临床表型和基因变异特点,并为其遗传咨询及产前诊断提供参考。方法 收集并分析NEDHSB一家系患儿、患儿妹妹及其父母的临床资料...目的 分析AFG2A基因新发复合杂合变异导致伴有听力损失、癫痫发作和大脑异常的神经发育障碍(NEDHSB)一家系的临床表型和基因变异特点,并为其遗传咨询及产前诊断提供参考。方法 收集并分析NEDHSB一家系患儿、患儿妹妹及其父母的临床资料,对患儿、患儿妹妹及其父母采用全外显子组测序(whole exome sequencing,WES)检测,Sanger测序验证位点,软件预测其复合杂合变异的危害性。查阅国内外文献数据库,收集已报道的AFG2A基因变异病例并进行文献复习。结果该家系1例患者(先证者)表现有发育性癫痫性脑病,患儿妹妹随访至今无临床表现。WES检出患儿AFG2A基因存在c.1678G>A(p.Val560Ile)错义变异和一个新发现的移码位点变异c.544delA(p.Thr182fsTer14),第9号外显子上的c.1678G>A遗传自父亲,第5号外显子上的c.544delA遗传自母亲,形成复合杂合变异,患儿妹妹为AFG2A基因c.1678G>A(p.Val560Ile)错义变异携带者。根据美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)变异分类指南,c.1678G>A(p.Val560Ile)位点为意义未明,c.544delA(p.Thr182fsTer14)位点为可能致病性的。其中,位点c.544delA为新发现的移码位点变异,且软件预测该变异使基因功能丧失。国内外的文献共报道该疾病38例,其中7例患者为移码位点变异,而本研究变异还未有记录。结论 本研究发现AFG2A新移码位点变异,丰富了AFG2A基因变异谱。AFG2A基因c.1678G>A和c.544delA新复合杂合变异为该家系患者的致病原因。展开更多
The asymptotic development method is applied to analyze the free vibration of non-uniform axially functionally graded(AFG) beams, of which the governing equations are differential equations with variable coefficients....The asymptotic development method is applied to analyze the free vibration of non-uniform axially functionally graded(AFG) beams, of which the governing equations are differential equations with variable coefficients. By decomposing the variable flexural stiffness and mass per unit length into reference invariant and variant parts, the perturbation theory is introduced to obtain an approximate analytical formula of the natural frequencies of the non-uniform AFG beams with different boundary conditions.Furthermore, assuming polynomial distributions of Young's modulus and the mass density, the numerical results of the AFG beams with various taper ratios are obtained and compared with the published literature results. The discussion results illustrate that the proposed method yields an effective estimate of the first three order natural frequencies for the AFG tapered beams. However, the errors increase with the increase in the mode orders especially for the cases with variable heights. In brief, the asymptotic development method is verified to be simple and efficient to analytically study the free vibration of non-uniform AFG beams, and it could be used to analyze any tapered beams with an arbitrary varying cross width.展开更多
Large deformation of a cantilever axially functionally graded (AFG) beam subject to a tip load is analytically studied using the homotopy analysis method (HAM). It is assumed that its Young’s modulus varies along the...Large deformation of a cantilever axially functionally graded (AFG) beam subject to a tip load is analytically studied using the homotopy analysis method (HAM). It is assumed that its Young’s modulus varies along the longitudinal direction according to a power law. Taking the solution of the corresponding homogeneous beam as the initial guess and obtaining a convergence region by adjusting an auxiliary parameter, the analytical expressions for large deformation of the AFG beam are provided. Results obtained by the HAM are compared with those obtained by the finite element method and those in the previous works to verify its validity. Good agreement is observed. A detailed parametric study is carried out. The results show that the axial material variation can greatly change the deformed configuration, which provides an approach to control and manage the deformation of beams. By tailoring the axial material distribution, a desired deformed configuration can be obtained for a specific load. The analytical solution presented herein can be a helpful tool for this procedure.展开更多
A new size-dependent axially functionally graded(AFG) micro-beam model is established with the application of a reformulated strain gradient elasticity theory(RSGET). The new micro-beam model incorporates the strain g...A new size-dependent axially functionally graded(AFG) micro-beam model is established with the application of a reformulated strain gradient elasticity theory(RSGET). The new micro-beam model incorporates the strain gradient, velocity gradient,and couple stress effects, and accounts for the material variation along the axial direction of the two-component functionally graded beam. The governing equations and complete boundary conditions of the AFG beam are derived based on Hamilton's principle. The correctness of the current model is verified by comparing the static behavior results of the current model and the finite element model(FEM) at the micro-scale. The influence of material inhomogeneity and size effect on the static and dynamic responses of the AFG beam is studied. The numerical results show that the static and vibration responses predicted by the newly developed model are different from those based on the classical model at the micro-scale. The new model can be applied not only in the optimization of micro acoustic wave devices but also in the design of AFG micro-sensors and micro-actuators.展开更多
文摘线粒体是真核细胞中最重要的能量产生细胞器,在物质代谢、细胞信号转导、氧化应激,以及多种形式的细胞死亡途径中发挥关键的调控作用。线粒体拥有独立于细胞核基因组的DNA——线粒体DNA(mtDNA),但是只编码13条多肽链、22个转运RNA(tRNA)和2个核糖体RNA(r RNA)。线粒体内的其他蛋白质都是由核基因(n DNA)编码的,这两个基因组协同工作,维持细胞的正常功能和稳态。已鉴定的人类细胞线粒体蛋白质组含有超过1158种蛋白质,它们分别定位于线粒体外膜、膜间隙、内膜和基质中,参与氧化磷酸化、三羧酸循环、分裂-融合动力学,以及维持线粒体稳态等重要功能。线粒体稳态和线粒体功能的正常发挥与线粒体蛋白酶密切相关,这些线粒体蛋白酶通过调节线粒体蛋白的活性,去除受损的或不必要的蛋白质,从而维持线粒体稳态并确保细胞存活。其中一组功能依赖于ATP结合和水解的线粒体AAA+蛋白酶(ATPases associated with diverse cellular activities,AAA+proteases),不仅执行降解错误折叠蛋白质的功能,还在线粒体融合蛋白的加工成熟、呼吸链复合物组装、mtDNA复制/转录等过程中发挥关键作用。研究发现,这些线粒体AAA+蛋白酶的基因突变或者表达异常导致其酶活性改变,严重损害线粒体结构和功能的完整性,并导致多种神经系统疾病的发生。本文主要以Lon蛋白酶1(Lon peptidase 1,LONP1)、酵母线粒体逃逸基因1样蛋白1(yeast mitochondrial escape 1 like 1,YME1L1)和ATP酶家族基因3样蛋白2(ATPase family gene 3-like 2,AFG3L2)等3种线粒体AAA+蛋白酶为例,详细阐述了它们的序列相似性和结构特点,以及在线粒体中的不同定位与功能。通过总结这3种蛋白酶基因突变与神经系统疾病的关系,发现已报道的疾病相关突变主要位于ATPase结构域和水解酶或肽酶结构域。因此,解析这些蛋白酶关键结构域的结构和突变导致的功能变化及其对线粒体乃至细胞稳态的影响,将为理解疾病机制和研发靶向干预策略提供参考。
文摘目的 分析AFG2A基因新发复合杂合变异导致伴有听力损失、癫痫发作和大脑异常的神经发育障碍(NEDHSB)一家系的临床表型和基因变异特点,并为其遗传咨询及产前诊断提供参考。方法 收集并分析NEDHSB一家系患儿、患儿妹妹及其父母的临床资料,对患儿、患儿妹妹及其父母采用全外显子组测序(whole exome sequencing,WES)检测,Sanger测序验证位点,软件预测其复合杂合变异的危害性。查阅国内外文献数据库,收集已报道的AFG2A基因变异病例并进行文献复习。结果该家系1例患者(先证者)表现有发育性癫痫性脑病,患儿妹妹随访至今无临床表现。WES检出患儿AFG2A基因存在c.1678G>A(p.Val560Ile)错义变异和一个新发现的移码位点变异c.544delA(p.Thr182fsTer14),第9号外显子上的c.1678G>A遗传自父亲,第5号外显子上的c.544delA遗传自母亲,形成复合杂合变异,患儿妹妹为AFG2A基因c.1678G>A(p.Val560Ile)错义变异携带者。根据美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)变异分类指南,c.1678G>A(p.Val560Ile)位点为意义未明,c.544delA(p.Thr182fsTer14)位点为可能致病性的。其中,位点c.544delA为新发现的移码位点变异,且软件预测该变异使基因功能丧失。国内外的文献共报道该疾病38例,其中7例患者为移码位点变异,而本研究变异还未有记录。结论 本研究发现AFG2A新移码位点变异,丰富了AFG2A基因变异谱。AFG2A基因c.1678G>A和c.544delA新复合杂合变异为该家系患者的致病原因。
基金Project supported by the National Natural Science Foundation of China(No.11672008)
文摘The asymptotic development method is applied to analyze the free vibration of non-uniform axially functionally graded(AFG) beams, of which the governing equations are differential equations with variable coefficients. By decomposing the variable flexural stiffness and mass per unit length into reference invariant and variant parts, the perturbation theory is introduced to obtain an approximate analytical formula of the natural frequencies of the non-uniform AFG beams with different boundary conditions.Furthermore, assuming polynomial distributions of Young's modulus and the mass density, the numerical results of the AFG beams with various taper ratios are obtained and compared with the published literature results. The discussion results illustrate that the proposed method yields an effective estimate of the first three order natural frequencies for the AFG tapered beams. However, the errors increase with the increase in the mode orders especially for the cases with variable heights. In brief, the asymptotic development method is verified to be simple and efficient to analytically study the free vibration of non-uniform AFG beams, and it could be used to analyze any tapered beams with an arbitrary varying cross width.
基金Project supported by the China Postdoctoral Science Foundation(No.2018M630167)
文摘Large deformation of a cantilever axially functionally graded (AFG) beam subject to a tip load is analytically studied using the homotopy analysis method (HAM). It is assumed that its Young’s modulus varies along the longitudinal direction according to a power law. Taking the solution of the corresponding homogeneous beam as the initial guess and obtaining a convergence region by adjusting an auxiliary parameter, the analytical expressions for large deformation of the AFG beam are provided. Results obtained by the HAM are compared with those obtained by the finite element method and those in the previous works to verify its validity. Good agreement is observed. A detailed parametric study is carried out. The results show that the axial material variation can greatly change the deformed configuration, which provides an approach to control and manage the deformation of beams. By tailoring the axial material distribution, a desired deformed configuration can be obtained for a specific load. The analytical solution presented herein can be a helpful tool for this procedure.
基金Project supported by the National Natural Science Foundation of China (No. 12002086)the Fundamental Research Funds for the Central Universities of China (No. 2242022R40040)。
文摘A new size-dependent axially functionally graded(AFG) micro-beam model is established with the application of a reformulated strain gradient elasticity theory(RSGET). The new micro-beam model incorporates the strain gradient, velocity gradient,and couple stress effects, and accounts for the material variation along the axial direction of the two-component functionally graded beam. The governing equations and complete boundary conditions of the AFG beam are derived based on Hamilton's principle. The correctness of the current model is verified by comparing the static behavior results of the current model and the finite element model(FEM) at the micro-scale. The influence of material inhomogeneity and size effect on the static and dynamic responses of the AFG beam is studied. The numerical results show that the static and vibration responses predicted by the newly developed model are different from those based on the classical model at the micro-scale. The new model can be applied not only in the optimization of micro acoustic wave devices but also in the design of AFG micro-sensors and micro-actuators.
